Pustular forms of psoriasis are a group of rare, debilitating, and often life-threatening inflammatory skin diseases characterized by episodic skin infiltration of neutrophils, pustule development, erythema and desquamation, which can manifest in the presence or absence of chronic plaque psoriasis. The skin involvement is frequently accompanied by a high-grade fever, fatigue and systemic inflammation. Despite having different genetic and environmental etiologies generalized pustular psoriasis (GPP), acute generalized exanthemous pustulosis (AGEP), palmo-plantar pustulosis (PPP) and acrodermatitis continua of Hallopeau (ACH) are all characterized by a massive influx of neutrophils into the epidermis, thus share some mechanistic aspects. To date, treatments for these diseases have been unsatisfactory with disease recurrence common; however, recent genetic data and ongoing clinical trials with biologic therapies are revealing hitherto unknown mechanisms, substantially improving our understanding and management of these diseases.
Contrasting characteristics of plaque and pustular psoriasis
Complex genetics: 80+ risk loci identified
3 loci identified: IL36RN, CARD14, AP1S3
Gradual (plaque), although guttate psoriasis onset is acute (often following streptococcal pharyngitis)
Onset is acute, often with high-grade fever and chills
Elevated skin and serum cytokines
Markers of systemic inflammation elevated
T cell driven; neutrophils present
Acanthosis (uniform elongation of the rete ridges), parakeratosis and orthokeratosis, loss of granular layer, pustules can be presentin spinous layer (Munro’s microabscess), upper part of epidermis (spongiform pustules of Kogoj), beneath the normal cornified layer or within the parakeratotic layer (intracorneal pustule)
Widespread intraepidermal or subcorneal pustules in erythrodermic and edematous skin, spongiosis, massive epidermal neutrophil infiltrate eosinophils, apoptotic keratinocytes
Generalized Pustular Psoriasis
A second pustular form of psoriasis is a severe cutaneous inflammatory drug reaction, acute generalized exanthematous pustulosis (AGEP). This is characterized by widespread sterile, non-follicular, fine, pinhead-sized pustules arising on edematous and erythemic skin (Fig. 11.1, middle). AGEP has a predilection for the major flexures, and is often accompanied with systemic inflammatory symptoms. AGEP is rare, occurring in one to five individuals per million per year , and the vast majority of cases are adverse reactions to medications; However, in rare instances AGEP has also been reported to be induced by triggers as diverse as spider bites, bacterial or viral infections, foods, and herbal remedies [9, 10, 11]. Offending medications include a variety of antibiotics, antimycotics and anticonvulsants. Several of the drugs reported to trigger AGEP are also known triggers of Stevens-Johnson syndrome [11, 12] a cutaneous drug reaction in which cytotoxic CD8+ T cell responses predominate; However, unlike Stevens-Johnson syndrome, no confirmed associations with HLA alleles exist for AGEP patients  and cutaneous responses in AGEP are typically much more rapid (24–48 h versus 1–3 weeks) . Notwithstanding, the activation of drug-specific CD4+ and CD8+ T cells is proposed to be involved in the initial triggering of neutrophil activation and infiltration of the skin in AGEP . As with other severe cutaneous inflammatory drug reactions, the identification and withdrawal of the offending drug are the essential first therapeutic steps, with subsequent glucocorticosteroids to induce disease remission. Despite their seemingly divergent initial triggers, to date no clear histological or immunohistochemical differences have been demonstrated between GPP and AGEP, and the recent identification of shared genetic mutations between these diseases strengthens the idea that they share pathological mechanisms and therapeutic targets [15, 16, 17]. Carriage of certain genetic mutations may also influence the disease phenotype , suggesting that as the disease allele influences the disease process, further sub-phenotyping based on genetics and clinical features will be necessary to better understand this disease and to optimize effective treatments. Other systemic forms of pustular psoriasis have been described, including impetigo herpetiformis (a form of pustular psoriasis occurring in pregnancy) , and annular pustular psoriasis where lesions develop in ring-like, circular forms.
Localized Forms of Pustular Psoriasis
Localized forms of pustular psoriasis include palmo-plantar pustulosis (PPP) and acrodermatitis continua of Hallopeau (ACH), where the disease has a predilection for the palms and soles, or the tips of the fingers and toes, respectively. PPP manifests as cyclic and erupting sterile pustules on the palms and soles, often under a thick cornified layer (Fig. 11.1, right). The pustules may be present on clear skin or erythematous and hyperkeratotic lesions. Despite its restricted anatomical pattern, patients with severe symptoms may have significant pain and be unable to stand, walk or do manual work, thus this disease has a profound impact on quality of life [19, 20]. PPP has a worldwide distribution and is associated with plaque psoriasis in about 20% of cases; PPP, without concomitant plaque psoriasis, has an incidence estimated between 1 and 5 in 10,000 [21, 22]. Onset of the disease occurs mostly between the ages of 20 and 60 years and, unlike plaque psoriasis, has a strong predilection for women [22, 23]. As with GPP, a number of early [24, 25] and more recent [23, 26] genetic observations, together with clinical and epidemiological features have suggested that PPP is an entity distinct from plaque psoriasis .
The cause of the disease predilection for the palms and soles is unknown, but these areas are differentiated by the presence of numerous eccrine sweat glands (acrosyringium) which have been implicated in the pathogenesis of PPP [28, 29, 30]. A number of studies found that the majority of their PPP cohort was either current or former tobacco smokers [22, 23, 31]. This led to the suggestion that PPP is an autoimmune reaction induced by tobacco smoking against the acrosyringium and the papillary endothelium . PPP has been associated with tonsillitis, in particular infections with α-streptococci have been implicated in triggering the disease. In support of this, increased numbers of α-streptococci-reactive T cells, have been detected in the tonsils of PPP compared with recurrent tonsillitis patients . Elevations in the frequency of both cutaneous lymphocyte-associated antigen positive (CLA, a molecule expressed by the majority of T cells in the skin) and CCR6 positive T cells have been detected in the tonsils of PPP patients compared with non-PPP (recurrent tonsillitis) patients [32, 33]. Moreover, the abundance of these CLA+ or CCR6+ T cells was reduced in the peripheral blood of these PPP patients in the months following tonsillectomy [32, 33]. These populations are thought to represent streptococci-specific skin-homing T cells, which on entering the skin can initiate an inflammatory reaction after misrecognition of their cognate antigens. This scenario is analogous to that posited for chronic plaque and guttate psoriasis patients, wherein β-hemolytic streptococcus is suspected of initiating the disease, particularly for patients carrying one or two copies of the HLA-Cw*0602 allele [34, 35, 36]. This contrasts with PPP, where no strong class I HLA association is known and α-streptococcus a suspected culprit. The mechanism whereby a bout of streptococcal tonsillitis leads to the elicitation of a chronic skin pustulosis is currently unknown, however tonsillectomy has been anecdotally associated with disease remission. The efficacy of tonsillectomy for PPP has not been properly assessed, yet is regarded as a routine treatment for PPP in Japan [32, 37, 38, 39].
Genetic Clues to Disease Mechanisms in Pustular Psoriasis
Until recently, the etiology and pathogenic mechanisms of pustular psoriasis were unknown, which critically stalled the development of specific and effective treatments. During the last decade, the situation has radically changed with the identification of inherited mutations in three genes each of which, through altered function of their respective proteins, cause inflammatory mechanisms to be dysregulated, leading to the development of neutrophilic skin disease.
The first gene found to be associated with GPP is IL36RN [40, 41]. These seminal observations brought IL-36, a cytokine which at the time was more of a curiosity than a critical and disease-inducing cytokine, into the limelight. The GPP-associated missense mutations in IL36RN affect the structure and function of the IL-36 receptor antagonist (IL-36Ra). Loss of functional IL-36Ra leads to unrestricted IL-36 activity, as evidenced by induction of IL-1β, IL-6, and CXCL8 production, and neutrophil infiltration of skin [40, 41]. Since these initial observations, mutations in IL36RN have been identified in numerous studies of GPP with and without concomitant plaque psoriasis, as well as cases of AGEP [15, 16, 17, 42], but not PPP [17, 23, 43], suggesting different a different etiology for PPP.
The three isoforms of IL-36 exist: IL-36α, β and γ, which form a trio of pro-inflammatory IL-1-like cytokines that are overexpressed in lesions of plaque psoriasis [44, 45, 46], GPP , and AGEP , where they can drive keratinocyte inflammatory responses , synergize with other pro-inflammatory cytokines [44, 47], and promote dendritic cell activation [48, 49]. The effects of IL-36 on skin have been modeled in mice [44, 45], where the transgenic expression of IL-36α in murine epidermis led to epidermal thickening, hyperkeratosis, mixed inflammatory cell infiltrate, and elevated chemokine expression . Backcrossing to an IL36RN-deficient mouse resulted in more severe skin lesions, reflecting the effect of nonsense IL36RN mutations in GPP. This phenotype was partly reversed by the use of a neutrophil-depleting antibody, suggesting a causative role for neutrophils in this IL-36α-induced skin hyperplasia. This is supported by our own observations that subcutaneous administration of IL-36α to mice induces acanthosis and prominent neutrophilic infiltration . IL-36 expression is also elevated in the skin of psoriasiform KC-Tie2 mice  and during imiquimod-induced skin inflammation [44, 50]. One of the early features of imiquimod-treated mouse skin is neutrophil infiltration, and the inflammatory phenotype is ablated in IL-36 receptor deficient mice  adding further support for a neutrophil/IL-36 axis as a central driver in the development of skin inflammation in GPP. Like their IL-1 family counterparts IL-1β, IL-18 and IL-33, the IL-36 cytokines require post-translational N-terminal peptide cleavage for activity  and it was recently demonstrated that IL-36 cleavage could be carried out by the neutrophil serine proteases elastase and cathepsin G [7, 52] as well as keratinocyte-derived cathepsin S . Cathepsin S is strongly upregulated in psoriasis lesions, likely by the synergistic actions of TNF and IFN-γ, and, unlike elastase and cathepsin G, cathepsin S has been demonstrated to cleave IL-36γ into its most potent form . Interestingly, these processes appear to be regulated by the activities of endogenous protease inhibitors expressed by the keratinocytes of psoriasis skin lesions, indicating the presence of a potential feedback inhibitory mechanism to restrain IL-36 driven inflammation .
Mutations in IL36RN have been shown to account for between 46 and 82% of cases of GPP without associated plaque psoriasis [54, 55]. The proportion of IL36RN mutant carriage is much lower (10–17%) in cases of GPP with concomitant plaque psoriasis , supporting the idea that divergent pathogenic mechanisms may be active in the two diseases. A recent meta-analysis of 233 GPP cases revealed that carriage of one or two IL36RN mutant alleles conferred a more severe clinical phenotype with an earlier age of onset and increased risk of systemic inflammation than non-carriage . Moreover, a gene-dosage effect was also evident as homozygous carriers had an earlier age of onset than heterozygotes.
Mutations in AP1S3 affecting the structure and function of the AP-1 complex subunit σ1C have been identified in ACH , GPP and PPP  patients. AP-1 is a member of the adaptor protein (AP) family which is a group of cytosolic heterotetrameric complexes that direct the assembly and trafficking of small transport vesicles . Each of the five known complexes (AP-1, AP-2, AP-3, AP-4, and AP-5) is active in a distinct subcellular compartment, where it mediates the delivery of transmembrane proteins to specific target organelles . AP-1 is involved in the transport of cargo between the trans-Golgi network and the endosomes, a process that requires the formation of specialized clathrin-coated vesicles . Similar to other AP complexes, AP-1 consists of two large (γ1 and β1), one medium (μ1), and one small (σ1) subunit. The σ1 subunit exists in three forms, σ1A, σ1B, and σ1C, encoded by AP1S1, AP1S2, and AP1S3 respectively. Of particular interest here, the σ subunit stabilizes the tetrameric complex and thus non-synonymous mutations in AP1S genes are predicted to destabilize the entire AP-1 complex disrupting protein transport . The two pustular psoriasis-associated AP1S3 mutations described (p.Phe4Cys and p.Arg33Trp) lead to loss of AP1S3 function by reducing the stability of AP1-σ1C and by disrupting the interaction between the AP1-σ1C and AP1-μ1A subunits, respectively [26, 57]. Loss of AP1S3 function was found to result in reduced autophagy, a process shown to modulate NF-κB signaling by degrading p62, an adaptor molecule which binds TRAF6 leading to NF-κB activation. Carriage of mutant alleles resulted in p62 accumulation, and enhanced IL-1β, IL-8 and IL-36γ cytokine production in response to Toll-like receptor or IL-1R stimulation by keratinocytes from patients carrying AP1S3 mutations .
Mutations in CARD14 leading to structural and functional changes in caspase recruitment family member 14 (CARD14, previously known as CARMA2), have been associated with plaque psoriasis [60, 61], GPP [60, 62, 63], PPP , and pityriasis rubra pilaris, a papulosquamous condition phenotypically related to psoriasis [64, 65]. CARD14 is a member of the CARD-containing membrane-associated guanylate kinase (MAGUK) protein (CARMA) family of scaffold proteins. The other two members, CARD11 (CARMA1) and CARD10 (CARMA3) are critical for the activation of NF-κB in response to antigen and G-protein-coupled receptor stimulation respectively. On activation, CARD14 forms a signaling complex with BCL10 and MALT1, leading to activation of NF-κB, JNK, and p38 MAP kinase pathways [66, 67, 68]. Thirty-two CARD14 mutations have been described for plaque and pustular psoriasis  with the majority of the variants affecting the CARD or coiled-coil domains of the protein. These disease-associated mutations alter the structure of an inhibitory domain which normally keeps CARD14 activity in check, thus bypassing the need for an activating stimulus [62, 66, 68]. The psoriasis-associated CARD14 mutant proteins induce spontaneous formation of CARD14-BCL10-MALT1 complexes, which triggers MALT1 to promote inflammation in two key ways: first, by initiating pro-inflammatory signal transduction via its scaffold function; second, as a paracaspase MALT1 has the ability to cleave A20, CYLD, and RelB, three negative regulators of NF-κB, thus disabling feedback inhibition and further driving the inflammatory response. Like AP1S3 , CARD14 appears to be preferentially expressed by epidermal keratinocytes, and also to a lesser extent endothelial cells [60, 70]. CARD14 expression is strongly upregulated in psoriasis skin lesions , particularly in the upper epidermis which is also the zone where many NF-κB response genes (e.g., IL-36, CCL20, CXCL1, CXCL8) are overexpressed in lesional psoriasis skin. This pattern of AP1S3 and CARD14 tissue expression likely explains why these gain of function mutations lead to inflammatory skin disease.
Emerging Treatments for Pustular Psoriasis
Pustular psoriasis utilizes signaling pathways both overlapping and separate from plaque psoriasis, and because of their efficacy in moderate-severe plaque psoriasis, a number of therapies specifically targeting cytokines are in use for GPP. Several reports describe the use of anakinra, an IL-1 receptor antagonist [71, 72, 73] or canakinumab, a human monoclonal antibody targeted at IL-1β , to treat GPP. Anakinra appears to induce a rapid normalization of systemic inflammatory symptoms followed by improvement of the pustular skin eruption. The responses to IL-1 receptor inhibition in the skin tend to be incomplete however, with erythema and hyperkeratosis remaining in some cases, which suggests that IL-1 is not playing a central role in GPP but acts in a positive feedback loop inducing and being induced by IL-36 . The relevance of using IL-1 receptor antagonism to tackle a disease which may be primarily driven by deviations in IL-36 signaling, particularly when IL36RN mutations are present, has recently been questioned . However, clinical trials are ongoing in the UK (APRICOT) and USA (NIH NCT01794117) assessing the efficacy of anakinra and PPP and pustular skin diseases (including PPP) respectively. The premise for these trials is the effectiveness of anakinra for treatment of diseases caused by IL-1RA deficiency and the elevated IL-1 and IL-36 activity in observed PPP. The outcome of these trials will be interesting given the reported lack of genetic associations between PPP and IL1RN and IL36RN mutations [17, 23, 43].
TNF-α is a central mediator in chronic plaque psoriasis as evidenced by the effectiveness of therapies that block TNF-α activity. Of the three TNF biologics in use for plaque psoriasis, infliximab has most commonly been used for GPP [76, 77] and as such has become one of the recommended treatment options for severe acute GPP despite the lack of adequate clinical trials . Infliximab has been reported to have a rapid effect, with systemic inflammation and skin pustules starting to recede in as little as 2 days from the first infusion. In this context, the efficacy of infliximab likely stems from the rapid availability of the drug following infusion, and its inhibition of the synergy between TNF and multiple inflammatory cytokines including IL-36, IL-17A, IL-1β [44, 47, 78, 79].
Given the plethora of recent studies highlighting the effectiveness of targeting of IL-17A in plaque psoriasis, this approach has now also been tested with success for treating GPP. The notion that IL-17 may have a prominent role in pustular psoriasis is not only supported by the efficacy of blocking IL-17, and the presence of increased tissue IL-17A , skin-homing Th17 T cells , IL-17+ neutrophils , and strong IL-17A signatures in the lesions [7, 8], but also the clinical observations of severe pustular flare after sudden discontinuation of IL-17 axis suppression by brodalumab in psoriasis patients . IL-17 is a key cytokine in the induction of chemokine-mediated neutrophil infiltration of skin , and neutrophils are an obvious and central mechanistic component of pustular diseases. Not only do neutrophils express IL-17 [82, 85, 86] but they have also been shown to respond to IL-17A  as they express both prerequisite receptor subunits for IL-17A response. Secukinumab, a biologic targeting IL-17A, was recently shown to rapidly improve both systemic symptoms and the skin disease in GPP patients [88, 89, 90]. Likewise brodalumab, a biologic targeting the IL-17 receptor A chain, was also shown to induce clinical improvement in 11 out of 12 GPP patients . Given the encouraging findings from biologics targeting IL-17, there are now several ongoing trials examining inhibition of IL-23, a cytokine thought to act upstream of IL-17, as a master regulator of IL-17 expression by T cells [92, 93] and neutrophils . Both guselkumab (NIH NCT02343744) and risankizumab (NIH NCT03022045) are biologics targeting IL-23p19 under test for treating GPP. Given the seemingly central role of the IL-36/IL-36R system in GPP, supported by a glut of genetic and mechanistic data, this is surely an attractive target for the development of new therapies for GPP [94, 95].
PPP is a very difficult disease to treat and is commonly recalcitrant to existing therapeutic options, a situation that is confounded by the paucity of robust clinical trials of new medications. As such, therapeutic recommendations have often relied on case reports, thus less rigorous data is currently available for the efficacy of biologics in PPP. Unlike GPP, reports on the usage of anti-TNF biologics in PPP have revealed only modest to poor responses with all three of the TNF biologics used for plaque psoriasis [96, 97, 98]. Moreover there exist several reports of new onset PPP following anti-TNF treatment of other diseases [99, 100, 101, 102, 103]. Studies using ustekinumab, an antibody directed at IL-12p40 (a shared subunit of IL-12 and IL-23), for PPP have also generated equivocal results [104, 105, 106, 107]. Much more promising data have emerged for two of the IL-17 biologics (secukinumab and ixekizumab), the use of which is supported by the detection of elevated levels of IL-17 [108, 109] and enrichment of IL-17 signature genes in PPP lesions . A recent study of secukinumab for moderate to severe PPP demonstrated a 50% improvement in disease severity and significant improvements in quality of life scores . Given that increased IL-23 has been detected in PPP lesions [109, 110], inhibition of IL-23p19 may also be an effective approach for PPP therapy.
The discovery of mutations in IL36RN, CARD14 and AP1S3 that lead to dysregulated inflammation have increased enormously our understanding of pustular psoriasis over the last decade; However, several pieces of the puzzle remain to be revealed. It is likely that carriage of a mutant allele in itself is not enough for disease initiation: many pustular psoriasis patients have their first episode of the disease as adults, despite being lifelong mutant allele carriers, and patients can be heterozygous at disease loci, suggesting that either a yet to be identified second disease locus, or environmental trigger may be necessary to precipitate the disease. The co-occurrence of plaque psoriasis, GPP, PPP, or AGEP has confounded the genetic and mechanistic study of these diseases, which highlights the importance of clear phenotyping and sequential screening of disease-associated genes to increase the power to detect new pathogenic mutations and thus shed more light on the disease mechanisms. Thus, despite recent major advances in the study and treatment of pustular skin diseases, there remain key genetic, environmental and mechanistic pieces to be identified to solve these puzzling and difficult to treat diseases.
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