Sun. Jul 21st, 2024

Nearly 3 percent of the world’s population has some form of psoriasis—that’s over 125 million people. Of those, an estimated 7.5 million are Americans, according to the National Psoriasis Foundation (NPF), making it the most common autoimmune disease in the country.

Although this skin disease is prevalent, many people are still unaware of its impact. Unfortunately, there are many misconceptions about the disease; for example, that it is contagious.

What is Psoriasis?

Psoriasis isn’t just a skin disease; it is actually am autoimmune condition that has the potential to cause widespread systemic effects. These widespread systemic effects are most commonly described as effects on the skin, joints and heart. There are different forms of Psoriasis and some are more common than others.

Psoriasis is a chronic autoimmune disease that causes skin cells to multiply up to 10 times faster than normal. This makes the skin build up into bumpy red patches covered with white scales that can grow anywhere, but typically appear on the scalp, elbows, knees, and lower back. Psoriasis is not contagious nor is it caused or worsened by poor personal hygiene. Psoriasis may be inherited and can range from a very mild, hardly noticeable rash to a severe eruption that covers large areas of the body. Affiliated Dermatology’s Dr. Andrew Newman shares some facts about psoriasis:

“Although psoriasis is typically thought to be a condition that only affects the skin, it affects the ENTIRE body.  In fact, joint disease, heart disease, and depression are common features in psoriasis. It’s caused by many factors including genetic predisposition, certain medications, and some infections such as strep throat. People with psoriasis most often are regularly taken care of by a dermatologist.”

In some patients, psoriasis causes nail changes and joint pain (psoriatic arthritis). The first episode usually strikes between the ages of 15 and 35. This chronic condition will then cycle through flare-ups and remissions throughout the rest of the patient’s life.

 

What are the different forms of Psoriasis?

The most common form of the disease, plaque psoriasis, appears as raised, red patches covered with an accumulation of white dead skin cells. Other areas affected by the different types of psoriasis include the face, skin folds, hands, feet, genitals, and nails.

Most individuals will be afflicted with one form of Psoriasis at a time, there are known treatments for Psoriasis, but currently there is no known cure. Occasionally, when one form of Psoriasis clears up and symptoms reside, another form may appear due to exposure to a trigger. Triggers include but are not limited to; skin injury, stress, certain medications, infections, weather, diet and allergies.

1. Plaque Psoriasis – Plaque Psoriasis is the most common type of Psoriasis; it can also be called ‘Psoriasis Vulgaris’. This type of Psoriasis appears as red, inflamed patches of skin covered with a white or silvery buildup of dead skin cells (known as plaque). It can cause the skin to feel painful to the touch and itchy and typically effects the knees, elbows, scalp or lower back, however … it can occur anywhere on the body.

2. Inverse Psoriasis – Inverse psoriasis makes bright red, shiny lesions that appear in skin folds, such as the armpits, groin, and under the breasts.

Inverse Psoriasis appears as areas od shiny, red and inflamed skin. This type of Psoriasis is typically located in the folds of the body; under the arm pits or breasts, behind the knees, around the groin or even the skin folds that surround the genitals.

3. Guttate Psoriasis – Guttate psoriasis often starts in childhood or young adulthood, causes small, red spots, mainly on the torso and limbs. Triggers may be respiratory infections, strep throattonsillitis, stress, injury to the skin, and taking antimalarial and beta-blocker medications.

Guttate Psoriasis will more commonly present in childhood or amongst young adults. Symptoms appear as small pinkish-red spots or lesions, typically on the arms, legs and torso.

4. Erythrodermic Psoriasis – Erythrodermic psoriasis causes fiery redness of the skin and shedding of scales in sheets. It’s triggered by severe sunburn, infections, certain medications, and stopping some kinds of psoriasis treatment. It needs to be treated immediately because it can lead to severe illness.

This is one of the least common types of Psoriasis but it one of the most serious. More severe symptoms include severe burning, itching and peeling of the skin, changes in body temperature and a faster heart rate. If you believe you are suffering from this type of Psoriasis, see your doctor immediately, it can cause severe illness.

5. Pustular Psoriasis –  Pustular psoriasis causes red and scaly skin with tiny pustules on the palms of the hands and soles of the feet.  Pustular Psoriasis is another typically uncommon type of Psoriasis that mainly appears in older adults. Symptoms include pus-filled bumps, known as pustules, the surrounding skin can appear red and inflamed, oftentimes looking infectious (however, it is not). This type of Psoriasis can appear mainly on the hands and feet but can appear on other parts of the body as well. Symptoms of Pustular Psoriasis can include; nausea, fever, chills, muscle weakness, and rapid heart rate.

6. Psoriatic Arthritis – Psoriatic Arthritis is a variant of the condition where the individual has both arthritis (joint inflammation) and psoriasis. Typically, this condition appears years after the onset of Psoriasis symptoms. Symptoms can include; warm or discolored joints, swelling of the joints – fingers and toes, and stiff, painful joints that are worse after rest or in the mornings.

7. Nail Psoriasis – Nail Psoriasis is another variant of the condition and it more commonly affects those who are afflicted by Psoriatic Arthritis. Symptoms can include; painful, tender nails, color changes to the nails, a white chalk-like material under your nails, pitting of your nails, separation of the nail from the nail bed.

8. Scalp psoriasis can cause dandruff-like itching and flaking. Psoriasis happens when the immune system triggers too many skin cells to grow on various parts of the body. That can include your scalp. People with psoriasis may be more likely to get dandruff, but psoriasis is not dandruff.

Living with Psoriasis can affect your quality of life; however, certain treatments are available. You can work with your doctor to develop a plan of care and guide you in figuring out what your environmental triggers are or other lifestyle factors. Triggers and lifestyle factors could be the culprit behind flare-ups.

What causes Psoriasis?

Although psoriasis appears on the skin, it is an immune system disease that is not caused or worsened by poor personal hygiene. People with the disease have a genetic tendency to develop it. There are certain things that can trigger flare-ups including skin injury, stress, hormonal changes, infection, and medications. Most people with the disease experience cycles of clear skin and outbreaks. Dr. Dustin Mullens of Affiliated Dermatology spoke on how Psoriasis starts:

“The nervous system and stress affect a multitude of skin conditions in humans. There are many types of cells in the skin affected such as immune cells and endothelial cells, both can be regulated by neuropeptides and neurotransmitters, which are chemicals released by the skin’s nerve endings. Stress can result in the skin’s nerve endings releasing an increased level of these chemicals and when this occurs, it can lead to inflammation of the skin. This is why people often experience a flare-up of their inflammatory skin conditions such as psoriasis during times of stress.”Things that can trigger an outbreak of psoriasis include:

  • Cuts, scrapes, or surgery
  • Emotional stress
  • Strep infections
  • Medications, including
  • Blood pressure medications (like beta-blockers)
  • Hydroxychloroquine, antimalarial medication

Symptoms of Psoriasis

The truth is that there are many people with psoriasis who don’t even know they have it! Skin rashes are not uncommon so dermatologists need to rule out a list of other possible causes like an allergy to food/medication and viruses. Careful visual inspection is needed for diagnosing psoriasis, but sometimes there is a need for a skin biopsy.

Is infection a possibility? Infections are actually quite rare due to the fact that psoriasis itself is due to an overactive immune system. That being said, repeated scratching and excoriation can disrupt the skin barrier and facilitate bacterial invasion and is thus strongly discouraged. All patients with psoriasis should be seen at the very least annually by a dermatologist and when treatment and medications are ineffective at controlling disease severity and flares. Patients requiring systemic treatment should be seen every 3 months for check-ups while on these more sophisticated/complex medications.

How to Treat Psoriasis?

There’s currently no cure for this chronic autoimmune condition, but caring for psoriasis can slow down the growth of skin cells and relieve pain, itching, and discomfort. Treatment of psoriasis depends on a patient’s overall health, presence of joint pain, and severity of skin involvement. When asked about treatment for psoriasis, Dr. Newman shares,

“The type of treatment used depends on the total body surface area involved and severity, etc. In mild psoriasis, I think natural medicines work well. Some people find benefit from taking the natural anti-inflammatories quercetin and curcumin. Additionally, they may find that applying aloe vera gel to the skin does wonders. Lastly, sunlight also helps with mild psoriasis. That’s right, the UV rays of the sun decrease the skin inflammation in psoriasis! In fact, this explains why my colleagues and I see less psoriasis where we practice in the sun-rich Phoenix, Arizona, compared to areas like the midwest.”

In mild cases, topical corticosteroids and medications are prescribed. Psoriasis is not curable, but it is controllable. No single approach works for everyone. Therapy is individually tailored and based on your health, goals, and a careful assessment of potential risks and benefits of treatment. Treatments can be divided into four main types:

  • Topical treatments
  • Light therapy
  • Systemic medications
  • Biologics

Dr. Newman goes on to say, “For more serious psoriasis, it will be almost impossible to successfully manage the disease without sophisticated prescription medicines. Usually, this will entail potent topical corticosteroids and/or certain oral or injectable medicines that help regulate the body’s immune system (which has gone haywire in psoriasis). Importantly, if you have psoriasis (mild or severe), you should discuss the use of both natural and prescription medicines with your primary care doctor and your dermatologist.”

Find Relief for Psoriasis

The best treatment varies by individual, taking into consideration the type of psoriasis you have, where it is on your body and the possible side effects of medications. Another AffDerm dermatologist, Dr. Mitchell Manway, gave us some extra tips on what to do when you have psoriasis.

Moisturizers: which kind are the best? “In general, the thicker or greasier the moisturizer, the better. Creams and ointments that come in a tub or jar are more effective at restoring the skin barrier than lotions or products that come in pump-dispensers. Products containing petrolatum or ceramides can be particularly effective or preferred,” says Dr. Manway.

Scale softening products? What ingredients work best? Dr. Manway advises, “Products that contain lactic acid (Amlactin/Lac Hydrin), salicylic acid (Salex), or urea are more effective at removing scale and improving skin texture.”

Cold showers/cold packs or warm baths/heating pads? According to Dr. Manway, “Ice-packs and heat may be effective at treating symptoms of itch by distracting nerve receptors, but I would avoid exposure to showers or bathing as this may promote further water-loss and drying of the skin.”

Stress relief options like meditation, acupuncture, etc? “Studies directly involving acupuncture and treatment of psoriasis are still inconclusive, with some proposing benefit and others with no significant results. However, anything that can promote stress relief may be helpful at preventing and controlling flare-ups as stress can be a major contributor for worsening of the disease,” said Dr. Manway

Exercise? “Daily or weekly exercise can stimulate and regulate the immune system and decrease stress levels, and thus is an important part of disease management.”

Over-the-counter remedies like calamine lotion? “In my experience calamine lotion is not very effective at reducing itch or pain. Topical preparations that contain pramoxine (Sarna Sensitive) or menthol (Sarna) are preferred.  Surprisingly, brief periods of exposure to sunlight and UV rays can also benefit psoriasis, but limited exposure should be stressed due to the increased risk of skin cancer associated with chronic UVA and UVB damage,” said Dr. Manway.

Prescription medications? Dr. Manway agrees, “Rx medications are by far the most effective topical treatment approach available and help to decrease inflammation at the site of disease. Potent topical steroids such as clobetasol or betamethasone are the most common medications prescribed, but other mechanisms such as vitamin D analogues and calcineurin inhibitors can provide significant and adjunct benefits towards the reduction of psoriatic plaques with less risk of long-term local side-effects. When local disease can not be maintained on topical medications or development of psoriatic arthritis is present, systemic oral medications or biologic therapy/injections are necessary.”

When should you see your dermatologist for psoriasis? Look out for any suspicious changes such as lesions that show signs of persistent flaking, scaling, roughness, redness, scabbing, bleeding, or otherwise non-healing areas. These symptoms are uncomfortable and could be an indication of something more serious.

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Genetics of Generalized Pustular Psoriasis: Current Understanding and Implications for Future Therapeutics

Abstract
Psoriasis is a chronic inflammatory skin disease characterized by the appearance of clearly demarcated erythematous and scaly plaques. It can be divided into various types, including plaque, nail, guttate, inverse, and pustular psoriasis. Plaque psoriasis is the most commonly occurring type, though there is another rare but severe pustular autoinflammatory skin disease called generalized pustular psoriasis (GPP), which manifests with acute episodes of pustulation and systemic symptoms. Though the etiopathogenesis of psoriasis is not yet fully understood, a growing body of literature has demonstrated that both genetic and environmental factors play a role. The discovery of genetic mutations associated with GPP has shed light on our comprehension of the mechanisms of the disease, promoting the development of targeted therapies. This review will summarize genetic determinants as known and provide an update on the current and potential treatments for GPP. The pathogenesis and clinical presentation of the disease are also included for a comprehensive discussion.

 

1. Introduction

Psoriasis is a common chronic inflammatory skin disease with a variety of clinical manifestations [1]. Psoriasis may be classified into non-pustular and pustular forms. Pustular psoriasis may be further stratified into localized and generalized forms [2]. It is believed that both environmental and genetic factors participate in the immune mechanisms of psoriasis [3]. Current studies have demonstrated genetic susceptibility to psoriasis involving components of both innate and adaptive immune systems [1]. Prolonged inflammation results in dysregulated keratinocyte proliferation and differentiation, and the keratinocytes participate in both the initiation and maintenance phases of psoriasis [4].
Psoriasis vulgaris (PV) is known to be the most common subtype of psoriasis. Both immune and genetic studies have identified interleukin (IL)-23 and IL-17 as the main drivers of psoriasis vulgaris [5,6]. It is characterized by relatively stable and localized erythematous scaly plaques. On the other hand, pustular psoriasis (PP) is rarer but potentially life-threatening and is associated with innate immune system overactivation. It may present with erythematous, scaly skin, including pustules and systemic neutrophilia. Pustular psoriasis can present in various forms, including localized pustules, as in acrodermatitis continua of Hallopeau (ACH) or palmoplantar pustulosis (PPP), or diffuse, non-acral pustules with systemic inflammation, as in generalized pustular psoriasis (GPP) [2].
GPP is a severe type of psoriatic disease. It is characterized by the onset of widespread, macroscopically visible pustules on non-acral skin with or without systemic symptoms such as fever, neutrophilia, and elevated serum levels of C-reactive protein [7]. The extent of systemic symptoms varies among patients as well as between flares within the same patient.
Clarifying the immune mechanisms behind GPP helps to develop potential therapeutic targets for this disease. Meanwhile, we should also keep in mind that the age of onset and the frequency of genetic mutations vary significantly among different subtypes [8].
In 2017, Akiyama et al. first proposed the term “autoinflammatory keratinization diseases” (AiKDs) to describe the inflammatory keratinization of the skin due to genetic autoinflammatory pathomechanisms [9]. As the pathogenic mechanism of AiKD becomes elucidated, there will be more appropriate treatment methods and precision medicines available [10]. This novel concept also sheds light on the development of therapeutic agents for pustular psoriasis.
Recent studies of the molecular pathomechanisms of pustular psoriasis suggest that the inhibition of specific cytokines, including the IL-36 axis, is a potential therapeutic strategy to control the disease activity of pustular psoriasis [11].
Autoimmunity is characterized by the activation of the adaptive immune system, including T and B cells, while autoinflammatory responses are driven by endogenous danger signals as well as inflammatory mediators and cytokines. In complex inflammatory conditions such as psoriasis, these two processes frequently coexist and can influence and trigger each other. This review will discuss the mechanism of psoriasis based on the autoimmune and autoinflammatory processes that are activated. We also aim to provide an up-to-date elucidation of the genetic mutations associated with different subtypes of pustular psoriasis and, ultimately, focus on biological treatments available for GPP.

2. Genetics of Pustular Psoriasis

Although the first GPP case was reported a century ago, its etiology and detailed pathogenesis have only been discussed within the last ten years (Table 1). It was not until 2011 that IL36RN was initially discovered as a gene responsible for causing GPP [12,13]. Since then, a growing number of genetic mutations such as CARD14, AP1S3, MPO, and the SERPIN family have been identified as associated with GPP. However, not all GPP patients carry mutations of these genes, suggesting that there are still other genetic factors to be discovered. These disease-causing genes may participate in common or similar pathogenic molecular pathways [14].
Table 1. Genetic mutations associated with generalized pustular psoriasis and their proposed effects.
Ethnic differences in GPP should also take into consideration. For example, pathogenic mutations of AP1S3 have been reported in individuals of European origin but not in Malaysian populations [15,16], while MPO and SERPINA3 variants were identified in patients of European descent [17,18]. Associations with other ethnic groups remain to be elucidated.
The cases of pustular psoriasis are classified into GPP, PPP, and ACH according to the ERASPEN criteria [2]. Assan et al. suggested that PPP and ACH might be separate diseases while still maintaining some overlap [19]. Accordingly, there are prospective phenotype–genotype and multi-omics studies to better recognize the mechanisms of each subgroup. Another study conducted in Italy in a real-life setting revealed the concomitant rate of plaque psoriasis, which was the greatest in GPP and the least in ACH [20]. To distinguish GPP alone from those with PV is quite important since the selection of treatment is based on the disease mechanism and the clinical phenotype, which can include GPP alone, ACH alone, predominate ACH, ACH evolving into GPP, and ACH with GPP.
Adult-onset immunodeficiency syndrome (AOID) is known as an AIDS-like illness with abnormal interferon-γ (IFN-γ)/IL12 signaling. It is associated with high-titer neutralizing antibodies to IFN-γ, the controller of numerous pathogens [21]. The majority of cases exhibit skin-related symptoms, such as reactive skin conditions (82%) and infectious skin diseases (45%), with neutrophilic dermatoses being the most common among them [21,22]. A recent study conducted by Piranit et al. supports that both GPP and AOID involving pustular reactions are diseases caused by dysregulated proteolytic and apoptotic processes [23]. Clinically and genetically, GPP and AOID are likely to share some common pathogenetic mechanisms. To date, there have been no reports of AOID and GPP occurring in the same individuals or within the same families. However, genetic research has found heterozygous variants in the SERPINA3 and SERPINA1 genes in patients with AOID and GPP, respectively [24,25].

2.1. IL36RN

IL-36 cytokines are relatively novel and belong to the IL-1 family, which has members that are produced by many sources, such as epithelial cells, myeloid dendritic cells, and monocytes. IL36RN encodes for IL-36Ra, which inhibits the pro-inflammatory effects of IL-36 cytokines by binding their receptors, then preventing the release of mediators that stimulate the pustule formation seen in GPP [26].
Onoufriadis et al. reported that IL-36RN mutations can cause sporadic GPP, and according to their study, IL-36 mutations underline sporadic European GPP, as well as Tunisian autosomal recessive GPP [12]. Additionally, the first Asian case of GPP associated with IL36RN mutations was reported in 2012, therefore indicating that IL36RN mutations are common in some GPP cases worldwide [27]. The prevalence of IL36RN mutations among pustular psoriasis subtypes is different; patients with GPP have the highest prevalence of these mutations (23.7%). This is followed by ACH, which has the second-highest prevalence (17.4%), and lastly, PPP demonstrates the lowest prevalence of these mutations (5.1%) [8].
Hence, in order to ascertain if IL36RN alleles are the crucial determinants of pustular psoriasis across various disease subtypes, a regression analysis was carried out, incorporating clinical diagnosis as a covariate [28]. Individuals with homozygous mutations of IL36RN tend to experience more severe disease manifestations compared to those with heterozygous mutations, and these mutations are inherited through an autosomal recessive pattern [29]. Another study indicated that IL36RN mutations are almost not seen in individuals with both PPP and GPP [30]. Accordingly, this finding suggests that a large proportion of cases of GPP alone are caused by homozygous or compound heterozygous mutations of IL36RN.
On the other hand, the presence of IL36RN disease alleles demonstrated a dose-dependent influence on the age of onset across all types of pustular psoriasis [28]. According to genetic analyses, the frequency of IL36 mutations plays a role in differentiating pustular psoriasis subtypes [8]. Sophie et al. found that the percentage of individuals carrying IL36RN disease-associated alleles was higher in those with GPP and ACH. Individuals with GPP and ACH were more likely to have biallelic mutations compared to those affected by PPP.

2.2. CARD14

Caspase recruitment domain family member 14 (CARD14) is a gene located in the psoriasis susceptibility locus 2 (PSORS2). CARD is a protein-binding molecule that facilitates the formation of complexes containing CARD proteins, which are involved in apoptosis and NF-κB signaling pathways. Among them, CARD14 is found to be specifically expressed in diseases of the skin and is primarily localized in the basal and suprabasal epidermal layers [31]. Some CARD proteins are related to chronic inflammatory skin diseases, such as early-onset sarcoidosis or amyopathic dermatomyositis [32]. The role of CARD14 mutations as either causal factors or disease susceptibility factors for PV, GPP, or pityriasis rubra pilaris may depend on the specific mutation or variant position within the CARD14 gene. [28].
Differences in ethnical groups and geographic areas affect the outcome to some extent. A study revealed that the carrier rate of the CARD14 variant in Japanese individuals is higher than in Europeans. Therefore, we can consider CARD14 an important predisposing factor for GPP with PV in the Japanese population [33,34].

2.3. AP1S3

The AP1S3 gene, which encodes adaptor protein complex 1 (AP-1), plays a crucial role in stabilizing AP-1 heterotetramers that participate in vesicular trafficking between the trans-Golgi network and endosomes [35]. Cells with mutations in AP1S3 have decreased autophagosome formation in keratinocytes, leading to p62 build-up and resulting in enhanced NF-κB signaling [16]. Loss-of-function mutations of the AP1S3 gene were found relevant in GPP, which implies pustular psoriasis as an autoinflammatory manifestation resulting from impaired vesicular trafficking [15].
The pathogenic variants are distributed mainly in Europeans and rarely in East Asians and Africans. The variant frequency of AP1S3 in GPP patients of European ancestry is about 10.8% [15]. Suppressing AP1S3 expression in human keratinocytes and HEK293 cells eliminates endosomal activation by polyinosinic-polycytidylic acid, a TLR3 agonist involved in responding to viral infections. Researchers suggested that abnormalities in vesicular trafficking could be a significant pathological basis for the autoinflammatory process in pustular psoriasis [15].
Another study investigating genetic variations in patients with pustular psoriasis found that AP1S3 mutations were in fewer GPP cases than IL36RN, and patients with AP1S3 disease alleles were mainly female [8].

2.4. MPO

Deficiencies in MPO, a heme-containing peroxidase secreted by neutrophil granulocytes that catalyzes the formation of reactive oxygen species (ROS), have just been identified in association with GPP [14]. The association between MPO deficiency and pustular skin disease was first recognized by Vergnano et al. with phenome-wide association studies [36], and in vitro functional studies showed that mutations in the MPO gene lead to elevated neutrophil accumulation and activity, suggesting a role of MPO mutations in the pathogenesis of GPP [37].
The quantity of mutant MPO alleles was positively correlated with a younger age of onset, which is similar to the genotype-phenotype correlation of the IL36RN gene and further validates the genetic correlation of GPP [17]. The discovery that the MPO gene plays a pathogenic role in GPP provides perspectives on understanding GPP pathogenesis.

2.5. SERPINA1, SERPINA3

SERPINA1 and SERPINA3 are inhibitors of cathepsin G, the primary serine protease involved in cleaving and activating IL-36 precursors. The loss of function of these protease inhibitors may induce severe inflammatory effects [25]. Additionally, heterozygous loss-of-function mutations in both SERPINA1 and SERPINA3 were identified in individuals with GPP, and decreased protease inhibitor activity may result in enhanced IL-36 activation [18].
A study conducted by Piranit et al. reinforced the concept that the biological functions of SERPINB3 involve inhibiting cysteine proteases when mutated, and the subsequent overactivation of proteases leads to an intensified inflammatory reaction accompanied by heightened neutrophil recruitment [23]. Patients carrying SERPINB3 mutations exhibit aberrant SERPINB3 expression. The accumulation of misfolded SERPINB3 proteins causes the overactivation of cathepsin L, followed by the inactivation of SERPINA1, finally evolves into AOID with pustular reactions [38,39].

2.6. BTN3A3

BTN3A3 belongs to the human butyrophilin (BTN) 3 family, which has the ability to activate the NF-κB pathway, resulting in an excessive inflammatory response by suppressing the expression of IL-36Ra. To investigate the molecular pathogenesis of GPP, Q. Zhang et al. conducted a whole-exome sequencing study in the Chinese Han population [40]. However, the result found only two loci identified with exome-wide significance: the strongest one was in the IL36RN gene, and the other was located within the MHC region. A subsequent gene burden test demonstrated a correlation between BTN3A3 and GPP. Subtype analysis revealed that both IL36RN and BTN3A3 were markedly linked to GPP alone and GPP with PV. The BTN3A3 gene carried two LOF mutations with the most significant association. As a previously unreported determinant of GPP, BTN3A3 acted as a key regulator of cell proliferation, and its expression was associated with inflammatory imbalance.

2.7. TGFBR2

TGF-β signaling is recognized for its inhibitory effects on cell proliferation and immune system suppression [41]. Thus, the hyperproliferation of keratinocytes in the psoriatic epidermis is consistent with disrupted TGF-β signaling because of heterozygous loss-of-function TGFBR2 mutations. Concomitant with the overexpression of KRT17, there is an increase in keratinocyte proliferation and subsequent recruitment of neutrophils [42]. The overexpression of KRT17 is thus in line with a potential role for diminished TGFBR2 function in both GPP and AOID. Whole-exome sequencing (WES) was carried out on a total of 53 patients, comprising 32 individuals exhibiting pustular psoriasis phenotypes and 21 individuals with AOID presenting with pustular skin reactions [43]. The result showed that 4 Thai patients displaying similar pustular phenotypes, including two diagnosed with GPP and two with AOID, were found to carry the same rare TGFBR2 frameshift mutation. It is concluded that AOID might share pathogenic mechanisms with GPP.
Mechanistically, TGFBR1 and TGFBR2 are transmembrane serine/threonine kinases [44]. TGFBR2 expression is remarkably reduced or absent in psoriatic skin. As a result, it has been suggested that genetic variations in TGFBR2 could enhance susceptibility to GPP and AOID in some patients.

3. Current and Potential Therapeutic Agents Targeting Immune Mediators in Generalized Pustular Psoriasis

The phenotype and pathogenesis of different psoriasis subtypes are on a spectrum. On the one hand, plaque psoriasis is associated with the overactivation of the adaptive immune system, including T and B cells, and is thought to involve self-perpetuating inflammatory mechanisms through the IL-23/Th17 axis [45]. On the other end, pustular psoriasis has been associated with the stimulation of innate immune responses and the activation of IL-36 cytokine pathways [46]. Based on the pathomechanism, therapeutic agents for patients who have plaque psoriasis and GPP at the same time need to target not only the adaptive immune pathways but also the innate immune axis [47].
IL-36 cytokines are members of the IL-1 superfamily, and the IL-1/IL-36–chemokine–neutrophil axis plays a significant role in driving disease pathology in GPP. The first pathogenic variant found to be linked with GPP was a homozygous mutation of the IL36RN gene [48], and further studies have looked into the distribution over different populations [48,49].
Progress in understanding the relationship between autoinflammation and clinical phenotypes has contributed to the development of highly efficacious targeted treatments such as TNF-α, IL-17, IL-23, IL-1α/β, or IL-36 inhibitors or receptor blockers, as well as small molecule drugs such as PDE4 inhibitors, JAK inhibitors, and ROR-γt inhibitors.
Well-established treatment guidelines for GPP are currently lacking, and multiple biologic and non-biologic treatments exist. Considering the variety of comorbidities and severity associated with GPP, personalized treatments should be tailored. Figure 1 shows a graphical abstract of current and emerging biologic agents for GPP.
Figure 1. Graphical abstract of mechanisms of current and potential biologic agents for generalized pustular psoriasis.

3.1. IL-36 Pathway Inhibitors

Anti-IL-36 receptor antibodies can be employed to block the signaling pathway responsible for GPP flares and can be effective for patients with mutant IL36RN [48].
At present, only a single GPP-specific treatment, spesolimab, an interleukin-36 receptor antagonist, has received approval for use in the United States. With the experience of GPP complete remission after two doses of spesolimab [50], spesolimab was then approved by European Commission in adult GPP flares [51]. Spesolimab has been demonstrated to reduce the levels of relevant serum biomarkers and cellular populations in the skin lesions of patients with GPP, such as CD3+ T, CD11c+, and IL-36γ+ cells and lipocalin-2-expressing cells.
In patients with GPP, spesolimab has been observed to induce rapid changes in commonly disrupted molecular pathways in both GPP and PPP, suggesting that it may have the potential to improve clinical outcomes [52]. The results of a randomized controlled trial indicated that a 900 mg intravenous infusion of spesolimab led to greater lesion resolution in a patient group experiencing active GPP flare-ups after one week [53]. The improvement of the condition was evaluated using the GPPGA, which is a standardized assessment of a subject’s skin status based on three factors: erythema, pustules, and scaling/crusting [54]. After one week, there were almost four times the number patients who received spesolimab and achieved a GPPGA total score of 0 or 1 compared to control patients. Furthermore, it was found that spesolimab may relate to a higher incidence of infection, though neither opportunistic nor severe [55]. Long-term management options also were assessed; patient-reported outcomes were improved, and markers of systemic inflammation were normalized [56]. Recent research also indicates that spesolimab is effective for patients with GPP without IL36RN mutations [57].
Additional potential therapies targeting the IL-36 pathway for GPP are currently under development. Imsidolimab, an IL-36 inhibitor, recently passed through a phase 3 clinical trial to evaluate its efficacy and safety [58]. Patients received 750 mg of IV imsidolimab on day 1 and added 100 mg of subcutaneous imsidolimab every 4 weeks until day 85. Imsidolimab exhibited a rapid and sustained alleviation of symptoms and pustular eruptions in patients with GPP.
There are currently efforts underway to develop small molecule inhibitors of IL-36γ, which could have the potential to treat GPP. A-552 was identified as a potent inhibitor of IL-36γ in humans [59]. Phenotypic analysis of individuals without the IL-36R-encoding gene disclosed that they do not exhibit severe immunodeficiency, further supporting that the IL-36 pathway is a promising therapeutic target with minimal side effects [60].

3.2. IL-1RAcP

Interleukin-1 receptor accessory protein (IL-1RAcP) antibodies represent another feasible treatment alternative for GPP patients. IL-1RAcP, a member of the immunoglobulin superfamily proteins, has a crucial function in the signaling of the IL-1 family cytokines, such as IL-1, IL-33, and IL-36. Blocking IL-1RAcP’s ability to form a dimer with IL-36R could prevent the overactivation of the IL-36 pathway and subsequent inflammation [61]. Zarezadeh et al. indicated IL-1RAcP as a potential therapeutic target for inflammatory and autoimmune diseases [62]. However, the long-term safety and effectiveness of IL-1RAcP antibodies need to be determined since IL-1RAcP is expressed in a wide range of cell types, and excessive suppression may result in multiple toxic effects [63].

3.3. TNF-α Inhibitors

TNF-α, produced by activated plasmacytoid dendritic cells (DCs) and damaged keratinocytes, can stimulate the IL-36 pathway. TNF-α inhibitors indirectly suppress the expression of IL-36γ, resulting in reduced activation of the pro-inflammatory IL-36 pathway [64]. Adalimumab, infliximab, and certolizumab pegol are TNF-α inhibitors that have been approved for GPP treatment in Japan [65]. Cases with rapid and sustained resolution of skin lesions after infliximab used were reported in Poland [66]. A retrospective study showed the treatment efficacy rate of pustule clearance, which was 100% in the adalimumab + acitretin group [67].
However, paradoxical GPP is a potential adverse effect of TNF-α inhibitors. A study conducted in Turkey involving 156 GPP patients revealed that TNF-α inhibitors were the only biologic that triggered paradoxical GPP [68]. It is estimated that 0.6%-5.3% of patients receiving TNF-α inhibitors developed paradoxical GPP, with infliximab being the most frequently associated biologic with this condition [69].

3.4. IL-17 Inhibitors

Secukinumab, ixekizumab, and brodalumab are biologics that have been proven to manage GPP patients in Japan [70,71,72]. A retrospective study in Germany compared the rate of excellent response to GPP patients, with 60.0% in the secukinumab group and 50.0% in the ixekizumab group [73]. A phase IV, multicenter, open-label randomized control trial in Japan demonstrated that skin lesions mostly resolved in GPP patients under ixekizumab treatment, and there were no side effects reported [74].
However, there was a case of a Japanese individual that developed increased serum levels of liver enzymes during treatment with brodalumab for generalized pustular psoriasis [75]. The relationship between brodalumab and autoimmune hepatitis (AIH)/primary biliary cholangitis (PBC) overlap syndrome should be noted.
These IL-17 inhibitors mentioned above have been shown to be effective in controlling flares in the acute phase or as maintenance therapy in adult patients with GPP.

3.5. IL-23 Inhibitors

IL-23 regulates the production of IL-17, which subsequently stimulates the synthesis of pro-inflammatory IL-36R agonists, leading to the overactivation of the IL-36 pathway. The IL-23 inhibitors risankizumab and guselkumab are indicated for the treatment of GPP in Japan [76,77]. Ustekinumab, as an IL-12/23 antagonist, has been introduced to GPP patients, who achieved complete remission after its dose was titrated [78]. Additionally, both newly diagnosed ACH cases and already known therapy-refractory ACH cases had satisfactory and sustained therapy responses to guselkumab and risankizumab [79].
This suggests that IL-23 inhibitors may control flares in the acute phase or as maintenance therapy in adult patients with GPP.

3.6. Additional Biological Therapy and Non-Biologic Options

While the TNF-α/IL-17/IL-23 axis is predominantly targeted in plaque psoriasis, the IL-1/IL-36–chemokine–neutrophil axis shows greater potential as a therapeutic target in GPP. Previous studies have explored the use of IL-1 targeting biologics, such as the IL-1α receptor antagonist anakinra, as well as the IL-1ββmonoclonal antibodies gevokizumab and canakinumab, in GPP patients [80]. Anakinra is a successful treatment in patients with GPP carrying mutant IL36RN genes, while gevokizumab and canakinumab are effective in blocking the pro-inflammatory cytokine IL-1β [81].
As for non-biologic immunomodulatory management, methotrexate, cyclosporine, apremilast, and retinoids have been used for the treatment of GPP, but the efficacy is only based on case reports and non-randomized studies. Japanese guidelines have suggested the use of topical treatments as maintenance therapy following flares or as a supplementary therapy to address psoriasis-like symptoms [65].

4. Conclusions

GPP is a severe inflammatory disease distinct from PV [82]. Recent genetic observations and investigations provided us with insight into the disease. We found specific genes that are associated with pustular skin disease, including IL36RN, CARD14, AP1S3, MPO, SERPINA1, SERPINA3, BTN3A3, and TGFBR2. The immunologic pathway implicates IL-36 as a central node cytokine. That is, GPP constitutes a large IL-36-dominated keratinocyte cytokine storm and epidermal neutrophil aggregation.
The advances in our comprehension of GPP and its treatment options have the potential to improve patient care. It is known that the IL-36 pathway is the main inflammatory pathway implicated in GPP, but it is neither necessary nor sufficient to cause the disease. Aside from genes that play a role in the regulation of IL-36 signaling, there are IL36RN-negative GPP cases that have been noted. Due to the rarity of GPP, it has been challenging to identify additional disease-causing genes in the past. However, by combining whole-exome sequence data from various centers and targeting cases that are more prone to be monogenic in origin, progress could be achieved.
Progressive biologic therapies that target different chemokine receptors show efficacy, but there are also safety considerations. As more relevant and efficacious treatment options become available, patient outcomes and quality of life will improve. We should also keep in mind that immediate treatment goals during GPP flares are to alleviate skin inflammation and minimize the impact of systemic symptoms to avoid complications such as cardiovascular aseptic shock, heart failure, acute respiratory distress syndrome, prerenal kidney failure, neutrophilic cholangitis, uveitis, and severe infections [80,83]. Prevention of flare-ups of GPP is another treatment goal, and further clinical studies are indicated to evaluate the efficacy of the prevention of GPP flares. Additionally, the prevalence of genetic mutations of GPP varies in different countries and ethnic groups. It is important to investigate if patients with different genetic mutations of GPP have different short-term and long-term treatment responses.

Author Contributions

Conceptualization, S.-F.Y., M.-H.L., P.-C.C., S.-K.H., S.-Y.S., H.-S.Y. and S.Y.; literature review, S.-F.Y., M.-H.L., P.-C.C., S.-K.H., S.-Y.S. and S.Y.; writing—original draft preparation, S.-F.Y.; writing—review and editing, S.-F.Y., M.-H.L., P.-C.C., S.-K.H., S.-Y.S., H.-S.Y. and S.Y.; supervision, H.-S.Y. and S.Y.; project administration, S.Y.; funding acquisition, S.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This study was supported by grants from the Taiwan National Science and Technology Council (MOST-110-2628-B-037-007 and NSTC-111-2314-B-037-042) to S.Y. and grants from Kaohsiung Medical University Hospital (KMUH110-0R61 and KMUH111-1R59) to S.Y.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

This study is supported partially by Kaohsiung Medical University Research Center Grant (KMU-TC111B02).

Conflicts of Interest

S.Y. a guest editor of the Special Issue: Genetics of Complex Cutaneous Disorders, had no role in the peer review process or decision to publish this article.

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  84. source

Generalized Pustular Psoriasis: Divergence of Innate and Adaptive Immunity

Abstract

Generalized pustular psoriasis (GPP) is a severe, relapsing, immune-mediated disease characterized by the presence of multiple sterile pustules all over the body. The exact pathomechanisms behind GPP remain elusive, although increased interest in the genetic basis and immunological disturbances have provided some revealing insights into the underlying signaling pathways and their mutual interaction. The genetic background of GPP has been thoroughly investigated over the past few years. The conducted studies have identified genetic variants that predispose to pustular forms of psoriasis. The loss-of-function mutation of the interleukin 36 receptor antagonist gene, along with rare gain-of-function mutations in the gene that encodes the keratinocyte signaling molecule (CARD14), are examples of the uncovered abnormalities. Interleukin 36 (IL-36), along with neutrophils, is now considered a central cytokine in GPP pathogenesis, with IL-36 signaling providing a link between innate and adaptive immune responses. More recently, a new concept of inflammation, caused by a predominantly genetically determined abnormal activation of innate immune response and leading to inflammatory keratinization, has arisen. GPP is currently considered a representative of this novel group of skin conditions, called autoinflammatory keratinization diseases. As no therapeutic agents have been approved for GPP to date in the United States and Europe, the novel anti-IL-36R antibodies are particularly promising and may revolutionize management of the disease.

 

1. Introduction

Generalized pustular psoriasis (GPP) is a rare, chronic, highly inflammatory, and potentially life-threatening variant of psoriasis [1,2,3]. GPP is more prevalent in Asians than Caucasians (annual prevalence of 7.46 cases/million people in Japan in contrast to 1.76 cases/million in France) and accounts for about 1% of all psoriasis cases [4,5,6,7]. GPP is approximately twice as common in women than in men, as was reported in both European and Asian cohort studies [8,9]. The mean age of onset of GPP is 31 years, which is lower than that of palmoplantar pustulosis or acrodermatitis continua Hallopeau [8]. Epidemiological data on GPP are in contrast to those on plaque psoriasis, which is reported to be equally prevalent among men and women and to occur most frequently between the ages of 15–20 years, with a second smaller peak occurring at 55–60 years [10]. GPP is characterized by recurrent episodes of widespread neutrophilic aseptic pustular eruptions, with accompanying symptoms of systemic inflammation [11]. The acute onset of GPP is usually associated with one or several general symptoms, such as pyrexia, malaise, and fatigue, and extracutaneous manifestations including arthritis, uveitis, acute respiratory distress syndrome, cardiovascular shock, and neutrophilic cholangitis [3,12,13]. Typical laboratory abnormalities include elevated C-reactive protein, leukocytosis, neutrophilia, and elevated liver function tests [3,13,14]. Acute GPP flares are associated with significant morbidity and mortality, if inadequately treated [2,15]. GPP may either be associated with pre-existing plaque psoriasis or can develop independently [16]. In a minority of cases, typical plaque-type psoriasis lesions arise after GPP has appeared [1]. Due to its low prevalence, GPP is regarded as an orphan disease (ORPHA:247353) [3,4,5,15]. GPP has a relapsing–remitting course with a highly variable clinical phenotype and pattern of flares. In some patients, the skin is entirely cleared between episodic acute flares, whereas in others a more persistent course is characterized by sharply defined localized or widespread erythematous plaques, with or without pustules [17]. GPP flares are idiopathic in most cases, although elicitation by certain endogenous and exogenous trigger factors, including infection, pregnancy, withdrawal of corticosteroids, and certain medications (e.g., ustekinumab, infliximab) is not uncommon [3,15,18,19]. Histologically, GPP is characterized by spongiform pustules of Kogoj and Munro’s subcorneal microabscesses, with the presence of an excessive amount of infiltrating neutrophils [20]. The most important clinical and histopathological differential diagnosis of GPP is acute generalized exanthematous pustulosis (AGEP), a rare and severe pustular skin reaction. Clinically, AGEP has a more abrupt onset, shorter duration, usually does not recur, and the patients do not have a personal or family history of psoriasis [21]. Moreover, AGEP has been strongly linked to certain drugs, such as ampicillin/amoxicillin, fluoroquinolones, sulfonamides, terbinafine, and diltiazem [21]. Although the microscopic features of these two pustular eruptions can be very similar, in most cases it is possible to differentiate them based on clinicopathological features [20].
GPP is traditionally classified as a variant of psoriasis. However, the distinct clinical, histological, and genetic features of the former suggest that these two diseases have, at least partially, different pathogenic mechanisms. It has been thus suggested that GPP should be regarded as a separate entity and that it requires a different therapeutic approach [4,16,22,23,24]. To date, no standard treatment guidelines exist for GPP in the United States and Europe; however, both conventional and biological agents used for plaque psoriasis have been incorporated into the therapeutic regime. Non-biological systemic therapy in adult patients typically includes acitretin, cyclosporine A, and methotrexate [25,26]. Only in Japan, several biologics have been approved for the treatment of GPP in patients who had an inadequate response to conventional therapy, including monoclonal antibodies against interleukin (IL)-17 (secukinumab and ixekizumab) or its receptor (brodalumab) and against IL-23 (risankizumab and guselkumab) [27,28,29,30,31,32,33,34]. Since the adaptive immune system plays a critical role in the pathogenesis of plaque psoriasis, agents specifically targeting elements of adaptive immunity are highly efficacious for the treatment of chronic plaque psoriasis [35]. It is worth noting that these therapies are generally less effective in the management of GPP than plaque psoriasis. This again suggests a divergent underlying pathogenic mechanism in the pustular variants of psoriasis [36]. It also needs to be pointed out that a paradoxical induction of GPP has been reported with biological agents [18,19,37,38]. Case reports, case series, and small open-label clinical trials have been published on novel biologics that target the cytokines involved in GPP pathogenesis. Recent gene expression analyses have demonstrated that the transcriptome of GPP shares some common features with that of plaque psoriasis. However, it is dominated by innate immune system activation and autoinflammation, whereas adaptive immune responses predominate in plaque psoriasis [39,40].
This article aims to elucidate and discuss the intricate interaction between the innate and adaptive immune mechanisms in the autoinflammatory pathogenesis of GPP. It also summarizes the up-to-date knowledge on the genetic background of this disease, discussing the clinical significance of the uncovered mutations. Moreover, it provides an overview of the current options for targeted therapies for GPP, including data from the most recent clinical trials.

2. Gene Mutations in GPP

The first indication that genetic abnormalities may lead to pustular dermatitis was the identification of homozygous mutations in IL-1 receptor antagonist (IL-1Ra) gene (IL1RN) in six families with a deficiency of IL-1Ra (DIRA) [41]. The absence of IL-1Ra allows the unopposed action of pro-inflammatory cytokines IL-1α and IL-1β, which results in life-threatening systemic inflammation with skin and bone involvement. This was first described in nine children harboring mutations that lead to the synthesis of a truncated non-functional form of IL-1Ra. All but one of those patients suffered from pustular skin disease of varied severity, ranging from localized pustules to generalized severe pustulosis [41]. Similar cases involving acute pustular rash with severe systemic symptoms have been reported by several other groups [42,43,44,45].
Although the first patient with GPP was described in 1910, it was not until over 100 years later that the etiology and detailed pathogenesis were elucidated. The high severity of inflammation seen in GPP patients and the existence of numerous familial cases led to the hypothesis of a monogenic inheritance pattern. This hypothesis was proved by the identification of homozygous and composite heterozygous loss-of-function mutations of IL-36 receptor antagonist gene (IL36RN) in 2011. The acronym DITRA (deficiency of interleukin thirty-six-receptor antagonist) is often used for those cases of GPP in which IL36RN mutation is detected [46]. Pathogenic IL36RN mutations were originally identified in consanguineous GPP pedigrees of Tunisian origin and in five isolated cases from the UK [46,47]. The knockout of the IL-36 receptor (IL-36R) in a murine model of deficiency of IL-36R antagonist led to the dramatic resolution of skin inflammation, making the blockade of IL-36R signaling a novel and promising therapeutic approach for patients with pustular variants of psoriasis [48,49]. Other important mutations that underlie the enhanced inflammatory cascade and the recruitment of neutrophils and macrophages have also been described in different groups of GPP patients. These include mutations in the CARD14 gene that encodes caspase-activating recruitment domain member 14 and in the AP1S3 gene that encodes adaptor protein complex 1 subunit sigma 3 [24,47,50,51,52]. Additional disease-associated variants in CARD14 and/or AP1S3 were identified in 15% of IL36RN mutation carriers, indicating an oligogenic instead of monogenic inheritance pattern [53].

2.1. Mutations of IL-36 Receptor Antagonist

The IL-36 family is a relatively novel group of cytokines that belongs to the IL-1 superfamily and consists of three pro-inflammatory agonists, IL-36α, IL-36β, and IL-36γ, and two antagonists, IL-36 receptor antagonist (IL-36Ra) and IL-38. These IL-36 cytokines are expressed in epithelial and immune cells and function through a shared receptor (IL-36R) to modulate innate and adaptive immune responses [54]. IL-36 cytokines can induce the downstream pro-inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) pathways via an intracellular signaling cascade by binding to IL-36R. Subsequently, the release of inflammatory mediators and chemotaxis that promote activation of neutrophils, macrophages, dendritic cells, and T cells is induced, ultimately causing the amplification of inflammatory responses [55].
IL36RN encodes the IL-36Ra, which suppresses the pro-inflammatory effects of IL-36 cytokines (namely IL-36α, IL-36β, and IL-36γ) by binding their receptor, interleukin-1 receptor-like 2 (IL-1RL2), and preventing the release of chemokines that stimulate the activation of neutrophils, macrophages, dendritic cells, and T cells; inducing neutrophil chemokine expression, infiltration, and pustule formation in GPP [56,57]. In vitro and ex vivo observations revealed that GPP alleles abolish the antagonistic effect of IL-36Ra; thus, IL-36 stimulation of patients’ cells results in enhanced production of pro-inflammatory cytokines such as IL-1, IL-6, and IL-8 [46,47]. Mutations in IL36RN, which were first described in 2009 in two families with severe pustular psoriasis, lead to functional impairment of IL-36Ra and subsequent amplification of the downstream inflammatory responses [46,47]. Such mutations in IL36RN gene were initially identified in north-African families suffering from autosomal recessive GPP. They were homozygous missense mutations, with the substitution of proline for leucine at position 27 (p.Leu27Pro) [46]. In another pioneering study of five European cases of GPP, three individuals were found to have mutations in IL36RN, including a novel homozygous missense mutation (p.Ser113Leu) and one compound heterozygote carrier (p.Ser113Leu and p.Arg48Trp) [47]. IL36RN mutations do not contribute to the risk of plaque psoriasis. In fact, most IL36RN mutations are identified in patients with GPP that do not suffer from concurrent plaque psoriasis [58]. This observation was confirmed by Sugiura et al., who first screened for IL36RN gene within two subgroups of patients with GPP (GPP alone and GPP with concurrent psoriasis vulgaris). They showed that all GPP patients without psoriasis vulgaris carried homozygous or compound heterozygous mutations in the IL36RN gene, whereas only 2 out of 20 cases of GPP with psoriasis vulgaris harbored compound heterozygous mutations [24]. Based on these results, it was suggested that GPP alone may represent a distinct subtype of GPP that is etiologically distinguishable from GPP occurring with psoriasis vulgaris [24].
Several types of IL36RN mutations, including substitution, frameshift, and splicing defects, have been reported as the causative genetic background in numerous GPP cases, in various geographical regions [8,24,46,47,53,59,60,61,62,63]. In addition, Hussain et al. demonstrated that IL36RN mutation carriers exhibit a more severe clinical phenotype (e.g., earlier age of disease onset, increased risk of systemic manifestations) and the absence of co-existing plaque psoriasis, when compared to individuals without IL36RN mutation [64]. The most recent analysis, which included a cohort of 251 unrelated patients with GPP from multiple countries, also showed that IL36RN gene mutations were associated with an early age of onset, prevalence of psoriasis vulgaris, and high recurrence rate of GPP [8]. On the basis of the findings of their study, the authors recommended that patients who present with GPP before the age of 30 should be screened for IL36RN mutations [8]. Overall, the prevalence of IL36RN mutations in patients with GPP has ranged between 10% and 82%, and was significantly lower in cases with associated plaque psoriasis than in those linked to GPP alone [23,65,66]. Biallelic IL36RN mutations are known to be disease-causing or disease-contributing in 21–41% of patients with GPP [24,46,47,53,64].

2.2. CARD14 Mutations/Variants

Rare gain-of-function mutations in the gene that encodes the keratinocyte signaling molecule (CARD14) were found to be causative of familial psoriasis vulgaris and familial pityriasis rubra pilaris in 2012 [67]. CARD14, expressed and localized predominantly in keratinocytes, is a scaffold protein that mediates NF-κB signal transduction, thus contributing to inflammatory responses within the epidermis [52,67,68,69,70]. Interestingly, CARD14 expression is essentially confined to the basal layer of epidermis in unaffected skin. However, it is upregulated in the granular layers in the skin of patients with GPP [69]. In 2019, Shao et al. reported that neutrophils isolated from patients with GPP induced the upregulated expression of inflammatory genes, including IL-1b, IL-36G, IL-18, tumor necrosis factor alpha (TNF-α), and C-X-C motif chemokine ligands in keratinocytes, and more than normal neutrophils. Moreover, neutrophils from patients with GPP secreted more exosomes than the controls. These neutrophils were then rapidly internalized by keratinocytes, which increased the expression of these inflammatory molecules by activating the NF-κB and MAPK signaling pathways [71]. Two independent groups reported that variants of the CARD14 gene are associated with GPP and palmoplantar pustular psoriasis [52,72]. Moreover, the first autosomal dominant familial pedigree of GPP associated with CARD14 mutations was described in [73]. Mutations in CARD14 gene account for only a small proportion of cases of GPP; in most cases they are present in GPP patients with concomitant psoriasis vulgaris, but were only rarely identified in GPP alone [8]. No mutations of the CARD14 gene that are specific to patients suffering from psoriasis vulgaris and GPP have yet been found. Therefore, the correlation between CARD14 gene mutations and the onset of GPP remains to be further elucidated.

2.3. AP1S3 Mutations

Adaptor-related protein complex 1 (AP-1) is a highly-conserved heterotetramer that plays a pivotal role in vesicular trafficking between the trans-Golgi network and endosomes [36]. In 2014, mutations in AP1S3, the gene encoding AP-1 complex subunit sigma 3, were found in unrelated individuals with severe pustular psoriasis, including patients with GPP not harboring IL36RN and CARD14 mutations [50]. In addition, Mahil et al. reported that knockout of AP1S3, which is highly expressed in keratinocytes, disrupted keratinocyte autophagy in several cell lines. This alteration results in the abnormal accumulation of p62, an adaptor protein mediating NF-κB activation, and thereby upregulation of IL-1 signaling and overexpression of IL-36α among other cytokines [51]. To date, there are fewer mutational reports on AP1S3 than on IL36RN or CARD14, as they only account for approximately 11% of GPP cases in Europe and are rarely found in East Asians [32,50].

2.4. TNIP1 Mutations

Three cytokine signaling pathways important in GPP pathogenesis (including angiopoietin signaling, NF-κB signaling, and retinoic acid receptor activation) were significantly associated with the TNIP1 gene encoding TNF-alpha induced protein 3-interacting protein 1 (TNIP1). This led to the designation of TNIP1 as a potential candidate susceptibility gene for GPP [74,75]. In a study of 73 patients with GPP in a Han Chinese population, six polymorphisms were identified in TNIP1 gene locus; however, they were shown to be only weakly associated with GPP [76].

2.5. SERPINA3 Mutations

SERPINA3 (Serpin Family A Member 3) encodes serine protease inhibitor A3 (serpin A3, also known as α1-antichymotrypsin), which specifically inhibits several proteases [77]. More recently, a new candidate gene for GPP was proposed in a publication by Frey et al. They detected a novel, rare loss-of-function variant in SERPINA3 in 2 out of 25 independent patients via whole exome sequencing [78]. SERPINA3 strongly inhibits the neutrophil protease cathepsin G (CTSG), which has been shown to process full-length secreted IL-36 cytokines to their more active forms, thereby increasing their pro-inflammatory activity ~500-fold [23,79,80].

2.6. MPO Mutation

The MPO gene encodes myeloperoxidase (MPO), an essential component of neutrophil azurophil granules [81]. Although the relationship between MPO deficiency and pustular psoriasis was first described in 1996 in an individual case report, it was only recently that a mutation in MPO gene was recognized as a background for GPP [82,83]. Vergnano et al. performed a whole-exome sequencing of 19 unrelated individuals with GPP and identified a subject harboring a homozygous splice-site mutation in MPOMPO screening in diseases phenotypically related to GPP uncovered further disease alleles in one patient with acral pustular psoriasis and in two subjects with AGEP [83]. Importantly, all three MPO gene variants that were observed in that study have a well-established impact on protein function, as they have been repeatedly observed in individuals with MPO deficiency [84,85]. Moreover, the phenotypic effects of MPO mutations were explored using a phenome-wide association study (PheWAS), which allowed identification of important relationships between genetic variants and a wide range of phenotypes. In vitro functional analysis revealed that mutations in the MPO gene cause an increase in neutrophil accumulation and activity, as well as a reduction in the number of apoptotic neutrophils. This observation further supported the role of this gene in neutrophil hemostasis and indicated its role in GPP pathogenesis [83]. These important findings regarding the significance of MPO gene variants in GPP were further confirmed by Haskamp et al., who discovered that 15 out of 74 patients affected by GPP carried eight variants in MPO gene that were all validated as loss-of-function mutations. They also performed a downstream analysis, which subsequently found that the activity of neutrophil elastase (NE), CTSG, and proteinase 3 (PR3), serine proteases that cleave IL-36 precursors into very active pro-inflammatory IL-36 cytokines, inversely correlated with MPO activity. This observation demonstrated that MPO deficiency was strongly linked to IL-36 pathway activation. Moreover, MPO deficiency caused defective formation of neutrophil extracellular traps (NETs) in the phorbol myristate acetate-induced pathway and reduced phagocytosis of neutrophils by monocytes (efferocytosis), thereby contributing to the prolonged persistence of harmful neutrophils and the reduced ability to resolve skin inflammation in GPP. Notably, a genotype–phenotype relationship similar to that of IL36RN gene was found in the abovementioned study, as the dosage of abnormal alleles of MPO gene negatively correlated with the age of disease onset [86]. Considering that the results of these studies implicated MPO as an important modulating enzyme of inflammation, MPO itself or MPO-related pathways represent attractive targets for anti-inflammatory therapies in GPP.
The above described mutations underlying GPP and their significance are depicted in Table 1.
Table 1. Summary of mutations associated with generalized pustular psoriasis. (ACH—acrodermatitis continua Hallopeau, GPP—generalized pustular psoriasis, IL-36—interleukin 36, NF-ƙB—nuclear factor kappa-light-chain-enhancer of activated B cells, PPP—palmoplantar pustulosis, PsV—psoriasis vulgaris).

3. Immunopathogenesis

3.1. Autoinflammation and Autoimmunity in GPP

Overexpression of IL-36 inflammatory cytokines in cutaneous lesions and loss-of-function mutations in IL36RN gene, as well as mutations in other genes related to the IL-36 pathway (e.g., CARD14, AP1S3, SERPINA3), have been identified in some patients; indicating that the IL-36 signaling pathway may be pivotal in the pathogenesis of GPP [46,50,52]. It has been discovered that IL36RNCARD14, and AP1S3 gene mutations activate pro-inflammatory signaling pathways via NF-κB, which further results in an increased expression of CXCL1-3, IL-1, IL-8, and IL-36 pro-inflammatory cytokines. In addition, MPO gene deficiency also promotes the activation of IL-36 signaling by regulating the activity of NE, CTSG, and PR3 serine proteases [32]. In addition, data from gene expression analyses have revealed that the transcriptome of GPP shares many similarities with that of plaque psoriasis, but it is inclined more towards innate immune mechanisms [23]. Thereby, subtypes of psoriasis are thought to exist within a continuum, wherein plaque psoriasis is characterized by an adaptive immunity involving a cluster of differentiation four-positive (CD4+) and CD8+ T cells and the key role of the IL-17/IL-23 immune pathway. Oppositely, in pustular variants of psoriasis, it is the innate immune responses involving IL-36 activation, neutrophil infiltration, and autoinflammation that are central to the pathogenesis [63].
Recent research on the interplay between IL-17- and IL-36-driven inflammation has shed a new light on how individual mediators may modify the spectrum of psoriasis via shifting innate to adaptive immunity or vice versa. The pathogenesis of GPP partly overlaps with the typical pathways of psoriasis vulgaris but exerts a more pronounced activation of the innate immune system. Therefore, cytokines such as IL-17A, IL-22, IL-23, and TNF-α were found to be elevated in both psoriasis vulgaris and GPP; however, GPP lesions yielded significantly higher IL-1 and IL-36, and lower IL-17A and interferon-gamma (IFN-γ) messenger RNA (mRNA) expressions, than plaque psoriasis lesions [23].
The discovery of the IL36RN mutation in GPP provided a rationale for blocking inflammasome, thus inhibiting autoinflammation. Antibodies targeting the IL-1–/IL-36–chemokine–neutrophil axis, including the recombinant IL-1 receptor antagonist anakinra and the anti-IL-1β monoclonal antibodies, canakinumab and gevokizumab, were beneficial in GPP, but the efficacy data comes only from isolated case reports and small case series [87,88,89,90]. More recently, as a result of better understanding of the immunopathogenesis of GPP, specific therapies targeting IL-36 have been developed. Two monoclonal antibodies targeting IL-36R, spesolimab (BI 655130) and ANB019, have shown promising initial results in GPP and have proceeded to phase II clinical trials [91,92,93,94].

3.2. GPP as an Autoinflammatory Keratinization Disorder

The term “autoinflammatory diseases” emerged in 1999, when germline mutations in tumor necrosis factor receptor superfamily 1A (TNFRSF1A) were reported as causative in tumor necrosis factor receptor-associated periodic syndrome (TRAPS) [95]. Autoinflammatory diseases, which are usually monogenic disorders with a systemic inflammatory component, are caused by genetic mutations in the molecules and signaling pathways involved in innate immune responses [95,96]. In order to highlight the major cutaneous manifestations of various autoinflammatory diseases, Akiyama et al. proposed a new term to encompass inflammatory keratinization diseases with a prominent autoinflammatory component, namely autoinflammatory keratinization disorders (AiKDs) [60]. AiKDs involve significant genetic factors causing the hyper-activation of innate immunity, primarily within the epidermis and the superficial dermis, which results in abnormally up-regulated keratinization [60]. Importantly, since AiKDs include conditions with mixed pathological mechanisms of autoinflammation and autoimmunity, they are unique, and in many ways different, from classic autoinflammatory diseases. Initially, AiKDs comprised pustular psoriasis and related entities, including GPP, impetigo herpetiformis, and acrodermatitis continua Hallopeau due to mutations in IL36RN, GPP and palmoplantar pustular psoriasis due to CARD14 variants [72], and pityriasis rubra pilaris caused by CARD14 mutations/variants [73]; the AiKDs spectrum has since been extended and now includes several entities [61,62].

3.3. IL-1/IL-36 Inflammatory Axis

IL36-chemokine–neutrophil axis appears to be central to the pathogenesis of GPP. The most prominent inflammatory response in pustular forms of psoriasis involves activation of IL-1 and IL-36 signaling [23]. IL-36 cytokines are part of the IL-1 family, which consists of 11 members: IL-1 (IL-1α, IL-1β, IL-1RA), IL-18, IL-33, IL-36 (IL-36α, IL-36β, IL-36γ, IL-36RA), IL-37, and IL-38 [97]. IL-36 signals to keratinocytes in an autocrine fashion, inducing the expression and enhancing the synthesis of more IL-36 cytokines. This further promotes the release of pro-inflammatory cytokines, antimicrobial peptides, and neutrophil chemokines, such as the chemokine (C-X-C) motif ligand 1 (CXCL1), CXCL2, and CXCL8, acting through six-transmembrane epithelial antigens of prostate (STEAP)1 and STEAP4 metalloreductases, and hence creating a feedback inflammatory loop in the epidermis that drives the disease [23,39,98,99]. To underline the important contrast between psoriasis vulgaris and pustular variants of psoriasis, STEAP1 and STEAP4 are only upregulated in the latter. This fact further confirms that neutrophil recruitment is preferentially active in pustular psoriasis, whereas plaque-type psoriasis is predominantly characterized by IL-17/IL-23 immune responses [26,100,101,102]. IL-36 acts on both naïve CD4+ T cells and dendritic cells [103]. With respect to dendritic cells, IL-36 activation promotes maturation and increases the expression of major histocompatibility complex class II molecules, along with the co-stimulatory molecules B7-1 (CD80) and B7-2 (CD86), in addition to promoting the secretion of such pro-inflammatory cytokines as IL-1, IL-23, TNF-α, and IL-6 [63,104]. IL-36 leads to the induction of IFN-γ, IL-4, and IL-17 by T cells and has also been shown to promote clonal CD4+ T cell expansion, T-helper type 17 (Th17) cells differentiation, and IL-17A production in GPP [105]. This activation, as well as the contribution of both T cells and dendritic cells in IL-36 responses, may be a justification for the good treatment response to anti-TNF-α, anti-IL-17A, and anti-IL-23 biologics that has been achieved in many patients with GPP [27,30,106].

3.4. IL-17/IL-36 Axis as a Bridge between Innate and Adaptive Immunity

IL-17 is one of the main cytokines produced by Th17/Th1 cells, which play a pivotal role in the immunopathogenesis of plaque psoriasis [107,108]. There are two highly homologous members of the IL-17 protein family, IL-17A and IL-17F [109]. Even though IL-36 is the main pathogenic cytokine in GPP, a strong expression of IL-17A is observed among patients with GPP. Nevertheless, the levels of its expression in the lesional skin of GPP patients are significantly lower than in patients with plaque psoriasis [23]. Due to the IL-36 pathway intertwining with the TNF-α/IL-23/IL-17/IL-22 axis, a positive inflammatory feedback loop is created, as explained above [110,111]. IL-17A promotes the chemotaxis and accumulation of inflammatory cells, such as neutrophils, at the sites of inflammation. However, it is believed that Th17 cells might not be solely responsible for IL-17 overexpression in GPP, with neutrophils being an additional source of IL-17 [26,112,113]. As mentioned previously, the CD4+ T cells, mainly CD4+ Th17 cells, secrete IL-17. Interestingly, the augmented proliferation of IL-17 producing CD4+ T cells is promoted via IL-36 signaling, as was first observed by Arakawa et al. [105]. This interlinking between innate and adaptive immune systems has unexpected consequences and links the IL-17 and IL-36 pathways in GPP pathogenesis (Figure 1) [105].
Figure 1. Pathogenesis of generalized pustular psoriasis and plaque psoriasis—a cross-talk between innate and adaptive immunity (modified from [63]). In GPP, skin injury causes dead keratinocytes to release cathelicidin LL-37, a protein that stimulates surrounding keratinocytes to release IL-36, which further enhances the production of different chemokines and recruitment of neutrophils, T cells, dendritic cells, and monocytes. IL-36 expression is induced by other pro-inflammatory cytokines, such as IL-1, TNF-α, and IL-17A. Additionally, neutrophil proteases process and activate IL-36 family cytokines that escalate the inflammatory process. The serine protease inhibitors SERPINA1 and SERPINA3 can inhibit neutrophil proteases, which have been shown to process full-length secreted IL-36 cytokines to their more active forms, thereby increasing their pro-inflammatory activity. The mutation of the IL36RN gene can lead to IL36Ra deficiency, aggravating the inflammatory response and triggering GPP. Other genes (CARD14AP1S3TNIP1) are also known to predispose to GPP. In plaque psoriasis, various triggers can cause activation of keratinocytes and the release of self-nucleic acids and antimicrobial peptides (e.g., cathelicidin LL-37), which, along with type I interferons (e.g., IFN-α and IFN-β), activate plasmacytoid and myeloid dendritic cells. Activated dendritic cells promote differentiation of naïve CD4+ cells into Th1, Th17, and Th22 cells. Cytokines produced by these T cells, such as IFNγ, IL-17, and IL-22, act on keratinocytes and cause hyperproliferation. Keratinocytes release chemokines and attract neutrophils and other leukocytes. In plaque psoriasis, a different cytokine pathway than in GPP subsequently results in the same pathophysiological outcome via chemokine and cytokine secretions from keratinocytes and both IL-17 and IL-22, promoting neutrophil infiltration. (AP1S3—adaptor related protein complex 1 subunit sigma 3, CARD14—caspase recruitment domain-containing protein 14, CD4+—cluster of differentiation four-positive, CXCL1—chemokine (C-X-C) motif ligand 1, CXCL2—chemokine (C-X-C) motif ligand 2, CXCL8—chemokine (C-X-C) motif ligand 8, DC—dendritic cell, IFN-α interferon-alpha, IFN-β—interferon-beta, IFN-γ—interferon-gamma, IL-1—interleukin 1, IL-8—interleukin 8, IL-17—interleukin 17, IL-17A—interleukin 17A, IL-17C—interleukin 17C, IL-17R—interleukin 17 receptor, IL-22—interleukin 22, IL-23—interleukin 23, IL-36—interleukin 36, IL-36R—interleukin 36 receptor, IL-36Ra—interleukin 36 receptor antagonist, MAPK—mitogen-activated protein kinase, mRNA—messenger RNA, NF-ƙB—nuclear factor kappa-light-chain-enhancer of activated B cells, SERPINA3—serpin family A member 3, STAT3—signal transducer and activator of transcription 3, Th1—T-helper 1 cells, Th17—T-helper 17 cells, Th22—T-helper 22 cells, TNF-α—tumor necrosis factor alpha, TNIP1—TNFAIP3 interacting protein 1). Parts of the figure were drawn by using pictures from Servier Medical Art (http://smart.servier.com/), licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/), accessed on 1 Jun 2021.

4. Biologic Therapeutics for GPP in the Light of Novel Genetic and Immunological Findings

Recently published findings of a survey regarding dermatologists’ opinions on the treatment efficacy in GPP revealed interesting and somewhat paradoxical results. While most physicians indicated that GPP flare treatments were adequate, they also stated that the response was slow and that many patients suffered from residual post-flare symptoms. It was indicated that the use of plaque psoriasis medications usually provides some benefits for GPP patients, but unmet needs clearly remain. The better utilization of the currently available therapies and the development of novel molecules will ensure safe long-term flare control [114].
TNF-α inhibitors (infliximab, adalimumab, and etanercept) were the first biologic agents to be used as an off-label treatment of GPP; therefore, the available data comprise a considerable number of GPP patients treated with those drugs [26,115]. The administration of those biologics results in rapid neutralization of TNF-α, which is also upregulated in GPP skin lesions [23]. Infliximab, the most-studied TNF-α blocking agent in GPP, showed a good response rate in 58% of patients and partial response in 28%. Notably, a quick onset of action was observed (pustule clearance in 1-3 days) [26]. Case report data also showed that infliximab can effectively treat juvenile GPP [116,117,118,119]. Treatment with TNF-α blockers was also highly effective in patients having IL-36Ra deficiency [120,121]. Interestingly, adalimumab has been shown to be a potential alternative treatment option in patients who fail infliximab, as Matsumoto et al. demonstrated significant improvement of GPP lesions in all four of their patients who had previously failed numerous systemic treatments, including infliximab, prior to switching to adalimumab [122]. It needs to be noted that most studies of TNF-α blocking agents in GPP are case reports. Therefore, further phase II and III clinical trials are necessary to evaluate the benefits and safety of these biologics in this indication.
Considering the upregulation of IL-17 and the pronounced neutrophilic infiltration in the skin of GPP patients, anti-IL-17 treatment appeared to be a very promising option [33]. Three IL-17 inhibitors (secukinumab, ixekizumab, and brodalumab) are currently licensed and approved for the treatment of moderate-to-severe plaque psoriasis [123]. All of the mentioned agents were used in GPP patients, including three open-label phase III clinical trials. Overall, a complete response was demonstrated in approximately two thirds of treated individuals, whereas only one in ten patients exhibited weak to no response [26]. The promising efficacy data for each of those compounds resulted in their approval for the treatment of GPP in Japan.
Since IL-23 plays a significant role in the pathogenesis of GPP, ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, has also been successfully utilized in the management of GPP [124]. Out of a total of seven described patients, complete remission has been achieved in six individuals; however, all but one of them were IL36RN-negative [26,124,125,126]. Risankizumab and guselkumab are both highly effective and safe inhibitors of the IL-23 p19 subunit, and which are approved for the treatment of moderate-to-severe plaque psoriasis [127,128]. Guselkumab was assessed in a phase III open-label study in GPP and was less efficient when compared to IL-17 inhibitors [30]. A phase III clinical trial to evaluate the efficacy and safety of risankizumab in Japanese patients with GPP has been completed but detailed results have to date not been published [129]
Even though blocking of the TNF-α/IL-17/IL-23 axis has resulted in some degree of success in GPP, the IL-1/IL-36-chemokine–neutrophil axis appears to be a more promising therapeutic target, especially in the context of the aforementioned immunopathogenetic findings [23].
IL-1 targeting with biologics has been previously performed in GPP patients using the IL-1α receptor antagonist (IL-1-RA) anakinra and the IL-1β monoclonal antibodies gevokizumab and canakinumab. Anakinra, a recombinant IL-1 receptor antagonist, frequently used in the treatment of other autoinflammatory diseases, was also documented to be successfully used in GPP, including a juvenile case [88,130]. However, further randomized control trials are needed to evaluate the efficacy and safety of anakinra in GPP. Gevokizumab is a monoclonal antibody blocking the pro-inflammatory cytokine IL-1β and its signal transduction in inflammatory cells [131]. Mansouri et al. reported a 79 and 65% reduction in GPP area and severity index scores at weeks 4 and 12 after treatment with gevokizumab in two patients with severe, recalcitrant GPP [90]. Another IL-1β antagonist, canakinumab, induced the complete and long-term clearance of GPP lesions in a patient in whom anakinra had been withdrawn due to hypersensitivity reactions [89].
The novel monoclonal antibody spesolimab (formerly BI 655130), targeting IL-36R, can effectively block the IL-36 signaling pathway, to alleviate inflammatory response in GPP patients [132]. Recently, a phase I clinical trial evaluated the safety and efficacy of this molecule in seven biologic-naïve adult patients with moderate GPP flare. The results showed that all patients carrying a homozygous IL36RN mutation (n = 3) or heterozygous mutation in CARD14 (n = 1) or wild-type alleles (n = 4) significantly responded to a single intravenous dose at week 4 [91,93]. None of these patients, nor any of the 124 healthy volunteers who participated in this study, experienced severe adverse effects [93]. This finding suggested that IL-36R inhibition with a single dose of spesolimab can effectively alleviate the severity of GPP, regardless of the presence of a disease-causing gene mutation, and has great potential for the future clinical treatment of GPP
Results of a healthy volunteer phase I study of another anti-IL-36R drug, imsidolimab (formerly ANB019), also suggested a favorable side effect profile of inhibiting the function of the IL-36 pathway, which supported the advancement of imsidolimab into a phase II trial (GALLOP) [94]. Preliminary results were encouraging, as six out of eight patients treated with imsidolimab monotherapy achieved the primary endpoint of improvement in the clinical global impression scale after 28 days of treatment. Imsidolimab was generally well-tolerated, and most treatment-emergent adverse events were mild to moderate in severity and resolved without sequelae. No infusion or injection site reactions were observed. Detailed information on the identified gene mutations in those patients were not disclosed [133]. More detailed characteristics and data on the efficacy of the abovementioned therapies are summarized in Table 2.
Table 2. Targeted therapies in generalized pustular psoriasis. (CD25—cluster of differentiation 25, CGI-I—clinical global impression of improvement, Fab’—humanized antigen-binding fragment, GPP—generalized pustular psoriasis, IFN-γ—interferon-gamma, IgG—immunoglobulin G, IgG1—immunoglobulin G1, IgG1κ—immunoglobulin G1 kappa, IgG1λ—immunoglobulin G1 lambda, IgG2—immunoglobulin G2, IgG4—immunoglobulin G4, IL-1—interleukin 1, IL-1β—interleukin 1 beta, IL-1R—interleukin 1 receptor, IL-2—interleukin 2, IL-2Rα—interleukin 2 receptor alpha, IL-12—interleukin 12, IL-12/23 p40—p40 subunit of interleukin 12 and interleukin 23, IL-17—interleukin 17, IL-17A—interleukin 17A, IL-17RA—interleukin 17 receptor A, IL-23—interleukin 23, IL-23 p19—p19 subunit of interleukin 23, IL-36—interleukin 36, IL-36R—interleukin 36 receptor, IL36RN—IL-36 receptor antagonist gene, Th1—T-helper 1 cells, Th17—T-helper 17 cells, TNF-α—tumor necrosis factor alpha).

5. Conclusions

GPP is a serious and potentially life-threatening disease that is often difficult to treat. The past decade has witnessed enormous progress in the understanding of the molecular and immunologic basis of GPP. Arguably, one of the most important discoveries leading to a better understanding of the pathogenesis of this exceptional type of psoriasis was the report of the association between IL36RN and GPP, which was shortly followed by other significant genetic findings [70]. However, numerous studies found that a large number of patients with GPP did not carry any known variations in the above described genes, which implies that some novel variants located in introns or regulatory regions and other genetic factors may contribute to GPP’s pathogenesis [53]. Further screening and identification of other genes will therefore complement the current genetic map of GPP and is likely to greatly contribute to novel therapeutic approaches. The last few years have shed some new light on the immunological disturbances behind GPP. As shown by the recent studies, the TNF-α/IL-23/IL-17/IL-22 axis and IL-36 pathway intertwine in GPP pathogenesis [105]. This significant observation allowed the use of biologics, known for being effective in the treatment of plaque psoriasis, to be also used in GPP, regardless of IL36RN mutation status. However, the emerging need for more effective targeted therapies resulted in the development of a novel group of drugs that directly inhibits IL-36R [91].
Therapeutic intervention in GPP is a significant challenge. Given the rarity of GPP, the recruitment of a sufficient number of patients to conduct a large, randomized, controlled clinical trial, to adequately investigate the efficacy and safety of therapeutics, is the main difficulty. Moreover, the variable and unpredictable course of GPP makes it even more difficult to assess the efficacy of any intervention in this indication.

Author Contributions

Conceptualization, D.S., J.S., A.R.; Resources, D.S., J.S.; Writing—Original Draft Preparation, D.S., J.S.; Writing—Review & Editing, D.S., J.S., A.R.; Supervision, A.R. All authors contributed equally to this work. All authors have read and agreed to the published version of the manuscript.

Funding

The publication fee was covered by the grant of the University of Rzeszow: “Analysis of clinical and molecular parameters and studies on new drugs in skin diseases” (Scientific Research of Institute of Medical Sciences University of Rzeszow, 500-3-60-601/2021).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data availability is not applicable to this article, as no new data were created or analyzed in this study.

Conflicts of Interest

The authors declare no conflict of interest.

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