An interview with Professor Jonathan Barker: Shining a light on Generalized Pustular Psoriasis

1. Although many of us are familiar with the more common psoriasis, or plaque psoriasis, GPP is not something that many of us come across. Can you start by telling us, what is GPP?

GPP, generalized pustular psoriasis, is a rare, heterogenous and potentially life-threatening neutrophilic skin disease, with a significant burden for patients that occurs in somewhere between 0.27 and 4.6 people per 10,000 – the exact prevalence is highly variable around the world and more common in the far east.

The clinical course of GPP is heterogenous and can be characterized as a relapsing disease with recurrent flares, or a persistent disease with intermittent flares. During these flares, or episodes, there is the sudden, widespread formation of small pustules across large areas of a patient’s skin. These pustules can expand and combine together, into “lakes of pus” and can last for a number of weeks. These pustules are not contagious and are the result of the infiltration of neutrophils into the skin.

To briefly compare, plaque psoriasis (or psoriasis vulgaris/PV) is estimated to occur in 2-3% of the general population, so it is much more common. The defining feature of plaque psoriasis is erythematosus plaques - raised, inflamed patches of skin with a grey/silvery white scaling. It’s important to note that although they both have “psoriasis” in their names, GPP and plaque psoriasis are distinct conditions, both in their presentation and underlying genetics; although in rare cases some pustules may be seen in plaque psoriasis, these are associated with established plaques and are not defining features of the condition.

GPP is not just a disease of the skin, and people with the condition experience systemic symptoms including severe pain, fever, chills, fatigue and muscle weakness and the flares can be associated with significant morbidity and, in some cases, mortality. Approximately 25-30% of all cases of GPP are caused by genetic mutations in IL-36 receptor. But even in cases without these mutations it is known that the IL-36 pathway is overactive, indicating that it is central to the disease pathogenesis.

For those with GPP, it impacts all aspects of their lives, including jobs and relationships, and the unpredictable nature of the flares causes many people to live in constant fear of when these symptoms may appear next.

2. Can you tell us about your own experience of working with GPP patients? How many roughly do you see in your practice/hospital?

For many years we have been interested in the genetic architecture of all forms of psoriasis. In 2010, when next generation sequencing became available, our team were the first to set up this technology to study psoriasis. We first applied this new approach to GPP in 2011 and found mutations in the IL-36 receptor as discussed above. Others discovered it at the same time using other methods independently validating this important finding. As a consequence of this finding we set up a consortium of clinical experts called European Rare and Severe Psoriasis Expert Network (ERASPEN) that is seeking to collaborate and jointly investigate these conditions further.

Regarding my experience with GPP, I see a higher number of GPP patients compared to many dermatologists, but the rarity of the disease means I still only see about 2-3 new patients each year. By the time I see someone with GPP, they have often been living with the condition for some time without an appropriate diagnosis or with suboptimal treatment. They may have been misdiagnosed and their symptoms treated as plaque psoriasis, a reaction to medication, or as an infection. Unfortunately, during this journey, many patients will experience a severe flare which can result in hospitalization. Systemic medical complications are common and often severe, so it is vital to recognize acute GPP as a potentially fatal condition so management can be initiated without delay.

3. How well understood do you think GPP is within the dermatology community today? What do you believe the barriers are to a better understanding of the condition?

Increasingly we understand that there are a range of diseases that are characterized by pustule formation, and dermatologists may be aware of GPP as one of these. However, many will not have ever seen someone living with GPP and this makes timely diagnosis and management difficult. The diagnosis of GPP is definitely made more challenging due to its rarity and heterogeneous presentation – some GPP patients may have comorbid plaque psoriasis and this can lead to some confusion in diagnosis.

Available information on GPP is another key barrier; there has been an increase in publications and interest since the discovery of key GPP genes in 2011, but as a rare disease the data and case studies available are still limited.

Further research into the demographics of GPP patients and the patient journey will help the dermatology community support people with GPP more effectively. As we await the findings from this research, we need to raise awareness of this rarer condition and its differential diagnosis within the healthcare community, to help us reduce the delay in diagnosis and the issues this can cause for patients.

4. When providing care to someone with GPP, what are the key things you consider?

There is currently no global standard management pathway for GPP, but the community is working towards this and in recent years we have seen some progress. In 2017 we created the European consensus statement on phenotypes of pustular psoriasis, which includes key diagnostic criteria for GPP, and the Japanese have also independently developed guidelines for the treatment of GPP. I believe the advances in the understanding of the genetics and immunology underlying pustular psoriasis represents a promising time for GPP - we can begin to differentiate our management pathways and work closely with patients to improve their experience where we can.

I think it’s worth noting here that there’s often a gap between the expectations of physicians versus patients regarding their management. Dermatologists may consider flare management a success when hospitalization is avoided, whereas understandably patients expect resolution of pustules and long-lasting action on residual symptoms. The impact of flares and residual symptoms is wide reaching, so it’s important that we really try to empathize with the patient’s experience and do more for them.

5. With the World Psoriasis Day theme of Be Informed, what is your key takeaway for the future of GPP management?

As a dermatology community we must continue to increase our understanding of the range of diseases currently grouped under the “psoriasis” umbrella, looking at the individual conditions and acknowledging the need for differentiation in management. There is a need for new classification of these diseases according to disease stratification – a better classification will lead to more targeted treatment and subsequently to better patient outcomes. People with GPP will have a very different experience to those with plaque psoriasis, or from those with other pustular conditions such as palmoplantar pustular psoriasis (PPP) or drug‐triggered acute generalized exanthematous pustulosis (AGEP). We must continue research into these conditions – their epidemiology, pathophysiology and management – and ensure we’re taking the time to listen to and work with our patients.

At Boehringer Ingelheim, our goal is to help the GPP patients who struggle with their disease every day and the healthcare professionals who are treating them. To find out more about the experience of those with GPP, please watch this short video.

References

¹ Benjegerdes, KE. et al. Pustular psoriasis: pathophysiology and current treatment perspectives. Psoriasis (Auckl). 2016;6:131–144

² Boehringer Ingelheim. GPP prevalence. Data on file. April 2019

³ Egeberg, A. et al. Epidemiology of psoriasis in hard-to-treat body locations: data from the Danish skin cohort. BMC Dermatology. 2020;20:3.

⁴ Fujita, H. et al. Japanese guidelines for the management and treatment of generalized pustular psoriasis: the new pathogenesis and treatment of GPP. J Dermatol. 2018;45(11):1235–1270

⁵ Gooderham, MJ. et al. An update on generalized pustular psoriasis. Expert Rev Clin Immunol. 2019;15(9):907–919

⁶ Jeon, C. et al. Generalized pustular psoriasis treated with apremilast in a patient with multiple medical comorbidities. JAAD Case Rep. 2017;3(6):495–497

⁷ Kelly-Sell, M. & Gudjonsson, JE. (2016). ‘Overview of Psoriasis’, in Therapy of Severe Psoriasis. Elsevier, pp. 1-15.

⁸ Kharawala, S. et al. The clinical, humanistic, and economic burden of generalized pustular psoriasis: a structured review. Expert Rev Clin Immunol. 2020;16:3,239-252

⁹ Ly, K. et al. Diagnosis and screening of patients with generalized pustular psoriasis. Psoriasis: Targets Ther. 2019;9:37–42

¹⁰ Navarini, AA. et al. European consensus statement on phenotypes of pustular psoriasis. Journal of the European Academy of Dermatology and Venereology. 2017; 1:1792-1799

¹¹ Onoufriadis, E. et al. Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. The American Journal of Human Genetics. 2011;89:432–437