How can acute generalized exanthematous pustulosis (AGEP) be distinguished from pustular psoriasis in terms of clinical presentation, laboratory findings, histopathology, and management?

Distinguishing AGEP from Pustular Psoriasis

AGEP is an acute, self-limiting drug reaction that resolves within 15 days after drug withdrawal, whereas generalized pustular psoriasis (GPP) is a chronic inflammatory disease requiring long-term systemic therapy—this fundamental difference in disease course is the most critical distinguishing feature. 1

Clinical Presentation

Onset and Timing

• AGEP develops rapidly (within hours to days) after drug exposure, with sudden appearance of dozens of sterile, non-follicular pustules on erythematous and edematous skin, typically starting from skin folds 2, 3
• GPP evolves more gradually, either from chronic plaque psoriasis or presenting acutely with minimal pre-existing disease, but the development is slower compared to AGEP 1

Skin Findings

• AGEP pustules are small, punctate, non-follicular, and appear on edematous erythematous skin with marked facial edema being common 2, 3
• GPP pustules appear on an erythematous background and are often associated with evidence of classic plaque-type psoriasis before, during, or after the pustular episode 4, 5
• AGEP may show atypical features including target-like lesions, purpura, and blisters, which are not typical for GPP 2, 6

Mucosal Involvement

• AGEP may have mild, non-erosive mucosal involvement, mostly oral, occurring in some cases 2
• GPP typically lacks significant mucosal involvement 4

Personal History

• A personal history of chronic plaque psoriasis strongly favors GPP over AGEP 1, 7
• Recent drug exposure (within days) strongly favors AGEP 2, 3

Laboratory Findings

Acute Phase

• Both conditions present with fever, neutrophilia, and systemic toxicity 4, 2
• AGEP specifically shows peripheral blood eosinophilia in approximately one-third of patients, which is less common in GPP 2
• Laboratory investigations are rarely helpful for definitive diagnosis in either condition 5

Histopathology

Key Discriminating Features Favoring AGEP

• Presence of eosinophils in the infiltrate strongly suggests AGEP over GPP 7
• Necrotic keratinocytes favor AGEP 7
• Mixed interstitial and mid-dermal perivascular infiltrate is more characteristic of AGEP 7
• Absence of tortuous or dilated blood vessels favors AGEP 7

Key Features Favoring GPP

• Prominent epidermal psoriatic changes (acanthosis, elongated rete ridges) are characteristic of chronic GPP 7
• Tortuous and dilated blood vessels in the papillary dermis suggest GPP 7

Shared Features

• Both show non-follicular subcorneal and/or intracorneal spongiform pustules that are large, contiguous, and tend to coalesce 2, 7
• Both demonstrate sterile neutrophilic infiltration 5, 2

Important Caveat

• Despite earlier reports, follicular pustules do not exclude AGEP, and vasculitis is not a specific feature of AGEP 7
• There is considerable histopathological overlap between AGEP and GPP, making biopsy alone insufficient for definitive diagnosis in many cases 7

Management Approach

AGEP Management

• Immediate withdrawal of the culprit drug is mandatory and usually sufficient 2, 3
• AGEP is self-limiting, with pustules spontaneously disappearing within a few days and complete resolution within 15 days 2, 3
• No systemic treatment is typically required for uncomplicated cases 2
• Systemic corticosteroids can be used for rapid resolution if needed, with most cases clearing quickly 6, 8
• Severe or recalcitrant cases may require cyclosporine or intravenous immunoglobulin 8
• Monitor for secondary infections, particularly in patients with poor general medical condition (mortality approximately 5%) 2

GPP Management

• GPP requires hospitalization and long-term systemic therapy due to risk of metabolic complications and mortality 1
• First-line therapy is spesolimab (anti-IL-36 receptor antibody) 1, 5
• Infliximab is a first-line biologic option with rapid efficacy and often complete disease clearance 4, 1, 9
• Alternative systemic options include acitretin (0.1-1 mg/kg/day), cyclosporine (2.5 mg/kg/day), and methotrexate 1, 9, 5
• Systemic corticosteroids are absolutely contraindicated in GPP due to risk of precipitating erythrodermic psoriasis or very unstable psoriasis upon withdrawal, potentially leading to fatal deterioration 1, 9

Critical Management Pitfall

• Never use systemic corticosteroids for GPP—this is the most important management distinction, as steroids can cause severe disease exacerbation and potentially fatal deterioration upon withdrawal 1, 9
• In contrast, systemic corticosteroids are safe and effective for AGEP 6, 8

Prognosis

• AGEP: Self-limited with favorable prognosis; complete resolution expected within 15 days after drug withdrawal 2, 3
• GPP: Chronic disease requiring ongoing monitoring with regular blood tests, liver function tests, and serum creatinine; recurrence is common after biologic discontinuation 1, 5