International Psoriasis Council

Advancing Knowledge. Improving Care.

Advancing Knowledge. Improving Care.

The Future of Treatment in Generalized Pustular Psoriasis

Blog -Expert Insights-Choon-Graphic
Siew Eng Choon, MB, FRCP
School of Medicine and Health Services
Monash University Malaysia Johor, Malaysia


Generalized pustular psoriasis (GPP) is a rare form of psoriasis characterized by painful, fiery-red skin; sterile pustules; and recurrent flares.

THE 101

  • Only 1.3% of psoriasis patients have generalized pustular psoriasis, making it one of the rarest forms of the disease. 
  • GPP places a significant burden on patients due to symptoms like fever, malaise, and fatigue — which are not as prevalent as other forms of psoriasis


2021: Recent studies into IL-36 have resulted in the availability of two molecules — spesolimab and imsidolimab — for targeting this novel pathway.


Iznardo, H., & Puig, L. (2021), Exploring the Role of IL-36 Cytokines as a New Target in Psoriatic Disease. International Journal of Molecular Sciences. 22(9), 4344.

Recurrent flares, painful fiery-red skin, and sterile pustules — are the characteristics of Generalized Pustular Psoriasis (GPP), a rare and potentially life-threatening autoinflammatory disease.

While it is the rarest form of psoriasis — only affecting 1.3% of psoriasis patients worldwide, it is the form to which Dr. Siew Eng Choon has dedicated her studies. 

Dr. Choon’s interest in psoriasis, particularly in GPP, was initially driven by her own struggle in managing patients with GPP. As a member of IPC’s Pustular Psoriasis working group, Dr. Choon is committed to enhancing the care of GPP patients through the education of healthcare professionals and the general public, research, and advocacy.

What is something that dermatologists might not necessarily know about Generalized Pustular Psoriasis?

Dermatologists may not necessarily appreciate the heterogeneity of GPP. 

GPP is a very heterogeneous disease with a wide spectrum of disease severity and a highly variable clinical course. The extent and severity of signs and symptoms vary between patients and even between each flare in the same patient. Flares may affect minimal or extensive areas of the skin and may occur with or without systemic inflammation. 

While some patients exhibit multiple severe flares yearly, others may only experience a flare every few years. Recognizing the distinctive and wide range of possible manifestations of GPP is necessary to enable a prompt diagnosis and timely treatment.

How is the disease burden of GPP different from plaque psoriasis? 

Unlike psoriasis vulgaris or plaque psoriasis (which is not life-threatening), GPP is a potentially life-threatening disease characterized by recurrent flares of widespread painful fiery-red skin studded with numerous sterile pustules and lakes of pus. 

Patients with GPP flares are usually extremely uncomfortable and ill with high fever, general malaise, and fatigue. Systemic symptoms such as fever, malaise, and fatigue are not features of plaque psoriasis. GPP flares have a huge impact on patients’ physical and mental health and their quality of life (QOL). 

Studies showed a higher prevalence of anxiety and depression in patients with GPP than those with plaque psoriasis. The impact on QOL has also been shown to be higher in patients with GPP than in those with plaque psoriasis. GPP patients have more clinic visits and hospital admissions than patients with other types of psoriasis, which translates into more financial burden.

GPP affects all aspects of patients’ lives, their everyday activities, work-life, and interpersonal and intimate relationships. Some of my patients have very supportive spouses. However, some were abandoned by their spouses or rejected by partners. Many chose to stay single. GPP during childhood alters a patient’s life course. The recurrent flares make it impossible for them to achieve their real potential in life. Juvenile GPP also imposes a huge burden on patients’ families. 

Patients with GPP also face discrimination. Many self-isolate to avoid discrimination and hide their disease even from family members. 

I once witnessed an emotional revelation of the burden of GPP when two sisters with recurrent GPP flares for more than ten years bumped into each other in my clinic. They met at least once a year for festivities but hid their GPP from each other and their family. Once they met each other in the clinic, they became a great support for each other.

What does the current landscape of GPP treatment look like?

There is a lack of high-quality evidence to guide treatment decisions for GPP. Widely used, currently available treatments such as acitretin, methotrexate, cyclosporin, and biologics have limited evidence on efficacy and safety for treating GPP. In my experience, currently available therapies are too slow to control flares, and they do not adequately prevent new flares or offer clear skin. 

In most countries, including Malaysia, no drug is specifically approved for the treatment of GPP, and there is no national or regional guidance for the management of GPP. Treatment recommendations made by available management guidelines for GPP, mainly from the US and Japan, are based on case series and single-arm, open-label studies. However, the era of targeted therapy and randomized controlled trials (RCT) for GPP is here. 

What new studies and drugs should dermatologists look at when considering GPP treatment?

Identifying IL-36 signaling as the key pathway driving the inflammation seen in GPP has resulted in the availability of two IL-36R antibodies — spesolimab and imsidolimab — targeting this novel pathway. 

In a phase I proof-of-concept trial, rapid skin and pustular clearance were observed in all seven patients with moderate to severe GPP flares after a single dose of IV spesolimab 900 mg, without any worrisome safety concerns when followed up till week 20, suggesting that IL-36 is a promising therapeutic target for GPP. This trial informed the design and rationale of the first double-blind, placebo-controlled trial (RCT) on GPP, the Effisayil 1 study. 

Effisayil 1 successfully randomized 53 patients with moderate to severe GPP to spesolimab or placebo in a 2-to-1 ratio and showed that spesolimab was significantly more efficacious than placebo in clearing pustules and all skin lesions at week one. The primary endpoint — pustular clearance at week one — was achieved by 54% of patients on spesolimab compared to 6% of patients on placebo, and clear/almost clear skin was achieved by 43% of patients on spesolimab versus 11% in the placebo arm. 

The speed of pustular clearance was awe-inspiring. Pustule clearance was seen as early as one day, and clear/almost clear skin as early as two days after IV spesolimab 900 mg. Pustules melted away in about four hours after spesolimab infusion in one of my patients.

Pustular and skin clearance with spesolimab were accompanied by: 

  • Clinically significant improvements in Pain VAS (visual analog scale) 
  • Clinically significant improvements DLQI (Dermatology Life Quality Index) 
  • Resolution of neutrophilia 
  • Elevated CRP

Overall, spesolimab showed an acceptable safety profile. The overall rates of adverse events were generally comparable between spesolimab and placebo treatment groups during week one.

Imsidolimab has also shown promising initial results in GPP. In a 16-week phase II study (Gallop study), the primary endpoint of improvement in Clinical Global Impression was achieved by six out of eight patients with moderate-to-severe GPP who received IV imsidolimab 750 mg on day one, followed by 100 mg subcutaneous doses every four weeks, confirming that IL-36 is the right therapeutic target for GPP.  

What will the next phase of testing look like, and what do you think this means for the future of GPP treatment?

This is the first time we have robust evidence of the efficacy of a therapeutic agent for GPP. Spesolimab is the first treatment that specifically targets the IL-36 pathway for treating GPP flares. It has been evaluated in an adequately powered, randomized, placebo-controlled trial and provided robust evidence of its efficacy in aborting GPP flares rapidly with an acceptable safety profile. 

Longer exposure to spesolimab is being evaluated in Effisayil 2, a 48-week, multi-center, randomized, double-blind, placebo-controlled, phase IIb dose-finding study and a 5-year open-label extension study. 

Another ongoing RCT on GPP is Germini 1, a phase III randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of imsidolimab in the treatment of adult subjects with GPP. 

These RCTs will provide robust evidence on the efficacy and safety of spesolimab and imsidolimab in treating GPP. If the impressive results of earlier studies are replicated, we may be able to offer patients with GPP a highly efficacious targeted therapy in a few years’ time.


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