Exploring a New Approach to Generalized Pustular Psoriasis

In this episode of Topical Conversations, Brad Glick, DO, and Erin Boh, MD, explore the evolving treatment landscape for generalized pustular psoriasis (GPP), with a focus on disease categorization, diagnostic challenges, and the role of spesolimab in managing both acute flares and chronic symptoms. 

Defining the spectrum of GPP 

Dr Boh categorizes GPP into 2 distinct clinical phenotypes: acute GPP, which often presents as a dermatologic emergency requiring immediate intervention, and chronic GPP, where patients exhibit persistent, low-grade symptoms punctuated by periodic flares. 

She emphasizes that understanding this distinction is critical for guiding treatment decisions. Compared to traditional plaque psoriasis, patients with chronic GPP often experience more prolonged flares and persistent systemic symptoms, necessitating tailored therapeutic strategies. 

Spesolimab: The only FDA-approved therapy for GPP 

Dr Glick outlines spesolimab’s approval as the first and only FDA-indicated treatment specifically for GPP. The intravenous (IV) formulation is approved for managing acute flares, and more recently, a subcutaneous (SC) formulation has been approved for use in patients between flares to address smoldering, chronic symptoms. 

Dr Boh explains her evolving approach to managing patients with chronic symptoms. Initially, she investigates potential flare triggers such as systemic steroids, infections, smoking, or other medications, and comorbidities like diabetes or cardiovascular disease for which patients may be receiving treatments from other providers. Historically, she used IV spesolimab for acute flares followed by maintenance with conventional biologics. However, with the SC formulation now available, she considers spesolimab monotherapy as a new maintenance option. 

Importantly, she stresses the need to distinguish between chronic plaque psoriasis with pustular features and true GPP, as the latter is more likely to benefit from spesolimab-based therapy. 

Pathophysiologic considerations and precision treatment 

Dr Boh discusses the evolving understanding of GPP's immunopathology. While IL-36 dysregulation is central, she notes overexpression of other cytokines such as IL-17 and IL-23 as well. This complexity raises questions about how patients may respond to IL-36 blockade alone versus requiring combination or sequential biologic therapy. Looking ahead, she sees potential for more personalized treatment approaches based on cytokine profiling. 

Chronic symptom burden and the role of maintenance therapy 

Dr Glick points out that, historically, no agent was specifically indicated for month-to-month stabilization in GPP. He highlights the unpredictable and often burdensome nature of flares compared to plaque psoriasis, making the new SC formulation of spesolimab a valuable addition for long-term control. 

Dr Boh adds that patients with GPP frequently report ongoing fatigue, pain, and emotional distress even after skin symptoms improve. She incorporates holistic strategies such as nutrition counseling, mindfulness, and therapy referrals into her care plans. She references findings from the Effisayil-2 trial, where continuous spesolimab treatment led to reductions in fatigue, pain, anxiety, and flare frequency, supporting a proactive treatment model over episodic flare-based management. 

Diagnostic challenges in GPP 

When patients present outside of a flare, diagnosing GPP can be difficult. Dr Glick asks how clinicians can differentiate GPP from other pustular presentations. Dr Boh explains that in acute settings, clinicians must rule out conditions like AGEP, drug reactions, steroid withdrawal, or infections. 

For more chronic or mixed presentations, such as plaque psoriasis with intermittent pustules, differentials include secondary infection, candida, vasculitis, or drug-induced eruptions. She distinguishes palmoplantar pustulosis as a separate entity within the pustular psoriasis spectrum. Ultimately, recognizing the degree and pattern of pustulation help guide diagnosis and treatment selection. 

An evolving practice model 

Dr Glick concludes by reiterating the clinical value of having both IV and SC formulations of spesolimab. The IV option offers rapid control during acute flares, while the SC formulation supports long-term maintenance. He highlights that in Effisayil-2, nearly half of the patients achieved complete skin clearance. With these new tools, dermatologists can now adopt a more structured and sustained approach to treating GPP, not only improving skin outcomes, but also enhancing overall quality of life for patients navigating this complex disease. 

Key takeaways 

• Two distinct GPP phenotypes: Acute GPP requires immediate intervention, while chronic GPP involves ongoing low-grade symptoms and periodic flares, each requiring different therapeutic approaches
• Spesolimab for both acute and chronic GPP: IV spesolimab is approved for acute flares, and the SC formulation offers an option for maintenance therapy between flares
• Differentiating GPP from plaque psoriasis: Accurate diagnosis is essential, especially when pustular features overlap with other conditions. Misclassification may delay appropriate treatment.
• Precision medicine potential: While IL-36 plays a central role, other cytokines like IL-17 and IL-23 may also contribute to disease expression, raising the possibility of tailored biologic regimens
• Evolving treatment strategies: The availability of SC spesolimab has shifted management from flare-based intervention to continuous control, with some patients now managed with spesolimab monotherapy
• Quality-of-life impact: Chronic GPP symptoms extend beyond the skin. Fatigue, pain, and psychological distress persist even after flares resolve, supporting a holistic, proactive care model