Regional differences in the prevalence of generalized pustular psoriasis in Japan

Generalized pustular psoriasis (GPP), a rare form of psoriasis, is characterized by neutrophil‐rich, sterile pustules. In Japan, GPP has intractable and rare disease designation, which allows patients to access support from national and local governments for medical expenses. Previously, similar numbers of patients in Tokyo and Hokkaido have been shown to have GPP designation, despite different population sizes. Here, we determine whether there are regional differences in the proportion of patients receiving GPP designation status in Japan and aim to identify causal factors. In this descriptive, retrospective cohort study, publicly available data were collected on the number of patients with intractable and rare disease designation for GPP in each prefecture and age classification (April 2018–March 2021). Three other designated intractable and rare disease cohorts were included: pemphigus, rare skin diseases, and all diseases. The primary outcome was the standardized morbidity ratio (SMR) of patients at prefecture level (observed numbers divided by expected). Regional differences were compared with the statistical expectation for the total population and age distribution of each prefecture. Regional differences were observed in all cohorts. Overall, 1910 patients had GPP as a designated intractable and rare disease in 2020. Regional differences in SMRs for GPP were observed with high SMRs (≥1.5) in Hokkaido, Tottori, Kagawa, and Miyazaki, and low SMRs (<0.6) in Gunma and Kanagawa. Regional differences in SMRs for GPP did not correlate with the number of medical doctors or dermatologists or internal migration. The number of medical doctors or dermatologists correlated with SMRs in the rare skin diseases and total cohorts. Regional differences in Japan exist in the number of patients with GPP who have an intractable and rare disease designation. Managing rare diseases is an important public health issue, and further research is required to elucidate the factors contributing to these differences.


| INTRODUC TI ON
4][5][6] The clinical course of GPP is heterogeneous, with patients experiencing relapsing disease with recurrent flares or persistent disease with intermittent flares. 2,6If left untreated, GPP may become life-threatening. 7timating the global prevalence of GPP is challenging because of the heterogeneity of the condition; however, a recent review of epidemiology estimated that between 1.76 and 124 patients per million of the general population are affected by GPP, depending on their geographic region. 7GPP prevalence in patients with psoriasis was between 0.6% and 2.4%. 7Approximately 2000 people in Japan were recorded as having GPP at the end of 2020. 8e features of rare diseases, such as GPP, pose a challenge for health care professionals, researchers, legislators, policymakers, and patients; therefore, rare diseases are an important public health issue. 91][12] As of November 2021, GPP was one of the 338 diseases to be designated as nanbyo. 8,13This designation encourages a stable support system to be established that includes subsidizing the medical expenses for patients with intractable and rare diseases, allowing patients to access national government support to continue treatment. 10Application forms for designations must be completed by designated medical doctors. 10Every year, approximately 80 patients with moderate to severe GPP are newly eligible for specified medical expenses based on designation. 11e medical expenses of a patient designated with an intractable and rare disease in Japan are shared between national and the local governments in the 47 prefectures in Japan. 9,14 2020, despite Tokyo having a population twice the size of Hokkaido, the number of patients with GPP designated as having an intractable and rare disease in Hokkaido and Tokyo were similar (160 and 183, respectively). 12,15Therefore, in this study we sought to investigate whether there are regional differences in the proportion of patients with GPP designation among the 47 prefectures across Japan.We also investigated whether regional differences were observed in all intractable, and rare diseases, and in intractable and rare skin diseases of interest.In this study, we also assessed regional differences in designation of pemphigus, a nonhereditary, intractable, and rare skin disease managed by dermatologists, as relatively similar numbers of patients with GPP and pemphigus received designation status in 2020 (GPP, n = 2058; pemphigus, n = 3515). 8

| Study design and patients
7][18][19] Aggregated data of the number of patients with intractable and rare disease designation in each prefecture and age classification data were collected in four cohorts: GPP cohort: all patients with a GPP intractable and rare disease designation; pemphigus cohort: all patients with a pemphigus intractable and rare disease designation; rare skin disease of interest cohort: all patients with an intractable and rare skin disease designation (diseases were selected as per the Ministry of Health, Labour and Welfare [MHLW]-funded research by the Rare and Interactable Skin Disease Research Group 20 [GPP, pemphigus, pemphigoid, epidermolysis bullosa, congenital ichthyosis, pseudoxanthoma elasticum, and oculocutaneous albinism]); and total cohort: all patients with any intractable and rare disease designation.
All patients with an intractable and rare disease designation in Japan within the study period were included in the study.Patients with an unknown age were excluded.
The study does not include any individual data and, therefore, is outside the scope of ethics guidance by the Ministry of Health, Labour, and Welfare.

| Outcomes
The primary outcome of the study was the standardized morbidity ratio (SMR) of patients at prefecture level in Japan in the four cohorts.The secondary outcome was the age distribution of patients at prefecture level in Japan in the four cohorts.Exploratory outcomes included the number of patients in the four cohorts per 100 000 people, assessment of correlation between SMRs in the four cohorts, and the number of medical doctors or dermatologists per 100 000 people, all at the prefecture level, and the correlation between internal migration of each prefecture and SMRs from the four cohorts.

| Data sources
All data used in this study are publicly available and were aggregated population-level data with no individual data included.Resident registration data were taken from the Ministry of Internal Affairs and Communications' annual report of the Japanese population in Japan. 19The statistics of Japanese designated intractable and rare diseases are reported every fiscal year by the Japan Intractable Diseases Information Center (JIDIC). 16Statistics on the number of medical doctors, dentists, and pharmacists are reported every 2 years by the MHLW in Japan, and the 2020 data were used in this analysis; the MHLW collect these data via a survey that all physicians in Japan are required to complete under the Medical Practitioners Act. 17Internal migration data from the Statistics Bureau of Japan for 2020 are used in the analysis. 18

| Bias
There is a delay between the actual occurrence of the outcomes and data availability from the government sources; therefore, to minimize information bias due to selecting a specific year, data were combined across 3 fiscal years.

| Data analysis
The number of patients among the four cohorts were stratified by prefecture and at the national level over the study period (fiscal years 2018-2020).The regional difference of patients with intractable disease designation was compared with the statistical expectation in each prefecture.Statistical expectation was calculated based on the total population and age distribution of each prefecture, based on the hypothesis that intractable disease onset was equal throughout Japan.
SMRs were calculated by dividing the actual observed number of patients by the expected number of patients of each cohort across each prefecture.SMRs (± 95% confidence interval [CI]) were calculated to describe geographic differences across the four cohorts.The differences of age category in each prefecture are one of the major confounding factors and, therefore, the expected numbers of patients with these diseases in each cohort (at the prefecture level) each year were calculated with the rates of the diseases (at the national level) multiplied by the population of each prefecture for each age category.
The total expected numbers over the 3-year period were calculated.

| Patient population
Overall, in 2020, 946 110 patients had designated intractable and rare diseases: 1910, 3091, and 8387 patients had GPP, pemphigus, or rare skin disease designations, respectively.During the study period, the number of patients with designated intractable and rare diseases increased in all cohorts, except in the pemphigus cohort (Table 1).The number of patients with a GPP designation between 2018 and 2020 increased by 6.8%, whereas there was a 7.7% decline in the pemphigus cohort.Overall, there was a 10.6% increase in the number of patients in the rare skin disease of interest cohort, and a 6.0% increase in the number of patients with any designated intractable and rare disease over the same period.
Overall, Tokyo had the most patients with designated intractable and rare diseases of interest in 2020 among the four cohorts (Table S1).The prefectures with the highest number of patients in each of the cohorts were Tokyo

| SMR of patients with GPP intractable and rare disease designation
Regional differences in SMRs for patients with intractable and rare diseases were observed among all cohorts.In the GPP cohort, no statistically significant differences between observed and expected morbidity rates were recorded in 29 of 47 (61.7%) prefectures (Figure 1); however, of the remaining prefectures, 10 had a high SMR and eight had a low SMR.Hokkaido, Tottori, Kagawa, and Miyazaki had the highest reported SMRs with ratios ≥1.5.Gunma and Kanagawa had the lowest reported SMRs, being ≥0.5 to <0.6 times lower than expected.In the pemphigus, rare skin diseases of interest, and total cohorts, respectively, 48.9%, 38.3%, and 12.8% of prefectures had no significant differences between observed and expected morbidity rates (Figures 2-4).Among all cohorts, there was a trend that SMRs from Western regions of Japan were higher than those observed in Eastern regions (except Hokkaido) (Figures 1-4; Table S2).

| Age distribution of patients with GPP intractable and rare disease designation
There was a trend toward increasing patient numbers with age among all cohorts (Table 1).The proportion of patients in the GPP cohort who were aged ≥70 years increased from 25% in 2018 to 27% in 2020.
F I G U R E 1 Standardized morbidity ratios (SMRs) for patients with generalized pustular psoriasis designated as an intractable and rare disease across all prefectures in Japan.a Prefectures without a statistically significant difference in SMRs with the expected patient numbers are not colored on the map (29 of 47; 61.7%).

SMR a
Observed numbers < expected numbers During the period, in the total cohort, there was a slight decline from 21% in 2018 to 19% in 2020 in the proportion of patients with intractable and rare diseases in the 60-to 69-year age group.A similar decline was seen in the pemphigus cohort (from 27% to 25%) and rare skin diseases of interest cohort (from 24% to 21%), but not in the GPP cohort.

| Number of patients with GPP intractable and rare disease designation per 100 000 people
The number of patients per 100 000 people with designated intractable and rare diseases, remained similar nationally between 2018 and 2020 after standardizing for the different prefecture populations (Table 2).Small increases were observed in all cohorts, except the pemphigus cohort, which declined slightly.

| Association between SMRs of GPP intractable and rare disease designation at prefecture level and the number of medical doctors or dermatologists
Regional differences in SMRs in the GPP and pemphigus cohorts did not correlate with the number of medical doctors or dermatologists per 100 000 people (Table S3).SMR regional differences in the rare skin diseases of interest and total cohorts correlated with the

| Association between SMRs of GPP intractable and rare disease designation at prefecture level and internal migration
There were no statistically significant correlations between the internal migration to or from other prefectures and SMRs of GPP, rare skin diseases of interest, and total designated intractable and rare diseases cohorts (Table S4).In the pemphigus cohort, SMRs correlated with migration to (−0.38 [95% CI, −0.60, 0.11] p < 0.01) but not from (−0.28 [95% CI, −0.52, 0.01]) other prefectures.

| DISCUSS ION
Regional differences in SMRs in patients with GPP designation were demonstrated in this analysis.SMRs >1.5 in some prefectures indicated that the patient numbers in these regions were 1.5 times higher than expected.The study provided an opportunity to assess F I G U R E 3 Standardized morbidity ratios (SMRs) for patients with intractable and rare skin b diseases across all prefectures in Japan.
a Prefectures without a statistically significant difference in SMRs with the expected patient numbers are not colored on the map (18 of 47; 38.3%).b Generalized pustular psoriasis, pemphigus, pemphigoid, epidermolysis bullosa, congenital ichthyosis, pseudoxanthoma elasticum, and oculocutaneous albinism.whether the regional differences observed for GPP were also reflected in local variations for other designated intractable and rare diseases in Japan.Regional differences were also observed in the other cohorts, although the range of SMRs in the total cohort was narrower than that for the GPP cohort (total cohort, 0.7-1.3;GPP cohort, 0.6-1.8).Variation was also seen in the pemphigus cohort, which was included because of the similarities between these conditions.
Although the coronavirus disease 2019 (COVID-19) pandemic has previously been shown to affect patient behavior in accessing health care, 21 we did not observe a decrease in the number of patients receiving intractable disease designation from 2019 to 2020.
In fact, we observed an increase of 5.5% in GPP designation from 2019 to 2020.A single-center study by Uchida et al also demonstrated an increase in patients newly diagnosed with GPP from 2019 to 2020. 22The limited effect of the COVID-19 pandemic on GPP diagnoses likely reflected the life-threatening and systemic nature of GPP in which patients have limited choices other than seeking medical attention.
Several factors may contribute to the differences in SMRs observed.Prior to the adoption of the system for the designation of intractable diseases, support for patients with intractable diseases was provided independently by some prefectures. 23The extent of measures previously in place to manage intractable diseases Access to medical resources may also partly explain the regional differences in SMRs observed in our study.As the number of designated hospitals in each prefecture intractable and rare disease designation is limited, access to that hospital by patients may cause regional differences, especially in rural areas where public transport may be limited.Having access to large, specialized hospitals providing specialist medical services and diagnosis may also contribute to patient outcomes and, thus, the regional differences seen in SMRs.
However, this hypothesis cannot explain why Tokyo has a lower SMR than Hokkaido, when Tokyo has the highest number of large and advanced hospitals in Japan.The differences in SMRs seen between Western and Eastern Japan may also be attributed to a higher number of hospitals, beds, and health care professionals in Western Japan than in Eastern Japan. 25,26e number of medical doctors or dermatologists per 100 000 people of each prefecture was shown to correlate with SMRs in the total and rare skin disease of interest cohorts but not in the GPP and pemphigus cohorts.The small cohort sizes could account for the failure to associate health care professional numbers and SMRs for GPP and pemphigus.However, it may also be that the rarity of these diseases means that the general dermatologists included in our analysis have limited experience diagnosing these conditions, and patients may have been incorrectly diagnosed in prefectures with low SMRs.It would be valuable to assess in the future whether the number of physicians with expertise in psoriasis was associated with the regional differences seen in this study.
Our analysis was not able to identify the reasons for the differences between prefectures for the GPP cohort.However, we can speculate that causal factors specific to GPP, as well as those related to the intractable and rare skin diseases designation system described earlier, may explain the findings.IL36RN gene mutations have been shown to play a pathogenic role in patients with GPP, 27,28 and other genes including CARD14, SERPINA3, AP1S3, and MPO have been implicated in the development of GPP. 29 It is plausible that the prevalence of familial mutations might not be uniform throughout Japan and may influence the regional differences observed.Of note, Hokkaido, Kochi, and Okinawa are known to have less migration than other regions, and therefore may be more susceptible to hereditary mutations.Although no correlation between migration and SMRs in the GPP cohort was shown in this study, this may be a result of the small numbers included.A further explanation could be that some patients with GPP could have had a history of psoriasis vulgaris, a relatively common skin condition. 5,30The mechanism behind the occurrence of GPP in patients with psoriasis vulgaris is unknown; however, it is possible that if the medications more often used to treat psoriasis vulgaris in some prefectures were also beneficial in GPP, then this could explain the observed differences in SMRs.
This study provided some useful insights into the characteristics of patients with GPP.Although the number of patients with GPP designation increased during the 3-year study period, the proportion of patients per 100 000 people in each prefecture showed only slight variation.There was a general trend among all cohorts increasing with age; however, this was interrupted in the group aged 70 to 74 years, which may reflect the lower birth rate in the early 1950s, following the increase in births after World War II. 31In Japan, other government funding systems are available for pediatric patients with chronic diseases, including GPP.However, if pediatric patients are designated in another government funding system, they will not apply for the JIDIC intractable disease designation, and, as a result, some pediatric patients will not have been captured in our analysis.
For example, based on the data provided by the Information Center for Specific Pediatric Chronic Diseases in fiscal year 2018, 396 patients with chronic skin diseases applied for this pediatric chronic disease designation, although the number with specific skin diseases such as GPP are not disclosed.
were analyzed by calculating Pearson correlation coefficient.The examined associated factors were the number of medical doctors, dermatologists, and migration from or to each prefecture.Excel for Microsoft 365 MSO (16.0.14326.20908)and R version 4.1.1(R Project for Statistical Computing) were used for the statistical analysis.

TA B L E 1
Number of patients with designated intractable and rare diseases stratified by age in Japan.
Standardized morbidity ratios (SMRs) for patients with pemphigus designated as an intractable and rare disease across all prefectures in Japan.a Prefectures without a statistically significant difference in SMRs with the expected patient numbers are not colored on the map (23 of 47; 48.9%).
Standardized morbidity ratios (SMRs) for patients with any intractable and rare diseases across all prefectures in Japan.a Prefectures without a statistically significant difference in SMRs with the expected patient numbers are not colored on the map (6 of 47; Number of patients with designated intractable and rare diseases per 100 000 people at prefecture level in Japan.
a TA B L E 2(Continued)