Patient characteristics and burden of disease in Japanese patients with generalized pustular psoriasis: Results from the Medical Data Vision claims database

Abstract Generalized pustular psoriasis (GPP) is a rare and severe systemic, neutrophilic skin disease. To date, accurate clinical profiling of patients with GPP remains poorly understood. In this study, we present the characteristics and estimate the burden of disease in patients with GPP compared with those with plaque psoriasis, in Japan. This retrospective study was conducted using the Medical Data Vision database between January 1, 2015, and December 31, 2019. Patients with at least one confirmed inpatient or outpatient diagnostic code for GPP (L40.1) or psoriasis vulgaris (L40.0) were included for analysis. The main outcome measures included comparisons of the prevalence of comorbidities, medication use, and healthcare resource utilization between patients with GPP, patients with plaque psoriasis, and a general population‐matched cohort. In total, 718 patients with GPP and 27,773 patients with plaque psoriasis were identified. Patients with GPP were more likely to be female than those with plaque psoriasis (51.6% vs. 38.7%). During the 12‐month follow‐up period, patients with GPP were more likely to experience comorbidities than those with plaque psoriasis, including psoriatic arthritis, other forms of psoriasis, osteoporosis, interstitial pneumonia, and peptic ulcer disease. Medication use also differed between those with GPP and those with plaque psoriasis: patients with GPP were more likely to be prescribed antibiotics and psychiatric medication. Patients with GPP were also more likely to require more healthcare resource utilization with longer hospitalizations than those with plaque psoriasis. Overall, in Japan, patients with GPP have a higher burden of illness than those with plaque psoriasis.

has reported that Japanese patients with GPP alone (n = 11) have a higher prevalence of mutations in IL36RN than those with concomitant plaque psoriasis (n = 20). 11 Compared with the frequency of IL36RN mutations reported in patients with GPP in other regions of the world, the frequency in Japanese patients with GPP (45.2%) is higher than in other East and South Asian populations (28.8% and 0.0%, respectively) and European populations (29.4─34.7%). [12][13][14] Also, an analysis in 30 Japanese patients with GPP identified a CARD14 variant as a predisposing factor for GPP with plaque psoriasis, but not in patients with plaque psoriasis only. 15 This suggests that the pattern of disease may be different in Japanese patients than in many other populations around the world. As such, the clinical profile of Japanese patients with GPP warrants further investigation.
In Japan, treatment guidelines for patients with GPP, as well as criteria for the diagnosis and severity of GPP, were revised in 2014. 2 Unlike in the USA or Europe, where no treatments are approved for the treatment of GPP specifically, there are currently eight approved biologics for the treatment of GPP in Japan. These are adalimumab, infliximab, certolizumab pegol, risankizumab, guselkumab, secukinumab, brodalumab, and ixekizumab. 2,16 Published data on the clinical characteristics of Japanese patients with GPP are sparse. This retrospective study using the Japanese Medical Data Vision (MDV) database was conducted to characterize the clinical profile of patients with GPP and assess the burden of disease, including healthcare resource utilization (HCRU), compared with those with plaque psoriasis. Outcome measures included comorbidities, dermatologic medication use, concomitant medication use, and all-cause HCRU during the 12-month follow-up data collection period.

| ME THODS
This was a retrospective cohort study using data obtained from the Japanese MDV database, a national acute hospital-based claims database that includes inpatients and outpatients under the diagnostic procedure combination (DPC) system, including diagnoses identified according to the International Classification of Diseases, 10 th revision (ICD-10) (as dictated by the World Health Organization), and standard disease codes (named by the Japanese Ministry of Health, Labour, and Welfare). Medications were identified through prescriptions containing generic or brand names of medication submitted on health insurance claims. The study period was between July 1, 2014 and December 31, 2019. The patient selection period was January 1, 2015 to December 31, 2019: patients could join the study at any time after January 1, 2015, once they had fulfilled the study eligibility criteria (index date) (Figure 1). The index date was the date of the first inpatient or outpatient claim with a diagnosis code of L40.0 or L40.1, respectively, with a preceding eligible 6-month baseline period. A data collection follow-up period of 12 months started on the index date.
Three cohorts were evaluated: patients with GPP (with an ICD-10 code of L40.1), patients with plaque psoriasis (with an ICD-10 code of L40.0), and a general population comparator control cohort, matched to patients with GPP (4:1) based on age (patients aged <95 years were matched exactly on age; patients aged ≥95 years were age group matched) and sex at the index month, without a diagnosis of GPP (L40.1), palmoplantar pustulosis (L40.3), or psoriasis (but allowing for a diagnosis of psoriatic arthritis) according to ICD-10 codes L40, L40.0, L40.2, L40.4, L40.8, and L40.9. Patients with GPP and concomitant plaque psoriasis were included in the GPP cohort. The comparator general population cohort is denoted throughout as the matched control cohort. Only patients with a confirmed diagnosis and at least one interaction with the DPC system in the 6 months before the index date were eligible for inclusion. All patients in the GPP and plaque psoriasis cohorts must still be active in the database after 12 months (365 days) post index date to be included in the 12-month follow-up analyses ( Figure 2). For all ICD-10 codes and medications utilized, see Tables S1─S4. Lower and upper age limits were not applied.
All analyses were performed using the Instant Health Data (IHD) software (Panalgo, Boston, MA, USA) and R software, version 3.5.2 (R Foundation for Statistical Computing, Vienna, Austria). No comparative statistical analysis was undertaken; descriptive statistics are used throughout, including the mean and standard deviation (SD), median and interquartile range (IQR) for continuous variables, F I G U R E 1 Study design. † Patients were eligible to enter a cohort when they fulfilled all study criteria at index date (a confirmed diagnosis and ≥1 DPC encounter during the 6 months before the index date). DPC, diagnostic procedure combination; GPP, generalized pustular psoriasis and frequencies and percentages for categorical variables. For HCRU analyses, all-cause visits were included. This study was approved by the ethics committee of Yoyogi Mental Clinic (approval number: NBI207-2). The study was conducted according to the Declaration of Helsinki.

| Patient demographics and characteristics at baseline
A total of 718 patients with GPP and 27,773 patients with plaque psoriasis who had at least one DPC recorded event during the baseline period were identified. A matched control cohort of 2867 patients was also identified ( Figure 2). Patient characteristics and demographics at baseline are shown in Table 1. There were slightly more female (51.5%) than male patients with GPP. In contrast, in the plaque psoriasis cohort, a minority of patients were female (38.7%).
The mean ages of patients with GPP and plaque psoriasis were 60.9 and 62.9 years, respectively (Table 1). A higher proportion of patients with GPP (53.1%) visited a large hospital (≥500 beds) than those with plaque psoriasis (40.8%) ( Table 1).

| Comorbidities during the 12-month followup period
During the 12-month follow-up period, patients with GPP had a higher proportion of diagnoses for comorbidities compared with   Figure 3).

| Comorbidities by age
Many of these comorbidities were generally more common in patients who were aged ≥65 years than in those who were aged 18- 23.9%) than those with plaque psoriasis. In addition, patients with GPP were as likely to receive biologic monotherapy (0.8% vs. 0.9%) and non-biologic monotherapy (9.8% vs 9.2%) as those with plaque psoriasis (Table 2). However, patients with GPP were more likely to receive biologic therapies in combination with topical steroids or non-biologic therapies than patients with plaque psoriasis (21.5% vs. 3.8%) ( Table 2).
Patients with GPP were more likely to receive topical steroids (multiple), systemic steroids, tumor necrosis factor inhibitors, and interleukin inhibitors than those with plaque psoriasis ( Figure 4). Of the biologic therapies, the most commonly prescribed medication in patients with GPP was infliximab (9.9%); the most commonly prescribed biologic in patients with plaque psoriasis was ustekinumab (1.5%). The most commonly prescribed non-biologic therapies in patients with GPP were etretinate (30.0%), ciclosporin (21.3%), and methotrexate (7.0%). Patients with plaque psoriasis were less often F I G U R E 3 Most common comorbidities in patients with GPP during the 12-month follow-up period. COPD, chronic obstructive pulmonary disease; GPP, generalized pustular psoriasis treated with etretinate (5.8%), ciclosporin (9.3%), and methotrexate (2.6%), although these were still the most frequently prescribed medications for this cohort. In addition, apremilast was prescribed in a higher proportion of patients with GPP (3.3%) than in patients with plaque psoriasis (1.9%). Of the topical medications, maxacalcitol was the most frequently prescribed medication in patients with GPP (26.6%); in addition, maxacalcitol was more likely to be prescribed in those with plaque psoriasis (32.5%). More patients with GPP received phototherapy than those with plaque psoriasis (8.8% vs. 7.9%), with 6.2% of patients with GPP also received apheresis with Adacolumn, compared with 0.1% of those with plaque psoriasis.

| Medication use by age in patients with GPP
When stratified, patients with GPP of all age groups were as likely to receive topical steroids and topical non-steroids; however, patients aged ≥65 years were slightly more likely than those who were

| Concomitant medication use during the 12-month follow-up period
During the 12-month follow-up period, a higher proportion of patients with GPP received concomitant medication for comorbidities than patients with plaque psoriasis and the matched control cohort.

| All-cause HCRU during the 12-month followup period
The mean number of outpatient visits for patients with GPP was higher than in the plaque psoriasis and matched control cohorts   Table 5).
Other common reasons for inpatient hospitalizations included essential primary hypertension and gastro-esophageal reflux disease (  Patients with GPP were more often treated with biologic and non-biologic systemic therapies than those with plaque psoriasis.
Although biologics and non-biologic systemic therapies are expensive, if a patient qualified for intractable disease designation, the cost of these medications was covered by national insurance increasing their accessibility; however, those who do not qualify, are required to cover the expenses themselves.
It would be interesting to investigate the regimens of treatments received, since this may indicate disease severity. 21 Although it is not possible to evaluate disease severity from this database, demonstrat-   24 which may affect the generalizability of the study. Also, the average age of those with GPP within the MDV database is higher than the epidemiologic data of patients with GPP in Asia suggests (i.e. 60.9 years vs. 40.0-50.0 years, respectively). 13 This, as well as the complexity of treating an older population, could impact the perceived severity of the disease, including the prevalence of comorbidities and potential contraindications between treatments.
Overall, the MDV database has enabled the assessment of longterm disease management and clinical characterization of patients with GPP. We have shown that, in Japan, patients with GPP have a higher burden of illness, including a higher prevalence of comorbidities and medication burden, than those with plaque psoriasis, as well as greater HCRU. It is hoped that these results, in addition to further investigation, will reinforce the need for a distinct treatment and management pathway for patients with GPP and will encourage the further development of disease management practices for patients with GPP. and funded by Boehringer Ingelheim.