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The clinical, humanistic, and economic burden of generalized pustular psoriasis: a structured review

The clinical, humanistic, and economic burden of generalized pustular psoriasis: a structured review EXPERT REVIEW OF CLINICAL IMMUNOLOGY 2020, VOL. 16, NO. 3, 239–252 https://doi.org/10.1080/1744666X.2019.1708193 REVIEW The clinical, humanistic, and economic burden of generalized pustular psoriasis: a structured review a b c d Saifuddin Kharawala , Amanda K. Golembesky , Rhonda L. Bohn and Dirk Esser a b Bridge Medical Consulting Ltd, Richmond, London, UK; Global Epidemiology & Real World Evidence Center of Excellence, Boehringer Ingelheim c d International GmbH, Rheinland-Pfalz, Germany; Bohn Epidemiology, Boston, MA, USA; Therapeutic Area Immunology & CNS, Boehringer Ingelheim International GmbH, Rheinland-Pfalz, Germany ABSTRACT ARTICLE HISTORY Received 15 November 2019 Introduction: Generalized pustular psoriasis (GPP) is characterized by widespread erythema and edema, Accepted 13 December 2019 superficial sterile coalescing pustules, and lakes of pus. Although the impact of GPP is thought to be substantial, emerging literature on its clinical, humanistic, and economic burden has not previously been described in KEYWORDS a structured way. Clinical burden; economic Areas covered: A structured search focused on the identification of studies in GPP using specific search burden; flare; generalized terms in PubMed and EMBASE® from 2005 onwards, with additional back-referencing and pragmatic pustular psoriasis; searches. Outcomes of interest included clinical, humanistic, and economic burden. humanistic burden; mortality; prevalence; Expert opinion: Despite its significant clinical, humanistic, and economic burden, GPP is poorly quality of life classified and inadequately studied. A recent European (ERASPEN) consensus classifies GPP into relap- sing and persistent disease and classifies patients on the presence or absence of psoriasis vulgaris. Classification of GPP lesions involving >30% body surface area or use of hospitalization as a surrogate may be a way to identify significant flares. Given the frequency of flares, the impaired quality of life during the post-flare period, and safety/tolerability issues, it is clear that current treatment options are not sufficient. Long-term studies utilizing the European consensus statement with subclassifiers are required to supplement our current understanding of the burden of GPP. 1. Introduction dermatoses, including subcorneal pustular dermatosis (Sneddon–Wilkinson syndrome; a localized variant of pustular Generalized pustular psoriasis (GPP), first described by von psoriasis) and acute generalized exanthematous pustulosis Zumbusch in 1910, is characterized by widespread erythema (AGEP) [4]. AGEP is a drug-induced pustular psoriasis, which, and edema, superficial sterile coalescing pustules, and lakes of like GPP, presents with rapid onset of generalized pustules. pus. Dermal eruptions are usually accompanied by fever and However, the two conditions can be differentiated on the leukocytosis. GPP is one recognized subtype of pustular psor- basis of their clinical features, especially the quicker resolution iasis (PP), alongside palmoplantar pustulosis (PPP) and acro- of symptoms with AGEP [5]. The classifications of GPP, PPP, dermatitis continua of Hallopeau (ACH). PP describes a group and ACH have been used historically and are retained in the of inflammatory skin conditions characterized by infiltration of recent ERASPEN consensus document. Consensus definitions neutrophil granulocytes in the epidermis to such an extent for the diagnosis of these three subtypes are provided in that clinically visible sterile pustules develop [1]. PP has tradi- Table 1 [1]. tionally been considered a subset of psoriasis alongside other In GPP, loss-of-function mutations of IL36RN were identified in phenotypes including psoriasis vulgaris (PV; also known as 23% to 37% of familial and sporadic cases, which seem to be plaque psoriasis), intertriginous psoriasis, guttate psoriasis, associated with a more severe clinical phenotype. These and and erythrodermic psoriasis [2]. However, the classification of other gene mutations found in patients with GPP (including muta- PP (and [PPP] in particular) within psoriasis has often been tions in CARD14 and AP1S3) lead to enhanced proinflammatory debated [3]. A recent collaboration from the European Rare cytokine secretion and recruitment of neutrophils and macro- and Severe Expert Network (ERASPEN) has classified PP as phages to the skin, and thus are directly contributing to the pathol- a distinct clinical entity rather than a subset of psoriasis, not- ogy of the disease [4]. ing clear distinctions in the genetic architecture of PP and PV, Recently,Akiyamaet al.[6]highlighted theroleof IL36RNand as well as differences in response to treatment. Primary pus- CARD14 mutations in GPP and proposed that GPP cases with tules are not considered to feature on the PV spectrum, and autoinflammatory pathomechanisms be classified within ‘autoin- conditions in which pustules arise within or at the edge of flammatory keratinization disease’ (AiKD).Thisisparticularlythe psoriasis plaques are described as ‘psoriasis cum pustulatione’ case with early-onset GPP without preceding plaque psoriasis, (psoriasis with pustules) and are not classified as PP [1]. It is which is often associated with IL36RN mutations [7]. Ethnic also important to distinguish GPP from other pustular CONTACT Dirk Esser dirk.esser@boehringer-ingelheim.com Boehringer Ingelheim International GmbH, Rheinland-Pfalz, Germany © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 240 S. KHARAWALA ET AL. concerns with the current treatments include teratogenicity risk Article highlights (acitretin and methotrexate) and osteoarticular symptoms (aci- tretin), while biologic agents can cause bone marrow depression ● Limited literature notwithstanding, it is clear that GPP confers a resulting in an increased risk of serious infections. Steroid treat- significant clinical, humanistic, and economic burden. ● Estimates of the prevalence of GPP vary widely across studies; in the ment carries the risk of triggering a GPP flare due to steroid single GPP-focused study identified, the prevalence rate was 1.76 withdrawal [4]. While genetic differences across ethnicities have cases per million population in France. been reported [8], data are lacking on potential differences in ● Three phases can be identified in the disease course of GPP; an initial pre-pustular phase is followed by a flare and then a post-flare treatment responses across ethnic groups [4]. chronic/quiescent period preceding the next flare. Although the burden of GPP is typically described in terms ● GPP flares are life-threatening episodes, while plaques/pustules con- of clinical consequences, the impact on the lives of patients tinue to occur in the post-flare period. ● The most common precipitating factors for flares are the withdrawal and their families and economic cost is thought to be sub- of steroid treatment, pregnancy, infections, and hypocalcemia. stantial, and we have not identified any previous review that ● Hospitalizations are relatively common during flares, and patient QoL has attempted to describe the emerging literature on clinical, is severely impaired during the course of disease. Patients with GPP experience one flare resulting in admission every 1–5 years. humanistic, and economic burden of GPP in a structured way. ● The persistence of lesions and recurrence of flares despite treatment The objective of the current review was, therefore, to charac- highlights the unmet medical need for these patients. terize the overall disease burden of GPP across the following ● It is understandable for a rare disease that data are limited; however, the scarcity of data is compounded by inconsistencies in definitions domains: (1) Clinical burden (epidemiology, core clinical fea- and classifications across studies. tures, and natural history of disease over time, including risk ● The availability of the recent consensus statement will be helpful in factors, clinical outcomes, and comorbidities); (2) Humanistic generating more consistent evidence to help better understand this condition. burden (functioning, quality of life [QoL], psychosocial burden, adherence/preference/satisfaction with treatment and care- giver burden); and (3) Economic burden (drivers of resource use and cost, actual costs, and utilities). In the sister publica- Table 1. ERASPEN consensus definitions for the diagnosis of pustular psoriasis. tion published in the same edition [13], the burden of disease Generalized pustular psoriasis of PPP is characterized in a similar way. Primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where pustulation is restricted to psoriatic plaques) Subclassifier: With or without systemic inflammation Subclassifier: With or without PV Subclassifier: Either relapsing (>1 episode) or persistent (>3 months) 2. Methodology Palmoplantar pustulosis Primary, persistent (>3 months), sterile, macroscopically visible pustules 2.1. Search strategy on palms and/or soles Subclassifier: With or without PV Based on the review objectives, a structured search focused on Acrodermatitis continua of Hallopeau the identification of observational studies in GPP using specific Primary, persistent (>3 months), sterile, macroscopically visible pustules affecting the nail apparatus search terms (‘pustular psoriasis’ OR ‘generalized pustular Subclassifier: With or without PV psoriasis’ OR ‘generalised pustular psoriasis’). Searches were ERASPEN, European Rare and Severe Expert Network; PV, psoriasis vulgaris. performed using the PubMed and EMBASE® databases from 2005 onwards (2005–2018). In addition, supplementary differences have been reported in genetic mutations associated searches were conducted through back-referencing of rele- with GPP; in a large recent study, IL36RN mutations were most vant articles, pragmatic searches in PubMed, Google Scholar, frequent in European patients (34.7%) with GPP, followed by East the gray literature, and conference abstracts. Asian patients, most of whom were from Malaysia (28.8%). None of the South Asian patients in the study had IL36RN mutations [8]. In Chinese Han patients, IL36RN mutations have been reported in 2.2. Study selection 46.8–60.5% of GPP patients; the frequency of mutations was much higher in GPP patients without psoriasis (70.6–79.2%) than Screening and extraction were conducted by a single reviewer. in those with psoriasis (36.8–37.8%) [9,10]. A high frequency of Titles and abstracts of the citations identified in the literature IL36RN mutations in GPP patients without psoriasis has also been search were screened according to predefined criteria, which reported in Japan (81.8%) [11] and Germany (46.2%) [12]. included patient population (individuals diagnosed with GPP), First-line systemic treatment for GPP in adults includes oral outcome measures of interest (clinical burden, humanistic retinoids (acitretin), cyclosporine, methotrexate, or a rapidly act- burden, economic burden), and study design (case reports ing biologic agent. Second-line treatment may involve combin- and case series were excluded). ing a biologic agent with conventional therapy. Topical Potentially relevant articles that met the eligibility criteria treatments such as corticosteroids, calcipotriene, and tacrolimus were selected for full-text review, and the criteria were then also have a role in GPP, either as a standalone treatment for mild applied to the full-text articles. To avoid duplication of infor- or localized illness, or as an adjunct to systemic therapy in more mation and in order to provide a useful overall summary, severe/generalized illness. Treatment for children with GPP is articles were further screened to ensure that 1) the highest broadly along similar lines and includes acitretin (with or without quality publications were selected and 2) the publications oral prednisolone), methotrexate, and cyclosporine. The treat- provided adequate representation of the population, includ- ments for GPP can themselves be burdensome; important safety ing pediatric studies. EXPERT REVIEW OF CLINICAL IMMUNOLOGY 241 3. Results a mean age of disease onset of 40.9 years among patients with adult-onset GPP (range: 21–81 years) [19], with other studies In total, 19 unique publications are included in this review, of which reporting a mean age at diagnosis of 45.6 (across all age 13 report on clinical outcomes only, two on economic outcomes groups) [20] to 50 years (adult-onset GPP) [18]. In the French only, one on QoL only, two on clinical and economic outcomes, and epidemiological study, the incidence and prevalence of GPP one which reports on all outcomes of interest. were highest between the ages of 40 and 60 years [14], which is consistent with an earlier retrospective study from the UK which reported the highest GPP prevalence between the fifth 3.1. Clinical burden of GPP and sixth decades of life [23]. This section describes the clinical burden experienced by Most publications reported GPP to be more frequent in patients with GPP as well as the natural history of GPP, includ- females than males, with the male-to-female ratio varying ing the evolution of signs and symptoms. The publications from 0.5 to 0.9 [14,18,19,23]. providing data to support the findings described in this sec- tion are summarized in Table 2. 3.1.2. Clinical characteristics and diagnosis While the definitions and classifications of GPP used across 3.1.1. Epidemiology studies were inconsistent, the occurrence of flares presenting One national study [14] focused on the prevalence of GPP, and throughout the course of the disease is the defining and diag- three studies provided supporting data [15–17](Table 2). nostic characteristic of the condition. In general, a GPP flare Augey et al. conducted a national GPP-focused study in France consists of a generalized pustular eruption all over the body. In and reported a prevalence rate of 1.76 cases per million population most cases, the onset of the flare is acute and GPP is then [14]. In this study, GPP data from hospitals were obtained by diagnosed based on the presence of systemic symptoms along sending a questionnaire to dermatological wards throughout with multiple sterile pustules (‘acute GPP’ or ‘von Zumbusch’), France for information on all in- and outpatients who visited although subacute and chronic onset may also be possible. these departments during 2004. Of the 121 dermatological wards, Navarini et al. recently proposed that GPP should only be diag- 112 responded to the questionnaire; 46 of these wards reported nosed when the condition (consisting of primary, sterile, macro- a total of 99 GPP patients. Ohkawara et al. assessed the prevalence scopically visible pustules on non-acral skin) has relapsed at of ‘GPP and related disorders’ by sending questionnaires to 575 least once or when it persists for more than 3 months [1]. community center hospitals throughout Japan to obtain informa- Flares are a potentially life-threatening and critical character- tion from medical records for patients with GPP and related dis- istic of GPP, consisting of dermal lesions accompanied by sys- orders who had visited the hospitals during 1983–89; and reported temic symptoms. Widespread erythematous plaques studded a prevalence of 7.46 cases per million population [17]. Much higher with sterile pustules all over the body are typically seen, which prevalence rates were described in a national insurance database often coalesce to form lakes of sterile pus [22]. Common symp- study in Korea (122.3 per million population [psoriasis prevalence: toms during GPP flares include fever with chills and rigors as well 453 per 100,000; GPP: 2.7% of all psoriasis]) [16]and aprospective as arthralgia. In one retrospective chart review, fever, and painful observational study across 104 centers in Italy (180.0 per million skin lesions were present in 89% of patients (n = 102) [19]. population [psoriasis prevalence: 2%; GPP: 0.9% of all psoriasis]) Other clinical features in acute GPP flares included uveitis, [15], with both studies reporting GPP prevalence as a subset of conjunctivitis, iritis, leg swelling, geographic or fissured ton- overall psoriasis (Figure 1). gue, and cheilitis [18,19,22]. On rare occasions, the acute stage Augey et al. also reported the incidence of GPP using two may be followed by pulmonary capillary leakage, pulmonary approaches [14]. The first approach used survey data as emphysema, jaundice, or renal failure [22]. described above, which yielded an incidence rate of 0.64 cases During the post-flare chronic phase, patients experienced per million person-years. The second approach utilized claims a variety of skin lesions including acropustulosis, annular pla- data from the national health insurance of France (Caisse que psoriasis, inverse psoriasis, plaque, erythroderma, and PP Nationale d’Assurance Maladie des Travailleurs Salariés) and [17,19]. Of these, plaque psoriasis lesions were the most com- reported an incidence rate of 0.5 cases per million person-years mon manifestation (50%), followed by pustular lesions (22%). in 1998 and 0.8 case per million person-years in 2001. Zelickson classified GPP patients into four subtypes (acute, 3.1.3. Disease course subacute annular, chronic acral, and mixed GPP) based on the GPP can broadly be described as having three phases. An onset of flare and lesion morphology [18]. However, the recent initial pre-pustular phase is followed by a flare and then ERASPEN consensus statement defines subtypes of GPP on the a post-flare chronic/quiescent period, which persists until the basis of the presence or absence of associated features, as shown next flare. A repeating pattern of flares and post-flare periods in Table 1 [1]. Although conventions for the subclassification of may continue to occur episodically throughout life (Figure 2). GPP were not applied consistently across studies, acute GPP was the most commonly reported subgroup. A high proportion of acute GPP (93%) was reported by Choon (n = 102) [19], while in 3.2. Pre-pustular phase the 1991 study by Zelickson, 56% of patients (n = 63) had a diagnosis of acute GPP [18]. In patients with preceding psoriasis (usually in the form of GPP is known to occur at all stages in life, including in plaque lesions), the pre-pustular phase persisted for approxi- children (juvenile GPP) [20–22]. Data from Malaysia reported mately 6–12 years prior to the first widespread flare [17– 242 S. KHARAWALA ET AL. Table 2. Characteristics of publications reporting on the clinical burden of GPP. Follow- up Publication (type) Ref Study design (country) Population (sample size) duration Objectives and outcomes Key data Augey 2006 (publication) 14 Questionnaire-based retrospective GPP (n = 99) N/A Objective: Prevalence of GPP: 1.76 per million population epidemiological survey conducted in 121 To describe the epidemiology of GPP and Incidence of GPP: 0.64 per million person-years dermatological wards (2004); additional data therapeutic strategies developed by hospital using the survey data; 0.5 per million person- retrieved from CNAMTS, the main French dermatologists years (1998) and 0.8 per million person-years health insurance program, covering 90% of the Outcomes: (2001) using the CNAMTS data; incidence and French population (France) Prevalence, therapeutic practices, treatment prevalence of GPP was highest between the failures, morbidity, mortality ages of 40 to 60 years; male-to-female 0.77 Mortality: 2 (2%); 1 each from congestive cardiac failure and septic shock Treatment failure was related to management in a university ward (OR: 2.9, p = 0.03), prescription of high or very high potency DC as first-line local therapy (OR: 7.6, p = 0.05), therapies other than retinoids as first-line systemic therapy (OR: 5.5, p = 0.04) Azura 2015 (conference 20 Database analysis of the Malaysian Psoriasis Psoriasis (n = 8,039; PP: NA Objective: Mean age of onset: 9.8 ± 4.4 years abstract) Registry (Malaysia) 1.6%) To determine the demographic features, Commonest aggravating factors: stress (57%), clinical pattern, treatment and QoL in sunlight (45%), infection (20.5%) pediatric patients with psoriasis in Malaysia Outcomes: Age at onset, aggravating factors Baker and Ryan, 1968 23 Retrospective observational study of cases in 1 GPP (n = 104; patients NA Objective: Prevalence of GPP: greatest between the fifth (publication) London hospital plus 43 dermatologists around with preceding plaque To report the natural history of GPP in the pre- and sixth decades of life; male-to-female ratio: the country (UK) psoriasis: 60%) pustular and pustular phases 0.70 Outcomes: Duration of pre-pustular psoriasis:10to20 Prevalence of GPP, duration of pre-pustular years psoriasis, diagnostic criteria Diagnostic criteria: ≥1 documented episode of widespread macroscopic noninfective pustulation Choon 2014 (publication) 19 Single-center retrospective analysis of medical GPP (n = 102; patients Objective: Mean age of onset: 40.9 years (range: 21–81 records (1989–2011) of all patients with adult- with preceding plaque To analyze the clinical profile of patients with years) onset GPP (Malaysia) psoriasis: 78%) adult-onset GPP Prevalence of GPP: male-to-female ratio: 0.5; Outcomes: acute GPP: 93% cases Demographic characteristics, morphological Duration of pre-pustular psoriasis: 11.7 years patterns, trigger factors, comorbidities, Flare: ~60% experienced a single flare over ~5 morbidity, and outcome years; precipitating factors identified in 85% of patients Symptoms: fever and painful skin lesions (89%), arthritis (34.7%), leukocytosis (78.4%) Comorbidities: Obesity (42.9%), hypertension (25.7%), hyperlipidemia (25.7%), diabetes mellitus (23.7%) Mortality: 7 (7%; all in acute GPP subgroup); cause of death was sepsis in 4 patients and multi-organ failure in 1 patient; 2 patients died when psoriasis was quiescent Fabbri 2004 (publication) 15 A study by AISP at 104 centers (specialized Psoriasis (n = 7,992) NA Objective: Prevalence of GPP: 0.9% of all psoriasis departments hospital dermatology clinics and To analyze epidemiology of psoriasis in Italy (180 per million population) university) Outcomes: Prevalence of GPP (Continued ) EXPERT REVIEW OF CLINICAL IMMUNOLOGY 243 Table 2. (Continued). Follow- up Publication (type) Ref Study design (country) Population (sample size) duration Objectives and outcomes Key data Jin 2015 (publication) 24 Retrospective analysis of medical records and GPP (n = 33; patients with >1 year Objective: Mean (SD) age at onset: 40.7 (22.0) years telephone survey (2002 to 2012) in two tertiary preceding plaque To investigate the clinical features of GPP Mortality: 1 (3%); from GPP of pregnancy (IH) hospitals (Korea) psoriasis: 42%) according to subtype, including the clinical Relapse rate: 76% over 1 year (persistence or course and relapse pattern of skin lesions relapse of skin lesions) according to a history of plaque-type Prognosis: Preceding plaque psoriasis may be psoriasis associated with increased risk of relapse Outcomes: during the chronic quiescent phase Diagnostic criteria, key signs and symptoms, natural history of disease, factors affecting disease progression, clinical outcomes and prognosis, risk/protective factors, precipitating factors, mortality Lee 2017 (publication) 16 Analysis of insurance claims data (2011–2015) GPP (n = 6,252 [2015]) NA Objective: Prevalence of GPP: 2.7% of all psoriasis from the data repository of the National Health To determine the prevalence of psoriasis in (122.31 per million population) Institution (Korea) Korea and to describe the demographic and social characteristics Outcomes: Prevalence of GPP Lin 2015 (conference 21 Retrospective analysis of GPP patients GPP (n = 103) NA Objective: Prevalence: GPP can occur at any age; the abstract) hospitalized in one center (2006–2014) (China) To study clinical features of children with GPP incidence in boys is higher than in girls; no with particular emphasis on inducing or gender differences can be observed in the age aggravating factors, clinical manifestation, of onset; preceding plaque psoriasis is more laboratory findings and the effectiveness seen in children; there were no significant and safety of therapeutic regimens differences in age of onset between the two Outcomes: groups Age of onset, incidence, prevalence of preceding plaque psoriasis Navarini 2017 1 Consensus document on clinical criteria for PP NA NA Objective: GPP is defined as primary, sterile, (publication) To present considerations on the macroscopically visible pustules on non-acral clinical features of PP and a consensus skin (excluding cases where pustulation is classification of phenotypes restricted to psoriatic plaques) Outcomes: GPP can occur with or without systemic Consensus definitions of GPP, PPP and ACH inflammation, with or without PV and can either be a relapsing (>1 episode) or persistent (>3 months) condition Ohkawara 1996 17 Multicenter study in which questionnaires sent to GPP and related disorders NA Objective: Prevalence of ‘GPP and related disorders’: (publication) 575 community center hospitals asking for (n = 541) To clarify prevalence, etiology, and standard 7.46 per million population. details of patients with GPP and related therapy of GPP; to describe heterogeneity of Age of onset: 32 years (patients with no disorders who visited the hospitals during clinical features and genetic background preceding plaque psoriasis); 37 years (patients 1983–89 (Japan) (HLA typing) of GPP patients with preceding plaque psoriasis) Outcomes: Duration of pre-pustular psoriasis: 6 years Prevalence; duration of pre-pustular psoriasis Popadic 2014 26 Data obtained from medical records of 18 GPP (n = 18) 2–19 Objective: The most frequent precipitating factor for (publication) patients with PP (1992–2011) (Serbia) years To present epidemiologic data, treatment disease worsening was upper respiratory tract approach, and course of the disease in 18 infection patients with all four forms of PP Outcomes: Diagnostic criteria, precipitating factors (Continued ) 244 S. KHARAWALA ET AL. Table 2. (Continued). Follow- up Publication (type) Ref Study design (country) Population (sample size) duration Objectives and outcomes Key data Ryan & Baker 1971 27 Review of data from GPP patients from GPP (n = 106) 3 years Objective: Mortality: 34 (32%). 8 patients died of (publication) dermatologists throughout the country (UK) To describe the prognosis in GPP uncontrollable PP; 9 deaths were attributable Outcomes: to treatments (steroids [n = 7] methotrexate Mortality [n = 2]); 8 deaths occurred when psoriasis was in remission Umezawa 2003 22 Expert guidelines for treatment in GPP to help NA NA Objective: Flares consist of dermal lesions and systemic (publication) improve QoL in GPP (Japan) To propose therapeutic guidelines for the symptoms. Widespread erythematous plaques treatment of GPP studded with sterile pustules all over the body Outcomes: were typically seen, accompanied by Clinical characteristics a burning sensation. These pustules often coalesce to form lakes of sterile pus; Other clinical features in acute GPP flares include uveitis, conjunctivitis, iritis, leg swelling, geographic or fissured tongue, and cheilitis Wu 2017 (publication) 25 Retrospective analysis of data of from the GPP (n = 82) NA Objective: Clinical features: Average age of onset 25.5 Department of Dermatology, Central South To analyze clinical features, laboratory tests, (±21.2) years (patients with preceding plaque University, Changsha (China) treatment and prognosis for patients with psoriasis), 32.7 (±18.0) years (patients with no GPP preceding plaque psoriasis) Outcomes: Key triggers: Most common triggers were Clinical features, laboratory tests, treatment infections (75.0%; preceding plaque psoriasis) and prognosis and drugs (41.7%; no preceding plaque psoriasis) Treatment response: Complete response in 28 (42%); Marked response in 24 (36%); Improvement in 8 (12%); no response in 6 (9%) [defined as lack of significant resolution of pustules; with <50% resolution of erythema and scales] Yamamoto 2015 3 Systematic review (Japan) NA NA Objective: Common comorbidities include cardiovascular (publication) To describe clinicopathological aspects of PPP disease, psoriatic arthropathy (12%) and differentiate PPP from pustular psoriasis Outcomes: Comorbidities Objective: Duration of pre-pustular psoriasis: 12 years Zelickson 1991 18 Medical record review in patients hospitalized at 63 (patients with To investigate precipitating factors, clinical Mortality: 2 (6%); 1 each from Guillain-Barré (publication) Mayo Clinic-affiliated hospitals (1961–1989) preceding plaque patterns, associated diseases, therapy, and syndrome and septic shock (USA) psoriasis: 51%) course. To differentiate between PPP and GPP Outcomes: Duration of pre-pustular psoriasis; mortality 1 2 Those with history of ‘ordinary’ psoriasis; Cases with history of PV ACH, Acrodermatitis continua of Hallopeau; AISP, Italian Intersiciplinare for Studio Psoriasis; CNAMTS, Caisse nationale de l’assurance maladie des travailleurs salaries; DC, dermatocorticosteroids; GPP, generalized pustular psoriasis; IH, impetigo herpetiformis; JNDB, Japanese national database of health insurance claims; NA, not applicable; OR, odds ratio; PP, pustular psoriasis; PPP, palmoplantar pustulosis; PV, psoriasis vulgaris; QoL, quality of life; SD, standard deviation. EXPERT REVIEW OF CLINICAL IMMUNOLOGY 245 Augey 2006 (France) 1.76 Ohkawara 1996* 7.46 Lee 2017 (Korea) 122.3 Fabbri 2004 (Italy) 180.0 0.0 20.0 40.0 60.0 80.0 100.0 120.0 140.0 160.0 180.0 200.0 Figure 1. Prevalence of GPP (per million population) across studies. *Ohkawara 1996 reported the prevalence of ‘GPP and related disorders’ [17]. Diagnosis of GPP Chronic/quiescent Pre-pustular phase* FLARE (Psoriatic lesions +/-) period First episode of widespread pustular flare Figure 2. Clinical course of GPP. *In patients with preceding psoriasis (usually manifesting as plaque lesions). 19,24]. During this phase, 31–78% of GPP patients experienced about 10% experiencing more than five flares over a 5-year psoriatic lesions [17–19,24]. period [19]. 3.3. Acute symptoms/flares 3.4. Post-flare chronic/quiescent period Data on the frequency of flares over time were limited. One Following the treatment of a flare, most patients showed single-center study, in which a flare was defined as involving partial or complete response. As an example, Wu et al. greater than 30% body surface area (BSA), reported a single reported that 42% of adult patients (n = 66) and 25% of flare in approximately 60% of patients (n = 102) over a follow- children (n = 16) demonstrated complete resolution of pus- up period of around 5 years [19]. In the same study, approxi- tules, erythema, and scales, while 36% and 50% of adults and mately 40% of patients reported a recurrence of flares, with children, respectively, showed a marked response [25]. Only 246 S. KHARAWALA ET AL. 9% of adults and 6% of children showed no response imme- a trigger for acute GPP flares [19]. Uveitis has been reported in diately following treatment. 3.2% of patients with acute GPP [19]. However, relapse of lesions (not amounting to a widespread flare) is common. In a report of patients with GPP across two 3.4.3. Mortality in GPP tertiary hospitals, relapse of skin lesions was subsequently seen Flares in GPP can be difficult to treat, and systemic complications after initial symptom clearance (following treatment) in 76% of during flares may occasionally result in death [14,18,19,24,27]. patients (n = 25) over a 1-year follow-up [24]. These relapses were In an analysis of 106 GPP patients, a mortality rate of 32% reported to manifest in the form of pustules alone (42%), plaques was reported (follow-up period was not specified). Twenty-six alone (32%), or both plaques and pustules (26%). Patients with of the 34 deaths were directly attributable to illness severity or preceding plaque psoriasis may have an increased risk of relapse to the treatment for GPP, especially the use of systemic ster- [24]. These findings were corroborated by cross-sectional data oids [27]. In more recent studies, deaths attributable to GPP from Choon et al. who found that, during the non-flare period, flares were reported in about 5–10% of GPP patients only a small proportion (<5%) of patients showed no psoriasis [14,18,19,24]. Sepsis or septic shock was the common cause symptoms [19]. In this study, during the non-flare period, almost of death in GPP [14,18,19]. all patients were receiving topical or systemic treatments, with most patients (nearly 73%) experiencing mild psoriasis (affecting <10% BSA) and about 10% of patients experiencing moderate-to 3.5. Humanistic burden of GPP -severe psoriasis (affecting ≥10% BSA). As discussed earlier, these No evidence was identified regarding activities of daily living, psoriasis symptoms consisted of plaque psoriasis in about 50% of caregiver burden, treatment adherence/satisfaction, occupa- the patients, followed by PP lesions in about 22% [19]. tional functioning, or psychosocial symptoms in GPP. Two publications provided data to support the findings described in this section, one of which was conducted exclusively in 3.4.1. Precipitating factors for flares patients with GPP, while the second was in a general psoriasis GPP flares tend to be triggered by specific factors. In the population in which ‘pustular psoriasis’ constituted 3% of the retrospective analysis by Choon, precipitating factors were sample (this study was included due to a paucity of data in identified in 85% patients (n = 102), with a spontaneous first GPP) (Table 3). episode of GPP flare occurring in 15% patients [19]. Slightly lower rates were reported by Zelickson et al. and Wu et al., 3.5.1. Quality of life with 46% and 50%, respectively, of flares being associated Data from Choon et al. indicated that GPP had a significant with specific triggers [18,25]. impact on QoL, even in the quiescent phase [19]. This study The most commonly reported precipitating factors for used the Dermatology Life Quality Index (DLQI), a 10-item flares were withdrawal of steroid treatment (approximately questionnaire in which a score above 10 suggests severe 30–40% of patients) [19,23]; pregnancy (two or more flares in QoL impairment, to assess how far GPP impacted patients’ 60% of pregnant women with GPP versus 40% in GPP as lives. This study reported a mean DLQI score during a follow- a whole) [19]; infections (particularly upper respiratory tract up visit (i.e., non-flare period) of 12.4 points in patients with infections) [17–19,21,23,25,26]; hypocalcemia [23]; and others, acute GPP (n = 102), indicating severe impairment. In the including sun exposure, seasonal variation, salicylates, exer- other subgroups, including subacute GPP, localized GPP, and tion, and menstruation [18]. impetigo herpetiformis (IH), the mean DLQI scores ranged Specific precipitating factors appeared to be associated from 13 to 17, again signifying severe impairment. At the with the type of GPP. Medications (75%) [25], including ster- time of QoL assessment, most (73%) patients had mild psor- oids (15–28%) [17], triggered flares more frequently in patients iasis symptoms while 10% had moderate-severe psoriasis (the with preceding plaque psoriasis, whereas in patients with no remaining were either asymptomatic or lost to follow-up). preceding plaque psoriasis, the most common precipitating Sampogna et al. reported QoL in a subsample of 380 factors included pregnancy (35%) [19] and respiratory tract psoriasis patients from the IDI Multipurpose Psoriasis infections (42%) [25]. Research on Vital Experiences (IMPROVE) study, including those with PP (3%) (GPP-specific data, including information 3.4.2. Key comorbidities on the proportion of the sample with GPP, were not reported Common comorbidities in GPP included obesity (42.9%), hyper- in this paper) [28]. QoL was measured using the 36-item short tension (25.7%), hyperlipidemia (25.7%), and diabetes mellitus form of the Medical Outcomes Study questionnaire (SF-36), in (23.7%) [19]. Other conditions seen with GPP included metabolic which responses to 36 questions are scored and summed syndrome, ophthalmological involvement, inflammatory bowel according to a standardized protocol and expressed as disease, cholestasis, and neutrophilic cholangitis [3,21]. In chil- a score on a 0–100 scale (a higher score represents better self- dren with GPP, hyperlipidemia, infection, and electrolyte disor- perceived health). Although no statistical analysis was pro- ders were commonly seen [21]. Joint involvement in the form of vided, this study reported that QoL in PP was lower than arthralgia or arthritis has been reported in 23.8% to 34.7% of GPP that in plaque and guttate psoriasis and was comparable to patients [19,22,24]. The presence of arthritis often necessitates that in palmoplantar and arthropathic psoriasis (Figure 3). the use of systemic steroids even in patients with mild GPP, and Sampogna et al. also reported that QoL decreased with increas- steroid withdrawal in these patients has been reported to be ing severity of psoriasis, as an example, SF-36 scores on the bodily EXPERT REVIEW OF CLINICAL IMMUNOLOGY 247 pain domain of SF-36 for those with very mild, mild, moderate, and severe psoriasis were 73, 66, 62, and 47, respectively (p < 0.01) [28]. In addition, emotional problems such as shame, anger, worry, and difficulties in daily activities and social life were seen in psoriasis patients, including those with PP. These problems increased with increasing disease severity. 3.6. Economic burden of GPP No evidence was identified relating to the direct and indirect costs (including the economic impact on caregivers) established in GPP or regarding utilities in GPP. The publications providing data to support the findings described are summarized in Table 4. Healthcare resource utilization and economic burden were very variable by country and healthcare system. 3.6.1. Healthcare resource utilization Resource utilization during flares is accounted for by man- agement of the acute episode of GPP using systemic treat- ments, often involving an inpatient hospitalization. In a large observational study (n = 102), an average of one hospitalization (range 1–20) was reported for each patient over a follow-up period of around 5 years [19]. Hospitalization data from the Federal Health Monitoring System in Germany indicated approximately 250–300 inpa- tient admissions each year due to GPP from 2011 onwards (Figure 4)[29]. In the study reported by Wu et al., the average duration of hospitalization was 11.6 (±10.2) days among patients with preceding plaque psoriasis and 12.1 (±6.7) days in those without preceding plaque psoriasis, and the difference was not statistically significant (p = 0.816) [25]. Across the three data sets [23,25,29], the duration of hospitalization was about 10–14 days, which was consider- ably shorter than the 30-day average hospitalization reported in an older study [18]. During the non-flare period, resource utilization occurs in the form of visits to physicians, including dermatologists, and receipt of topical and systemic treatments for the prevention of flare recurrences and for the management of skin lesions [19]. Detailed information regarding resource utilization dur- ing this period was not available. 3.6.2. Drivers of healthcare resource utilization Hospitalization is a key driver for resource utilization in GPP. Specific triggers for hospitalization in PP were reported in a retrospective study [30] in 38 recorded hospitalizations in France over a 15-year period (1990–2005). Triggers were iden- tified in approximately 45% of hospitalizations, with the most common being infection (18%), treatment discontinuation (16%), and stress (16%) (n = 211 hospitalizations). In a retrospective study in the Mayo Clinic [18], female patients spent more time on average in hospital (38 days versus 22 days for male patients). The duration of hospitaliza- tion was also longer in patients with a positive history of PV (31 days versus 24 days for no PV history) and in those with hypocalcemia (37 days versus 27 days among those with no hypocalcemia). Table 3. Characteristics of publications reporting on the humanistic burden of GPP. Population Publication Ref Study design (country) (sample size) Follow-up duration Objectives and outcomes Key data Choon 2014 19 Single-center retrospective GPP (n = 102) ~5 years (mean) Objectives: Mean DLQI scores: ranged from 12 to 17, suggesting a high impact of GPP (publication) analysis of medical To analyze demographic characteristics, on QoL records (1989–2011) morphological patterns, trigger factors, (Malaysia) comorbidities, morbidity and outcomes in GPP Outcomes: DLQI when the patient was out of acute GPP during the last follow-up Sampogna 2006 28 Cross-sectional study of Psoriasis (n = NA Objectives: SF-36: two distinct patterns of impairment of QoL, with a greater burden of (publication) inpatients with psoriasis; 380); 3% had To describe the QoL in patients with disease for palmoplantar, pustular and arthropathic psoriasis when subset of IMPROVE study pustular different clinical types of psoriasis compared to guttate and localized and generalized plaque psoriasis; QoL (Italy) psoriasis Outcomes: in patients with psoriasis was worse than in some other medical SF-36, DLQI conditions, especially psychosocial aspects GPP, generalized pustular psoriasis; DLQI, Dermatology Life Quality Index; QoL, quality of life; SF-36, 36-item short form of the Medical Outcomes Study questionnaire. 248 S. KHARAWALA ET AL. palmoplantar pustular guttate localized plaques generalized plaques arthropathic PF RP BP GH VT SF RE MH Figure 3. Comparison of SF-36 scores across psoriasis subtypes. Figure adapted, with permission, from Sampogna 2006 [28]. PF: Physical functioning; RP: Role physical; BP: Bodily pain; GH: General health; VT: Vitality; SP: Social functioning; RE: Role emotional; MH: Mental health. 7.46 cases per million population in that study. The other pre- 4. Conclusion valence studies identified were focused on psoriasis overall, 4.1. Summary with an analysis of GPP within the overall population, and reported much higher prevalence rates. These studies were This is the first structured review of the clinical, humanistic, and economic burden in GPP, and yields several interesting not focused on GPP, and it was not clear if the GPP diagnoses results. A major finding is the high burden of GPP, not only in these studies were sufficiently validated, which may explain the higher rates in these studies [17]. during acute flares but also during the post-flare period. Acute A complete understanding of the economic impact of GPP flares, which are serious episodes with considerable morbidity and mortality, are a hallmark of GPP. The morphology and could not be achieved as limited information was available and this was limited to the flare period. The available data suggest that distribution of cutaneous lesions and systemic manifestations patients with GPP experience at least one flare resulting in admis- have been thoroughly described in the literature. During the post-flare period, patients continue to experience plaque or sion to a hospital every 1–5 years. Given the serious and potentially fatal nature of a flare, this represents a serious risk to GPP patients. pustular lesions and still require treatment, either to manage the lesions or to prevent widespread flares. Unfortunately, many of the treatments are associated with considerable 4.2. Limitations side effects or precautions, such as osteoarticular symptoms, teratogenicity risk, and bone marrow depression. Finally, One limitation is that although this is a comprehensive over- although QoL appears to be severely impaired during the view, it is not a systematic review, and the fact that studies post-flare period (noting that data to support this were were prioritized during selection may have resulted in the drawn from a single study in an exclusive GPP population), exclusion of potentially relevant data. However, most reliable little is known about the impact on other humanistic burden studies were selected for detailed analysis, and it is therefore parameters during this period. not expected that the conclusions of this review will be sub- GPP is a rare disease, and the number of prevalence studies stantially impacted by the excluded literature. identified was small, with a wide range of prevalence rates In terms of the data included in this review, these were very reported. Differences in study design and definitions contribute limited. In particular, few reliable studies were available on the to variability in prevalence estimates. The single GPP-focused epidemiology of GPP, and the definitions and classifications of population-based study reported a prevalence of 1.76 - GPP used across studies were inconsistent, making inter-study per million population [20]. However, this study was conducted comparisons difficult. more than a decade ago, and only a subset of the dermatology Evidence on the clinical burden of GPP is limited to a few wards (46 of 112) reported data on GPP patients. Ohkawara studies of modest quality. Data on the population-level epide- et al. [17] reported data for a wider group of diagnoses (‘GPP miology of GPP were very limited; therefore, comparisons and related disorders’), which may explain the higher rate of across geographic regions or assessment of variations due to EXPERT REVIEW OF CLINICAL IMMUNOLOGY 249 Table 4. Characteristics of publications reporting on the economic burden of GPP. Population (sample Publication Ref Study design (country) size) Follow-up duration Objectives and outcomes Key data Choon 2014 (publication) 19 Single-center retrospective analysis GPP (n = 102) ~5 years (mean) Objectives: Mean duration of hospital stay: 10.3 days (3–44 days) of medical records (1989–2011) To analyze demographic characteristics, Mean number of admissions:1(1–20) (Malaysia) morphological patterns, trigger factors, comorbidities, morbidity and outcomes in GPP Outcomes: Mean numbers of admission and mean duration of hospitalization The German Federal 29 Online database that supplies data GPP (n = 286 From the year Objectives: Hospitalization: ~250–300 inpatient admissions each year due Health Monitoring and information on the state of hospitalizations 2000 onwards To improve the availability of health to GPP from 2011 onwards. System (database health and healthcare services in in 2016) data in Germany and to create analysis) Germany a database which can be used to inform discussions Outcomes: Mean numbers of admission and mean duration of hospitalization Lapeyre 2007 30 Retrospective study performed in Psoriasis (n = 211 NA Objective: Triggers: identified for 17 of the 38 hospitalizations (~45%) (publication) a single-center over a 15-year hospitalizations); To assess the main reasons for Most common triggers: infection (18%), treatment period (1990–2005) (France) PP (n = 38 hospitalization of psoriasis patients discontinuation (16%), and stress (16%); for these factors, no hospitalizations) Outcomes: significant differences were noted across the psoriasis Triggers for hospitalization subgroups Wu 2017 (publication) 25 Retrospective analysis of data of GPP (n = 82) NA Objective: Hospitalization: Average duration of hospitalization was 11.6 from the Department of To analyze clinical features, laboratory (±10.2) days (patients with preceding plaque psoriasis) and Dermatology, Central South tests, treatment and prognosis for 12.1 (±6.7) days (patients with no preceding plaque psoriasis) University, Changsha (China) patients with GPP (p = 0.816). Outcomes: Duration of hospitalization Zelickson 1991 18 Medical record review in patients 63 (patients with Objective: Mean duration of hospitalization: 10.3 days (range 3–44 (publication) hospitalized at Mayo Clinic- preceding plaque To investigate precipitating factors, days); female patients spent more time in the hospital affiliated hospitals (1961–1989) psoriasis: 51%) clinical patterns, associated diseases, (average, 38 days) than male patients (22 days) (USA) therapy, and course Factors associated with hospital stay: Hypocalcemia (37 days Outcomes: vs 27 days, presence vs absence), female sex (38 days vs 22 Duration of hospitalization; factors days, female vs male), previous history of PV or PP (31 days vs associated with hospital stay 24 days, presence vs absence) GPP, generalized pustular psoriasis; NA, not applicable; PP, pustular psoriasis; PV, psoriasis vulgaris. 250 S. KHARAWALA ET AL. 2000 2005 2010 2011 2012 2013 2014 2015 2016 All Males Females Figure 4. Total number of GPP hospitalizations in a year in Germany 2000–2016. Source: Federal Health Monitoring System http://www.gbe-bund.de/. Hospitalization data in the website (http://www.gbe-bund.de/) are reported at 5-year intervals for 2000–2010, and then annually from 2010. race/ethnicity could not be conducted. Several of the larger For economic burden, data on direct/indirect costs and studies on clinical burden were conducted and published utilities were not identified, and very little data on resource many years ago, thus reducing the generalizability of the utilization in the form of hospitalization and drivers of data to current patients. The published data consisted of resource utilization were obtained. Resource utilization during cross-sectional studies or retrospective analyses, with no the post-flare period has not been fully reported but needs to large, high-quality prospective observational studies. be considered as the lifetime economic burden for someone Additionally, the reporting of clinical burden differed across diagnosed with GPP would appear to be very high. publications due to the absence of standardized instruments used for the assessment of disease severity and progression in 5. Expert opinion observational studies. There is, therefore, insufficient informa- tion to understand the long-term burden in terms of fre- Until very recently, GPP has been both poorly classified and quency of flares, severity of disease in the post-flare/chronic inadequately studied, despite its significant clinical, humanistic, period, and prognostic factors. Autoimmune conditions such and economic burden. The recent ERASPEN consensus state- as uveitis and inflammatory bowel disease are important ment proposes a new and valuable classification system that comorbidities in psoriasis, although their occurrence and may help to provide consistency in terms of how GPP is impact in GPP have not been sufficiently described in the described and characterized in the future. This consensus classi- literature [31,32]. fies GPP into relapsing disease (more than one episode) and The humanistic burden data included only one GPP- persistent disease (maintained over the course of more than 3 focused study in which QoL was assessed during the post- months) and also classifies patients on the basis of the presence flare/chronic period. Lack of data notwithstanding, it should or absence of PV. This differs slightly from the separation of GPP be noted that although objective measurement of QoL is into patients with and without preceding plaque psoriasis, which precluded during a flare because of the life-threatening nature tends to be seen across the literature. Multiple studies have of the episode, the humanistic burden is clearly higher during reported the proportion of patients with and without preceding a flare than in the post-flare period. The impact of GPP on plaque psoriasis, and there are some data to suggest that these functioning, occupational performance, or caregivers has not subtypes are actually phenotypically different. As recent findings been examined. from genetic studies suggest, patients with GPP without Total number of inpatient admissions in a year with a diagnosis of GPP EXPERT REVIEW OF CLINICAL IMMUNOLOGY 251 preceding plaque psoriasis may potentially be classified under Declaration of interest AiKDs [6,7]. AK Golembesky and D Esser are employees of Boehringer Ingelheim It is surprising that the frequency of flares associated with GPP International GmbH. S Kharawala and RL Bohn are paid consultants of is not generally reported in the literature. This could simply be Boehringer Ingelheim International GmbH. The authors have no other rele- vant affiliations or financial involvement with any organization or entity with because GPP is a rare and therefore a rarely studied condition. a financial interest in or financial conflict with the subject matter or materials However, it may also be due to difficulties encountered in deter- discussed in the manuscript apart from those disclosed. mining what constitutes a ‘flare’, as no consensus definition exists. The definition used by Choon et al. (GPP lesions involving more than 30% of the BSA) may be a useful way to define Reviewer disclosures a significant flare [19]. Alternatively, hospitalization may be used as a surrogate for the identification of significant flares. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Validated scales to define and quantify disease activity including persistent disease and flares are needed. Given the frequency and seriousness of flares, impaired qual- ity of life, and limited safe treatment options available, it is clear References that there exists a significant unmet need in this area. The Papers of special note have been highlighted as either of interest (� )orof frequency of hospitalizations due to GPP also does not appear considerable interest (�� ) to readers. to have changed over recent years. There is, therefore, a pressing 1. Navarini AA, Burden AD, Capon F, et al. on behalf of the ERASPEN requirement for the development of better treatments to reduce Network. European consensus statement on phenotypes of pustu- the overall burden of GPP not only for patients but also for their lar psoriasis. J Eur Acad Dermatol Venereol. 2017;31:1792–1799. � This paper reports the European (ERASPEN) consensus state- families and health-care providers overall. ment on pustular psoriasis, providing consensus definitions for The paucity of data in some aspects of this review highlights the diagnosis of GPP. areas in which future studies are required to supplement our 2. WHO [Internet]. Global report on psoriasis; 2015 [cited 2018 Jul 02]. current understanding of the burden of GPP. Reliable studies are Available from: https://apps.who.int/iris/bitstream/handle/10665/ needed that focus on the population-level prevalence and inci- 204417/9789241565189_eng.pdf 3. Yamamoto T. Palmoplantar pustulosis: A distinct entity with a close dence of GPP, to allow for comparisons across race/ethnicities relationship to psoriasis. Dermatol Clin Res. 2015;1:1–7. and geographic regions. Future studies should utilize the 4. Gooderham MJ, Van Voorhees AS, Lebwohl MG. An update on gen- European consensus statement, complete with subclassifiers. eralized pustular psoriasis. Expert Rev Clin Immunol. 2019;15:907–919. Long-term studies are required to characterize the clinical bur- 5. Feldmeyer L, Heidemeyer K, Yawalkar N. Acute generalized den in terms of the frequency of flares (defined objectively), exanthematous pustulosis: Pathogenesis, genetic background, clin- ical variants and therapy. Int J Mol Sci. 2016;17: E1214. pii. despite treatment. Additional information on disease severity 6. Akiyama M, Takeichi T, McGrath JA, et al. Autoinflammatory kera- in the post-flare/chronic period, and the proportion of patients tinization diseases: an emerging concept encompassing various who require continuous topical or systemic treatment for the inflammatory keratinization disorders of the skin. J Dermatol Sci. prevention of flare recurrences, would also be valuable. 2018;90:105–111. Studies to better characterize the humanistic and economic 7. Akiyama M. Early-onset generalized pustular psoriasis is represen- tative of autoinflammatory keratinization diseases. J Allergy Clin burden of disease during the natural history of this disease are Immunol. 2019;143(2):809–810. urgently required in order to address our existing poor under- 8. Twelves S, Mostafa A, Dand N, et al. Clinical and genetic differences standing of this area. Future studies should also aim to better between pustular psoriasis subtypes. J Allergy Clin Immunol. describe the inter-relationship between clinical, humanistic, and 2019;143:1021–1026. economic burden, particularly the impact of clinical improve- 9. Li X, Chen M, Fu X, et al. Mutation analysis of the IL36RN gene in Chinese patients with generalized pustular psoriasis with/without ment or worsening on quality of life and resource utilization. psoriasis vulgaris. J Dermatol Sci. 2014;76:132–138. Five years from now, we expect that the ERASPEN consen- 10. Li Z, Yang Q, Wang S. Genetic polymorphism of IL36RN in Han sus statement will have obtained widespread acceptance, and patients with generalized pustular psoriasis in Sichuan region of that observational studies will report more consistent data by China: A case-control study. Medicine (Baltimore). 2018;97:e11741. using the definitions and classifications provided in this state- 11. Sugiura K, Takemoto A, Yamaguchi M, et al. The majority of gen- eralized pustular psoriasis without psoriasis vulgaris is caused by ment. We also expect more data to be generated on the deficiency of interleukin-36 receptor antagonist. J Invest Dermatol. frequency of flares in GPP, perhaps aided by the use of vali- 2013;133:2514–2521. dated disease measures for flare assessment. 12. Körber A, Mössner R, Renner R, et al. Mutations in IL36RN in patients with generalized pustular psoriasis. J Invest Dermatol. 2013;133:2634–2637. Acknowledgments 13. Kharawala S, Golembesky AK, Bohn RL, et al. The clinical, humanis- tic, and economic burden of palmoplantar pustulosis: a structured The authors would like to thank Rachel Danks for assistance with the review. Expert Rev Clin Immunol. 2020;16:2. preparation of this manuscript. Editorial assistance was funded by 14. Augey F, Renaudier P, Nicolas JP. Generalized pustular psoriasis Boehringer Ingelheim International GmbH. (Zumbusch): A French epidemiological survey. Eur J Dermatol. 2006;16:669–673. � This paper reports incidence and prevalence rates from a GPP- focused population-based study in France. Funding 15. Fabbri P. Psoriasis. From clinical diagnosis to new therapies. This work was funded by Boehringer Ingelheim International GmbH. Florence, Italy: SEE-Firenze; 2004. ((ISBN:978L000002112)). 252 S. KHARAWALA ET AL. 16. Lee J, Kang YS, Park JS, et al. Prevalence of psoriasis in Korea: A a proposed classification of disease severity. Arch Dermatol Res. population-based epidemiological study using the Korean 2003;295(Suppl 1):S43–S54. National Health Insurance Database. Ann Dermatol. 2017; 23. Baker H, Ryan TJ. Generalized pustular psoriasis. A clinical and 29:761–767. epidemiological study of 104 cases. Br J Dermatol. 17. Ohkawara A, Yasuda H, Kobayashi H, et al. Generalized pustular 1968;80:771–793. psoriasis in Japan: two distinct groups formed by differences in � This paper reports burden of disease data across 104 GPP symptoms and genetic background. Acta Derm Venereol. patients. 1996;76:68–71. 24. Jin H, Cho HH, Kim WJ, et al. Clinical features and course of 18. Zelickson BD, Muller SA. Generalized pustular psoriasis: A review of generalized pustular psoriasis in Korea. J Dermatol. 63 cases. Arch Dermatol. 1991;127:1339–1345. 2015;42:674–678. � This paper reports burden of disease data across 63 GPP 25. Wu X, Li Y. Clinical analysis of 82 cases of generalized pustular patients. psoriasis. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2017;42:173–178 19. Choon SE, Lai NM, Mohammad NA, et al. Clinical profile, morbidity, (article in Chinese). and outcome of adult-onset generalized pustular psoriasis: 26. Popadic S, Nikolic M. Pustular psoriasis in childhood and adolescence: A ANALYSIS of 102 cases seen in a tertiary hospital in Johor, 20-year single-center experience. Ped Dermatol. 2014;31:575–579. Malaysia. Int J Dermatol. 2014;53:676–684. 27. Ryan TJ, Baker H. The prognosis of generalized pustular psoriasis. Br � This paper reports burden of disease data across 102 GPP J Dermatol. 1971;85:407–411. patients. 28. Sampogna F, Tabolli S, Söderfeldt B, et al. Measuring quality of life 20. Azura MA, Alias F, Nurakmal B, et al. Epidemiology and clinical of patients with different clinical types of psoriasis using the SF-36. pattern of psoriasis in paediatric population in Malaysia. Poster Br J Dermatol. 2006;154:844–849. session presented at: 23rd World Congress of Dermatology– 29. The Federal Health Monitoring System [Internet] [cited 2018 Jun International League of Dermatological Societies (ILDS); 2015 Jun 20]. Available from: http://www.gbe-bund.de/ 8–13; Vancouver, Canada. 30. Lapeyre H, Hellot MF, Joly P. Current reasons for in-patient 21. Lin M, Zhaoyang W, Lixin Z, et al. A clinical analysis of 103 cases of psoriasis management. Ann Dermatol Et Venereol. children with generalized pustular psoriasis. Poster session pre- 2007;134:433–436. sented at: 23rd World Congress of Dermatology–International 31. Fraga NA, Oliveira Mde F, Follador I, et al. Psoriasis and uveitis: League of Dermatological Societies (ILDS); 2015 Jun 8–13; a literature review. An Bras Dermatol. 2012;87:877–883. Vancouver, Canada. 32. Shimizu A, Kamada N, Matsue H. Generalized pustular psoriasis 22. Umezawa Y, Ozawa A, Kawasima T, et al. Therapeutic guidelines for associated with ulcerative colitis. J Clin Exp Dermatol Res. the treatment of generalized pustular psoriasis (GPP) based on 2013;4:192–193. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Expert Review of Clinical Immunology Taylor & Francis

The clinical, humanistic, and economic burden of generalized pustular psoriasis: a structured review

The clinical, humanistic, and economic burden of generalized pustular psoriasis: a structured review

Abstract

Introduction: Generalized pustular psoriasis (GPP) is characterized by widespread erythema and edema, superficial sterile coalescing pustules, and lakes of pus. Although the impact of GPP is thought to be substantial, emerging literature on its clinical, humanistic, and economic burden has not previously been described in a structured way.Areas covered: A structured search focused on the identification of studies in GPP using specific search terms in PubMed and EMBASE® from 2005 onwards, with additional back-referencing and pragmatic searches. Outcomes of interest included clinical, humanistic, and economic burden.Expert opinion: Despite its significant clinical, humanistic, and economic burden, GPP is poorly classified and inadequately studied. A recent European (ERASPEN) consensus classifies GPP into relapsing and persistent disease and classifies patients on the presence or absence of psoriasis vulgaris. Classification of GPP lesions involving >30% body surface area or use of hospitalization as a surrogate may be a way to identify significant flares. Given the frequency of flares, the impaired quality of life during the post-flare period, and safety/tolerability issues, it is clear that current treatment options are not sufficient. Long-term studies utilizing the European consensus statement with subclassifiers are required to supplement our current understanding of the burden of GPP.

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EXPERT REVIEW OF CLINICAL IMMUNOLOGY 2020, VOL. 16, NO. 3, 239–252 https://doi.org/10.1080/1744666X.2019.1708193 REVIEW The clinical, humanistic, and economic burden of generalized pustular psoriasis: a structured review a b c d Saifuddin Kharawala , Amanda K. Golembesky , Rhonda L. Bohn and Dirk Esser a b Bridge Medical Consulting Ltd, Richmond, London, UK; Global Epidemiology & Real World Evidence Center of Excellence, Boehringer Ingelheim c d International GmbH, Rheinland-Pfalz, Germany; Bohn Epidemiology, Boston, MA, USA; Therapeutic Area Immunology & CNS, Boehringer Ingelheim International GmbH, Rheinland-Pfalz, Germany ABSTRACT ARTICLE HISTORY Received 15 November 2019 Introduction: Generalized pustular psoriasis (GPP) is characterized by widespread erythema and edema, Accepted 13 December 2019 superficial sterile coalescing pustules, and lakes of pus. Although the impact of GPP is thought to be substantial, emerging literature on its clinical, humanistic, and economic burden has not previously been described in KEYWORDS a structured way. Clinical burden; economic Areas covered: A structured search focused on the identification of studies in GPP using specific search burden; flare; generalized terms in PubMed and EMBASE® from 2005 onwards, with additional back-referencing and pragmatic pustular psoriasis; searches. Outcomes of interest included clinical, humanistic, and economic burden. humanistic burden; mortality; prevalence; Expert opinion: Despite its significant clinical, humanistic, and economic burden, GPP is poorly quality of life classified and inadequately studied. A recent European (ERASPEN) consensus classifies GPP into relap- sing and persistent disease and classifies patients on the presence or absence of psoriasis vulgaris. Classification of GPP lesions involving >30% body surface area or use of hospitalization as a surrogate may be a way to identify significant flares. Given the frequency of flares, the impaired quality of life during the post-flare period, and safety/tolerability issues, it is clear that current treatment options are not sufficient. Long-term studies utilizing the European consensus statement with subclassifiers are required to supplement our current understanding of the burden of GPP. 1. Introduction dermatoses, including subcorneal pustular dermatosis (Sneddon–Wilkinson syndrome; a localized variant of pustular Generalized pustular psoriasis (GPP), first described by von psoriasis) and acute generalized exanthematous pustulosis Zumbusch in 1910, is characterized by widespread erythema (AGEP) [4]. AGEP is a drug-induced pustular psoriasis, which, and edema, superficial sterile coalescing pustules, and lakes of like GPP, presents with rapid onset of generalized pustules. pus. Dermal eruptions are usually accompanied by fever and However, the two conditions can be differentiated on the leukocytosis. GPP is one recognized subtype of pustular psor- basis of their clinical features, especially the quicker resolution iasis (PP), alongside palmoplantar pustulosis (PPP) and acro- of symptoms with AGEP [5]. The classifications of GPP, PPP, dermatitis continua of Hallopeau (ACH). PP describes a group and ACH have been used historically and are retained in the of inflammatory skin conditions characterized by infiltration of recent ERASPEN consensus document. Consensus definitions neutrophil granulocytes in the epidermis to such an extent for the diagnosis of these three subtypes are provided in that clinically visible sterile pustules develop [1]. PP has tradi- Table 1 [1]. tionally been considered a subset of psoriasis alongside other In GPP, loss-of-function mutations of IL36RN were identified in phenotypes including psoriasis vulgaris (PV; also known as 23% to 37% of familial and sporadic cases, which seem to be plaque psoriasis), intertriginous psoriasis, guttate psoriasis, associated with a more severe clinical phenotype. These and and erythrodermic psoriasis [2]. However, the classification of other gene mutations found in patients with GPP (including muta- PP (and [PPP] in particular) within psoriasis has often been tions in CARD14 and AP1S3) lead to enhanced proinflammatory debated [3]. A recent collaboration from the European Rare cytokine secretion and recruitment of neutrophils and macro- and Severe Expert Network (ERASPEN) has classified PP as phages to the skin, and thus are directly contributing to the pathol- a distinct clinical entity rather than a subset of psoriasis, not- ogy of the disease [4]. ing clear distinctions in the genetic architecture of PP and PV, Recently,Akiyamaet al.[6]highlighted theroleof IL36RNand as well as differences in response to treatment. Primary pus- CARD14 mutations in GPP and proposed that GPP cases with tules are not considered to feature on the PV spectrum, and autoinflammatory pathomechanisms be classified within ‘autoin- conditions in which pustules arise within or at the edge of flammatory keratinization disease’ (AiKD).Thisisparticularlythe psoriasis plaques are described as ‘psoriasis cum pustulatione’ case with early-onset GPP without preceding plaque psoriasis, (psoriasis with pustules) and are not classified as PP [1]. It is which is often associated with IL36RN mutations [7]. Ethnic also important to distinguish GPP from other pustular CONTACT Dirk Esser dirk.esser@boehringer-ingelheim.com Boehringer Ingelheim International GmbH, Rheinland-Pfalz, Germany © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 240 S. KHARAWALA ET AL. concerns with the current treatments include teratogenicity risk Article highlights (acitretin and methotrexate) and osteoarticular symptoms (aci- tretin), while biologic agents can cause bone marrow depression ● Limited literature notwithstanding, it is clear that GPP confers a resulting in an increased risk of serious infections. Steroid treat- significant clinical, humanistic, and economic burden. ● Estimates of the prevalence of GPP vary widely across studies; in the ment carries the risk of triggering a GPP flare due to steroid single GPP-focused study identified, the prevalence rate was 1.76 withdrawal [4]. While genetic differences across ethnicities have cases per million population in France. been reported [8], data are lacking on potential differences in ● Three phases can be identified in the disease course of GPP; an initial pre-pustular phase is followed by a flare and then a post-flare treatment responses across ethnic groups [4]. chronic/quiescent period preceding the next flare. Although the burden of GPP is typically described in terms ● GPP flares are life-threatening episodes, while plaques/pustules con- of clinical consequences, the impact on the lives of patients tinue to occur in the post-flare period. ● The most common precipitating factors for flares are the withdrawal and their families and economic cost is thought to be sub- of steroid treatment, pregnancy, infections, and hypocalcemia. stantial, and we have not identified any previous review that ● Hospitalizations are relatively common during flares, and patient QoL has attempted to describe the emerging literature on clinical, is severely impaired during the course of disease. Patients with GPP experience one flare resulting in admission every 1–5 years. humanistic, and economic burden of GPP in a structured way. ● The persistence of lesions and recurrence of flares despite treatment The objective of the current review was, therefore, to charac- highlights the unmet medical need for these patients. terize the overall disease burden of GPP across the following ● It is understandable for a rare disease that data are limited; however, the scarcity of data is compounded by inconsistencies in definitions domains: (1) Clinical burden (epidemiology, core clinical fea- and classifications across studies. tures, and natural history of disease over time, including risk ● The availability of the recent consensus statement will be helpful in factors, clinical outcomes, and comorbidities); (2) Humanistic generating more consistent evidence to help better understand this condition. burden (functioning, quality of life [QoL], psychosocial burden, adherence/preference/satisfaction with treatment and care- giver burden); and (3) Economic burden (drivers of resource use and cost, actual costs, and utilities). In the sister publica- Table 1. ERASPEN consensus definitions for the diagnosis of pustular psoriasis. tion published in the same edition [13], the burden of disease Generalized pustular psoriasis of PPP is characterized in a similar way. Primary, sterile, macroscopically visible pustules on non-acral skin (excluding cases where pustulation is restricted to psoriatic plaques) Subclassifier: With or without systemic inflammation Subclassifier: With or without PV Subclassifier: Either relapsing (>1 episode) or persistent (>3 months) 2. Methodology Palmoplantar pustulosis Primary, persistent (>3 months), sterile, macroscopically visible pustules 2.1. Search strategy on palms and/or soles Subclassifier: With or without PV Based on the review objectives, a structured search focused on Acrodermatitis continua of Hallopeau the identification of observational studies in GPP using specific Primary, persistent (>3 months), sterile, macroscopically visible pustules affecting the nail apparatus search terms (‘pustular psoriasis’ OR ‘generalized pustular Subclassifier: With or without PV psoriasis’ OR ‘generalised pustular psoriasis’). Searches were ERASPEN, European Rare and Severe Expert Network; PV, psoriasis vulgaris. performed using the PubMed and EMBASE® databases from 2005 onwards (2005–2018). In addition, supplementary differences have been reported in genetic mutations associated searches were conducted through back-referencing of rele- with GPP; in a large recent study, IL36RN mutations were most vant articles, pragmatic searches in PubMed, Google Scholar, frequent in European patients (34.7%) with GPP, followed by East the gray literature, and conference abstracts. Asian patients, most of whom were from Malaysia (28.8%). None of the South Asian patients in the study had IL36RN mutations [8]. In Chinese Han patients, IL36RN mutations have been reported in 2.2. Study selection 46.8–60.5% of GPP patients; the frequency of mutations was much higher in GPP patients without psoriasis (70.6–79.2%) than Screening and extraction were conducted by a single reviewer. in those with psoriasis (36.8–37.8%) [9,10]. A high frequency of Titles and abstracts of the citations identified in the literature IL36RN mutations in GPP patients without psoriasis has also been search were screened according to predefined criteria, which reported in Japan (81.8%) [11] and Germany (46.2%) [12]. included patient population (individuals diagnosed with GPP), First-line systemic treatment for GPP in adults includes oral outcome measures of interest (clinical burden, humanistic retinoids (acitretin), cyclosporine, methotrexate, or a rapidly act- burden, economic burden), and study design (case reports ing biologic agent. Second-line treatment may involve combin- and case series were excluded). ing a biologic agent with conventional therapy. Topical Potentially relevant articles that met the eligibility criteria treatments such as corticosteroids, calcipotriene, and tacrolimus were selected for full-text review, and the criteria were then also have a role in GPP, either as a standalone treatment for mild applied to the full-text articles. To avoid duplication of infor- or localized illness, or as an adjunct to systemic therapy in more mation and in order to provide a useful overall summary, severe/generalized illness. Treatment for children with GPP is articles were further screened to ensure that 1) the highest broadly along similar lines and includes acitretin (with or without quality publications were selected and 2) the publications oral prednisolone), methotrexate, and cyclosporine. The treat- provided adequate representation of the population, includ- ments for GPP can themselves be burdensome; important safety ing pediatric studies. EXPERT REVIEW OF CLINICAL IMMUNOLOGY 241 3. Results a mean age of disease onset of 40.9 years among patients with adult-onset GPP (range: 21–81 years) [19], with other studies In total, 19 unique publications are included in this review, of which reporting a mean age at diagnosis of 45.6 (across all age 13 report on clinical outcomes only, two on economic outcomes groups) [20] to 50 years (adult-onset GPP) [18]. In the French only, one on QoL only, two on clinical and economic outcomes, and epidemiological study, the incidence and prevalence of GPP one which reports on all outcomes of interest. were highest between the ages of 40 and 60 years [14], which is consistent with an earlier retrospective study from the UK which reported the highest GPP prevalence between the fifth 3.1. Clinical burden of GPP and sixth decades of life [23]. This section describes the clinical burden experienced by Most publications reported GPP to be more frequent in patients with GPP as well as the natural history of GPP, includ- females than males, with the male-to-female ratio varying ing the evolution of signs and symptoms. The publications from 0.5 to 0.9 [14,18,19,23]. providing data to support the findings described in this sec- tion are summarized in Table 2. 3.1.2. Clinical characteristics and diagnosis While the definitions and classifications of GPP used across 3.1.1. Epidemiology studies were inconsistent, the occurrence of flares presenting One national study [14] focused on the prevalence of GPP, and throughout the course of the disease is the defining and diag- three studies provided supporting data [15–17](Table 2). nostic characteristic of the condition. In general, a GPP flare Augey et al. conducted a national GPP-focused study in France consists of a generalized pustular eruption all over the body. In and reported a prevalence rate of 1.76 cases per million population most cases, the onset of the flare is acute and GPP is then [14]. In this study, GPP data from hospitals were obtained by diagnosed based on the presence of systemic symptoms along sending a questionnaire to dermatological wards throughout with multiple sterile pustules (‘acute GPP’ or ‘von Zumbusch’), France for information on all in- and outpatients who visited although subacute and chronic onset may also be possible. these departments during 2004. Of the 121 dermatological wards, Navarini et al. recently proposed that GPP should only be diag- 112 responded to the questionnaire; 46 of these wards reported nosed when the condition (consisting of primary, sterile, macro- a total of 99 GPP patients. Ohkawara et al. assessed the prevalence scopically visible pustules on non-acral skin) has relapsed at of ‘GPP and related disorders’ by sending questionnaires to 575 least once or when it persists for more than 3 months [1]. community center hospitals throughout Japan to obtain informa- Flares are a potentially life-threatening and critical character- tion from medical records for patients with GPP and related dis- istic of GPP, consisting of dermal lesions accompanied by sys- orders who had visited the hospitals during 1983–89; and reported temic symptoms. Widespread erythematous plaques studded a prevalence of 7.46 cases per million population [17]. Much higher with sterile pustules all over the body are typically seen, which prevalence rates were described in a national insurance database often coalesce to form lakes of sterile pus [22]. Common symp- study in Korea (122.3 per million population [psoriasis prevalence: toms during GPP flares include fever with chills and rigors as well 453 per 100,000; GPP: 2.7% of all psoriasis]) [16]and aprospective as arthralgia. In one retrospective chart review, fever, and painful observational study across 104 centers in Italy (180.0 per million skin lesions were present in 89% of patients (n = 102) [19]. population [psoriasis prevalence: 2%; GPP: 0.9% of all psoriasis]) Other clinical features in acute GPP flares included uveitis, [15], with both studies reporting GPP prevalence as a subset of conjunctivitis, iritis, leg swelling, geographic or fissured ton- overall psoriasis (Figure 1). gue, and cheilitis [18,19,22]. On rare occasions, the acute stage Augey et al. also reported the incidence of GPP using two may be followed by pulmonary capillary leakage, pulmonary approaches [14]. The first approach used survey data as emphysema, jaundice, or renal failure [22]. described above, which yielded an incidence rate of 0.64 cases During the post-flare chronic phase, patients experienced per million person-years. The second approach utilized claims a variety of skin lesions including acropustulosis, annular pla- data from the national health insurance of France (Caisse que psoriasis, inverse psoriasis, plaque, erythroderma, and PP Nationale d’Assurance Maladie des Travailleurs Salariés) and [17,19]. Of these, plaque psoriasis lesions were the most com- reported an incidence rate of 0.5 cases per million person-years mon manifestation (50%), followed by pustular lesions (22%). in 1998 and 0.8 case per million person-years in 2001. Zelickson classified GPP patients into four subtypes (acute, 3.1.3. Disease course subacute annular, chronic acral, and mixed GPP) based on the GPP can broadly be described as having three phases. An onset of flare and lesion morphology [18]. However, the recent initial pre-pustular phase is followed by a flare and then ERASPEN consensus statement defines subtypes of GPP on the a post-flare chronic/quiescent period, which persists until the basis of the presence or absence of associated features, as shown next flare. A repeating pattern of flares and post-flare periods in Table 1 [1]. Although conventions for the subclassification of may continue to occur episodically throughout life (Figure 2). GPP were not applied consistently across studies, acute GPP was the most commonly reported subgroup. A high proportion of acute GPP (93%) was reported by Choon (n = 102) [19], while in 3.2. Pre-pustular phase the 1991 study by Zelickson, 56% of patients (n = 63) had a diagnosis of acute GPP [18]. In patients with preceding psoriasis (usually in the form of GPP is known to occur at all stages in life, including in plaque lesions), the pre-pustular phase persisted for approxi- children (juvenile GPP) [20–22]. Data from Malaysia reported mately 6–12 years prior to the first widespread flare [17– 242 S. KHARAWALA ET AL. Table 2. Characteristics of publications reporting on the clinical burden of GPP. Follow- up Publication (type) Ref Study design (country) Population (sample size) duration Objectives and outcomes Key data Augey 2006 (publication) 14 Questionnaire-based retrospective GPP (n = 99) N/A Objective: Prevalence of GPP: 1.76 per million population epidemiological survey conducted in 121 To describe the epidemiology of GPP and Incidence of GPP: 0.64 per million person-years dermatological wards (2004); additional data therapeutic strategies developed by hospital using the survey data; 0.5 per million person- retrieved from CNAMTS, the main French dermatologists years (1998) and 0.8 per million person-years health insurance program, covering 90% of the Outcomes: (2001) using the CNAMTS data; incidence and French population (France) Prevalence, therapeutic practices, treatment prevalence of GPP was highest between the failures, morbidity, mortality ages of 40 to 60 years; male-to-female 0.77 Mortality: 2 (2%); 1 each from congestive cardiac failure and septic shock Treatment failure was related to management in a university ward (OR: 2.9, p = 0.03), prescription of high or very high potency DC as first-line local therapy (OR: 7.6, p = 0.05), therapies other than retinoids as first-line systemic therapy (OR: 5.5, p = 0.04) Azura 2015 (conference 20 Database analysis of the Malaysian Psoriasis Psoriasis (n = 8,039; PP: NA Objective: Mean age of onset: 9.8 ± 4.4 years abstract) Registry (Malaysia) 1.6%) To determine the demographic features, Commonest aggravating factors: stress (57%), clinical pattern, treatment and QoL in sunlight (45%), infection (20.5%) pediatric patients with psoriasis in Malaysia Outcomes: Age at onset, aggravating factors Baker and Ryan, 1968 23 Retrospective observational study of cases in 1 GPP (n = 104; patients NA Objective: Prevalence of GPP: greatest between the fifth (publication) London hospital plus 43 dermatologists around with preceding plaque To report the natural history of GPP in the pre- and sixth decades of life; male-to-female ratio: the country (UK) psoriasis: 60%) pustular and pustular phases 0.70 Outcomes: Duration of pre-pustular psoriasis:10to20 Prevalence of GPP, duration of pre-pustular years psoriasis, diagnostic criteria Diagnostic criteria: ≥1 documented episode of widespread macroscopic noninfective pustulation Choon 2014 (publication) 19 Single-center retrospective analysis of medical GPP (n = 102; patients Objective: Mean age of onset: 40.9 years (range: 21–81 records (1989–2011) of all patients with adult- with preceding plaque To analyze the clinical profile of patients with years) onset GPP (Malaysia) psoriasis: 78%) adult-onset GPP Prevalence of GPP: male-to-female ratio: 0.5; Outcomes: acute GPP: 93% cases Demographic characteristics, morphological Duration of pre-pustular psoriasis: 11.7 years patterns, trigger factors, comorbidities, Flare: ~60% experienced a single flare over ~5 morbidity, and outcome years; precipitating factors identified in 85% of patients Symptoms: fever and painful skin lesions (89%), arthritis (34.7%), leukocytosis (78.4%) Comorbidities: Obesity (42.9%), hypertension (25.7%), hyperlipidemia (25.7%), diabetes mellitus (23.7%) Mortality: 7 (7%; all in acute GPP subgroup); cause of death was sepsis in 4 patients and multi-organ failure in 1 patient; 2 patients died when psoriasis was quiescent Fabbri 2004 (publication) 15 A study by AISP at 104 centers (specialized Psoriasis (n = 7,992) NA Objective: Prevalence of GPP: 0.9% of all psoriasis departments hospital dermatology clinics and To analyze epidemiology of psoriasis in Italy (180 per million population) university) Outcomes: Prevalence of GPP (Continued ) EXPERT REVIEW OF CLINICAL IMMUNOLOGY 243 Table 2. (Continued). Follow- up Publication (type) Ref Study design (country) Population (sample size) duration Objectives and outcomes Key data Jin 2015 (publication) 24 Retrospective analysis of medical records and GPP (n = 33; patients with >1 year Objective: Mean (SD) age at onset: 40.7 (22.0) years telephone survey (2002 to 2012) in two tertiary preceding plaque To investigate the clinical features of GPP Mortality: 1 (3%); from GPP of pregnancy (IH) hospitals (Korea) psoriasis: 42%) according to subtype, including the clinical Relapse rate: 76% over 1 year (persistence or course and relapse pattern of skin lesions relapse of skin lesions) according to a history of plaque-type Prognosis: Preceding plaque psoriasis may be psoriasis associated with increased risk of relapse Outcomes: during the chronic quiescent phase Diagnostic criteria, key signs and symptoms, natural history of disease, factors affecting disease progression, clinical outcomes and prognosis, risk/protective factors, precipitating factors, mortality Lee 2017 (publication) 16 Analysis of insurance claims data (2011–2015) GPP (n = 6,252 [2015]) NA Objective: Prevalence of GPP: 2.7% of all psoriasis from the data repository of the National Health To determine the prevalence of psoriasis in (122.31 per million population) Institution (Korea) Korea and to describe the demographic and social characteristics Outcomes: Prevalence of GPP Lin 2015 (conference 21 Retrospective analysis of GPP patients GPP (n = 103) NA Objective: Prevalence: GPP can occur at any age; the abstract) hospitalized in one center (2006–2014) (China) To study clinical features of children with GPP incidence in boys is higher than in girls; no with particular emphasis on inducing or gender differences can be observed in the age aggravating factors, clinical manifestation, of onset; preceding plaque psoriasis is more laboratory findings and the effectiveness seen in children; there were no significant and safety of therapeutic regimens differences in age of onset between the two Outcomes: groups Age of onset, incidence, prevalence of preceding plaque psoriasis Navarini 2017 1 Consensus document on clinical criteria for PP NA NA Objective: GPP is defined as primary, sterile, (publication) To present considerations on the macroscopically visible pustules on non-acral clinical features of PP and a consensus skin (excluding cases where pustulation is classification of phenotypes restricted to psoriatic plaques) Outcomes: GPP can occur with or without systemic Consensus definitions of GPP, PPP and ACH inflammation, with or without PV and can either be a relapsing (>1 episode) or persistent (>3 months) condition Ohkawara 1996 17 Multicenter study in which questionnaires sent to GPP and related disorders NA Objective: Prevalence of ‘GPP and related disorders’: (publication) 575 community center hospitals asking for (n = 541) To clarify prevalence, etiology, and standard 7.46 per million population. details of patients with GPP and related therapy of GPP; to describe heterogeneity of Age of onset: 32 years (patients with no disorders who visited the hospitals during clinical features and genetic background preceding plaque psoriasis); 37 years (patients 1983–89 (Japan) (HLA typing) of GPP patients with preceding plaque psoriasis) Outcomes: Duration of pre-pustular psoriasis: 6 years Prevalence; duration of pre-pustular psoriasis Popadic 2014 26 Data obtained from medical records of 18 GPP (n = 18) 2–19 Objective: The most frequent precipitating factor for (publication) patients with PP (1992–2011) (Serbia) years To present epidemiologic data, treatment disease worsening was upper respiratory tract approach, and course of the disease in 18 infection patients with all four forms of PP Outcomes: Diagnostic criteria, precipitating factors (Continued ) 244 S. KHARAWALA ET AL. Table 2. (Continued). Follow- up Publication (type) Ref Study design (country) Population (sample size) duration Objectives and outcomes Key data Ryan & Baker 1971 27 Review of data from GPP patients from GPP (n = 106) 3 years Objective: Mortality: 34 (32%). 8 patients died of (publication) dermatologists throughout the country (UK) To describe the prognosis in GPP uncontrollable PP; 9 deaths were attributable Outcomes: to treatments (steroids [n = 7] methotrexate Mortality [n = 2]); 8 deaths occurred when psoriasis was in remission Umezawa 2003 22 Expert guidelines for treatment in GPP to help NA NA Objective: Flares consist of dermal lesions and systemic (publication) improve QoL in GPP (Japan) To propose therapeutic guidelines for the symptoms. Widespread erythematous plaques treatment of GPP studded with sterile pustules all over the body Outcomes: were typically seen, accompanied by Clinical characteristics a burning sensation. These pustules often coalesce to form lakes of sterile pus; Other clinical features in acute GPP flares include uveitis, conjunctivitis, iritis, leg swelling, geographic or fissured tongue, and cheilitis Wu 2017 (publication) 25 Retrospective analysis of data of from the GPP (n = 82) NA Objective: Clinical features: Average age of onset 25.5 Department of Dermatology, Central South To analyze clinical features, laboratory tests, (±21.2) years (patients with preceding plaque University, Changsha (China) treatment and prognosis for patients with psoriasis), 32.7 (±18.0) years (patients with no GPP preceding plaque psoriasis) Outcomes: Key triggers: Most common triggers were Clinical features, laboratory tests, treatment infections (75.0%; preceding plaque psoriasis) and prognosis and drugs (41.7%; no preceding plaque psoriasis) Treatment response: Complete response in 28 (42%); Marked response in 24 (36%); Improvement in 8 (12%); no response in 6 (9%) [defined as lack of significant resolution of pustules; with <50% resolution of erythema and scales] Yamamoto 2015 3 Systematic review (Japan) NA NA Objective: Common comorbidities include cardiovascular (publication) To describe clinicopathological aspects of PPP disease, psoriatic arthropathy (12%) and differentiate PPP from pustular psoriasis Outcomes: Comorbidities Objective: Duration of pre-pustular psoriasis: 12 years Zelickson 1991 18 Medical record review in patients hospitalized at 63 (patients with To investigate precipitating factors, clinical Mortality: 2 (6%); 1 each from Guillain-Barré (publication) Mayo Clinic-affiliated hospitals (1961–1989) preceding plaque patterns, associated diseases, therapy, and syndrome and septic shock (USA) psoriasis: 51%) course. To differentiate between PPP and GPP Outcomes: Duration of pre-pustular psoriasis; mortality 1 2 Those with history of ‘ordinary’ psoriasis; Cases with history of PV ACH, Acrodermatitis continua of Hallopeau; AISP, Italian Intersiciplinare for Studio Psoriasis; CNAMTS, Caisse nationale de l’assurance maladie des travailleurs salaries; DC, dermatocorticosteroids; GPP, generalized pustular psoriasis; IH, impetigo herpetiformis; JNDB, Japanese national database of health insurance claims; NA, not applicable; OR, odds ratio; PP, pustular psoriasis; PPP, palmoplantar pustulosis; PV, psoriasis vulgaris; QoL, quality of life; SD, standard deviation. EXPERT REVIEW OF CLINICAL IMMUNOLOGY 245 Augey 2006 (France) 1.76 Ohkawara 1996* 7.46 Lee 2017 (Korea) 122.3 Fabbri 2004 (Italy) 180.0 0.0 20.0 40.0 60.0 80.0 100.0 120.0 140.0 160.0 180.0 200.0 Figure 1. Prevalence of GPP (per million population) across studies. *Ohkawara 1996 reported the prevalence of ‘GPP and related disorders’ [17]. Diagnosis of GPP Chronic/quiescent Pre-pustular phase* FLARE (Psoriatic lesions +/-) period First episode of widespread pustular flare Figure 2. Clinical course of GPP. *In patients with preceding psoriasis (usually manifesting as plaque lesions). 19,24]. During this phase, 31–78% of GPP patients experienced about 10% experiencing more than five flares over a 5-year psoriatic lesions [17–19,24]. period [19]. 3.3. Acute symptoms/flares 3.4. Post-flare chronic/quiescent period Data on the frequency of flares over time were limited. One Following the treatment of a flare, most patients showed single-center study, in which a flare was defined as involving partial or complete response. As an example, Wu et al. greater than 30% body surface area (BSA), reported a single reported that 42% of adult patients (n = 66) and 25% of flare in approximately 60% of patients (n = 102) over a follow- children (n = 16) demonstrated complete resolution of pus- up period of around 5 years [19]. In the same study, approxi- tules, erythema, and scales, while 36% and 50% of adults and mately 40% of patients reported a recurrence of flares, with children, respectively, showed a marked response [25]. Only 246 S. KHARAWALA ET AL. 9% of adults and 6% of children showed no response imme- a trigger for acute GPP flares [19]. Uveitis has been reported in diately following treatment. 3.2% of patients with acute GPP [19]. However, relapse of lesions (not amounting to a widespread flare) is common. In a report of patients with GPP across two 3.4.3. Mortality in GPP tertiary hospitals, relapse of skin lesions was subsequently seen Flares in GPP can be difficult to treat, and systemic complications after initial symptom clearance (following treatment) in 76% of during flares may occasionally result in death [14,18,19,24,27]. patients (n = 25) over a 1-year follow-up [24]. These relapses were In an analysis of 106 GPP patients, a mortality rate of 32% reported to manifest in the form of pustules alone (42%), plaques was reported (follow-up period was not specified). Twenty-six alone (32%), or both plaques and pustules (26%). Patients with of the 34 deaths were directly attributable to illness severity or preceding plaque psoriasis may have an increased risk of relapse to the treatment for GPP, especially the use of systemic ster- [24]. These findings were corroborated by cross-sectional data oids [27]. In more recent studies, deaths attributable to GPP from Choon et al. who found that, during the non-flare period, flares were reported in about 5–10% of GPP patients only a small proportion (<5%) of patients showed no psoriasis [14,18,19,24]. Sepsis or septic shock was the common cause symptoms [19]. In this study, during the non-flare period, almost of death in GPP [14,18,19]. all patients were receiving topical or systemic treatments, with most patients (nearly 73%) experiencing mild psoriasis (affecting <10% BSA) and about 10% of patients experiencing moderate-to 3.5. Humanistic burden of GPP -severe psoriasis (affecting ≥10% BSA). As discussed earlier, these No evidence was identified regarding activities of daily living, psoriasis symptoms consisted of plaque psoriasis in about 50% of caregiver burden, treatment adherence/satisfaction, occupa- the patients, followed by PP lesions in about 22% [19]. tional functioning, or psychosocial symptoms in GPP. Two publications provided data to support the findings described in this section, one of which was conducted exclusively in 3.4.1. Precipitating factors for flares patients with GPP, while the second was in a general psoriasis GPP flares tend to be triggered by specific factors. In the population in which ‘pustular psoriasis’ constituted 3% of the retrospective analysis by Choon, precipitating factors were sample (this study was included due to a paucity of data in identified in 85% patients (n = 102), with a spontaneous first GPP) (Table 3). episode of GPP flare occurring in 15% patients [19]. Slightly lower rates were reported by Zelickson et al. and Wu et al., 3.5.1. Quality of life with 46% and 50%, respectively, of flares being associated Data from Choon et al. indicated that GPP had a significant with specific triggers [18,25]. impact on QoL, even in the quiescent phase [19]. This study The most commonly reported precipitating factors for used the Dermatology Life Quality Index (DLQI), a 10-item flares were withdrawal of steroid treatment (approximately questionnaire in which a score above 10 suggests severe 30–40% of patients) [19,23]; pregnancy (two or more flares in QoL impairment, to assess how far GPP impacted patients’ 60% of pregnant women with GPP versus 40% in GPP as lives. This study reported a mean DLQI score during a follow- a whole) [19]; infections (particularly upper respiratory tract up visit (i.e., non-flare period) of 12.4 points in patients with infections) [17–19,21,23,25,26]; hypocalcemia [23]; and others, acute GPP (n = 102), indicating severe impairment. In the including sun exposure, seasonal variation, salicylates, exer- other subgroups, including subacute GPP, localized GPP, and tion, and menstruation [18]. impetigo herpetiformis (IH), the mean DLQI scores ranged Specific precipitating factors appeared to be associated from 13 to 17, again signifying severe impairment. At the with the type of GPP. Medications (75%) [25], including ster- time of QoL assessment, most (73%) patients had mild psor- oids (15–28%) [17], triggered flares more frequently in patients iasis symptoms while 10% had moderate-severe psoriasis (the with preceding plaque psoriasis, whereas in patients with no remaining were either asymptomatic or lost to follow-up). preceding plaque psoriasis, the most common precipitating Sampogna et al. reported QoL in a subsample of 380 factors included pregnancy (35%) [19] and respiratory tract psoriasis patients from the IDI Multipurpose Psoriasis infections (42%) [25]. Research on Vital Experiences (IMPROVE) study, including those with PP (3%) (GPP-specific data, including information 3.4.2. Key comorbidities on the proportion of the sample with GPP, were not reported Common comorbidities in GPP included obesity (42.9%), hyper- in this paper) [28]. QoL was measured using the 36-item short tension (25.7%), hyperlipidemia (25.7%), and diabetes mellitus form of the Medical Outcomes Study questionnaire (SF-36), in (23.7%) [19]. Other conditions seen with GPP included metabolic which responses to 36 questions are scored and summed syndrome, ophthalmological involvement, inflammatory bowel according to a standardized protocol and expressed as disease, cholestasis, and neutrophilic cholangitis [3,21]. In chil- a score on a 0–100 scale (a higher score represents better self- dren with GPP, hyperlipidemia, infection, and electrolyte disor- perceived health). Although no statistical analysis was pro- ders were commonly seen [21]. Joint involvement in the form of vided, this study reported that QoL in PP was lower than arthralgia or arthritis has been reported in 23.8% to 34.7% of GPP that in plaque and guttate psoriasis and was comparable to patients [19,22,24]. The presence of arthritis often necessitates that in palmoplantar and arthropathic psoriasis (Figure 3). the use of systemic steroids even in patients with mild GPP, and Sampogna et al. also reported that QoL decreased with increas- steroid withdrawal in these patients has been reported to be ing severity of psoriasis, as an example, SF-36 scores on the bodily EXPERT REVIEW OF CLINICAL IMMUNOLOGY 247 pain domain of SF-36 for those with very mild, mild, moderate, and severe psoriasis were 73, 66, 62, and 47, respectively (p < 0.01) [28]. In addition, emotional problems such as shame, anger, worry, and difficulties in daily activities and social life were seen in psoriasis patients, including those with PP. These problems increased with increasing disease severity. 3.6. Economic burden of GPP No evidence was identified relating to the direct and indirect costs (including the economic impact on caregivers) established in GPP or regarding utilities in GPP. The publications providing data to support the findings described are summarized in Table 4. Healthcare resource utilization and economic burden were very variable by country and healthcare system. 3.6.1. Healthcare resource utilization Resource utilization during flares is accounted for by man- agement of the acute episode of GPP using systemic treat- ments, often involving an inpatient hospitalization. In a large observational study (n = 102), an average of one hospitalization (range 1–20) was reported for each patient over a follow-up period of around 5 years [19]. Hospitalization data from the Federal Health Monitoring System in Germany indicated approximately 250–300 inpa- tient admissions each year due to GPP from 2011 onwards (Figure 4)[29]. In the study reported by Wu et al., the average duration of hospitalization was 11.6 (±10.2) days among patients with preceding plaque psoriasis and 12.1 (±6.7) days in those without preceding plaque psoriasis, and the difference was not statistically significant (p = 0.816) [25]. Across the three data sets [23,25,29], the duration of hospitalization was about 10–14 days, which was consider- ably shorter than the 30-day average hospitalization reported in an older study [18]. During the non-flare period, resource utilization occurs in the form of visits to physicians, including dermatologists, and receipt of topical and systemic treatments for the prevention of flare recurrences and for the management of skin lesions [19]. Detailed information regarding resource utilization dur- ing this period was not available. 3.6.2. Drivers of healthcare resource utilization Hospitalization is a key driver for resource utilization in GPP. Specific triggers for hospitalization in PP were reported in a retrospective study [30] in 38 recorded hospitalizations in France over a 15-year period (1990–2005). Triggers were iden- tified in approximately 45% of hospitalizations, with the most common being infection (18%), treatment discontinuation (16%), and stress (16%) (n = 211 hospitalizations). In a retrospective study in the Mayo Clinic [18], female patients spent more time on average in hospital (38 days versus 22 days for male patients). The duration of hospitaliza- tion was also longer in patients with a positive history of PV (31 days versus 24 days for no PV history) and in those with hypocalcemia (37 days versus 27 days among those with no hypocalcemia). Table 3. Characteristics of publications reporting on the humanistic burden of GPP. Population Publication Ref Study design (country) (sample size) Follow-up duration Objectives and outcomes Key data Choon 2014 19 Single-center retrospective GPP (n = 102) ~5 years (mean) Objectives: Mean DLQI scores: ranged from 12 to 17, suggesting a high impact of GPP (publication) analysis of medical To analyze demographic characteristics, on QoL records (1989–2011) morphological patterns, trigger factors, (Malaysia) comorbidities, morbidity and outcomes in GPP Outcomes: DLQI when the patient was out of acute GPP during the last follow-up Sampogna 2006 28 Cross-sectional study of Psoriasis (n = NA Objectives: SF-36: two distinct patterns of impairment of QoL, with a greater burden of (publication) inpatients with psoriasis; 380); 3% had To describe the QoL in patients with disease for palmoplantar, pustular and arthropathic psoriasis when subset of IMPROVE study pustular different clinical types of psoriasis compared to guttate and localized and generalized plaque psoriasis; QoL (Italy) psoriasis Outcomes: in patients with psoriasis was worse than in some other medical SF-36, DLQI conditions, especially psychosocial aspects GPP, generalized pustular psoriasis; DLQI, Dermatology Life Quality Index; QoL, quality of life; SF-36, 36-item short form of the Medical Outcomes Study questionnaire. 248 S. KHARAWALA ET AL. palmoplantar pustular guttate localized plaques generalized plaques arthropathic PF RP BP GH VT SF RE MH Figure 3. Comparison of SF-36 scores across psoriasis subtypes. Figure adapted, with permission, from Sampogna 2006 [28]. PF: Physical functioning; RP: Role physical; BP: Bodily pain; GH: General health; VT: Vitality; SP: Social functioning; RE: Role emotional; MH: Mental health. 7.46 cases per million population in that study. The other pre- 4. Conclusion valence studies identified were focused on psoriasis overall, 4.1. Summary with an analysis of GPP within the overall population, and reported much higher prevalence rates. These studies were This is the first structured review of the clinical, humanistic, and economic burden in GPP, and yields several interesting not focused on GPP, and it was not clear if the GPP diagnoses results. A major finding is the high burden of GPP, not only in these studies were sufficiently validated, which may explain the higher rates in these studies [17]. during acute flares but also during the post-flare period. Acute A complete understanding of the economic impact of GPP flares, which are serious episodes with considerable morbidity and mortality, are a hallmark of GPP. The morphology and could not be achieved as limited information was available and this was limited to the flare period. The available data suggest that distribution of cutaneous lesions and systemic manifestations patients with GPP experience at least one flare resulting in admis- have been thoroughly described in the literature. During the post-flare period, patients continue to experience plaque or sion to a hospital every 1–5 years. Given the serious and potentially fatal nature of a flare, this represents a serious risk to GPP patients. pustular lesions and still require treatment, either to manage the lesions or to prevent widespread flares. Unfortunately, many of the treatments are associated with considerable 4.2. Limitations side effects or precautions, such as osteoarticular symptoms, teratogenicity risk, and bone marrow depression. Finally, One limitation is that although this is a comprehensive over- although QoL appears to be severely impaired during the view, it is not a systematic review, and the fact that studies post-flare period (noting that data to support this were were prioritized during selection may have resulted in the drawn from a single study in an exclusive GPP population), exclusion of potentially relevant data. However, most reliable little is known about the impact on other humanistic burden studies were selected for detailed analysis, and it is therefore parameters during this period. not expected that the conclusions of this review will be sub- GPP is a rare disease, and the number of prevalence studies stantially impacted by the excluded literature. identified was small, with a wide range of prevalence rates In terms of the data included in this review, these were very reported. Differences in study design and definitions contribute limited. In particular, few reliable studies were available on the to variability in prevalence estimates. The single GPP-focused epidemiology of GPP, and the definitions and classifications of population-based study reported a prevalence of 1.76 - GPP used across studies were inconsistent, making inter-study per million population [20]. However, this study was conducted comparisons difficult. more than a decade ago, and only a subset of the dermatology Evidence on the clinical burden of GPP is limited to a few wards (46 of 112) reported data on GPP patients. Ohkawara studies of modest quality. Data on the population-level epide- et al. [17] reported data for a wider group of diagnoses (‘GPP miology of GPP were very limited; therefore, comparisons and related disorders’), which may explain the higher rate of across geographic regions or assessment of variations due to EXPERT REVIEW OF CLINICAL IMMUNOLOGY 249 Table 4. Characteristics of publications reporting on the economic burden of GPP. Population (sample Publication Ref Study design (country) size) Follow-up duration Objectives and outcomes Key data Choon 2014 (publication) 19 Single-center retrospective analysis GPP (n = 102) ~5 years (mean) Objectives: Mean duration of hospital stay: 10.3 days (3–44 days) of medical records (1989–2011) To analyze demographic characteristics, Mean number of admissions:1(1–20) (Malaysia) morphological patterns, trigger factors, comorbidities, morbidity and outcomes in GPP Outcomes: Mean numbers of admission and mean duration of hospitalization The German Federal 29 Online database that supplies data GPP (n = 286 From the year Objectives: Hospitalization: ~250–300 inpatient admissions each year due Health Monitoring and information on the state of hospitalizations 2000 onwards To improve the availability of health to GPP from 2011 onwards. System (database health and healthcare services in in 2016) data in Germany and to create analysis) Germany a database which can be used to inform discussions Outcomes: Mean numbers of admission and mean duration of hospitalization Lapeyre 2007 30 Retrospective study performed in Psoriasis (n = 211 NA Objective: Triggers: identified for 17 of the 38 hospitalizations (~45%) (publication) a single-center over a 15-year hospitalizations); To assess the main reasons for Most common triggers: infection (18%), treatment period (1990–2005) (France) PP (n = 38 hospitalization of psoriasis patients discontinuation (16%), and stress (16%); for these factors, no hospitalizations) Outcomes: significant differences were noted across the psoriasis Triggers for hospitalization subgroups Wu 2017 (publication) 25 Retrospective analysis of data of GPP (n = 82) NA Objective: Hospitalization: Average duration of hospitalization was 11.6 from the Department of To analyze clinical features, laboratory (±10.2) days (patients with preceding plaque psoriasis) and Dermatology, Central South tests, treatment and prognosis for 12.1 (±6.7) days (patients with no preceding plaque psoriasis) University, Changsha (China) patients with GPP (p = 0.816). Outcomes: Duration of hospitalization Zelickson 1991 18 Medical record review in patients 63 (patients with Objective: Mean duration of hospitalization: 10.3 days (range 3–44 (publication) hospitalized at Mayo Clinic- preceding plaque To investigate precipitating factors, days); female patients spent more time in the hospital affiliated hospitals (1961–1989) psoriasis: 51%) clinical patterns, associated diseases, (average, 38 days) than male patients (22 days) (USA) therapy, and course Factors associated with hospital stay: Hypocalcemia (37 days Outcomes: vs 27 days, presence vs absence), female sex (38 days vs 22 Duration of hospitalization; factors days, female vs male), previous history of PV or PP (31 days vs associated with hospital stay 24 days, presence vs absence) GPP, generalized pustular psoriasis; NA, not applicable; PP, pustular psoriasis; PV, psoriasis vulgaris. 250 S. KHARAWALA ET AL. 2000 2005 2010 2011 2012 2013 2014 2015 2016 All Males Females Figure 4. Total number of GPP hospitalizations in a year in Germany 2000–2016. Source: Federal Health Monitoring System http://www.gbe-bund.de/. Hospitalization data in the website (http://www.gbe-bund.de/) are reported at 5-year intervals for 2000–2010, and then annually from 2010. race/ethnicity could not be conducted. Several of the larger For economic burden, data on direct/indirect costs and studies on clinical burden were conducted and published utilities were not identified, and very little data on resource many years ago, thus reducing the generalizability of the utilization in the form of hospitalization and drivers of data to current patients. The published data consisted of resource utilization were obtained. Resource utilization during cross-sectional studies or retrospective analyses, with no the post-flare period has not been fully reported but needs to large, high-quality prospective observational studies. be considered as the lifetime economic burden for someone Additionally, the reporting of clinical burden differed across diagnosed with GPP would appear to be very high. publications due to the absence of standardized instruments used for the assessment of disease severity and progression in 5. Expert opinion observational studies. There is, therefore, insufficient informa- tion to understand the long-term burden in terms of fre- Until very recently, GPP has been both poorly classified and quency of flares, severity of disease in the post-flare/chronic inadequately studied, despite its significant clinical, humanistic, period, and prognostic factors. Autoimmune conditions such and economic burden. The recent ERASPEN consensus state- as uveitis and inflammatory bowel disease are important ment proposes a new and valuable classification system that comorbidities in psoriasis, although their occurrence and may help to provide consistency in terms of how GPP is impact in GPP have not been sufficiently described in the described and characterized in the future. This consensus classi- literature [31,32]. fies GPP into relapsing disease (more than one episode) and The humanistic burden data included only one GPP- persistent disease (maintained over the course of more than 3 focused study in which QoL was assessed during the post- months) and also classifies patients on the basis of the presence flare/chronic period. Lack of data notwithstanding, it should or absence of PV. This differs slightly from the separation of GPP be noted that although objective measurement of QoL is into patients with and without preceding plaque psoriasis, which precluded during a flare because of the life-threatening nature tends to be seen across the literature. Multiple studies have of the episode, the humanistic burden is clearly higher during reported the proportion of patients with and without preceding a flare than in the post-flare period. The impact of GPP on plaque psoriasis, and there are some data to suggest that these functioning, occupational performance, or caregivers has not subtypes are actually phenotypically different. As recent findings been examined. from genetic studies suggest, patients with GPP without Total number of inpatient admissions in a year with a diagnosis of GPP EXPERT REVIEW OF CLINICAL IMMUNOLOGY 251 preceding plaque psoriasis may potentially be classified under Declaration of interest AiKDs [6,7]. AK Golembesky and D Esser are employees of Boehringer Ingelheim It is surprising that the frequency of flares associated with GPP International GmbH. S Kharawala and RL Bohn are paid consultants of is not generally reported in the literature. This could simply be Boehringer Ingelheim International GmbH. The authors have no other rele- vant affiliations or financial involvement with any organization or entity with because GPP is a rare and therefore a rarely studied condition. a financial interest in or financial conflict with the subject matter or materials However, it may also be due to difficulties encountered in deter- discussed in the manuscript apart from those disclosed. mining what constitutes a ‘flare’, as no consensus definition exists. The definition used by Choon et al. (GPP lesions involving more than 30% of the BSA) may be a useful way to define Reviewer disclosures a significant flare [19]. 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Journal

Expert Review of Clinical ImmunologyTaylor & Francis

Published: Mar 3, 2020

Keywords: Clinical burden; economic burden; flare; generalized pustular psoriasis; humanistic burden; mortality; prevalence; quality of life

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