Pustular psoriasis: Pathogenesis, clinical manifestations, and diagnosis

INTRODUCTION — Psoriasis is a common skin disorder characterized by the development of erythematous, scaling plaques on the skin and a wide spectrum of clinical presentations. The most common presentation of psoriasis is chronic plaque psoriasis, which manifests as well-defined, inflammatory, red, scaling plaques on the skin. Pustular psoriasis is a less common subtype of psoriasis that presents as an acute, subacute, or chronic pustular eruption. Pustular psoriasis primarily affects adults but can also occur in children.

Pustular psoriasis develops independently or in association with pre-existing psoriasis and may occur in a generalized or localized distribution. Generalized pustular psoriasis (GPP) presents as an acute or subacute, widely distributed eruption of pustules arising on inflamed, erythematous skin (picture 1A-C). Localized forms of pustular psoriasis primarily affect the palms, soles, or extremity digits.

Some cases of generalized or localized pustular psoriasis may actually represent a new genetic autoinflammatory disease based on mutations in the interleukin (IL) 36 receptor antagonist. Other specific genetic abnormalities have also been identified in patients with pustular psoriasis. These major advances in the understanding of the pustular psoriasis disease pathogenesis have led to the design and ongoing development of tailored therapeutic approaches [1-3]. (See 'Genetics' below and "Pustular psoriasis: Management".)

The epidemiology, pathogenesis, and clinical manifestations of pustular psoriasis will be reviewed here. Other forms of psoriasis and the management of pustular psoriasis are reviewed separately. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis" and "Guttate psoriasis" and "Pustular psoriasis: Management".)

CLASSIFICATION — A consensus statement from the European Rare and Severe Psoriasis Expert Network (ERASPEN) supports classification of pustular psoriasis into three phenotypes: generalized pustular psoriasis (GPP), acrodermatitis continua of Hallopeau, and palmoplantar pustulosis [4]. Traditionally, the term "localized pustular psoriasis" has been considered inclusive of acrodermatitis continua and palmoplantar pustulosis.

The major clinical variants of GPP include acute generalized pustular psoriasis (also known as generalized pustular psoriasis of von Zumbusch) and generalized annular pustular psoriasis (also known as subacute GPP) [5]. Acute GPP is characterized by the abrupt onset of numerous pustules, widespread erythema, and systemic symptoms. The terms "pustular psoriasis of pregnancy" and "impetigo herpetiformis" are used to refer to acute GPP that occurs during pregnancy. Generalized annular pustular psoriasis is a less acute presentation of GPP in which patients develop widespread annular or figurate erythematous plaques studded by pustules. (See "Dermatoses of pregnancy", section on 'Pustular psoriasis of pregnancy'.)

Acrodermatitis continua of Hallopeau is a chronic pustular condition that primarily involves the digits, and palmoplantar pustulosis is a chronic condition in which the pustular eruption is primarily limited to the palms and soles. It is controversial whether palmoplantar pustulosis is a variant of psoriasis or an independent entity [6,7]. Alternative terms used to refer to palmoplantar pustulosis include palmoplantar pustular psoriasis, pustulosis palmoplantaris, and pustulosis palmaris et plantaris. (See 'Localized pustular psoriasis' below and "Palmoplantar pustulosis: Epidemiology, clinical features, and diagnosis".)

Some authors have used the term "localized generalized pustular psoriasis" to describe an additional clinical presentation of psoriasis with pustules in patients with chronic plaque psoriasis [8]. This term describes the development of pustules within existing psoriatic plaques in the absence of systemic symptoms, as can often occur during a period of increased disease activity. We categorize these patients as having psoriasis with pustulosis, rather than a subtype of GPP [5].

GENERALIZED PUSTULAR PSORIASIS

Epidemiology — Although psoriasis is a relatively common condition for which worldwide estimates of prevalence have ranged between 0.91 to 8.5 percent [9], chronic plaque psoriasis accounts for the vast majority of psoriasis cases. The exact prevalence of generalized pustular psoriasis (GPP) is unknown, but the condition appears to be rare [10].

GPP develops in individuals from all racial backgrounds. There does not appear to be a strong sex predilection for non-pregnancy-associated GPP [11], although a female preponderance has been reported in some series [5,12,13]. GPP occurs most frequently in middle-aged adults, and in published reports the average age of affected patients typically ranges between 40 and 60 years [5,14-16]. GPP may also occur in infants and children [17-19]. Annular pustular psoriasis is the most common presentation of pustular psoriasis in children [20,21]. A male preponderance has been reported in pediatric pustular psoriasis [18].

Many patients with GPP have a preceding history of another form of psoriasis, though estimates of the proportion of patients with preceding psoriasis vary [5,11,15,22]. In a Malaysian retrospective study, 78 percent of 95 patients with acute GPP had a preceding history of psoriasis [5], most of whom had a history of chronic plaque-type disease. In contrast, a Japanese review of hospital records from patients treated for GPP in community center hospitals found a history of plaque psoriasis in only 31 percent of 208 patients with acute GPP [22]. Multiple years often elapse after the development of psoriasis prior to the onset of GPP [5,11,15,22]. Patients without a history of psoriasis are more likely to harbor an IL36RN mutation [23]. (See 'Genetics' below.)

Pathogenesis — Although the pathogenesis of GPP is not fully understood, studies evaluating the role of genetics in GPP have yielded new insights into the pathogenesis of this condition. Potential triggers are also recognized, including roles for drugs, infections, and pregnancy in the induction of GPP.

Genetics — GPP is traditionally classified as a variant of psoriasis; however, evidence suggests that genetic factors distinct from those associated with chronic plaque psoriasis contribute to GPP. In particular, mutations in the IL36RN gene that encodes the interleukin-36 receptor antagonist (IL-36Ra), an anti-inflammatory cytokine in the IL-1 family that inhibits proinflammatory signal pathways by preventing the binding of IL-36 to its receptor, have been detected in some patients with GPP.

Sustained activation of IL-1 and IL-36 in GPP suggests that the IL-1/IL-36 inflammatory axis is the main driver of disease pathology in GPP [24-27]. Because sole IL-1 inhibition tends to produce an incomplete response in the skin of patients with pustular psoriasis, IL-1 may not play a central role in GPP. Instead, IL-1 may act in a positive loop, inducing and being induced by IL-36 [26]. IL-36 activity promotes T cell responses with increased production of lL-17A, a key mediator in GPP [28]:

●IL36RN gene mutations – A homozygous mutation in IL36RN was first associated with GPP based upon the findings of a linkage analysis study in nine Tunisian families with autosomal recessive GPP [29]. The authors of this study proposed the term "deficiency of interleukin-36-receptor antagonist" (DITRA) to refer to the disease resulting from IL-36Ra deficiency [29].

Since the initial study, additional mutations in IL36RN have been identified in patients with GPP and childhood pustular eruptions with clinical and histologic features of GPP; moreover, IL36RN mutations have been detected in patients with sporadic GPP [30-34]. However, not all patients with GPP appear to harbor IL36RN mutations [32,35,36]. In a study in which IL36RN mutations were sought in 84 unrelated patients with sporadic GPP, homozygous or compound heterozygous IL36RN mutations were observed in only seven patients (8 percent) [32]. In a separate study of 67 patients with pustular skin diseases (including 61 patients with GPP), biallelic and monoallelic IL36RN mutations were identified in 15 and 5 patients with GPP, respectively [37]. The only significant genotype-phenotype correlation observed for IL36RN mutation carriers was early age at disease onset. Homozygous or compound heterozygous IL36RN mutations were detected in 7 of 19 patients with GPP (39 percent) in another report [35].

GPP presenting as an independent disorder is likely genetically different from GPP with psoriasis vulgaris [38,39]. There are data that suggest that the link between IL36RN mutations and GPP is stronger in patients with GPP that develops independently of other forms of psoriasis than in patients with pre-existing psoriatic disease [40]. As an example, a Japanese study of patients with GPP found IL36RN mutations in only 2 of 20 patients with a history of psoriasis compared with 9 of 11 patients without a preceding history of this disease [23]. It has been proposed that early-onset GPP is part of the postulated "autoinflammatory keratinization diseases" (AIKDs) [41,42].

●Relevance of IL36RN mutations – Growing understanding of the molecular basis of GPP associated with IL36RN mutations may aid in therapeutic decisions for patients with this type of GPP. Case reports documenting successful treatment of GPP in patients with IL36RN mutations with anakinra, an IL-1 receptor antagonist, support the importance of this pathway [43,44]. In addition, preliminary findings of clinical trials suggest that treatment with IL-1 antagonists (picture 2) and anti-IL-36R antibodies can improve GPP [45,46].

IL36RN mutations are not exclusive to GPP. Mutations in the gene have been detected in patients with palmoplantar pustulosis, acrodermatitis continua of Hallopeau, or acute generalized exanthematous pustulosis [32,36,47-50]. It has been suggested that pustular eruptions occurring in the setting of IL36RN mutations, whether diagnosed as GPP or acute generalized exanthematous pustulosis (AGEP), should be considered a distinct genetic disease [34,51]. This is also supported by the fact that GPP and AGEP share common immunohistochemical pathway features [52].

●Other gene mutations – Knowledge of other genetic contributions to GPP is increasing. Mutations in caspase recruitment domain family member 14 (CARD14) have been associated with pustular psoriasis in children and adults who lack IL36RN mutations [53,54]. A gain-of-function impact may lead to enhanced IL36G gene transcription via nuclear factor KB activity [55,56]. Pustular psoriasis has also been associated with mutations in the adapter protein family 1 (AP1S3) [36,37,57]. This may lead to disruption of toll-like receptor function and increased expression of IL36A [57,58]. The frequency of specific gene associations may vary across populations [59].

Ideally, identification of specific genetic mutations will lead to targeted immune therapy [2,3,60-63]. (See "Pustular psoriasis: Management", section on 'IL36RN mutations'.)

Precipitating factors — Case reports and case series suggest that the withdrawal or administration of certain medications can stimulate the development of GPP. As examples, the onset of GPP has occurred subsequent to withdrawal of systemic glucocorticoids, cyclosporine, ustekinumab, and potent topical corticosteroid therapy [5,15,64-66]. The association with systemic glucocorticoids is commonly reported; in a retrospective study of 102 patients with adult-onset GPP (including 95 with acute GPP), systemic glucocorticoids were considered a precipitating factor for 44 percent of patients [5].

The development or worsening of GPP during treatment with biologic tumor necrosis factor-alpha inhibitors and ustekinumab also has been reported [67-72], although these agents have also been reported to be effective for patients with pustular psoriasis [73-75]. These paradoxical flares may be related to a cytokine imbalance and unopposed interferon-alpha activation [76,77].

Other medications that have been cited as potential inducers of GPP include amoxicillin [47], terbinafine [78], codeine [79], ceftriaxone [80], oxacillin [81], rituximab [77], pegylated interferon-alpha-2b [82], and the bacillus Calmette-Guérin vaccine [83]. Differentiating GPP from drug-induced AGEP can be difficult. (See 'Differential diagnosis' below.)

Infections may be precipitating factors for GPP [5,11,22,84,85]. In the retrospective study of 102 patients with adult-onset GPP, 16 (16 percent) had documentation of a preceding upper respiratory tract infection [5]. Moreover, of the 39 patients with acute GPP tested for antistreptolysin antibodies, 15 (38 percent) had positive tests. Other infections that have been associated with the precipitation of GPP include cytomegalovirus [86,87], varicella zoster virus [88], Epstein-Barr virus [89], and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections [90].

A common thread for patients who harbor an IL36RN mutation is that many precipitating factors may lead to uncontrolled IL-36 signaling and enhanced production of other interleukins giving rise to the phenotypic expression of pustular skin lesions [49,91].

The reason for the rare occurrence of pustular psoriasis in pregnancy (impetigo herpetiformis) is unclear [92], though hormonal changes related to pregnancy have been proposed as potential contributing factors [93]. Most affected women do not have a preceding history of psoriasis. Pustular psoriasis in pregnancy is reviewed separately. (See "Dermatoses of pregnancy", section on 'Pustular psoriasis of pregnancy'.)

Clinical manifestations — The two major clinical presentations of GPP are acute GPP (generalized pustular psoriasis of von Zumbusch) and generalized annular pustular psoriasis. The clinical manifestations of pustular psoriasis in pregnancy, which may be considered a subtype of acute GPP, are reviewed separately [5,92] (see "Dermatoses of pregnancy", section on 'Pustular psoriasis of pregnancy'):

●Acute (von Zumbusch-type) GPP – Acute GPP is characterized by the abrupt development of widespread, painful erythematous patches or thin plaques that rapidly become studded with numerous pinhead-sized sterile pustules (picture 1A-C). Frequently, the coalescence of pustules results in larger purulent collections often referred to as "lakes of pus." The pustules resolve within several days, leaving erythema and extensive scaling. Erythroderma may occur [84].

Recurrent episodes of pustulation during which new crops of pustules emerge is a classic feature of acute GPP. Episodes are accompanied by fever, chills, and malaise, and patients appear systemically ill. Other extracutaneous symptoms that may occur in acute GPP include arthralgias, lower extremity edema, jaundice, and ocular abnormalities (eg, conjunctivitis, iritis, or uveitis) [5,15,94].

Mucosal involvement, manifesting as oral pustules or geographic tongue, can accompany the cutaneous findings of GPP [5,11,94]. Intraoral involvement may suggest a higher chance of an IL36RN mutation [51]. Patients may also exhibit cheilitis and nail involvement [5,84,94].

●Generalized annular pustular psoriasis – Generalized annular pustular psoriasis presents as a recurring, subacute eruption characterized by the development of annular or figurate erythematous plaques with peripheral pustules and scale [21]. The plaques expand centrifugally over the course of hours to days [8]. Skin pain or fever also may be present [5].

Similar to acute GPP, pustules from generalized annular GPP resolve with residual scale. Occasionally, pustules may be evident only on histologic examination [21].

Clinical course — The clinical course of GPP is usually unstable and prolonged without treatment, with periods of disease quiescence and recurrence over the course of years. Flares may occur upon re-exposure to a precipitating factor or for unknown reasons [5]. Patients usually require continued therapy to avoid resurgence of flares. (See "Pustular psoriasis: Management".)

Complications of acute GPP may be life-threatening. Potential complications include sepsis; serious renal, hepatic (neutrophilic cholangitis) or respiratory (neutrophilic pneumonitis, acute respiratory distress syndrome) abnormalities; and death [5,15,95-97].

Histopathology — Classic pathology findings of GPP include [14,98]:

●Psoriasiform changes in the epidermis (parakeratosis and elongation of the rete ridges)

●Numerous neutrophils migrating from the papillary capillaries into the epidermis

●Spongiform pustules of Kogoj (aggregates of neutrophils between degenerated and flattened keratinocytes within the upper malpighian layer of the epidermis, forming a subcorneal macropustule) (picture 3A-B)

●Perivascular lymphocyte-predominant infiltrate in the upper dermis

The spongiform pustule of Kogoj is a characteristic histologic feature of psoriasis that is most prominent in the pustular variant (picture 3A-B) [14].

Laboratory abnormalities — Laboratory abnormalities are common in patients with acute GPP. Frequent laboratory findings include [5,15,95]:

●Leukocytosis (up to 30,000 cells/microliter)

●Elevated erythrocyte sedimentation rate (ESR)

●Hypocalcemia and other electrolyte imbalances

●Lymphopenia

●Elevated liver enzymes

●Hypoalbuminemia

●Elevated antistreptolysin antibody

An elevated ESR and leukocytosis are among the most common laboratory abnormalities in acute GPP. In a review of 102 patients with GPP in Malaysia (including 95 with acute GPP), an elevated ESR or leukocytosis was detected in 100 percent and 70 percent of the patients with acute GPP, respectively [5]. Electrolyte abnormalities may occur as a consequence of the skin barrier disruption that results from the widespread desquamation that follows pustulation in acute GPP. Laboratory abnormalities such as leukocytosis and elevated liver enzymes also have also been reported in patients with the generalized annular pustular psoriasis variant of GPP [5,21].

Diagnosis — A diagnosis of GPP should be suspected in patients who present with widespread pustules arising on erythematous skin. The diagnosis is made based upon recognition of a constellation of clinical and histologic features. Serologic studies that demonstrate laboratory findings consistent with GPP offer further support for the diagnosis. This approach is reflected in the diagnostic criteria proposed by some authors.

Our typical initial workup for patients with suspected GPP consists of the following:

●Patient history and review of symptoms

●Total body skin examination

●Skin biopsy for hematoxylin and eosin staining

●Basic serologic studies

In cases in which there is suspicion for cutaneous or systemic infection, we add cultures of skin or blood to the clinical investigation.

History and physical examination — The patient history is helpful for identifying GPP. Because many patients with GPP have a preceding history of psoriasis, confirmation of previous psoriasis provides support for the diagnosis. Moreover, a history of associated symptoms of fever and malaise, and a clinical course characterized by rapid disease onset and relapsing episodes support a diagnosis of acute GPP. (See 'Epidemiology' above and 'Clinical manifestations' above.)

In addition to inquiries about the medical history, the course of disease, and associated symptoms, a thorough drug history is an essential part of the work-up for patients with suspected GPP. The withdrawal or initiation of certain drugs has been linked to GPP. Systemic glucocorticoid therapy is a commonly cited predisposing factor for GPP [5]. Of note, drugs may also induce acute generalized exanthematous pustulosis, a widespread pustular eruption that clinically resembles acute GPP. (See 'Precipitating factors' above and 'Differential diagnosis' below.)

A full examination of the skin and oral mucosa should be performed to evaluate the extent of involvement. Recognition of concomitant lesions consistent with other forms of psoriasis can support the diagnosis, although the absence of this does not rule out GPP. Occasionally, examination of the oral mucosa reveals geographic tongue or pustules. (See 'Clinical manifestations' above.)

Skin biopsy — We usually perform a skin biopsy in patients with suspected GPP to aid in distinguishing GPP from other widespread pustular eruptions, such as acute generalized exanthematous pustulosis (AGEP), secondarily infected spongiotic dermatitis, and Sneddon-Wilkinson disease. (See 'Differential diagnosis' below.)

A 4 mm punch biopsy that ideally includes an entire intact pustule (eg, a 4 mm punch biopsy of a 2 mm pustule) usually provides a sufficient specimen for histopathologic examination. We usually take two to three punch biopsies from different sites (preferably above the waist) in an attempt to increase the likelihood of detecting features that are helpful for diagnosis.

A diagnosis of GPP is strongly supported by the detection of psoriasiform changes, epidermal neutrophils, and spongiform pustules of Kogoj. AGEP can be particularly difficult to distinguish from GPP, particularly in patients with IL36RN mutations. Eosinophils and necrotic keratinocytes are among the histologic findings that suggest a diagnosis of AGEP rather than GPP [14,47,51,91,99]. (See "Skin biopsy techniques", section on 'Punch biopsy' and 'Histopathology' above and "Acute generalized exanthematous pustulosis (AGEP)", section on 'Diagnosis'.)

Laboratory tests — No serologic tests provide a definitive diagnosis of GPP. Laboratory studies are obtained to evaluate for abnormalities consistent with the diagnosis (eg, leukocytosis and lymphopenia) as well as to evaluate for complications of the disease. (See 'Laboratory abnormalities' above.)

Our initial laboratory work-up for patients with suspected GPP includes:

●Complete blood count with differential (to evaluate for leukocytosis and lymphopenia)

●Comprehensive metabolic panel (to evaluate for hypocalcemia, other electrolyte abnormalities, and hypoalbuminemia and to evaluate liver and renal function)

Pustules caused by pustular psoriasis are sterile in the absence of secondary infection. If there is uncertainty regarding the diagnosis or concern for secondary infection we usually culture the contents of a pustule. Blood cultures should be obtained if there is suspicion of systemic infection.

Genetic testing for IL36RN mutations can be performed in patients with GPP. However, it is not commonly performed, and commercial availability is limited.

Testing for IL36RN mutations may become more relevant as data on new therapeutic options for patients with GPP associated with IL36RN mutations (eg, IL-1 antagonists [3,43-46,63]) evolve. Testing may prove to be of greatest value in patients who exhibit features suggestive of an IL36RN mutation. Patients without a history of psoriasis or who have intraoral involvement may be more likely to harbor the mutation [23,51,100]. In addition, children with the mutation are more likely to have certain clinical features, including flexural or perianal erosions or confluent lakes of pus [101]. IL36RN mutations are associated with an earlier age of onset across all variants of pustular psoriasis [36]. (See "Pustular psoriasis: Management", section on 'IL36RN mutations'.)

Differential diagnosis — Multiple disorders may present with clinical features that resemble pustular psoriasis. Examples of other disorders that present with widespread pustules and erythematous plaques are reviewed below. In most cases, the clinical history, physical examination, and biopsy results are useful for differentiating these diseases:

●Acute generalized exanthematous pustulosis – Differentiating acute generalized exanthematous pustulosis (AGEP) from acute GPP can be difficult because the clinical manifestations of the two conditions are similar (picture 4) [14,78,102,103]. Patients have been described having AGEP and GPP on separate occasions depending on the stimulating factor. It may not be possible to distinguish between AGEP and GPP in patients who harbor an IL36RN mutation, as various stimuli may produce similar clinical pictures in these patients. It has been suggested that the disease taxonomy of these pustular eruptions should be based on their genetic profiling rather than the current classification [47,51,52,91,99].

Clinical signs that favor AGEP include an abrupt onset, short duration (usually less than two weeks after discontinuation of the offending drug), polymorphous lesions, an association with recently started drugs, rapid improvement after drug withdrawal, absence of arthritis, and no personal or family history of psoriasis. Skin biopsy findings that favor AGEP include the presence of eosinophils and necrotic keratinocytes as well as a mixed neutrophil-rich infiltrate in the dermis and the absence of tortuous blood vessels [14]. Additionally, significant psoriasiform changes of the epidermis are common in chronic lesions of GPP but absent in AGEP. Patch testing may also aid in differentiating these entities. Elucidating the nature of the T cell in the infiltrate may permit discrimination between AGEP and GPP [104]. (See "Acute generalized exanthematous pustulosis (AGEP)".)

●Dermatitis with secondary infection – Patients with widespread dermatitis such as atopic dermatitis may present with extensive pustules indicating a secondary infection (picture 5). A skin biopsy revealing spongiotic dermatitis and bacterial cultures of pustules can differentiate these conditions from GPP. Knowledge of the patient's history of skin disease prior to the onset of pustules is also helpful. (See "Treatment of atopic dermatitis (eczema)", section on 'Management of infection'.)

●Subcorneal pustular dermatosis – Subcorneal pustular dermatosis is a rare chronic pustular dermatosis that presents with annular erythematous plaques with superficial sterile, pea-sized, flaccid pustules (picture 6A-B). The disease often occurs in middle-aged women. Skin involvement of subcorneal pustular dermatosis is most likely to affect the trunk, intertriginous areas, and flexor aspects of the extremities [105]. Subcorneal pustular dermatosis may occur in association with various conditions, including pyoderma gangrenosum, monoclonal IgA gammopathy, and multiple myeloma [105]. Histologic examination reveals subcorneal pustules, but unlike GPP, subcorneal pustular dermatosis does not exhibit spongiform pustules (picture 7). (See "Neutrophilic dermatoses", section on 'Subcorneal pustular dermatosis'.)

●IgA pemphigus – IgA pemphigus is a rare autoimmune blistering disorder that most commonly occurs in middle-aged or elderly adults. Two forms of IgA pemphigus have been described: the subcorneal pustular dermatosis-type IgA pemphigus and the intraepidermal neutrophilic type of IgA pemphigus. Both types present as an annular or circinate eruption of pustules, erythematous plaques, and crusts that primarily involves the trunk and proximal extremities. Subcorneal or intraepidermal pustules are seen on histopathologic examination. The disorder is distinguished from other diseases by the detection of intercellular IgA deposits in the epidermis on direct immunofluorescence. Rarely, other forms of pemphigus may present with pustules [106-108]. (See "Pathogenesis, clinical manifestations, and diagnosis of pemphigus", section on 'IgA pemphigus'.)

●Tinea corporis – Similar to annular pustular psoriasis, extensive tinea corporis may present with annular, erythematous plaques with peripheral scale and pustules (picture 8). Systemic symptoms are absent. A potassium hydroxide preparation or skin biopsy revealing fungal hyphae confirms this diagnosis [109,110]. (See "Dermatophyte (tinea) infections", section on 'Tinea corporis' and "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation'.)

LOCALIZED PUSTULAR PSORIASIS — Localized pustular psoriasis primarily involves the hands and feet. The two major clinical presentations are acrodermatitis continua of Hallopeau, which begins on the distal digits and palmoplantar pustulosis, which primarily involves the palms and soles.

Acrodermatitis continua of Hallopeau — Acrodermatitis continua of Hallopeau (ACH, also known as acropustulosis, pustular acrodermatitis, acrodermatitis perstans, and dermatitis repens) is a rare form of localized pustular psoriasis [111-115]. ACH presents as a chronic, relapsing, inflammatory eruption with sterile pustules that primarily involves the distal fingers or toes, nail folds, and nail beds. ACH most frequently occurs in middle-aged women [111].

The etiology and pathogenesis of ACH are not well understood. The onset of the disorder may be preceded by trauma or infection of a digit [111]. Mutations in the IL36RN gene, similar to those identified in generalized pustular psoriasis (GPP), have been detected in patients with ACH, suggesting that some cases of ACH may be a clinical phenotype of deficiency of interleukin-36-receptor antagonist (DITRA) [48,50]. The significance of the finding for the general population of patients with ACH remains to be determined. (See 'Genetics' above.)

The initial clinical manifestations of ACH usually are restricted to the distal areas of one or two digits. Involvement of the fingers is more common than involvement of the toes [111]. As in GPP, individual pustules may coalesce to form larger purulent collections. Pustules eventually rupture, leaving shiny erythema and hyperkeratosis.

Over time, ACH may progress to involve other digits and may extend proximally to the hand, forearm, or foot (picture 9). Chronic involvement of the nail bed and matrix can lead to onychodystrophy and anonychia [116]. Atrophy of the distal phalanx and underlying osteolysis also can develop. Infrequently, progression to generalized pustular psoriasis occurs [117].

The diagnosis of ACH is made via recognition of consistent clinical and histologic findings. A Gram stain and culture should be performed to rule out pustules secondary to bacterial infection [111]. A potassium hydroxide preparation should also be performed as part of the diagnostic work-up to rule out cutaneous candidiasis and dermatophytosis. Additional acral disorders to consider in the differential diagnosis are herpetic whitlow and dyshidrotic eczema. (See "Office-based dermatologic diagnostic procedures", section on 'Potassium hydroxide preparation'.)

The histologic findings of involved skin in ACH resemble pustular psoriasis. Spongiform pustules are present in the upper epidermis and the dermis demonstrates a lymphohistiocytic infiltrate and focal edema. Thinning of the epidermis and severe atrophy of the papillary dermis may be evident in areas of longstanding disease [111].

The treatment of ACH is reviewed separately. (See "Pustular psoriasis: Management", section on 'Localized pustular psoriasis'.)

Palmoplantar pustulosis — There is controversy over whether palmoplantar pustulosis is a variant of psoriasis or an independent disorder that occurs with increased frequency in patients with psoriasis [118]. The condition presents with clusters of white to yellow-brown, sterile pustules, erythema, and scale on the palms and soles and appears strongly associated with smoking (picture 10A-B) [119]. The associated symptoms of itching, burning, and pain can be severe and disabling. A skin biopsy may aid in distinguishing between psoriasis and chronic dermatitis [120]. (See "Palmoplantar pustulosis: Epidemiology, clinical features, and diagnosis".)

Characteristics of palmoplantar pustulosis that support the condition as an entity distinct from GPP include a high female predominance in palmoplantar pustulosis, less frequent association with psoriasis vulgaris, and a lower prevalence of IL36RN mutations [36].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Psoriasis" and "Society guideline links: Palmoplantar pustulosis".)

SUMMARY AND RECOMMENDATIONS

●Pustular psoriasis can be divided into generalized and localized clinical presentations. Generalized pustular psoriasis (GPP) consists of acute GPP (also known as generalized pustular psoriasis of von Zumbusch) and generalized annular pustular psoriasis. Acrodermatitis continua of Hallopeau is a localized form of pustular psoriasis. There is controversy over whether palmoplantar pustulosis is a subtype of psoriasis or a distinct entity. (See 'Classification' above.)

●GPP most commonly occurs in adults, but may also occur in children. The recognition of mutations in the gene encoding the IL-36-receptor antagonist (IL36RN) in some patients with GPP has yielded new insights into the pathogenesis of this condition. (See 'Epidemiology' above and 'Pathogenesis' above.)

●Certain exposures may contribute to the development of GPP. Medications (particularly systemic glucocorticoids), infections, and pregnancy have been linked to the onset of GPP. (See 'Precipitating factors' above.)

●Acute GPP is characterized by the acute development of widespread erythematous plaques and pustules along with systemic symptoms of fever and malaise. Generalized annular pustular psoriasis is less acute and is characterized by the development of annular or figurate erythematous plaques with pustules. (See 'Clinical manifestations' above.)

●The diagnosis of GPP is based upon the recognition of consistent clinical, pathologic, and laboratory features. A thorough patient history and skin biopsy should be performed. Common laboratory abnormalities include leukocytosis, an elevated erythrocyte sedimentation rate, lymphopenia, electrolyte abnormalities (particularly hypocalcemia), hypoalbuminemia, elevated liver enzymes, and an elevated antistreptolysin antibody level. (See 'Diagnosis' above.)

●GPP can closely resemble acute generalized exanthematous pustulosis (AGEP), a drug-induced condition. In patients with IL36RN mutations, it may not be possible to differentiate AGEP and GPP. (See 'Differential diagnosis' above.)

●Acrodermatitis continua of Hallopeau is a rare localized and chronic form of pustular psoriasis that primarily involves the extremity digits. Pustules, erythema, scale, and nail dystrophy are characteristic clinical features. Involvement may lead to nail loss and osteolysis in involved digits. (See 'Acrodermatitis continua of Hallopeau' above.)