What is pustular psoriasis?

Psoriasis (suh·RY·uh·sis) is a long-term, relapsing inflammatory skin condition that affects millions worldwide. There are different subtypes of psoriasis. While plaque psoriasis is the most common type, pustular psoriasis is a more severe and rare type, accounting for only 3% of psoriasis patients.¹ Pustular psoriasis is characterised by white pus-filled blisters surrounded by pink or red inflamed skin.² There is no known single cause; research suggests that a combination of genetic, environmental, and immune-related factors can cause or worsen the skin condition.

Presentation of pustular psoriasis

There are two types of pustular psoriasis: Generalised Pustular Psoriasis (GPP), which affects patients across their whole body, and localised pustular psoriasis, which affects one area.³ GPP has four subtypes:^3–6

• Annular pustular psoriasis: Presents with red ring-shaped marks with scaly and pus-filled blister corners
• Exanthematous pustular psoriasis: A drug-induced reaction where white pus-filled blisters form on skin folds, such as the armpits or groin, and spread
• Impetigo herpetiformis: Usually occurs during the third trimester of pregnancy
• Von Zumbusch pustular psoriasis: Presents with severe, large, pus-filled blisters that cover large areas of the body, along with other symptoms such as fever and fatigue

Localised pustular psoriasis (LPP) only affects specific areas and has two subtypes:^7,8

• Palmoplantar pustular psoriasis (PPP): The most common type, with blisters forming only on the palms of the hands or soles of the feet
• Acrodermatitis continua of Hallopeau (ACH): Blisters form around the nail beds of the fingers and toes

Worldwide prevalence and geographic variations

Globally, the frequency of pustular psoriasis varies by ethnicity and location. Typically, it affects approximately 1–7 people per million, but estimates differ significantly between countries. For example, frequency ranges from fewer than 2 cases per million in France to over 180 cases per million in Italy, with other countries such as Japan and Korea reporting 7 and 124 cases per million.⁷ This has led researchers to question whether pustular psoriasis has an environmental or genetic cause.

Causes of pustular psoriasis

Understanding the cause of pustular psoriasis is important for improved diagnosis, treatment, and management. Most cases of pustular psoriasis are idiopathic (no known specific cause) and are not well understood. However, several risk factors may contribute to its development. Notably, research suggests that pustular psoriasis may also result from complex interactions among multiple factors, for example, genetic factors, immune system malfunction, and environmental triggers.

Genetic factors

Genetics is a significant contributor to the development of pustular psoriasis. Although it is not purely hereditary, studies have shown that individuals with a family history of psoriasis are more likely to develop pustular psoriasis.^9,10 Various genes have been shown to play a significant role in the disease.

IL36RN (Interleukin-36 receptor antagonist gene)

The IL36RN gene encodes the interleukin-36 receptor antagonist. This receptor plays a functional role in regulating skin inflammation. When gene mutations occur, they can disrupt the body’s ability to control inflammatory processes in the skin, consequently resulting in excessive immune activation and the formation of pus-filled blisters. Studies have found that mutations in this gene are particularly associated with generalised pustular psoriasis (GPP).^11,12,13

CARD14 (Caspase recruitment domain family member 14)

A protein complex involved in immunological responses, nuclear factor kappa B (NF-κB), is activated in part by the CARD14 gene. Both plaque and pustular psoriasis have been associated with mutations in CARD14, particularly among those with a family history of the condition. Increased inflammation and immune cell recruitment in the skin can result from dysregulation of NF-κB signalling. This mechanism may malfunction in certain individuals due to mutations in the CARD14 gene. The immune system overreacts, causing unnecessary inflammation.¹⁴

AP1S3 (Adaptor-related protein complex 1 subunit sigma 3)

Another gene, AP1S3, which specifies the adaptor-related protein complex 1, has been identified in patients with pustular psoriasis. This gene is involved in cellular trafficking – managing the movement and delivery of important molecular packages within and between cells – and immune responses. When this gene is mutated, it disrupts the normal sorting and transport of immune system components, leading to:

• Abnormal accumulation of immune system messengers
• Disrupted communication between cells
• Improper sorting of inflammatory molecules

These alterations contribute to excessive immune activation and inflammation, playing a role in the development of pustular psoriasis. Genetic studies have shown that these mutations are not universally present in all pustular psoriasis patients, indicating that additional genetic or environmental factors influence disease development.

Immune-related factors

The underlying cause of pustular psoriasis is notably influenced by the immune system. An overactive immune response is the main cause of skin inflammation, leading to rapid turnover of skin cells and the formation of pus-filled blisters.

Cytokine dysregulation

Small proteins called cytokines control immune responses. Pustular psoriasis has been linked to several cytokines, including two key interleukins that regulate skin inflammation: Interleukin-1 (IL-1) and Interleukin-36 (IL-36). Patients with IL36RN mutations have increased inflammation and blister formation due to IL-36 overactivation.

Additionally, tumour necrosis factor-alpha (TNF-alpha) is a cytokine involved in systemic inflammation and implicated in a number of autoimmune conditions, including psoriasis.

How TNF-alpha contributes to pustular psoriasis

• Overproduction: The body produces too much TNF-alpha or becomes hypersensitive, reacting even when no immune response is needed
• Inflammatory cascade: Excess TNF-alpha triggers activation of other immune cells, creating a domino effect of inflammation throughout the skin
• Neutrophil recruitment: TNF-alpha specifically attracts neutrophils (a type of white blood cell) to the skin, where they accumulate and form the visible blisters that characterise pustular psoriasis
• Skin cell growth: TNF-alpha accelerates the growth cycle of skin cells, causing them to multiply much faster than normal and leading to the thickened, scaly patches seen in psoriasis
• Blood vessel effects: TNF-alpha causes blood to flow more rapidly to affected skin areas, leading to redness and warmth

These mechanisms reinforce one another, making the cause of pustular psoriasis very difficult to pinpoint. This feedback mechanism is triggered when neutrophils accumulate in the skin due to a false immune system signal, which subsequently releases more TNF-alpha. This cycle, driven by TNF-alpha and other cytokines, has been shown to result in chronic inflammation, blistering, and scaling observed in pustular psoriasis.^12,14

Environmental factors

Research has shown that there are several environmental triggers that can contribute to the onset or exacerbation of pustular psoriasis, including:^15–17

• Stress
• Rapid withdrawal of systemic corticosteroids
• Skin damage through injury
• Infections
• Smoking
• Pregnancy
• Exposure to certain drugs

The following medications are among the drugs that have been associated with the onset of the disease:¹⁸

• Terbinafine
• Ramipril
• Progestins
• Lithium
• Potassium iodide
• Hydroxychloroquine
• Topical calcipotriol and steroid combinations

People with pustular psoriasis can effectively manage their illness by identifying and addressing environmental factors. For individualised treatment plans, speaking with a healthcare provider is crucial if symptoms worsen or new triggers appear. Although intricate interactions among genes, immunological responses, and environmental triggers pose challenges, there are also opportunities for intervention. Dermatologists can customise therapy to each patient’s unique manifestations, possibly focusing on the specific inflammatory pathways that are most active in that patient’s situation.

Summary

Pustular psoriasis is a rare, long-term, relapsing inflammatory skin condition, characterised by pink or red scaly skin with pus-filled white blisters. Research suggests there is no single cause of the skin condition and that it differs across patients of distinct ethnicities and locations. However, it is likely that there are multiple complex, interlinked causes of pustular psoriasis. One plausible cause is genetic mutations of genes involved in the immune response, such as IL36RN, CARD14 and AP1S3. Similarly, immune response mediators, such as overproduced cytokines, have been shown to be involved in the formation of pus-filled blisters and scaly skin. Another group of causes is environmental risk factors, which research highlights can trigger pustular psoriasis. These include exposure to, or cessation of, certain drugs, infection, pregnancy, skin trauma, and stress, among other factors. Although there are difficulties associated with the complex interactions among genes, immunological responses, and environmental triggers, there are also treatment and management options for patients and healthcare professionals to consider.