Generalized Pustular Psoriasis: A Review of the Pathophysiology, Clinical Manifestations, Diagnosis, and Treatment
Generalized pustular psoriasis (GPP) is a rare severe variant of psoriasis that is characterized by the abrupt widespread onset of small pustules accompanied by systemic manifestations of inflammation. It can arise in patients with a history of psoriasis as well as in those without, sometimes due to medication initiation or withdrawal, pregnancy, or infection. Generalized pustular psoriasis is thought to be driven primarily by innate immunity and unrestrained IL-36 cytokine activity. Recent genetic analyses have identified 3 genetic mutations that are associated with GPP—IL36RN, CARD14, and AP1S3—though these mutations only account for a minority of cases. There are many cutaneous pustular diseases that must be ruled out in the evaluation of a patient with suspected GPP, especially acute generalized exanthematous pustulosis (AGEP), and histologic analysis is the cornerstone of diagnosis. Although the quality of evidence to generate treatment recommendations for GPP is limited, management often includes utilization of systemic agents and/or biologics, usually with adjunctive topical treatment. Accumulating evidence suggests that biologic agents, especially infliximab, may be considered as first-line treatment of GPP, especially in severe acute cases, due to their abrupt onset of action and favorable side-effect profiles compared with oral systemic agents.
Practice Points
- Generalized pustular psoriasis (GPP) is a rare severe variant of psoriasis that is characterized by the abrupt widespread onset of small pustules.
- Although no treatments have specifically been approved for GPP, various biologics, especially infliximab, may be effective in achieving rapid clearance in patients with GPP. Other oral systemic agents including acitretin, cyclosporine, and methotrexate also have been shown to be effective.
AP1S3—A loss-of-function mutation in AP1S3 results in abnormal endosomal trafficking and autophagy as well as increased expression of IL-36α.20,21
Clinical Presentation and Diagnosis Cutaneous Manifestations of GPP
Generalized pustular psoriasis is characterized by the onset of widespread 2- to 3-mm sterile pustules on erythematous skin or within psoriasiform plaques4 (Figure). In patients with skin of color, the erythema may appear less obvious or perhaps slightly violaceous compared to White skin. Pustules may coalesce to form “lakes” of pus.5 Cutaneous symptoms include pain, burning, and pruritus. Associated mucosal findings may include cheilitis, geographic tongue, conjunctivitis, and uveitis.4
The severity of symptoms can vary greatly among patients as well as between flares within the same patient.2,3 Four distinct patterns of GPP have been described. The von Zumbusch pattern is characterized by a rapid, generalized, painful, erythematous and pustular eruption accompanied by fever and asthenia. The pustules usually resolve after several days with extensive scaling. The annular pattern is characterized by annular, erythematous, scaly lesions with pustules present centrifugally. The lesions enlarge by centrifugal expansion over a period of hours to days, while healing occurs centrally. The exanthematic type is an acute eruption of small pustules that abruptly appear and disappear within a few days, usually from infection or medication initiation. Sometimes pustules appear within or at the edge of existing psoriatic plaques in a localized pattern—the fourth pattern—often following the exposure to irritants (eg, tars, anthralin).5
Impetigo Herpetiformis—Impetigo herpetiformis is a form of GPP associated with pregnancy. It generally presents early in the third trimester with symmetric erythematous plaques in flexural and intertriginous areas with pustules present at lesion margins. Lesions expand centrifugally, with pustulation present at the advancing edge.6,7 Patients often are acutely ill with fever, delirium, vomiting, and tetany. Mucous membranes, including the tongue, mouth, and esophagus, also may be involved. The eruption typically resolves after delivery, though it often recurs with subsequent pregnancies, with the morbidity risk rising with each successive pregnancy.7
Systemic and Extracutaneous Manifestations of GPP
Although the severity of GPP is highly variable, skin manifestations often are accompanied by systemic manifestations of inflammation, including fever and malaise. Common laboratory abnormalities include leukocytosis with peripheral neutrophilia, a high serum C-reactive protein level, hypocalcemia, and hypoalbuminemia.22 Abnormal liver enzymes often are present and result from neutrophilic cholangitis, with alternating strictures and dilations of biliary ducts observed on magnetic resonance imaging.23 Additional laboratory abnormalities are provided in Table 2. Other extracutaneous findings associated with GPP include arthralgia, edema, and characteristic psoriatic nail changes.4 Fatal complications include acute respiratory distress syndrome, renal dysfunction, cardiovascular shock, and sepsis.24,25
Histologic Features
Given the potential for the skin manifestations of GPP to mimic other disorders, a skin biopsy is warranted to confirm the diagnosis. Generalized pustular psoriasis is histologically characterized by the presence of subcorneal macropustules (ie, spongiform pustules of Kogoj) formed by neutrophil infiltration into the spongelike network of the epidermis.6 Otherwise, the architecture of the epithelium in GPP is similar to that seen with plaque psoriasis, with parakeratosis, acanthosis, rete-ridge elongation, diminished stratum granulosum, and thinning of the suprapapillary epidermis, though the inflammatory cell infiltrate and edema are markedly more severe in GPP than plaque psoriasis.3,4
Differential Diagnosis
There are many other cutaneous pustular diagnoses that must be ruled out when evaluating a patient with GPP (Table 1).26 Acute generalized exanthematous pustulosis (AGEP) is a common mimicker of GPP that is differentiated histologically by the presence of eosinophils and necrotic keratinocytes.4 In addition to its distinct histopathologic findings, AGEP is classically associated with recent initiation of certain medications, most commonly penicillins, macrolides, quinolones, sulfonamides, terbinafine, and diltiazem.27 In contrast, GPP more commonly is related to withdrawal of corticosteroids as well as initiation of some biologic medications, including anti-TNF agents.3 Generalized pustular psoriasis should be suspected over AGEP in patients with a personal or family history of psoriasis, though GPP may arise in patients with or without a history of psoriasis. Acute generalized exanthematous pustulosis usually is more abrupt in both onset and resolution compared with GPP, with clearance of pustules within a few days to weeks following cessation of the triggering factor.4
