Pustular Psoriasis: From Pathophysiology to Treatment

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.


Introduction
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.

Main features of AGEP
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].

Impetigo Herpetiformis (Pustular Psoriasis of Pregnancy)
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].

Annular Pustular Psoriasis
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.

Infantile/Juvenile Pustular Psoriasis
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].

Palmoplantar Pustulosis/Palmoplantar Pustular Psoriasis
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].

Acrodermatitis Continua of Hallopeau
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].

Pathogenesis
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 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].

Pathophysiology of Generalized Forms
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].

Pathophysiology of Localized Forms
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].

Treatment
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

Treatment of Generalized Pustular Psoriasis
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].
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].

Treatment of Pustular Psoriasis of Pregnancy
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].

Treatment of Palmoplantar Pustulosis/Palmoplantar Pustular Psoriasis
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 of Acrodermatitis Continua of Hallopeau
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].

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

Conflicts of Interest:
All authors declare no conflicts of interest.