Epidemiology, Comorbidities, and Prescription Patterns of Korean Prurigo Nodularis Patients: A Multi-Institution Study

Prurigo nodularis (PN) is a chronic dermatosis typified by extraordinarily itchy nodules. However, little is known of the nature and extent of PN in Asian people. This study aimed to describe the epidemiology, comorbidities, and prescription pattern of PN in Koreans based on a large dermatology outpatient cohort. Patients with PN were identified from the Catholic Medical Center (CMC) clinical data warehouse. Anonymized data on age, sex, diagnostic codes, prescriptions, visitation dates, and other relevant parameters were collected. Pearson correlation analysis was used to calculate the correlation between PN prevalence and patient age. Conditional logistic regression modeling was adopted to measure the comorbidity risk of PN. A total of 3591 patients with PN were identified at the Catholic Medical Center Health System dermatology outpatient clinic in the period 2007–2020. A comparison of the study patients with age- and sex-matched controls (dermatology outpatients without PN) indicated that PN was associated with various comorbidities including chronic kidney disease (adjusted odds ratio (aOR), 1.48; 95% confidence interval (CI), 1.29–1.70), dyslipidemia (aOR, 1.88; 95% CI, 1.56–2.27), type 2 diabetes mellitus (aOR, 1.37; 95% CI, 1.22–1.54), arterial hypertension (aOR, 1.50; 95% CI, 1.30–1.73), autoimmune thyroiditis (aOR, 2.43; 95% CI, 1.42–4.16), non-Hodgkin’s lymphoma (aOR, 1.95; 95% CI, 1.23–3.07), and atopic dermatitis (aOR, 2.16, 95% CI, 1.91–2.45). Regarding prescription patterns, topical steroids were most favored, followed by topical calcineurin inhibitors; oral antihistamines were the most preferred systemic agent for PN. PN is a relatively rare but significant disease among Korean dermatology outpatients with a high comorbidity burden compared to dermatology outpatients without PN. There is great need for breakthroughs in PN treatment.


Introduction
Prurigo nodularis (PN) is a skin condition characterized by extremely pruritic and hyperkeratotic nodules on the extremities and body [1]. While vigorous scratching is an important trigger [2], the etiology of PN remains unclear.
PN is frequently linked with a personal history or atopy and can present concurrently with atopic dermatitis [3], with some recognizing it as a subtype of atopic dermatitis [4]. However, given that multiple pruritogenic diseases are associated with the emergence and resolution of PN upon treatment, it is more likely that the cause of PN is diverse [5].
A retrospective cross-sectional study was conducted among outpatients from the Catholic Medical Center (i.e., the largest health organization in Korea with 7 affiliated hospitals-Incheon, Yeouido, Uijeongbu, Bucheon, Eunpyeong, and Seoul St. Mary's Hospital and St. Vincent's Hospital). The data were extracted from the institution's clinical data warehouse (CDW), which contains various operational data (i.e., demographics, diagnosis, prescriptions, visitation dates) of both subsidized and non-subsidized cases.

Ethics
The study protocol was reviewed and approved by the Catholic Medical Center Ethics Committee (XC21WIDI0011).

Study Population
The study population of patients that were primarily diagnosed with PN based on the KCD (L28.1) over a 14-year period (from 2007 to 2020) were selected from the CDW. To maximize diagnostic accuracy, subjects were limited to those diagnosed by a dermatologist at the dermatology outpatient clinic. The control population for comorbidity analyses included sex-and age (determined on 1 January 2020)-matched dermatology outpatients without PN during the same time span (1:4 matching).

Study Outcomes
The annual prevalence of PN (per thousand, ‰) was defined as follows: number of PN patients/number of patients who visited the dermatologic outpatient clinic at the CMC during a one-year time-period × 1000. Sample record of patients diagnosed with PN in a specific year were classified as PN patients of that year. An individual's age was determined as that on 1 January each year, and PN patients were categorized into 10-year age groups, except for the 0-20-and 81-100-year-old groups; the two lowest and two highest age groups were merged due to the small numbers of PN samples.

Statistical Analysis
Python 3 version 3.6.7 (Python Software Foundation, DE, US) was used for basic data processing and statistical analysis. The correlation between PN prevalence (annual prevalence of each age group summed over the entire study period (2007-2020)) and age (median age of the age groups: 10, 25, 35, 45, 55, 65, 76, and 90 years) was calculated using Pearson correlation analysis. Conditional logistic regression modeling (survival package (Therneau, 2014) within the R tool (version 3.5.1)) was adopted to identify the comorbidity risk of PN and the associated subgroup analysis based on sex and age. Subgroups by sex were corrected by setting age as strata, and vice versa. Because the median and mean ages of the PN population (2007-2020) were 60 and 58.1 years, respectively, we divided our population based on 60 years of age (≥60 vs. <60 years) for subgroup analysis. Conditional logistic regression was used to analyze the prescription patterns for PN according to sex and age. p ≤ 0.05 was recognized as statistically significant.

Epidemiology of PN
The average annual prevalence of PN (per 1000 dermatology outpatient population) increased from the first half of the study period (4.11, 2007-2013) to the second (5.53, 2014-2020; p = 0.03) ( Table 1). The annual PN prevalence was higher among males than females throughout the observation period (p < 0.001; Figure 1a). It also increased with age, which was a trend in both male and female populations (Figure 1b-d). A positive correlation was seen between age and prevalence of PN over 2007-2020 (R = 0.95, p = 0.0003), which remained significant in both sexes (females, R = 0.94, p = 0.0006; males, R = 0.90, p = 0.002).

Comorbidities of PN
A total of 3591 patients with PN were identified between 2007-2020. Of the 3591 PN patients, the mean age was 58.1 ± 19.4 years, and 56.8% were male ( Table 2). Demographics of the control population (sex-and age-matched dermatology outpatients without PN, 1:4 matching) are shown in Table 2.

Discussion
Based on the current data, the estimated annual prevalence of PN in Korea is 4.82 cases per 1000 dermatology outpatients. Considering that our population is limited to dermatology outpatients, it is understandable that the number is higher than the nationwide annual prevalence of PN reported from Poland (6.52 cases per 100,000 population) [8], Germany (40 cases per 100,000 population) [9], and the US (72 cases per 100,000 population) [10].
Our long-term, real-world dataset suggests an increasing trend in the annual prevalence of PN (4.11, 2007-2013 vs. 5.53, 2014-2020), which is likely due to the longer lifespan (supported by the positive correlation shown between age and prevalence of PN) and increased awareness of the disease.
The mean age of our PN subjects was 58.1 years, which is similar to the findings from previous studies (61.5 years; Poland [8], 50.9 years; US [10]). A predominance in females was noted in the Caucasian and African American PN population in the US [11]; however, the sex ratio of our PN patients was male dominant (56.8%), which matches the findings from Boozalis et al. [11] in Asians (58.1% male, 41.9% female).
Our patient population had increased likelihood of carrying mental and neurologic, vascular, allergic and respiratory, autoimmune, cancer, metabolic, nutritional, and renal disease diagnoses, which emphasizes the increased disease burden associated with PN relative to other skin conditions. Psychiatric health conditions have been linked not only with PN [10,11,16,17] but also with skin diseases such as atopic dermatitis and psoriasis [18,19]. The increased presence of schizophrenia, anxiety, depression, and other conditions in our study patients compared to dermatologic outpatients stresses a psychological component to PN as well as the strong impact of PN on mental wellbeing [20]. Our PN population also had a higher prevalence of systemic illnesses and non-Hodgkin's lymphoma. The associations between PN and CKD, arterial hypertension, and ischemic heart disease in excess to the risk in other skin conditions supports the systemic nature of PN and is in line with findings from previous studies [10,11]. Our data also support prior reports that indicated an association of PN with hepatitis B infection and non-Hodgkin's lymphoma, as well as with type 2 DM, thyroid disease, dyslipidemia, anemia, and osteoporosis [10][11][12]21,22]. Interestingly, the patients with PN in our study were less likely to have rheumatoid arthritis, which was observed in African Americans with PN compared to those with psoriasis (OR, 0.3; 95% CI, 0.1-0.8) [11]. Finally, the heightened likelihood of allergic conditions in our PN population can be accredited to the patient subset who were atopic. Allergic susceptibility is recognized in PN, particularly in early-onset PN [5,23].
In addition to confirming previous links between PN and comorbidities, our subgroup analyses showed that female patients and individuals 60 years of age and over experienced dementia and depression, while only males and patients 60 and over had heightened risk of non-Hodgkin's lymphoma. Accordingly, there is need for a heightened index for clinicians to suspect and diagnose patients and for appropriate screening for PN patients to account for a patient's race, age, and sex.
Analysis of prescription patterns for PN in Korea indicated that steroids and calcineurin inhibitors were the two most frequent topical treatments, both of which address the immunologic component of PN [6]. These were followed by topical capsaicin, which modulates the neural component of PN [6]. It is likely that topical capsaicin is less preferred due to reported intense burning and irritation associated with its use.
Korean dermatologists most frequently prescribed oral antihistamines for PN, followed by oral steroids. This differs drastically from the treatment pattern in the US [24], where oral antihistamines are prescribed rarely. The discrepancy likely is related to the medical insurance system in Korea, which is controlled strictly by the Korean government. The use of oral medications other than antihistamines and steroids (oral cyclosporin, gabapentinoids, antidepressants, methotrexate) for PN are restricted, leaving limited options. Oral antihistamines were recommended as a first-line treatment in a review paper on PN (evidence level IV) [25], but there is insufficient evidence for its use in PN [26].
International experts do not recommend systemic steroids for PN (evidence level VI) [25], but it is frequently prescribed both in Korea and the US [24] in real-world settings. The analysis from this study indicated that dermatologists in Korea are more cautious with prescribing systemic steroids in the elderly population (60 years and over) who are more prone to developing complications.
Recently, a number of newer drugs have been introduced and are under clinical trials. The IFSI (International Forum for the Study of Itch) guideline in 2020 has recommended opioid modulators, biologics, and small molecules as promising agents for the treatment of PN [27]. Although we have limited experience with these agents in Korean PN, a bright future lies ahead.

Strengths and Limitations
This study analyzed real-world Korean PN data utilizing a large cohort of dermatology outpatients in Korea and is the first and only study to describe the epidemiology, comorbidities, and prescription patterns of PN in Korea. Study limitations include the retrospective analysis of registry data, where information on the severity of PN and lifestyle risk factors is not available. Our data also showed that PN was associated with conditions and comorbidities, but we were unable to establish causality. Furthermore, due to the rarity of HIV, we were not able to check the association between HIV and incidence of PN in Korean patients.

Conclusions
Overall, our data show that PN is an important disease among Korean dermatology outpatients with a high comorbidity burden compared to dermatology outpatients without PN. Korean patients with PN suffer not only due to the debilitating nature of the disease, but also due to the lack of effective treatment which may be resolved with use of the promising new drugs (i.e., opioid modulators, biologics, and small molecules). Further research is warranted to better understand the pathogenesis, identify risk factors associated with PN, and employ optimal care.

Institutional Review Board Statement:
The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of the Catholic University of Korea (XC21WIDI0011).

Informed Consent Statement: Not applicable.
Data Availability Statement: Data available on request due to restrictions. The data presented in this study are available on request from the corresponding author.

Conflicts of Interest:
The authors declare no conflict of interest.