A narrative review of the socioeconomic burden associated with generalised pustular psoriasis

Generalised pustular psoriasis (GPP) is a rare, chronic and life‐threatening inflammatory skin disease characterised by widespread eruption of sterile pustules. With the approval of a GPP flare treatment in several countries occurring only recently, the socioeconomic burden associated with GPP is not well established. To highlight current evidence for patient burden, healthcare resource utilization (HCRU) and costs associated with GPP. Patient burden results from serious complications including sepsis and cardiorespiratory failure causing hospitalization and death. HCRU is driven by high hospitalization rates and treatment costs. The mean duration of a GPP hospital stay ranges from 10 to 16 days. A quarter of patients require intensive care, and the mean intensive care stay is 18 days. In comparison to patients with plaque psoriasis (PsO), patients with GPP have: a 64% higher score on the Charlson Comorbidity Index; higher hospitalization rates (≤36.3% vs. ≤23.3%); lower overall quality of life, and higher symptom scores for pain, itch, fatigue, anxiety and depression; direct costs associated with treatment 1.3‐ to 4.5‐fold higher; higher rates of disabled work status (20.0% vs. 7.6%); and increased presenteeism (i.e. worse impairment at work), impaired daily activities, and medically related absenteeism. Current medical management and drug treatment utilising non‐GPP‐specific therapies impose a significant patient and direct economic burden. GPP also imposes an indirect economic burden by increasing work productivity impairment and medically related absenteeism. This high level of socioeconomic burden reinforces the need for new therapies with proven efficacy in the treatment of GPP.

GPP can also have serious life-threatening complications that include sepsis, acute renal failure, neutrophilic cholangitis, congestive heart failure and acute respiratory distress syndrome. 5,8,9 GPP (ICD-10 code, L40.1) is an orphan disease, 10 so estimates of prevalence are sparse in the literature. Prevalence estimates published since 2000 range from approximately 1.8 per 1 000 000 people in France 11 to 459 per 1 000 000 people in Germany 12 ; however, the wide range reflects not only potential differences related to geographical region and ethnicity, but also to the study setting and GPP identification algorithm, and the majority of prevalence estimates are between 70 and 140 per 1 000 000 persons. [13][14][15][16] The reported mean age at diagnosis ranges between 45 and 50 years. 6,13,17 Historically, GPP has been viewed as a subset of plaque psoriasis (PsO) (psoriasis vulgaris, ICD-10 code L40.0), but more recent literature recognises GPP has a distinct aetiology and pathophysiology. 18,19 Prompt systemic, disease-modifying therapy is essential to control flares and life-threatening complications. 20 Prior to the recent approvals of spesolimab in the US, Japan, the EU, and China, there were no GPP-specific treatments approved for the treatment of GPP flares (US, EU, and China) or for the improvement of acute symptoms of GPP (Japan). [21][22][23] Although other immunomodulatory therapies, including biologics, and topical and systemic therapies have been used in the treatment of GPP, their utilization is based mainly on use in routine care in patients with plaque PsO or non-randomised study results from single-arm trials in Japan. 21 Additionally, strong evidence of the efficacy and safety of these other treatments in patients with GPP is limited, in part due to the lack of studies, the study designs, and the small number of patients. 21 The availability of evidence for the socioeconomic burden of rare diseases is correlated to the availability of specific therapies to treat such diseases. 24 Thus, with the only recent approvals in the US, Japan, the EU and China of the first therapy approved for the treatment of GPP flares (US, EU and China) and improvement of acute symptoms of GPP (Japan), the socioeconomic burden of illness associated with GPP has not yet been well characterised. This review aims to highlight the available evidence for the patient burden, healthcare resource utilization (HCRU), and the costs (direct and indirect) associated with GPP.  Almost all patients present with erythematous pustular lesions that are mostly generalised, but can begin in localised areas such as the trunk or limbs. 5,29 Scalp involvement, nail damage, uveitis, cheilitis, geographic tongue and bilateral leg edema have also been observed in affected patients. 5,29 Alongside the discernible skin symptoms, patients experience symptoms consistent with systemic inflammation such as high fever (45%-96%), 3,5,26,28 pain (61%-97%), 5,28 and general malaise/fatigue (58%). 3,26 Laboratory analysis in patients with a GPP flare show characteristic elevated erythrocyte sedimentation rate, positive c-reactive protein, leukocytosis, hypoproteinemia, hypocalcemia and elevated immunoglobulin G or A levels. 20 GPP flares can have serious complications, such as sepsis, and renal, hepatic, respiratory and heart failure causing hospitalisation and mortality. 11,26,32 Mortality associated with GPP flares ranges from 2% to 16%. 5,11,16,27,33 Choon et al. reported a mortality rate of 7%, with 2% of deaths resulting from sepsis and multiorgan failure during the first episode of GPP, and 3% of deaths occurring in subsequent GPP flares also due to sepsis. 5 GPP presents with a very high burden of comorbidities including other autoimmune diseases, arthritis, hypertension, peptic ulcer disease, osteoporosis, hyperlipidemia, diabetes mellitus, psoriatic arthritis, obesity and asthma. 5,23,28,[34][35][36][37][38][39] In a study utilising the Swedish National Patient Register, 70% of the identified GPP cases (N = 1093) had any selected comorbidity compared with 63% of the matched plaque PsO controls (1:3) and 46% of the matched general population controls (1:5). 38 In particular, comorbid nephritic nonhypertensive disease, Crohn's disease, chronic renal failure, type 1and type 2 diabetes, and peptic ulcer disease were all more likely to occur within GPP cases than plaque PsO controls. 38 Compared to the general population, Crohn's disease, type 2 diabetes, peptic ulcer disease, celiac disease, sinusitis and stroke occurred more frequently within the GPP population. 38 Additionally, a large proportion of patients have a history of or concomitant diagnosis of PsO (plaque PsO or other types). 5,28,29,32,36 In another comparison of a GPP population (N = 975) to a matched plaque PsO population (N = 2915), more patients with GPP experience comorbid autoimmune conditions (32.6% vs. 25 respectively). 23 The increase was even greater between the GPP population (N = 982) and the matched general population (N = 2946)

| G PP PATIENT BURDEN
where the CCI score was more than double for the GPP population (0.470 [1.01] and 0.208 [0.77], respectively). 23 Within a GPP population, patients with flares documented in their electronic healthcare records were significantly more likely to experience a higher burden of comorbid conditions than those without documented flares over the study observation period (34% higher mean CCI score: 2.80 vs. 2.09, respectively). 28 The severe symptoms and serious complications of GPP have a negative impact on the patient's quality of life (QoL). Overall QoL and symptom scores for pain, itch and fatigue were higher in patients with GPP than in patients with plaque PsO indicating the greater negative impact of GPP (Table 1). 35 The impact on QoL extends into the quiescent phase as shown by a reported mean score of 12.4 (range 1-28) for the Dermatology Life Quality Index (DLQI) for patients out of the acute GPP phase (score > 10 indicates severe QoL impairment). 5 New research suggests GPP is associated with considerable emotional burden. An analysis of US healthcare claims found patients with GPP (N = 975) compared to matched plaque PsO controls (N = 2915) were more likely to be diagnosed with an anxiety disorder (15.4% vs. 11.6%) or with depression (10.4% vs. 7.3%) (both comparisons p < 0.001). 23 In the CorEvitas Registry (previously Corrona) study, a higher proportion of the 60 patients with GPP had a history of clinician-reported anxiety (28.3% vs. 17.1%) and clinician-reported depression (31.7% vs. 17.1%) compared to the 4848 patients with plaque PsO. 35 In the same study but using an EQ-5D-3L score, patients with GPP reported symptoms of anxiety and depression more than patients with plaque PsO (Table 1), demonstrating the negative impact GPP has on the psychosocial aspects of patients' QoL. 35 Further research suggests patients with GPP can experience feelings of shame, anger and worry that can impact daily activities and their social life. 40

| ECONOMIC BURDEN
The full economic impact of GPP is not well known. Studies post-2020 suggest GPP is associated with significant HCRU, direct costs, as well as indirect costs, such as lost productivity. Before 2020 there was no published literature on the direct and indirect costs of GPP. 40 Since 2020, four population-based studies reporting on the economic burden, including direct costs, for patients in the US (n = 990 with GPP), 23 Sweden (n = 914), 41 and Japan (n = 718 and n = 110) 34,42 have been published. All four analysed patients with GPP with two matched controls: patients with plaque PsO, and the general population.

| Healthcare resource utilization
HCRU is higher in the GPP population than in the plaque PsO and general populations. 13,23,34 This is driven by increased inpatient, outpatient and drug costs. 23

| Treatment utilization
Non-biologic therapies are used more often than biologic therapies. 16,26,34 In Germany between 2005 and 2019, 86 patients with GPP received 201 treatment courses with methotrexate (20.9%) and acitretin (13.9%) being the most common treatments received by patients. 26 In this sample of patients, more than half of the treatment courses (58.7%) resulted in a partial or non-response. 26 The most frequent reasons reported for treatment discontinuation across all treatment types were ineffectiveness (38.0%) and adverse events (36.4%). 26 Topical corticosteroids (35%), oral dermatological therapies (methotrexate, cyclosporine, tacrolimus) (13%), and oral corticosteroids (11%) were the most common treatments used during flare episodes in the US from 2015 to 2020. 28 Additionally, opioids were prescribed in 21% of flare episodes. 28 Overall, the use of biologics to treat GPP flares was low in the US (<10% patients) 28

| Direct costs
The direct costs associated with treating GPP are substantial, ranging from 1.3-to 4.5-fold higher than direct costs associated with treating plaque PsO, and 3.1-to 7.9-fold higher than the general population (Table 2). 13

| Indirect costs
There is limited evidence that describes the impact that GPP has on patients' ability to work and participate in daily activities. Two recent studies suggest there is an indirect burden of illness associated with GPP. 35,43 In a US CorEvitas study based on the existing psoriasis registry, 60 patients with GPP were compared to patients with 4894 patients with plaque PsO. 35  than non-GPP controls. The GPP and plaque PsO populations were comparable when analysed for these same outcomes. 43

| DISCUSS ION
GPP is a heterogeneous disease that is different from plaque PsO. 9,44 Moreover, the current guidance for the diagnosis and treatment of GPP is limited and not standardised. 2,20,44 Due to the potential for sepsis, cardiorespiratory failure, renal failure or other complications that can lead to death, a prompt diagnosis and systemic treatment initiation are essential. 5,8,9,20 Patients frequently require hospitalisation regardless of severity level. 7,27,34,41,42 Despite being a distinctly different disease from plaque PsO, the current treatment paradigm for GPP relies on treatments used to  Our understanding of the socioeconomic burden associated with GPP is beginning to increase with recent studies making a comparison to patients with plaque PsO and highlighting the increased burden of comorbidities and symptoms including pain, itch and fatigue. 23,35 Increased HCRU and direct costs for the treatment of patients with GPP compared to plaque PsO were also evident. 34,41,42 Recent studies have shown GPP is associated with psychosocial burden. 23,35,37 GPP is an unpredictable disease with severe life-threatening complications. Although known causes of previous flares may be avoided, future flares may result from different triggers or are idiopathic. 5,29 The combination of discernible skin symptoms, comorbidities and the unpredictable nature of the disease, provide a potential rationale as to why recent literature suggests patients with GPP have higher rates of documented anxiety and depression, as well as higher scores on PROs measuring anxiety and depression than patients with plaque PsO. 23,35,37 The higher cost of treating GPP compared to plaque PsO is driven by hospital and treatment costs. 23,34,41,42 The prevention of life-threatening complications requires prompt treatment and a high level of HCRU, including intensive care. 5,27,29,40 Hospital admissions for GPP have increased in recent years in Germany. 40 While the exact reason for this is unknown, is it cause for further exploration and suggests that more therapies approved for the treatment of GPP flares are needed.
The use of biologics for the treatment of GPP is increasing albeit without economic evaluations nor regulatory approvals as treatments for GPP flares or acute symptoms of GPP. 16

| CON CLUS ION
In conclusion, the clinical manifestations of GPP and associated severe comorbidities put patients at risk of life-threatening complications and potential mortality. Unsurprisingly, patients' QoL is significantly impacted, even in comparison to other autoimmune diseases. Current medical management and drug treatment utilising non-GPP-specific therapies are associated with high hospitalisation rates and costs that impose a significant direct economic burden.
GPP also imposes an indirect economic burden by increasing work productivity impairment and medically related absenteeism. This high level of socioeconomic burden reinforces the need for new therapies with proven efficacy in the treatment of GPP. Spesolimab is anticipated to reduce the overall burden of GPP, but remains to be evaluated.

AUTH O R CO NTR I B UTI O N S
All authors (Thomas M. Zimmermann, Patrick Hofmann and Gretchen R. Chiu) were involved in the planning/conduct of study, collecting and/or interpreting data, drafting manuscript and provided approval to submit this work for publication.

ACK N O WLE D G E M ENTS
Elizabeth Hubscher, PhD, and Leah Wiltshire, BPharm, of Cytel, Inc.
provided writing, editorial support, and formatting assistance, which was contracted and funded by Boehringer Ingelheim (BI).

FU N D I N G I N FO R M ATI O N
This study was funded by Boehringer Ingelheim. All authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole and have given their approval for this version to be published. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

CO N FLI C T O F I NTE R E S T S TATE M E NT
The authors are employees of Boehringer Ingelheim (BI).

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.

D I SCLOS U R E S
The authors did not receive payment related to the development of the manuscript.