Introduction

Generalized pustular psoriasis (GPP) is a rare chronic inflammatory, very burdensome and potentially life-threatening disease. GPP shares some signs and symptoms with psoriasis vulgaris but is now a distinct disease that requires accurate diagnosis and specific treatment approaches.¹ GPP is characterized by eruptions of sterile pustules on erythematous ground which mostly affect the non-acral skin,² and by occurrence of acute flares with often severe systemic symptoms. In many cases, the flares require hospitalization.³ The frequency and duration of GPP flares differ widely among patients.³

To date, there is little and contradicting literature on the epidemiology of the disease in the general population. In published data, GPP annual prevalence varies between 0.18 and 46 per 100,000 persons^4–8 and incidences between 0.06 and 0.8 per 100,000 persons.^4,6 Sex differences manifest with a greater disease incidence in women compared to men, and GPP typically afflicts individuals aged between the fourth and sixth decade of life.^3,4,6,9 Furthermore, little is known about the comorbidities of people with GPP. Publications suggest that between 30 and 70% also have a history of or concomitant psoriasis vulgaris.^4,9

Adequate medical care for people with GPP is crucial, but robust data on patient care in Germany and evidence-based guidelines are still lacking. Such health care data are essential to develop effective and efficient health care strategies since patients with GPP require intensive outpatient and frequently inpatient treatment,^10,11 resulting in higher drug costs and longer hospital stays compared to psoriasis vulgaris.^11,12

Due to limited literature on this rare disease, new population-based epidemiology data as well as data on health care are of great importance for understanding the disease burden of GPP in Germany, particularly for appropriate health care planning. A related pending question is the internal validation of GPP diagnoses in claims data which might give a clue to a better understanding of the differences in published literature.

The objective of the current study was to analyze epidemiology of GPP, comorbidities and health care in Germany based on claims data. To do so, different methodological approaches were used and differences explained.

Materials and Methods

Study Design, Data Source and Study Population

This is a retrospective claims data analysis based on a representative anonymized 40% sample of a large nationwide statutory health insurance (SH) (N = 2,885,984; 56.8% women, average age 49.1 years) of all persons who were insured for at least one day between 01/01/2016 and 12/31/2020. The study population consists of insured persons who were at least 18 years old. Depending on the research question, different insurance periods were observed.

Case Definitions

In order to obtain the most valid prevalence of GPP, three distinct case definitions were applied (Table 1). To calculate GPP incidence, the case definitions were extended to include a diagnosis-free period of eight quarters before the incidence quarter. The results were validated by sensitivity analysis with a diagnosis-free period of at least 12 quarters.

Table 1 Case Definitions to Determine the Prevalence of Generalized Pustular Psoriasis (GPP)

Differential Diagnosis and Comorbidities

Miscoding of persons with a diagnosis of GPP was accounted for as follows: a) any psoriasis diagnoses (L40) among prevalent GPP in 2019 (cross-diagnoses) and b) other dermatological diseases among prevalent GPP in 2019 without a GPP diagnosis in 2018 (differential diagnoses) (Table S1). Comorbidity related to GPP to be investigated based on the literature (Table S2). Insured persons with differential diagnosis or comorbidities were included if they had at least one other main or secondary relevant diagnosis in an outpatient or inpatient setting in the GPP prevalence year 2019. Comorbidities of GPP were compared to two comparison groups, persons with psoriasis but without GPP and persons without any psoriasis diagnosis (L40).

Outpatient Care

Drug prescriptions were analyzed based on case definition 1 (Table S3). Prescribers were classified into:¹³ general practitioner (01–03), dermatologist (21), pediatrician (34−47), internist (23−30, 32−33), rheumatologist (12,31). For the analysis of long-term medication, at least one relevant prescription per quarter had to be available for all four quarters of a year. In addition, phototherapy (Fee schedule item, EBM Number 30430, 30,431, 10,350)¹³ was evaluated. In order to determine the course of drug treatment, insured persons with incident GPP in 2018 were followed up for eight quarters. The first observation quarter does not correspond to the prescription quarter.

Statistics

Epidemiology estimates are expressed per 100,000 persons. Direct standardization by age and sex was performed using the German population on 31 December of the respective year. Relative frequencies (in per cent) were calculated for categorical variables. When comparing comorbidities, the relative risk (RR) of people with GPP compared with controls was calculated and reported with the corresponding 95% confidence intervals. For the calculation of the relative risk for each comorbidity, the controls were first compared with respect to their mean age. Drug costs were considered as gross amounts without deduction of VAT and manufacturer rebates (payer perspective). Analyses were calculated using SAS version 9.4 German (SAS Institute, Cary, NC, USA).

Results

Epidemiology

In 2019, the prevalence of GPP ranged from 8 to 39 per 100,000 adults and the incidence from 1 to 15 per 100,000 adults. Extrapolated to Germany, between 5805 and 28,529 adults would likely have received a diagnosis of GPP, with incident cases estimated at 992 and 10,820 persons (Table S4). About 1.5% of prevalent persons were hospitalized due to GPP (average hospital days 17.2 days, SD: 14.02, min-max: 3–92 days) and 32.6% had at least one inpatient stay, a certificate of incapacity for work or relevant systemic medication. Different case definitions of incidence rate showed no differences. Prevalence and incidence remained stable throughout the period from 2016 to 2020. Irrespective of the case definition, the prevalence and incidence of GPP was lower in men than in women and peaked in the 60 to under 80 age group before declining in older age groups (Figure 1 - case definition 1; Figure S1 - case definition 2).

Figure 1 Standardized annual prevalence and incidence rates of insured persons coded with ICD-10-L40.1 generalized pustular psoriasis (GPP) per 100.000, sex and age in 2019 (definition 1: N=875).

Cross- and Differential Diagnosis

Cross-diagnosis showed that almost two-thirds of GPP prevalent persons had at least one other psoriasis diagnosis (case definition 1). Another skin condition (differential diagnosis) was coded in 58.2% of people with GPP (case definition 1). Psoriasis vulgaris was most commonly diagnosed as a cross or differential diagnosis (Table S5).

Comorbidity

In contrast to persons with other codings of psoriasis, those with GPP had significant differences in five conditions (Table 2). When comparing people with GPP and without any psoriasis diagnosis, people with GPP showed a significantly higher RR of skin diseases as well as cardiovascular and mental diseases. No differences in the frequency of comorbidities were found related to the case definitions.

Table 2 Comorbidity of Generalized Pustular Psoriasis (GPP) in 2019: Relative Risks in Insured Persons with GPP vs Those with Psoriasis but Not GPP (Comparison Group A; N=64,047) and vs Individuals Without Psoriasis (Comparison Group B; N=2,008,03)

Outpatient Care

Of the people with GPP, 68.1% received at least one relevant drug prescription. Of all systemic prescriptions, systemic glucocorticosteroids were prescribed most frequently (56.4%), followed by methotrexate (25.4%) (Table 3). In the group of biologics, adalimumab (6.8%) followed by secukinumab (6.3%) was prescribed most frequently.

Table 3 Prescriptions and Defined Daily Doses (DDD) of Systemic Treatments in Patients with Generalized Pustular Psoriasis (GPP) and Without GPP and Psoriasis in 2019

The average total annual cost of drugs in the cohort observed was €1,22 million (€2050 per person). Total annual costs of persons receiving biologics were €978,014 (€15,524 per person) compared to €181,146 (€1485 per person) for non-biologic systemic treatments.

About 12.7% of persons with GPP received long-term drug therapy. Most of these were topical preparations (49.9%), followed by systemic conventional drugs (28.0%) and biologics (21.9%). About 3.2% of insured persons with GPP received phototherapy (Table 3).

About 50.7% of all drugs were prescribed by dermatologists, 28.1% by general practitioners, 9.5% by rheumatologists and 1.2% by internists. Biologics were prescribed mainly by dermatologists and rheumatologists (Figure 2). Systemic glucocorticosteroids were prescribed more often by general practitioners, whereas dimethyl fumarate and retinoids were mainly prescribed by dermatologists.

Figure 2 Shares of daily drug doses (DDD) related to drugs prescribed for generalized pustular psoriasis (GPP) by specialist groups in 2019 (N=875).

The drug treatments for incident persons with GPP were prescribed by a dermatologist or general practitioner in the vast majority of cases. While the proportion of persons treated by dermatologists decreased steadily over time (to 42.31% in the last quarter of observation), the proportion of persons treated by general practitioners or rheumatologists increased (Figure 3).

Figure 3 Share of medical specialties being the first prescribers of drugs for incident people with generalized pustular psoriasis (GPP) in 2018 (N=334).

Discussion

The objective of the current large-scale claims data analysis was to gain robust data on the prevalence, incidence and health care of GPP in Germany. The methodology followed previous studies showing good internal and external validity in chronic inflammatory skin diseases.^14,15 Our data suggest that there are large variations in prevalence data depending on the methods of data work-up. The prevalence of GPP in countries, such as Korea (12 per 100,000)^5,8 and the United States (14 per 100,000),^5,8 was comparable to the observed prevalence in this study. The prevalence of GPP was lower with 1.5 per 100,000 in Sweden,^4,6 0.18 per 100,000 in France,⁶ and 0.7 per 100,000 in Brazil.⁷ Differences between countries may be due to differences in study design, case definitions, coding habits, population structure and health care systems. A published German claims data study using the same selection criteria as case definition 1 described a similarly high GPP crude prevalence of 45 per 100,000.¹⁶ The incidence of GPP was 0.06 per 100,000 in France in 2001⁶ and 0.8 per 100,000 in Sweden in 2015,⁴ compared with 1 and 15 per 100,000 in our study. The studies differed in the selection of incident cases according to the diagnosis-free period prior to GPP diagnosis. The French study did not include information on diagnosis-free time⁶ and Löfvendahl et al⁴ defined diagnosis-free time as ten years. Against this background, it can be assumed that the chosen diagnosis-free time of up to 3 years is too short for an accurate estimation which most likely resulted in overestimated incidences. However, the most important determinant of the high rate of GPP codings in Germany most probably is overcoding of false GPP cases. Further validation studies based on statutory health insurance (SHI) data with a longer diagnosis-free period should be sought.

The findings align with the existing literature, which indicates that GPP occurs less frequently in men than in women.^3,4,6 The highest prevalence was observed in the age group 70 to under 80 across all case definitions. In other studies, the highest prevalences were observed in younger age groups, such as those between 40 to 60 or 60 to under 70 years old.^{3,4,6,9,17,18} Such differences are not unexpected and are likely due to the differing underlying populations, which differ significantly not only in size but also in their age structures, making them difficult to compare.

The utilization of diagnostic data from hospitals indicates that the available data (1.5% hospitalized for GPP extrapolated to 425 cases) is comparable with the hospital cases of the federal government’s health monitoring (GBE) (with 395 inpatient GPP cases in 2019).¹⁹ It can be postulated that all inpatient stays were associated with an acute GPP episode, ie flare, given that 1.5% of all inpatient stays lasted at least three days. In the study by Zema et al,¹⁰ the proportion of GPP persons experiencing a flare was found to be higher at 18%. The study also found that 36% were treated as inpatients and 53% as outpatients. When a certificate of incapacity for work due to GPP and systemic medicines is also taken into account, the proportion rises to 32.6%. Nevertheless, the proportion is likely to be overestimated when considering systemic therapies, as these therapies are also used for moderate or less severe GPP.

Concomitant psoriasis vulgaris occurred in 38.2% of persons with GPP, compared to the literature with 43% and 50%.^4,9,20 RR for concomitant diseases reveals GPP is associated with significantly higher rates of skin diseases and cerebrovascular diseases compared to psoriasis but no GPP. In addition to genetic factors, a higher degree of systemic inflammation in GPP may be important. Ichthyosis, pemphigus, viral skin infections, impetigo and dermatitis are comorbidities that are raised as potential differential diagnoses for GPP. However, the SHI data do not permit to assure whether these are true comorbidities or misdiagnoses.

In the current cohort, topical therapy plays the greatest role in drug supply for persons coded with GPP. A reason may be frequent association (or confounding) with psoriasis vulgaris. Systemic drugs frequently used in the treatment of GPP include acitretin, ciclosporin, methotrexate and infliximab.^10,21,22 General practitioners are distinguished by a very high utilization of systemic glucocorticosteroids. The relatively high proportion of dermatologists (56%) indicates a high demand for highly qualified specialist dermatological care for persons with GPP. A small proportion of persons with GPP received continuous drug therapy, which most probably results from the predominant interval-like occurrence of GPP (flares) and the fact that no suitable regimens for recurrence prevention had yet been developed in the observation period. With respect to treatment costs, the costs of outpatient medication often represent the largest share. A primary study determined higher drug costs of €4324 per persons with psoriasis per year than our present study (€2050).²³ However, in the primary study medication use was collected for the last three months and then extrapolated to a full year, which may lead to overestimates. Furthermore, biologics are associated with higher costs compared to conventional systemic therapies,^24,25 as this study also shows.

Strengths and Limitations

The fundamental strength of this analysis is the extensive data set on SHI, which offers valuable insights into the population coverage of SHI, since it covers around 90% of the German population.²⁶ However, it is important to consider the limitations of the data and the methodology employed when interpreting the results. For instance, the demographic profiles of the various health insurance funds exhibit notable differences.²⁷ To minimize these discrepancies, epidemiology rates were standardized. Furthermore, a study on psoriasis demonstrated that the epidemiological findings of the DAK-G data can be extrapolated without limitation to the SHI population, provided that they are standardized.¹⁴ As GPP can also present as an episodic disease, it is also possible that insured persons do not visit their physician annually, which may result in an underestimation of true prevalences and an overestimation of incidences.⁴ In addition, topical emollients are over-the-counter drugs not covered by SHI. This may result in an underestimation of the drug costs. Since OTC drugs are cheap, they, however, do not lead to marked changes in the drug costs for severe skin diseases.

Conclusion

According to the claims data, GPP is a rare but highly relevant disease. Determining the specific diagnosis of GPP is not trivial, and epidemiologic rates vary widely. In Germany, a marked overuse of the coding for GPP needs to be assumed since the wide case definition exceeds all international data by far. Further studies are needed to assess the extent and reason of incorrect coding in the claims data. This would also allow to control the reliability and validity of the results. The study data highlight the high disease burden of comorbidities in persons with GPP. GPP is now regarded as a distinct entity from psoriasis vulgaris. It requires diagnosis-specific management and an evidence-based guideline which is currently lacking. Patients with GPP have a high need for qualified, explicitly dermatological care. In treatment, there are differences between specialties. To fill the remaining knowledge gaps, primary health care studies, particularly well-established patient registries, are needed, and international collaboration and data exchange are key.