Diversity in the clinical presentation of generalized pustular psoriasis (GPP): A series of case vignettes from around the world

A key principle of clinical studies and case reports is that they should reflect the demographics and epidemiology of the patient population concerned. Here, we have compiled a diverse group of clinical cases of generalized pustular psoriasis (GPP) to showcase the differences in GPP presentation in patients worldwide. We attempt to capture the broad spectrum of clinical presentations of GPP and showcase the diversity of the patient population. The patients included in this series are diverse in age, genetic background, skin phototype and medical history. Moreover, they present with a variety of clinical courses of GPP and different degrees of systemic involvement, and experience flares triggered by different inciting factors. The key learnings from this case series may support physicians in identifying and managing patients with this rare and multifaceted disease that can affect patients both physically and psychologically.


Sicily Mburu, Peter van de Kerkhof
A key principle of clinical studies and case reports is that they should reflect the demographics and epidemiology of the patient population concerned. Despite this, information on dermatologic diseases continues to be inadequately representative. There is a need for greater diversity when reporting clinical cases, 1,2 with Caucasian patients often overrepresented in dermatology studies. 3,4 A greater awareness of the diverse clinical presentation of dermatologic diseases is needed to support improvements in the clinical evaluation of patients and to promote early, accurate diagnoses. The clinical presentation and course of GPP is highly heterogeneous, both between flares in an individual, and between patients. [5][6][7] GPP can present at any age and whereas some patients experience recurrent disease with periodic GPP flares, others have persistent mild pustular lesions with episodes of increased severity. 8,9 Moreover, flares may be associated with symptoms of systemic inflammation. 9,10 Skin inflammation can also cause systemic effects, especially when large areas of skin are involved. 11 A range of complications are associated with GPP, such as septic shock, cardiac failure, liver disease, acute respiratory distress syndrome (ARDS), acute renal failure and capillary leak syndrome. [12][13][14][15] This heterogeneity of GPP signs and symptoms presents a considerable barrier to accurate, early diagnosis.
In addition to the diversity of patients and heterogeneous clinical course of GPP, establishing a diagnosis is further complicated by the rarity of the disease. Dermatologists may have limited clinical experience with GPP, making the exclusion of differential diagnoses challenging. 16,17 There is also a paucity of literature describing the global spectrum of GPP. At this time of prevalent global travel and relocation, the chance of dermatologists seeing an unfamiliar GPP presentation is increased; thus an awareness of the variety of clinical presentations is crucial for reducing misdiagnoses. 17 Further complexity is added by the many different terms used to describe GPP and the lack of consensus regarding potential triggers. Although many different terms may be used to refer to GPP, they are all the same disease, for example, von Zumbusch type psoriasis; deficiency of the interleukin-36 receptor antagonist (DITRA); and impetigo herpetiformis (GPP of pregnancy). 18 Several inciting factors can trigger GPP flares in patients including stress 13 ; pregnancy 19 ; initiation/ withdrawal of medications such as steroids and non-steroidal antiinflammatories; 13,19,20 and infection (e.g., upper respiratory tract infections and staphylococcal or streptococcal infections). 21,22 In our series of case reports, we attempt to capture the broad spectrum of clinical presentations of GPP and showcase the diversity of the patient population.

| Clinical summary
A female, neonatal patient developed widespread erythematous, desquamative plaques studded with pustules 2 months after being delivered by caesarean section at 34 weeks' gestation. Her skin lesions, initially localized to skin folds, rapidly became generalized (within 1 week) and tended to have an annular morphology with fine peripheral desquamation ( Figure 1); she also presented with oral mucosa erosion. The patient required hospital admission twice; at the time of both hospital admissions, she was afebrile, had negative skin and blood cultures, and had leukocytosis with a white blood cell (WBC) count ranging between 16 × 10 9 /L and 36 × 10 9 /L. A skin biopsy revealed epidermal acanthosis with hypogranulosis, subcorneal collections of polymorphonuclear leukocytes and mild periadnexal mixed inflammatory infiltrate.
Genetic analysis identified a heterozygous mutation of the CARD14 gene (c.956G > A [p.Arg319Gln]) and a heterozygous mutation of the IL36RN gene (c.227C > T [p.Pro76Leu]). These mutations were identified in the patient's father and mother, respectively, both of whom are healthy and asymptomatic. Both mutations are of uncertain significance according to the National Center for Biotechnology Information's ClinVar archive 26,27 ; however, the specific IL36RN mutation has previously been reported in patients with GPP, 28

| Discussion
Deficiency of the interleukin-36 receptor antagonist (IL-36Ra), or DITRA, is a genetic form of GPP that presents early in life and is associated with mutations in IL36RN (Table 1). 30 IL36RN mutations are present in 21%-24% of all patients with GPP, but the prevalence is higher in patients with GPP but without concomitant plaque psoriasis. [31][32][33] These IL36RN mutations result in a loss of function in IL-36Ra, uncontrolled IL-36 signalling and amplification of downstream inflammatory responses. 30 Patients with loss-of-function mutations in IL36RN have a distinct clinical phenotype of GPP, often presenting at an earlier age, and with a higher risk of systemic inflammation and higher recurrence rates than patients without mutations. 31,32,[34][35][36][37] In addition to an IL36RN mutation, the patient in this case also carried an alteration in CARD14, which has previously been identified in a small proportion of patients with GPP (Table 1). Although the precise pathogenesis of CARD14 mutations is not fully understood, it has been suggested that gain-of-function alterations upregulate activity of the nuclear factor kappa B (NF-κB) in keratinocytes, leading to the development of psoriatic diseases. 38 Studies suggest that the presence of co-occurring mutations or compound IL36RN mutations may affect the phenotypic presentation of GPP as well as response to treatment. 39,40 Affected patients with genetic mutations have lifelong GPP symptoms; therefore, identifying effective long-term therapeutic strategies is key to improving patient outcomes and minimising the impact of GPP on quality of life.
This case demonstrates the importance of recognising early signs and symptoms of GPP in neonatal patients and the need for long-term therapies for effective disease management as patients progress through childhood and into adulthood. Furthermore, this case report illustrates the genetic heterogeneity of GPP, which can make it difficult to determine genotype-phenotype correlations.

| Clinical summary
This 18-year-old woman was diagnosed with GPP shortly after birth and had experienced repeated outbreaks of skin pustules and oedema ever since. There was no family history of psoriasis or GPP and genetic testing was not available. Throughout the patient's childhood, GPP flares were associated with symptoms of systemic inflammation (malaise, asthenia and fever) and lasted for 2-3 weeks.
At age 5 years (Figure 2A), the patient was started on a course of treatment with a retinoid, which resulted in disease remission for the following 5 years. At age 12 years, the decision was made to gradually reduce and then discontinue her treatment because of the drug's teratogenic adverse reactions, which make it unsuitable for women F I G U R E 1 Patient's GPP lesions at 60 days old. factor alpha (TNFα) inhibitor was initiated, but after 45 days the patient presented with a further GPP flare with no apparent trigger factors ( Figure 2B). TNFα inhibitor treatment was continued; however, the patient developed sepsis with massive pulmonary involvement, ARDS, hepatitis and septic shock. Despite admission to the intensive care unit, the patient died 1 month after presenting with the GPP flare.

| Discussion
Childhood diagnosis of GPP is rare but accounts for up to 13% of childhood psoriasis. 42 In cases of GPP presenting in child-

| Discussion
GPP can be triggered and exacerbated by pregnancy [43][44][45] and typically presents in the third trimester; this form of GPP is often referred to as impetigo herpetiformis. The development of GPP in pregnancy presents a considerable clinical challenge and is associated with poor foetal outcomes (e.g., placental insufficiency, stillbirth, foetal abnormalities). 46 GPP can also become life-threatening to the mother if not effectively treated.
Effective clinical management requires close monitoring of the foetus and mother as well as therapeutic intervention with rapid onset of action. However, there is a paucity of evidence for effective treatments for GPP in pregnancy and no international consensus on the optimal therapeutic approach. The only guidelines that discuss GPP in pregnancy are those published by the JDA; they note that retinoids and methotrexate are contraindicated for pregnant patients, limiting the number of therapeutic options available. 10 Furthermore, many women experience recurring GPP in subsequent pregnancies. 46 Overall, cases of GPP during pregnancy present a particular challenge for physicians, with a lack of guidance and treatment options for effective management. There remains a need to improve clinical outcomes for the mother and foetus.

| PATIENT 4: CHALLENG E S OF D IAG NOS ING G PP IN S KIN OF COLOUR
Boni E. Elewski

| Discussion
At the time of writing, Caucasian patients are largely overrepresented in published case reports and clinical studies in patients with GPP. 3,4 It is particularly important to fully represent the diversity of patients with GPP as its clinical presentation may be influenced by patient ethnicity and skin type. Erythema, a hallmark of GPP and a key factor in assessing disease severity, may be more difficult to detect in patients with skin of colour, often presenting as a brown hue rather than the pink flush seen in patients with lighter skin. In this case, the patient was misdiagnosed twice, potentially because the skin erythema was difficult to detect due to her skin phototype, which was complicated further by inappropriate antibiotic treatment resulting in the development of IgA bullous dermatitis.
Owing to the rarity of GPP, there is a paucity of literature describing its presentation in patients of colour; however, studies in plaque psoriasis have shown that patient ethnicity may affect the extent of disease involvement and its impact on quality of life. 48 Achieving clear skin is also more challenging in skin of colour than in white skin, as patients are more likely to develop skin hyperpigmentation or hypopigmentation that may never resolve; physicians should consider and discuss these risks with patients. There is an important need for data describing the long-term effects of GPP on skin of colour.
Overall, this case demonstrates the challenges associated with diagnosing GPP in patients with more pigmented skin, and highlights the damaging consequences of misdiagnosis. A better understanding of the distinct presentations of GPP in a broad range of patients will support widespread improvements in the clinical evaluation of GPP and in achieving rapid and accurate GPP diagnoses.

| Clinical summary
A 60-year-old woman presented with superficial pustules arising on erythematous patches and erythematous, desquamative plaques ( Figure 5).

Key learnings
• The patient had a family history of psoriasis on her mother's side, and she had experienced plaque psoriasis limited to the scalp from the age of 30. The patient had undergone a total thyroidectomy because of a multinodular goitre at the age of 33 but had never received vitamin D/calcium supplements. Severe hypocalcaemia due to post-surgical, untreated hypoparathyroidism was therefore identified as a possible triggering factor for the patient's GPP flare.

| Discussion
GPP flares can be triggered by a variety of inciting factors. In this case, we report a patient with a GPP flare triggered by hypocalcaemia due to hypoparathyroidism following a total thyroidectomy 27 years prior.
Other commonly reported triggers of GPP include stress, infection and the initiation or withdrawal of corticosteroids. 13,20,21 Hypocalcaemia has previously been reported as a trigger of GPP in several case reports, frequently secondary to hypoparathyroidism. [49][50][51][52][53] However, in this case, it is unclear why the patient developed GPP almost three decades after her thyroidectomy; this suggests an interaction with other triggering factors, such as the stress-induced modulation of calcium levels. Although the exact mechanism has not been elucidated, the roles of calcium and vitamin D in cell-cell adhesion and skin cell proliferation, respectively, may contribute to the link between hypocalcaemia and GPP. 49,53 Systemic inflammation associated with GPP flares can lead to severe, life-threatening conditions, including ARDS and congestive heart failure. The patient reported here was re-admitted to hospital for acute renal failure, another common complication associated with systemic inflammation in GPP, 1 week after being discharged. [54][55][56][57] The clinical management of patients with acute renal failure requires a multidisciplinary approach, and treatment should aim to rapidly resolve nephrological symptoms and avoid other systemic complications. It is also important for physicians to consider that some treatments commonly used to treat GPP (e.g., retinoids and cyclosporine) may complicate pre-existing renal conditions and, therefore, may be contraindicated in patients with renal complications. 10 Overall

| Discussion
Although the mean age of onset is between 41 and 58 years, GPP can also present in older patients with no previous history. 58 Prognosis is particularly poor in elderly patients, due to the development of systemic complications such as infection, sepsis or cardiorespiratory failure. 58,59 Moreover, the occurrence of comorbidities is higher in patients with GPP compared with the general population and also compared with patients with plaque psoriasis. 60 The comorbidities presented in this case report (hypertension, obesity and type 2 diabetes) are among those most frequently identified in patients with GPP. 61,62 The presence of comorbidities exacerbates the risks associated with GPP flares; patients are more likely to develop life-threatening complications such as congestive heart failure, acute renal failure and sepsis. 9 Comorbid conditions also increase the impact on quality of life, with patients commonly reporting feelings of depression and anxiety. 24,61 When managing patients with GPP and multiple comorbid-

| Clinical summary
A 67-year-old man presented with erythema and pustules covering 70% BSA, which had appeared 1 week prior ( Figure 7A). He also ex-

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