Introduction

The past decade has been influential in shaping our understanding of pustular psoriasis; generally considered to be a rarer, more severe variant of plaque psoriasis (psoriasis vulgaris), it is now regarded as its own distinct manifestation in patients, along with variants like inverse, guttate, and erythrodermic psoriasis.¹ 

To get a clearer understanding of the role of genetic factors in pustular psoriasis, we must first understand the condition itself and the immunological pathways affected. 

What is pustular psoriasis? 

Pustular psoriasis is a rare, chronic inflammatory skin disorder characterised by the sudden onset of painful, pus-filled bumps (pustules) on the skin.^1,2,3 However, the presence of these sterile pustules is not a determining factor of pustular psoriasis; it is a notoriously difficult condition to diagnose due to the rarity of the disease and its similarity to various other inflammatory skin disorders.² 

In general, patients diagnosed with pustular psoriasis have repeating symptoms such as:

• Adeep rooted fatigue
• Fever
• Intense flushing of the skin, extra-articular manifestations like fissured tongue and conjunctivitis, and nail abnormalities^1,2 

Types of pustular psoriasis

There are various subtypes of pustular psoriasis, including:¹

Generalised pustular psoriasis

• von Zumbusch psoriasis: Also known as generalised pustular psoriasis (GPP), is characterised by systemic recurrent pustules along with fever and fatigue
• Annular psoriasis: psoriasis characterised by ring-shaped lesions 
• Exanthematic psoriasis: generally milder, shallow pustules that clear up quickly without systemic symptoms 
• Impetigo herpetiformis: psoriasis associated with pregnancy

Localised pustular psoriasis

• Acrodermatitis continua of Hallopeau: psoriasis that affects the fingers, toes and nail beds
• Palmoplantar psoriasis: psoriasis that affects the extra-articular parts of the body, like the palms and soles

The vast number of subtypes with psoriasis variants results in subtle yet overwhelming differences that require explanation. Exploring the various driving genetic factors is imperative to not only accurately and efficiently distinguish the variants of the condition but also to develop safer, more effective treatments with specific targets. 

One of the main discoveries within the field of pustular psoriasis in the past decade is the crucial role of the interleukin IL-36 in propagating inflammation in pustular psoriasis.³

The inflammatory cascade 

Most inflammatory conditions, like pustular psoriasis, occur when certain environmental or genetic factors interfere with normal immunological activity. These inflammatory triggers usually increase the levels of certain proteins in your system known as cytokines. 

These cytokines can then activate other immune cells, like T cells, macrophages, and neutrophils, which leads to sustained and exacerbated inflammation in affected people, hence making pustular psoriasis a chronic inflammatory skin disorder, as the inflammation has no pathway to resolve itself.⁴ 

The Il-1 superfamily: IL-36

IL-36, or interleukin-36, is a type of pro-inflammatory cytokine that is widely considered the crucial mediator of inflammation in pustular psoriasis. They are part of the IL-1 interleukin family, a group of proteins whose genes are coded for and located on chromosome 2. 

IL-36 activity is usually at its most intense in organs that come directly in contact with pathogens, like skin cells (keratinocytes) and cells of the lung and intestines.⁵ Environmental triggers like bacterial infection can cause keratinocytes to produce increased levels of IL-36. These interleukins can work by activating receptors within the same keratinocytes (autocrine signalling) or on other keratinocytes (paracrine signalling). 

IL-36 binds to surface receptors on keratinocytes, activating key signalling molecules like NF-κB, leading to the upregulation of genes promoting pro-inflammatory cytokines like IL-1, IL-8, IL-36, TNF-α and chemokines like CXCL1-3. These cytokines can then involve a host of other immune cells, such as neutrophils, T cells, and dendritic cells, while also increasing the levels of IL-36 even further, leading to a sustained positive feedback loop of inflammatory cytokine recruitment (Figure 1). 

The involvement of other immune cells leads to the propagation of different interleukin axes, like the IL-23/IL-17 axis, which are also potent drivers of inflammation.^4,5,6

Anti-inflammatory cytokine: IL-36Ra

The immune system has “plugs” to prevent these rivers of cytokines from spilling into our system and causing great damage. We call these plugs anti-inflammatory cytokines. These cytokines are responsible for reigning in the immune system and preventing things from getting out of hand. One of the main mediators of the IL-36 pathway is known as IL-36Ra. This cytokine binds to and blocks the IL-36 receptors, making it impossible for IL-36 to bind, attenuating inflammation.⁸

When the IL36RN gene encoding IL-36Ra is mutated, the resulting protein cannot adequately bind or block the receptor. This means that the pro-inflammatory IL-36 is free to bind to its receptor, leading to unregulated expression (Figure 1). The inability of the mutated gene to arrest such an important and dangerous pathway is largely the reason why patients with possible pustular psoriasis are usually genetically tested.^2,5

When reading about genetic mutations, it is important to understand what the numbers, symbols and letters stand for. When cells make proteins, they read the genetic message in threes (codons), and each codon tells the cell to add a specific amino acid to the growing protein chain. 

Proteins are polymers, or chains, of many amino acid building blocks. The sequence of bases in a gene (that is, its sequence of A, T, C, G nucleotides) translates to an amino acid sequence. 

However, not every part of the original gene ends up in the final protein. The useful parts, called exons, are stitched together to form the final genetic message (mRNA). In between them are introns, which do not code for protein and are removed in a step called RNA splicing before the mRNA is ready to be used.

Gene mutations commonly observed in patients with psoriasis include:

• c.115+6T>C: a thymine (T) is replaced with cytosine (T>C) in the mRNA, disrupting RNA splicing and leading to an incomplete form of the Il-36Ra protein
• c.338C>T: a cytosine (C) is replaced with thymine (T), leading to the formation of a different protein⁴

Clinical relevance 

Mapping out the IL-36 pathway and its genetic drivers has been crucial to giving pustular psoriasis its own unique identity. A study conducted on the levels of cytokines in both plaque psoriasis (PV) and GPP found that there were higher mRNA levels of IL-1 and IL-36, and lower levels of IL-17 and IFN-γ when compared to PV. This indicates that the Il-1/Il-36 pathway is crucial to GPP pathogenesis, and helps provide a clear clinical difference when compared to other skin disorders.⁴

Some drugs being developed to block the actions of relevant interleukins include:⁴

Anti Il-1 

• Anakinra: It blocks IL-1 receptors and helps prevent the upregulation of proinflammatory cytokines
• Gevokinumab and Canakinumab: They act by blocking the IL-1β proinflammatory pathway

Anti Il-36 

• BI655130: It blocks the IL-36 pathway, leading to a reduction in inflammation

Other genetic factors

Other genes associated with pustular psoriasis include:^4,6,9

• CARD14: This gene activates signalling pathways like NF-kB and MAPK by working with proteins such as BCL10 and MALT1. Mutations in these proteins lead to enhanced signalling of this proinflammatory pathway (gain-of-function mutation)
• AP1S3: This gene encodes the AP1S3 protein that helps keratinocytes recycle damaged proteins and waste in a process called autophagy. Loss-of-function mutations in AP1S3 lead to an accumulation of a protein called p62, which leads to enhanced NF-κB activation and signalling

Summary

Advances over the last decade have transformed our understanding of pustular psoriasis from a clinical subtype of plaque psoriasis into a genetically and immunologically distinct disease entity. Central to this shift has been the identification of the IL-36 pathway as a key driver of inflammation, particularly in patients carrying pathogenic IL36RN mutations that impair the regulatory action of IL-36Ra. These discoveries have not only clarified disease mechanisms but have also paved the way for targeted therapeutic development, including agents directed against IL-1 and IL-36.

Although additional genes such as CARD14 and AP1S3 further broaden the genetic landscape, much remains to be elucidated regarding the interplay between these pathways, environmental triggers, and clinical phenotypes. Continued genomic research, coupled with translational studies, will be vital in refining diagnostic approaches, improving subclassification, and ultimately offering more effective, personalised treatment strategies for individuals living with pustular psoriasis.