Diagnosis of Generalized Pustular Psoriasis

Generalized pustular psoriasis (GPP) is a severe rare skin disease characterized by widespread eruptions of sterile pustules with or without systemic inflammation [1]. Because of the extracutaneous manifestations of the disease, which include fever, leukocytosis, general malaise, and may include multiorgan involvement, GPP flares can be life threatening if not diagnosed accurately and treated promptly [2]. However, there is a lack of international consensus on the diagnosis and management of patients with GPP, and the rarity of the disease and absence of consistent diagnostic criteria and methodologies are substantial hurdles to achieving an accurate diagnosis [3, 4]. Although there are similarities among the available guidelines [1, 5], recent advances in our understanding of the pathogenesis of GPP offer new opportunities to develop internationally standardized guidelines and adopt new methodologies for accurate and rapid diagnosis of the disease. In this article, we highlight the clinical spectrum of GPP and the diagnostic challenges due to the lack of standardized guidelines, provide an overview of the current methods for the diagnosis of GPP, and describe the available differential diagnostic strategies.

Generalized pustular psoriasis is most common during the fourth decade of life and more prevalent in female than male individuals [6]. Patients with GPP typically present with a rapid onset of widespread pustules on ill-defined areas of erythema and edema [6, 7]. According to the Japanese guidelines, GPP is diagnosed based on the repeated recurrence of systemic symptoms, such as fever and fatigue, extensive flushing accompanied by the eruption of multiple sterile pustules that can merge to form “lakes of pus”, and the presence of Kogoj’s spongiform pustules [5]. The severity of GPP is categorized as mild, moderate, or severe based on the total score of skin signs, which includes a rating of erythema, pustules, and edema in combination with a systemic inflammation score of fever, white blood cell count, and serum C-reactive protein and albumin levels [5]. Based on a recent international consensus by the European Rare and Severe Psoriasis Expert Network (ERASPEN), GPP is defined as primary sterile visible pustules on non-acral skin and can be subclassified into GPP with or without systemic inflammation and with or without plaque psoriasis [1]. In addition, the disease course can be relapsing or persistent [1]. A complete physical examination of the skin and mucosae is mandatory to evaluate the extent of involvement [6]. The mucosal examination findings typically include a geographic or fissured tongue, cheilitis, and ocular involvement (e.g., conjunctivitis, uveitis, and iritis). In addition, the cutaneous symptoms associated with GPP flares may include pain, burning, and pruritus. Because of the systemic nature of the disease, extracutaneous manifestations may include nail abnormalities, arthralgia, jaundice, and edema of the lower extremity [6].

History of concurrent or previous plaque psoriasis is helpful for confirming a GPP diagnosis; however, not all patients with GPP have a history of plaque psoriasis [6, 8]. In addition, potential triggers of GPP flares, which may include medications, infections, stress, and pregnancy, should be investigated [2, 8‐10]. As several patterns of medication use have been found to trigger GPP flares, a complete medication history should be explored. For example, GPP flares can be triggered by rapid tapering or sudden withdrawal of systemic corticosteroids or cyclosporine, drugs such as amoxicillin and terbinafine, or ointments including calcipotriol and betamethasone [11‐14]. Paradoxical eruption of GPP flares has also been reported with the use of tumor necrosis factor-α inhibitors and ustekinumab [15‐17]. However, differential diagnosis of medication-induced GPP flares vs acute generalized exanthematous pustulosis (AGEP) represents a clinical challenge that requires careful clinical and laboratory assessments. Recent reports indicate that GPP can also be triggered by certain vaccines [18]. For example, several recent case studies have shown a possible induction of GPP flares following the administration of vaccines for severe acute respiratory syndrome coronavirus 2, possibly through the induction of cytokines involved in the pathogenesis of GPP flares [19, 20]. Moreover, during the global COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2, there were reports of cases of GPP exacerbation and evolution of acrodermatitis continua of Hallopeau into GPP following COVID-19 infection [21, 22].

Several infections have been linked to GPP flares, including streptococcal, Trichophyton rubrum, cytomegalovirus, Epstein–Barr virus, and varicella zoster virus [6]. Generalized pustular psoriasis can also be triggered by certain medical conditions, such as hypocalcemia, which can be caused by hypoparathyroidism [6, 23]. Pregnancy has also been reported to trigger a rare, potentially life-threatening variant of GPP known as impetigo herpetiformis. This form of GPP usually occurs during the third trimester and may recur during subsequent pregnancies (see Sect. 7.2) [24].

Laboratory tests are needed to confirm a GPP diagnosis and to assess the level of systemic inflammation and possible systemic complications of the disease [6]. These tests are summarized in Table 1 [6, 25]. A potassium hydroxide test can also be performed to exclude other causes of scaling and pustulosis, such as generalized tinea corporis and disseminated candidiasis [26, 27].

Skin biopsies may be performed to confirm a diagnosis of GPP [6, 28]. A key distinct histopathologic feature of GPP is the presence of Kogoj’s spongiform pustules, which form due to the accumulation of neutrophils beneath the stratum corneum. Other features include parakeratosis, acanthosis, hyperkeratosis, elongated rete ridges, diminished stratum granulosum, and capillary dilation of the papillary dermis. Munro’s microabscesses and superficial perivascular mononuclear cell infiltrations can also be observed [6].

Although genetic tests are not yet routinely used to confirm a GPP diagnosis, the future implementation of genetic screening may offer the opportunity to identify certain forms of GPP and personalize treatment strategies. Increased knowledge of genetic variants involved in the pathogenesis of GPP and other pustular skin diseases will pave the way for the adoption of genetic screens in patient care. Among the most notable recent findings is the identification of IL36RN variants in patients with GPP and is seen in approximately 24% of patients with GPP [29]. Genotype–phenotype studies have shown that variants in IL36RN, encoding the interleukin-36 receptor antagonist, are associated with an earlier age of GPP onset and widespread inflammation, and are reported not to be related to concurrent or prior plaque psoriasis [7, 30]. IL36RN variants that result in interleukin-36 receptor antagonist deficiency are associated with severe forms of GPP and AGEP, another pustular skin disease triggered mainly by medications [31]. The breakthrough discovery of IL36RN variants in the pathogenesis of GPP led to the identification of a new form of GPP termed deficiency of the interleukin-36 receptor antagonist (DITRA) [32]. Variants in CARD14, which encodes a keratinocyte adaptor protein, were also identified in patients with GPP. The CARD14 p.Asp176His gain-of-function variant was identified as a predisposing factor for GPP with plaque psoriasis; however, this variant was not associated with GPP alone in a Japanese population [30]. Variants in AP1S3, which encodes a subunit of the adaptor protein 1 complex, were also identified in patients with pustular psoriasis of European origin [33]. Most recently, MPO loss-of-function variants were discovered in patients with GPP; MPO variants cause an increase in neutrophil accumulation and activity [34]. In addition, a rare loss-of-function variant in SERPINA3, which encodes serine protease inhibitor A3 (serpin A3) that inhibits several proteases, was identified in patients with GPP; specifically, the heterozygous deletion c.966delT/p.Tyr322Ter in two patients with GPP was confirmed by Sanger sequencing. This rare variant was found to be associated with GPP and may impact the inhibitory effect of serpin A3 on cathepsin G [35].

As several pustular skin conditions present with similar clinical features and symptoms, GPP requires effective differential diagnostic strategies (Fig. 1) [6, 25, 31, 36‐41]. Below, we summarize two key differential diagnoses.

Several variants of pustular psoriasis have been identified. These variants share similar clinical presentations, which involve the eruption of widespread sterile pustules of various distributions and histopathologic features [47]. However, it is worth noting that in certain countries, the classification of acrodermatitis continua of Hallopeau and palmoplantar pustulosis as variants of GPP remains controversial as they may be considered distinct disease entities. Below, we describe the key features of these variants.

The accurate diagnosis of GPP remains challenging because of its rarity, the heterogeneity of its cutaneous and systemic symptoms, and the number of differential diagnoses and variants of psoriasis from which it must be distinguished. As such, there is a clear need for standardized international guidelines to aid healthcare professionals in diagnosing GPP. Beyond the development of guidelines, advances in the discovery of GPP-specific biomarkers will allow the creation of objective quantitative strategies to define disease severity and optimize treatment regimens. For example, the recent discovery of elevated levels of high-mobility group box 1 in the serum and skin of patients with GPP may serve as a marker for disease severity upon further validation [55]. Better understanding of the biological mechanisms that lead to the development and exacerbation of GPP in patients without GPP-associated genetic mutations will allow the identification of more effective differential diagnostic strategies. In addition, for patients with GPP caused by genetic mutations, advances in our understanding of the genetics of GPP and other pustular diseases will pave the way for improved, rapid, and accurate diagnostic methods. The routine clinical implementation of genetic testing in the future will enhance our ability to define patient populations with specific GPP subtypes. Combining genetic testing with knowledge of the patient’s medical history, physical examinations, laboratory tests, and histopathologic assessments will offer a powerful diagnostic method for GPP and provide pathways to diagnose and treat patients with GPP rapidly and accurately.