key: cord-0976180-v7ltraip
authors: Genovese, Giovanni; Moltrasio, Chiara; Cassano, Nicoletta; Maronese, Carlo Alberto; Vena, Gino Antonio; Marzano, Angelo Valerio
title: Pustular Psoriasis: From Pathophysiology to Treatment
date: 2021-11-23
journal: Biomedicines
DOI: 10.3390/biomedicines9121746
sha: 3e93534400d8bc815aee283e801bbff35cc039b3
doc_id: 976180
cord_uid: v7ltraip

Pustular psoriasis (PP) is a clinicopathological entity encompassing different variants, i.e., acute generalized PP (GPP), PP of pregnancy (impetigo herpetiformis), annular (and circinate) PP, infantile/juvenile PP, palmoplantar PP/palmoplantar pustulosis, and acrodermatitis continua of Hallopeau (ACH), which have in common an eruption of superficial sterile pustules on an erythematous base. Unlike psoriasis vulgaris, in which a key role is played by the adaptive immune system and interleukin (IL)-17/IL-23 axis, PP seems to be characterized by an intense inflammatory response resulting from innate immunity hyperactivation, with prominent involvement of the IL-36 axis. Some nosological aspects of PP are still controversial and debated. Moreover, owing to the rarity and heterogeneity of PP forms, data on prognosis and therapeutic management are limited. Recent progresses in the identification of genetic mutations and immunological mechanisms have promoted a better understanding of PP pathogenesis and might have important consequences on diagnostic refinement and treatment. In this narrative review, current findings in the pathogenesis, classification, clinical features, and therapeutic management of PP are briefly discussed.

Pustular psoriasis (PP) encompasses a heterogeneous group of nosological entities sharing cardinal clinicopathological features [1] . Such diseases are typified by an eruption of superficial sterile pustules, usually on an erythematous base. Histopathological features include hyperkeratosis, parakeratosis, acanthosis, diffuse dermal mononuclear and neutrophilic inflammatory infiltrates, intraepidermal collections of neutrophils, rete ridge elongation and dilated tortuous vessels in the papillary dermis [2, 3] .

The relative rarity and heterogeneity of PP forms have hampered the collection of precise data on prognosis and management. Recent progresses in the identification of genetic mutations and immunological mechanisms have led to a better understanding of PP pathogenesis and might have relevant consequences on diagnostic refinement and treatment.

Some nosological aspects of PP are still debated. The classification of PP distinguishes localized variants [palmoplantar PP (PPPP) and acrodermatitis continua of Hallopeau (ACH)], and generalized variants, i.e., acute generalized PP (GPP), PP of pregnancy [also Table 1 . Main clinical characteristics of acute generalized exanthematous pustulosis (AGEP) and differentiation from acute generalized pustular psoriasis (GPP).

Rare disorder attributed mostly to drugs (infections, hypersensitivity to mercury and spider bite have sporadically been implicated) Sudden occurrence of a generalized skin rash with sterile nonfollicular pinhead-sized pustules on an oedematous erythema, often associated with systemic symptoms, including fever, leucocytosis and neutrophilia Spontaneous resolution of pustules within a few days followed by pin-point desquamation Mild, nonerosive mucous membrane involvement (mostly oral) in about 20% of cases Factors favoring the diagnosis of AGEP over GPP Absence of family/personal history of psoriasis (however, history of psoriasis possible in AGEP) Recent drug administration (very frequent in AGEP, possible but less frequent in GPP, that can also be drug-elicited) Predominance of lesions in the folds, especially at the onset Shorter duration of fever and pustules Spontaneous rapid resolution (within 15 days after withdrawal of the culprit drugs) and nonrecurrent tendency Arthritis (rare in AGEP, affecting about 30% of cases in GPP) Peripheral eosinophilia (present in about one-third of cases and usually mild) Histopathological features:

superficial spongiform pustules, exocytosis of neutrophils and eosinophils, occasional necrotic keratinocytes, papillary dermal oedema, mixed dermal infiltrates containing neutrophils and eosinophils (classical psoriasis changes infrequent and usually mild) -presence of eosinophils, absence of PDCs and absence of tortuous dilated capillaries favoring a diagnosis of AGEP over PP (perivascular and intraepidermal PDCs, dilated tortuous vessels and MxA expression in the dermal inflammatory infiltrate significantly in favor of PP)

Information extracted from References [2, [21] [22] [23] [24] . AGEP: acute generalized exanthematous pustulosis; GPP: generalized pustular psoriasis; MxA: human myxovirus resistance protein 1; PDCs: plasmacytoid dendritic cells; PP: pustular psoriasis.

Von Zumbusch psoriasis may exhibit an unfavourable prognosis, especially in cases evolving from ACH [1, 29] . Mortality in GPP has mostly been attributed to complications resulting from sepsis, acute respiratory distress syndrome and cardiac failure [14] . Secondary amyloidosis is mentioned as another potential complication of GPP [30] .

IH is a form of pregnancy-associated PP first described in 1872 by Ferdinand von Hebra [31] . It is controversial whether this entity should be considered distinct from PP [32, 33] . It is most frequently observed in the last trimester of pregnancy [34] . Multiple sterile pustules on an erythematous base are observed in an annular configuration at the folds with subsequent spreading over the body [34, 35] . Systemic symptoms, such as fever, chills, fatigue, nausea, diarrhea, and polyarthralgias, may be observed [32] [33] [34] . Leukocytosis with neutrophilic predominance, anemia, increased erythrocyte sedimentation rate, hypocalcemia, hypophosphatemia and hypoalbuminemia are notable laboratory findings [33, 35] . IH, especially if severe and long-lasting, may lead to poor neonatal outcomes, including placental insufficiency, fetal abnormalities, stillbirth, and early neonatal death [36] , as well as to maternal death [31] . Most patients experience prompt remission in the post-partum period [37, 38] . Recurrences with subsequent pregnancies are frequent, sometimes with earlier onset and greater severity, and can also occur while on treatment with oral contraceptives [33, 39, 40] .

Circinate or annular PP is a rare variant, consisting in an erythematous eruption with annular or polycyclic lesional morphology, small sterile pustules at the periphery of the lesions, and fine desquamation with mild-to-no systemic symptoms. Usual sites of involvement are flexural areas of the trunk and proximal extremities, buttocks and abdomen [41] . Formerly included within the spectrum of GPP, it is now considered a separate entity [42] , with a preference for younger age groups and an overall benign, sub-acute and self-resolving course.

PP is extremely rare in patients aged under 18 years [43] , with evidence limited to individual reports and small case series [44] [45] [46] . Onset of infantile/juvenile PP typically occurs at 6 to 7 years [47] . The clinical presentation is either with a circinate/annular lesional pattern, which is more common, or GPP-like [48] . Systemic involvement with fever, leucocytosis and elevation of acute phase reactants is possible [45] .

PPP involves the palms and/or soles exclusively and presents with sterile pustules, background erythema, hyperkeratosis and scaling [5, 49] . Cutaneous involvement favors the thenar, hypothenar and central areas of the palms, and the soles at the corresponding levels [8, 50] . Coalescence of pustules and hyperpigmentation after resolution are common features. PPP has been differentiated into two types by some Japanese authors: type A, as originally reported by Andrews, in which vesicles precede pustules and the association with PV is rare, and type B, as reported by Barber, characterized by a frequent association with PV and by the presence of pustules without a vesicular component [51] . PPP is regarded as a common dermatosis in Japan where its classical presentation is consistent with Andrews' type A-PPP [51] . PPP typically affects middle aged women, especially smokers [8, 13, 50] . Possible comorbidities are arthro-osteitis, metabolic syndrome and thyroid disease [4, 10, 50] . The Japanese literature reports that around 30% of PPP patients develop musculoskeletal manifestations [9] . Finally, PPP is a frequent feature of the so-called SAPHO syndrome [9] .

ACH is a very rare, localized form of PP with a chronic course and characteristic involvement of the distal digits and nail apparatus [52, 53] . It is more common in middleaged females.

ACH can progress to GPP, including severe acute GPP, strengthening the concept of a shared disease spectrum [52] [53] [54] . ACH is characterized by painful sterile pustules on the distal portions of the fingers and toes with severe nail involvement, possibly leading to onychodystrophy and anonychia. Osteitis can occur, rarely resulting in osteolysis of the distal phalanges [52, 53, 55] .

Its differential diagnosis includes other acral pustular conditions, including PPP and infectious dermatoses. Localization in periungual areas and a tendency to remain localized to a limited number of digits for many years are useful diagnostic clues [56, 57] .

Despite some degree of overlap, clinical, histological, and pathophysiological differences exist between PP and PV.

The available data seem to indicate that PP is dominated by an intense inflammatory response resulting from innate immunity hyperactivation, with a crucial involvement of the interleukin (IL)-36 axis, while a prominent role of the adaptive immune system and IL-17/IL-23 axis is seen in PV.

IL-36 cytokines belong to the IL-1 superfamily and comprise three proinflammatory agonists, IL-36α, -β, -γ, and one receptor antagonist (IL-36Ra). IL-36 cytokines are expressed in various cell types, including keratinocytes and immune cells [58, 59] , and are abundantly present in the skin [60] . They are released as a precursor and require processing by specific proteases, especially derived from neutrophils, to become bioactive [61] [62] [63] [64] . IL-36α, -β, and -γ through the IL-36 receptor (IL-36R) activate nuclear factor-κB (NF-κB) and mitogen activated protein kinase (MAPK), thus inducing the activation of downstream pathways responsible for the production of pro-inflammatory cytokines, chemokines and costimulatory molecules. IL-36Ra acts as regulator, by competing with the agonistic IL-36 cytokines for attachment to IL-36R [65, 66] .

IL-36 agonists also signal to keratinocytes in an autocrine manner and regulate T cell proliferation and polarization and dendritic cell maturation [64] [65] [66] [67] , supporting a possible involvement in the crosstalk between innate and adaptive immunity [65] . IL-36 may stimulate IL-17 pathway either directly or through IL-23 induction and synergize with IL-17A [68] .

A number of allelic variants have been found to cause or contribute to PP onset or susceptibility, primarily GPP [1, 69] . The interaction between genetic predisposition and environmental factors is thought to have a relevant pathogenetic role. Stress, infections, pregnancy and rapid withdrawal of systemic corticosteroids have been hypothesized to precipitate and/or trigger various PP forms [15, [70] [71] [72] [73] . Vaccination has been identified as a possible precipitating factor particularly in juvenile forms [74] . Recently, PP has been described in the setting of Coronavirus disease 2019 (COVID-19) [75] , as well as after COVID-19 vaccination [76] . Hypocalcemia is mentioned as a potential trigger, particularly in IH, even if evidence supporting causality is lacking [34, 77, 78] .

Different medications have also been implicated, including terbinafine, penicillin, lithium, iodine, progesterone, hydroxychloroquine, some nonsteroidal antinflammatory drugs, topical irritating agents and even anti-tumor necrosis factor (TNF) agents and more rarely other biologics [1, [79] [80] [81] . Treatment with TNF-α inhibitors can cause paradoxical flares of PP, especially PPPP [82, 83] , but the underlying pathomechanism remains to be elucidated.

The main triggering factors of PPP include smoking, metal hypersensitivity, focal infections (e.g., tonsillitis, chronic sinusitis, and dental infections), stress, and drugs [84] [85] [86] [87] . Precipitating factors most closely associated with ACH are localized trauma to the distal portion of a digit and localized infections [13, 88, 89] .

Immunological pathways in GPP and PV are thought to be partly overlapping, with a more prominent role of the innate immune system, IL-1 and IL-36 in GPP pathogenesis. However, TNF-α and IL-17A also seem to be involved [62, 90] . A gene expression study on lesional skin revealed a significant overexpression of IL-17A, TNF, IL-1, IL-36 and interferons in both PV and GPP with a significantly greater abundance of transcripts for IL-1β, IL-36α and -γ in GPP versus PV lesions [62] .

The pathogenic landscape of IH is poorly understood [32, 91, 92] and a key issue is the relationship with GPP. During pregnancy, immune responses shift towards an overall Th2 polarization, although emerging evidence indicates a much more nuanced immunological rewiring. Recent research hints at a regulatory role for IL-36 cytokines in the immunology of reproduction [93] providing a conceptual framework for the understanding of PP during pregnancy, which could represent the result of deranged IL-36 cytokines physiologic changes in the setting of a predisposing genetic background.

Annular PP-like lesions have been reported in few cases of hereditary lactate dehydrogenase M-subunit deficiency, that is responsible for an imbalance between oxidized and reduced forms of nicotinamide adenine dinucleotide (NAD/NADH), leading to dysregulation of intracellular calcium. Takeo et al. hypothesized that calcium dysregulation may lead to epidermal infiltration by neutrophils and elevated serum levels of IL-8, two hallmarks of PP [94] . Annular PP was observed in an individual with Noonan syndrome, supporting a putative shared pathomechanism involving the RAS/MAPK signaling pathway [95] .

As concerns genetic factors in GPP, a list of the main genes involved in GPP pathogenesis is summarized in Loss-of-function pathogenic variants of the IL36RN gene, encoding IL-36Ra, have been found with a frequency close to 24% in GPP [1, 12] . More specifically, mutations in IL36RN have been shown to be associated with GPP without PV and with an earlier age of disease onset [69, 101, 102] .

Deficiency of IL-36Ra (DITRA) has been classified as a subgroup of GPP with a specific monogenetic defect [103] consisting in null mutations of IL36RN, associated with severe clinical phenotypes. Hypomorphic variants with decreased or unchanged protein expression have also been found and may account for clinical heterogeneity of GPP [104] .

IL36RN variants have been detected also in IH, and, in particular, East Asian founder mutations might be implicated in IH pathogenesis [105] . Curiously, identical IL36RN mutations led to both isolated IH and IH with a preceding history of GPP and/or PV.

Recently, CARD14 causal variants have been linked to GGP. Heterozygous gain-offunction variants in CARD14 occur in up to 21% of GPP patients with concomitant PV [1, 97] while a homozygous gain-of-function CARD14 variant has been described in a mild case of IH [106] .

Accordingly, IL36RN-related pustulosis and CARD14-mediated PP have been classified within the spectrum of autoinflammatory keratinization diseases, a group of inflammatory keratinization disorders with autoinflammatory pathomechanisms [107] .

AP1S3 is another gene recently associated with GPP [108] . AP1S3 pathogenic variants are mainly found in Europeans and rarely in East Asians [69] . AP1S3 mutations can be co-inherited with IL36RN genetic changes, modifying the phenotypic effect of the latter [98] .

The mutational analysis of IL36RN, CARD14, and AP1S3 genes in a group of 61 GPP patients showed that almost two-thirds of them did not carry variants in any of the three genes, reiterating the complexity of GPP pathogenesis [102] .

Additional genetic factors might contribute to GPP pathogenesis (Table 2) , like SER-PINA3 [109] , TNIP1 [110, 111] , and MPO [63, 112] variants. MPO gene variants can increase neutrophil counts and activity of neutrophil serine proteases, capable of activating IL-36 precursors [63, 69] . Interestingly, GPP was also documented in two patients with my-cobacterial infection and interferon (IFN)-γ receptor deficiency, due to IFNGR1 or IFNGR2 gene mutations [113] .

Many authors in support of the theory that PPP is a distinct entity from palmoplantar PV argue genetic differences [4, 20, 51, 114, 115] .

IL36RN pathogenic variants have been revealed in approximately 5% of PPP patients [12] , and hypomorphic variants seem to be relatively more prevalent in localized forms of PP as compared to GPP [6] . Further, in a small number of PPP patients, also APS13 and CARD14 pathogenic variants have been detected [108, 116] . Although the pathophysiology of PPP remains obscure, it is now widely accepted that the role of the eccrine sweat gland is critical. Specifically, the acrosyringium serves as the primary site of inflammation and pustule formation [51, 117] . Interestingly, an increase in Langerhans cells can be found in both lesional and non-lesional skin of PPP patients, indicating an antigen-driven process [118] . The antimicrobial peptide hCAP-18/LL37 appears to act as an inducer of inflammation in PPP by upregulating the levels of pro-inflammatory cytokines [119] .

IL-17A is highly expressed in the palms and soles of PPP patients in comparison to healthy subjects, while IL-12 and IL-23 are not predominant [117] .

The association between smoking and PPP is well recognized [50, 84, 120] . Smoking has been demonstrated to increase IL-17 levels [117, 121] . Moreover, the expression of the acetylcholine receptor α7nAChR within the acrosyringium may be decreased by smoking, with consequent impairment of the activation of the endogenous nicotinic anti-inflammatory pathway [122] . Conversely, smoking cessation can lead to improvement of PPP [123] .

Likewise, the pathophysiology of ACH has long been debated. Case reports documenting ACH transitioning to GPP together with the possible association with IL36RN, CARD14 and AP1S3 variants support the existence of shared disease spectrum, with ACH at one end and GPP at the other [12, [52] [53] [54] .

Therapeutic management of PP is challenging and depends on multiple factors [124, 125] , especially disease severity, extent of involvement and patients' comorbidities. Owing to the rarity of PP, clinical trials focused on PP forms are scarce and evidence-based guidelines for treatment are lacking [124] . Table 3 contains information about the main recent clinical trials regarding treatment of PP . Ongoing clinical trials and other completed studies not included in Table 3 are reported in Table 4 . Betamethasone ointment applied once daily or betamethasone ointment + maxalcitol ointment (both applied once daily) for 8 weeks Improvement rates in skin symptoms at week 8 significantly higher with the combination therapy than with the monotherapy 

Acitretin, cyclosporine, methotrexate and infliximab have been indicated as first-line therapies for GPP [125, 151] . Retinoids are considered one of the preferred treatment options [125, 152] . Due to their quick onset of action, infliximab or cyclosporine may be useful in severe and extensive disease [125, 153] . According to US Medical Board of the National Psoriasis Foundation recommendations published in 2012 [125] , second-line treatments are adalimumab, etanercept, psoralen plus ultraviolet-A (PUVA) phototherapy, topical therapy (corticosteroids, calcipotriol, and tacrolimus, for more localized disease or as adjunctive tools) or combination therapy for recalcitrant disease, which can comprise a first-line systemic conventional agent associated with a biologic drug such as an anti-TNF agent [125] .

Dapsone has also been proposed as a possible therapeutic option [30, 154] . Systemic corticosteroids are usually discouraged-with a few exceptions-due to the increased risk of pustulation, as well as flares during treatment or upon discontinuation [30, 155] , although a recent study has shown low rates of psoriasis flare in such circumstances [156] .

Weighing in on the relative efficacy of available biologics in GPP, TNF-α inhibitors, in particular infliximab, and ustekinumab, an anti-IL-12/23 monoclonal antibody, seem to be backed up by more robust evidence [153, 157] . Additional biologic therapies have been evaluated. The IL-1 receptor antagonist anakinra and IL-1β inhibitors have been successfully administered in isolated cases [158] [159] [160] . Most recently, the anti-IL17A monoclonal antibodies secukinumab and ixekizumab and the anti-IL-17A receptor monoclonal antibody brodalumab have shown encouraging results [130, [133] [134] [135] 161] . Guselkumab, an anti-IL-23p19 agent, demonstrated efficacy in Japanese patients with GPP [136] , whereas a phase III trial with risankizumab, another IL23p19 inhibitor, in Japanese GPP patients has been completed (Table 4) .

Noteworthily, there appears to be no influence of IL36RN mutational status on treatment outcome in GPP patients treated with biologics [162] , but further studies are needed.

Interesting data have been collected from real-life experiences. An analysis of 1516 Japanese patients with GPP hospitalized from July 2010 to March 2019 showed better outcomes with biologics compared to other treatments, but patients treated with biologics were younger and had fewer comorbidities. IL-17 inhibitor use was associated with comparable in-hospital mortality and morbidity to those of TNF inhibitors. Indeed, about half of the patients in the biologics group were treated with concomitant oral agents, sometimes in addition to systemic corticosteroids [155] .

In a retrospective German multicenter study examining 201 treatment series of 86 GPP patients, biological treatment was found to be significantly more effective than nonbiological therapies and the median drug survival was significantly higher with biologicals vs. nonbiologicals. When the drugs were grouped according to the target cytokine, the best retention time was observed for IL-17A inhibitors, followed by IL-(12)/23 inhibitors and TNF-α blockers [163] .

In a phase I proof-of-concept study in 7 patients with a GPP flare, a rapid improvement was obtained after a single intravenous dose of spesolimab, a novel anti-IL-36R antibody [126] . The drug proved to be effective regardless of the IL36RN mutational status and is currently being investigated in further trials [164, 165] (Table 4) .

Imsidolimab is another anti-IL36R monoclonal antibody currently under investigation for GPP (Table 4) .

Although not widely available, granulocyte and monocyte adsorption apheresis (GMA) has yielded positive results in the management of GPP [30, 166] .

Limited data exist for pediatric PP. Among the conventional systemic drugs, oral retinoid treatment is the most commonly administered, even if there are concerns about growth disturbances. Cyclosporine and methotrexate have also been used as first-line treatment, whereas etanercept may be regarded as one of the preferred second-line choices for children with GPP [167] .

The risk of complications implies the need for close monitoring and adequate supportive treatment. Early induction of labor, if appropriate, is suggested in the management of severe or refractory IH [168] . The data regarding treatment of PP of pregnancy are extremely limited. Current treatment regimens include systemic corticosteroids, which are the most frequently used drugs, cyclosporine, narrow-band ultraviolet-B (NB-UVB), adjuvant antibiotic therapy and topical agents [30, 36, 78, 91, 125] . Biologic therapy can be cautiously considered for severe refractory IH, and there are only very few reports mostly regarding TNF inhibitors, especially infliximab [30, 78, 125] . Certolizumab might be an interesting therapeutic agent for IH in terms of safety for the mother and fetus [169] . GMA appears to be particularly appealing during pregnancy as it represents one of the safest therapeutic options [166] .

PPPP/PPP is notoriously treatment-refractory [170] . The most commonly used treatments remain topical agents, mainly topical corticosteroids regarded as more effective if used under occlusion [171] . Other topical therapies are vitamin D derivatives, topical PUVA, photodynamic therapy and tacrolimus [10, 125] . Topical treatment is frequently not satisfactory and systemic treatment is therefore required [6] .

First-line systemic treatments for PPPP are represented by cyclosporine, retinoids and oral PUVA or retinoid-PUVA [125] . Among systemic non-biological agents, cyclosporine has the highest level of evidence for efficacy in PPPP [6] . Nevertheless, high-quality evidence is lacking for most PPP treatments [171] . Other oral treatments include tetracyclines [171] and the phosphodiesterase inhibitor apremilast that has been described as effective in few patients with moderate-to-severe or refractory disease [10, 146, 172] .

The successful use of TNF-α inhibitors or ustekinumab in PPP/PPPP has been documented in case reports and small studies [10, 49] . However, a randomized placebocontrolled trial failed to demonstrate a statistically significant efficacy of ustekinumab in PPPP and PPP patients [117] .

Treatment with brodalumab was unsuccessful or only moderately effective in a series of 4 PPPP patients [173] .

Data from the 2PRECISE trial showed that at week 52 the Palmoplantar Psoriasis Area and Severity Index (PPPASI) had at least a 75% reduction from baseline (PPPASI-75) in 41.8% of subjects treated with 300 mg/month of secukinumab [131, 132] . Despite potential benefits, the primary end point (PPPASI-75 response with secukinumab at week 16 versus placebo) was not met.

The therapeutic potential of guselkumab was revealed in Japanese patients with moderate-to-severe PPP. A significantly higher proportion of patients in the guselkumab 100-mg group achieved at least 50% reduction of PPPASI (PPPASI-50) at week 16 versus placebo, but the result was not significant for the guselkumab 200-mg group [138] .

In a phase 2a study investigating the efficacy of spesolimab in PPP, the primary endpoint (PPPASI-50 at week 16) was not met, although post hoc analyses demonstrated a greater efficacy of spesolimab over placebo in patients with more severe disease [127] .

Imsidolimab was shown not to determine a significant improvement over placebo in a phase 2 clinical trial in moderate-to-severe PPP [174] .

Treatment options for ACH, which is particularly treatment-refractory, are mainly grounded on data from case reports. Several therapeutic options have been tried with variable and sometimes equivocal results [53, 55] . Topical treatments (i.e., corticosteroids, calcipotriol, tacrolimus, and fluorouracil, or a combination of these drugs) have a limited efficacy and alternative treatments are often necessary. These include cyclosporine, systemic corticosteroids, retinoids, methotrexate, PUVA, UVB phototherapy, GMA, and biologic agents (e.g., anti-TNF agents, IL-17 inhibitors, IL-12/23 inhibitors, and anakinra) [53, 55, 170] and also apremilast and baricitinib [175, 176] .

In a series of 39 patients with ACH, the overall effectiveness of systemic treatments was low (excellent response rate: 14.8%) [177] . A treatment algorithm was suggested, starting with acitretin or methotrexate as first-line therapy, followed by biologics, particularly adalimumab and secukinumab, and possibly guselkumab, whereas cyclosporin might be used for short-term control [177] . 

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

All authors declare no conflicts of interest.

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Extra-palmoplantar lesions associated with palmoplantar pustulosis

The role of psychological factors in palmoplantar pustulosis

Chronic pustular eruption of the thumbs. Diagnosis: Acrodermatitis continua of Hallopeau (ACH)

Acrodermatitis continua

Generalized pustular psoriasis-a model disease for specific targeted immunotherapy, systematic review

Pregnancy dermatoses: Diagnosis, management, and controversies

Impetigo herpetiformis followed by generalized pustular psoriasis: More evidence of same disease entity

IL-36 Cytokines: Regulators of Inflammatory Responses and Their Emerging Role in Immunology of Reproduction

Hereditary lactate dehydrogenase M-subunit deficiency with late-developing pustular psoriasis-like lesions

Possible correlations between annular pustular psoriasis and Noonan syndrome

CARD14-Mediated Activation of Paracaspase MALT1 in Keratinocytes: Implications for Psoriasis

Generalized pustular psoriasis-Dawn of a new era in targeted immunotherapy

AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36

TNIP1, a retinoic acid receptor corepressor and A20-binding inhibitor of NF-κB, distributes to both nuclear and cytoplasmic locations

The Enzymatic and Non-Enzymatic Function of Myeloperoxidase (MPO) in Inflammatory Communication

Association between mutation of interleukin 36 receptor antagonist and generalized pustular psoriasis: A PRISMA-compliant systematic review and meta-analysis

The genetic basis for most patients with pustular skin disease remains elusive

Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis

Mutations in IL36RN are associated with geographic tongue

Significance of IL36RN mutation analyses in the management of impetigo herpetiformis: A case report and review of published cases

Impetigo herpetiformis with a CARD14 Thr79Ile variant successfully treated with granulocyte and monocyte adsorption apheresis

Autoinflammatory keratinization diseases: An emerging concept encompassing various inflammatory keratinization disorders of the skin

AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking

Rare Loss-of-Function Mutation in SERPINA3 in Generalized Pustular Psoriasis

Identification of Two Loci Associated with Generalized Pustular Psoriasis

Tumor Necrosis Factor-alpha Induced Protein 3 Interacting Protein 1 Gene Polymorphisms and Pustular Psoriasis in Chinese Han Population

Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease

Generalized Pustular Psoriasis in Patients with Interferon Gamma (IFN-γ) Receptor Deficiency and Mycobacterial Infection

Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis

Association of TNF -238 and -308 promoter polymorphisms with psoriasis vulgaris and psoriatic arthritis but not with pustulosis palmoplantaris

Palmoplantar Pustular Psoriasis Is Associated with Missense Variants in CARD14, but Not with Loss-of-Function Mutations in IL36RN in European Patients

Increased expression of IL-17A and limited involvement of IL-23 in patients with palmo-plantar (PP) pustular psoriasis or PP pustulosis; results from a randomised controlled trial

Novel findings of Langerhans cells and interleukin-17 expression in relation to the acrosyringium and pustule in palmoplantar pustulosis

Vesicular LL-37 contributes to inflammation of the lesional skin of palmoplantar pustulosis

Palmoplantar pustulosis: A clinical and immunohistological study

Patients with palmoplantar pustulosis have increased IL-17 and IL-22 levels both in the lesion and serum

Expression of nicotinic receptors in the skin of patients with palmoplantar pustulosis

The psoriasis variant palmoplantar pustulosis can be improved after cessation of smoking

A Narrative Review of Recent Developments in Pathophysiology and Therapeutic Options

Treatment of pustular psoriasis: From the Medical Board of the National Psoriasis Foundation

Inhibition of the Interleukin-36 Pathway for the Treatment of Generalized Pustular Psoriasis

Patients with Palmoplantar Pustulosis: Results of a Phase IIa, Multicenter, Double-Blind, Randomized, Placebo-Controlled Pilot Study

Adalimumab treatment in Japanese patients with generalized pustular psoriasis: Results of an open-label phase 3 study

SPREAD Study Group. Efficacy and safety of dose escalation of infliximab therapy in Japanese patients with psoriasis: Results of the SPREAD study

Efficacy and safety of secukinumab in patients with generalized pustular psoriasis: A 52-week analysis from phase III open-label multicenter Japanese study

Secukinumab for moderate-to-severe palmoplantar pustular psoriasis: Results of the 2PRECISE study

Efficacy and safety of secukinumab in moderate to severe palmoplantar pustular psoriasis over 148 weeks: Extension of the 2PRECISE study

Japanese Ixekizumab Study Group. Efficacy and safety of ixekizumab treatment for Japanese patients with moderate to severe plaque psoriasis, erythrodermic psoriasis and generalized pustular psoriasis: Results from a 52-week, open-label, phase 3 study (UNCOVER-J)

Long-term efficacy and safety of ixekizumab in Japanese patients with erythrodermic or generalized pustular psoriasis: Subgroup analyses of an open-label, phase 3 study (UNCOVER-J)

Japanese Brodalumab Study Group. Efficacy and safety of brodalumab in patients with generalized pustular psoriasis and psoriatic erythroderma: Results from a 52-week, open-label study

Guselkumab, a human interleukin-23 monoclonal antibody in Japanese patients with generalized pustular psoriasis and erythrodermic psoriasis: Efficacy and safety analyses of a 52-week, phase 3, multicenter, open-label study

Monoclonal Antibody, for Palmoplantar Pustulosis: A Randomized Clinical Trial

Efficacy and Safety of Guselkumab in Japanese Patients With Palmoplantar Pustulosis: A Phase 3 Randomized Clinical Trial

Sustained efficacy and safety of guselkumab in patients with palmoplantar pustulosis through 1.5 years in a randomized phase 3 study

APRICOT Study Group. Anakinra for palmoplantar pustulosis: Results from a randomized, double-blind, multicentre, two-staged, adaptive placebo-controlled trial (APRICOT)

A randomized prospective study of different dose regimens using the 308-nm excimer laser in the treatment of palmoplantar pustulosis

UVA1 phototherapy in the treatment of palmoplantar pustulosis: A pilot prospective study

UVA1 vs. narrowband UVB phototherapy in the treatment of palmoplantar pustulosis: A pilot randomized controlled study

Short-and long-term efficacy of fumaric acid esters or acitretin in combination with a 12-week course of PUVA in the treatment of palmoplantar pustulosis: Results from a prospective randomized trial

Oral alitretinoin treatment in patients with palmoplantar pustulosis inadequately responding to standard topical treatment: A randomized phase II study

A multicentre open-label study of apremilast in palmoplantar pustulosis (APLANTUS)

Tofacitinib for the Treatment of Nail Lesions and Palmoplantar Pustulosis in Synovitis, Acne, Pustulosis, Hyperostosis, and Osteitis Syndrome

A single cohort, open-label study of the efficacy of pamidronate for palmoplantar pustulosis in synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome

Phase III clinical study of maxacalcitol ointment in patients with palmoplantar pustulosis: A randomized, double-blind, placebo-controlled trial

Topical combination therapy with vitamin D3 and corticosteroid ointment for palmoplantar pustulosis: A prospective, randomized, left-right comparison study

Review of treatments for generalized pustular psoriasis

Systemic Monotherapy Treatments for Generalized Pustular Psoriasis: A Systematic Review

Biological therapy for pustular psoriasis: A systematic review

Dapsone therapy for pustular psoriasis: Case series and review of the literature

Treatments and outcomes of generalized pustular psoriasis: A cohort of 1516 patients in a nationwide inpatient database in Japan

Psoriasis Flares Following Systemic Glucocorticoid Exposure in Patients with a History of Psoriasis

Groupe de Recherche sur le Psoriasis de la Société Française de Dermatologie. Efficacy and safety of tumor necrosis factor inhibitors in acute generalized pustular psoriasis

Successful response in a case of severe pustular psoriasis after interleukin-1beta inhibition

Successful therapy with anakinra in a patient with generalized pustular psoriasis carrying IL36RN mutations

Treatment of two patients with generalized pustular psoriasis with the interleukin-1β inhibitor gevokizumab

The role of IL-17 and IL-17 receptor inhibitors in the management of generalized pustular psoriasis

Biologics in the treatment of pustular psoriasis

Drug survival in the treatment of generalized pustular psoriasis: A retrospective multicenter study

Spesolimab: A Novel Treatment for Pustular Psoriasis

Study protocol of the global Effisayil 1 Phase II, multicentre, randomised, double-blind, placebo-controlled trial of spesolimab in patients with generalized pustular psoriasis presenting with an acute flare

Intensive granulocyte and monocyte adsorption apheresis for generalized pustular psoriasis

Pharmacological Management of Pediatric Pustular Psoriasis

A case of impetigo herpetiformis in which termination of pregnancy was required

Efficacy and safety of treatment with anti-tumor necrosis factor-α drugs for severe impetigo herpetiformis

Pustular psoriasis: Pathophysiology and current treatment perspectives. Psoriasis: Targets Ther

Interventions for chronic palmoplantar pustulosis: Abridged Cochrane systematic review and GRADE assessments

Successful Treatment of Refractory Palmoplantar Pustular Psoriasis with Apremilast: A Case Series

Interleukin-17 receptor a blockade with brodalumab in palmoplantar pustular psoriasis: Report on four cases

AnaptysBio Reports Imsidolimab POPLAR Phase 2 Clinical Trial in Moderate-to-Severe Palmoplantar Pustulosis (PPP) Did Not Meet Primary Endpoint

Successful treatment of acrodermatitis continua of Hallopeau with apremilast

Inhibition of Progression of Acrodermatitis Continua of Hallopeau with Baricitinib

Treatment of acrodermatitis continua of Hallopeau: A case series of 39 patients