Diseases categorized as autoinflammatory keratinization diseases (AiKDs), and their pathologies and treatments

ABSTRACT

Whole-exome and whole-genome sequencing have become widespread in approximately the last 15 years, and the predisposing factors and pathomechanisms of inflammatory keratinization diseases, which have been unknown for a long time, have gradually been revealed. Hence, various inflammatory keratinization diseases are recognized to cause innate immunity hyperactivation. Therefore, we have been advocating for the clinical entity, “autoinflammatory keratinization diseases (AiKDs)” since 2017. AiKDs are inflammatory keratinization diseases caused by autoinflammatory-related pathomechanisms in the skin. The aberrant activation of innate immunity and the resultant autoinflammation in the epidermis and the superficial dermis in AiKDs cause hyperkeratosis in the epidermis. Our initially proposed concept of AiKDs included generalized pustular psoriasis and related conditions, pityriasis rubra pilaris type V, and familial keratosis lichenoides chronica. Since then, the number of diseases known to be AiKDs has increased as previously unknown disease-causing factors and pathogenetic mechanisms of inflammatory keratinization diseases have been clarified one by one. To date, porokeratosis, hidradenitis suppurative, keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome, and AiKDs associated with epidermal growth factor receptor (EGFR) deficiency or with hepatitis and autism have been recognized as AiKDs. The concept of AiKDs is considered extremely useful in our precise understanding of the pathogeneses behind inflammatory keratinization diseases and our appropriate treatment method selection. The number of AiKDs is expected to grow with the clarification of the pathomechanisms of further inflammatory keratinization diseases.

INTRODUCTION: WHAT ARE AUTOINFLAMMATORY KERATINIZATION DISEASES (AiKDs)?

The concept of autoinflammatory diseases or syndromes, whose pathogeneses are closely associated with autoinflammation (innate immunity hyperactivation due to genetic factors), has long been well known.¹ Systemic autoinflammatory diseases contain several different types, including familial Mediterranean fever, cryopyrin-associated periodic syndrome, and tumor necrosis factor (TNF) receptor-associated periodic syndrome. Systemic autoinflammatory diseases or syndromes are usually monogenic diseases characterized by innate immunity hyperactivation as the pathogenic mechanism, and the majority exhibited recurrent fever.² Unlike autoimmune diseases, autoinflammatory diseases do not exhibit antigen-specific tolerance breakdown nor B-cell or T-cell hyperactivation but instead demonstrate upregulated innate immune responses, such as neutrophil infiltration, which play a crucial role in their pathogeneses.¹ Autoinflammatory diseases and syndromes affect various organs throughout the body, and various symptoms generally occur in the skin.³

In contrast, inflammatory reactions in the epidermis and the superficial part of the dermis affect the epidermal cell turnover and keratinization processes in a group of skin diseases termed inflammatory keratinization diseases, resulting in excessive keratinization (hyperkeratosis). Inflammatory keratinization diseases are a vast and diverse group of diseases, including relatively prevalent conditions, such as psoriasis and lichen planus, which affect a significant number of patients. The pathogenic mechanisms and causative factors of inflammatory keratinization diseases have long been unknown although they are prevalent disorders. However, whole-exome and whole-genome sequencing have become widespread in approximately the last 15 years, and the predisposing factors and pathomechanisms of inflammatory keratinization diseases, which had been long unknown, have gradually been revealed.^4-16 The pathogeneses of various inflammatory keratinization diseases have been closely related to genetic predispositions to innate immunity hyperactivation caused by genetic factors, ie, autoinflammation.

To date, IL36RN loss-of-function variants and CARD14 gain-of-function variants have been identified as causative factors in pustular psoriasis and related disorders.¹⁷ CARD14 gain-of-function variants have been demonstrated as causative genetic factors of pityriasis rubra pilaris (PRP) type V.¹¹ Furthermore, familial chronic lichenoid keratosis (KLC) is caused by gain-of-function variants in NLRP1.¹⁰ The pathogenesis-related genes for each of these diseases all encode molecules that play important roles in innate immunity in the skin, especially in the epidermis. Interleukin-36 (IL-36) binds to the IL-36 receptor, causing downstream inflammatory responses.^18,19 The IL-36 receptor antagonist, which is encoded by IL36RN, constrains the IL-36 binding to the IL-36 receptor and controls IL-36 pathway-mediated inflammatory responses. CARD14, which is encoded by CARD14, induces skin inflammation by activating NF-κB in epidermal keratinocytes.⁶ NLRP1 encodes NLR family pyrin domain-containing protein 1 (NLRP1), which is the major inflammasome sensor in keratinocytes. NLRP1 inflammasome activation causes IL-1β and IL-18 release from epidermal keratinocytes, resulting in skin inflammation.¹⁰ Molecules that are predisposing factors for these various types of inflammatory keratinization diseases are important in innate skin immunity, and autoinflammation is considered to play a crucial role in the pathogenic mechanisms of inflammatory keratinization diseases.²⁰

In 2017, we advocated for a new disease concept from newly obtained knowledge about the etiology of inflammatory keratinization diseases, the “autoinflammatory keratinization diseases (AiKDs)”, which widely encompasses various inflammatory keratinization diseases mainly caused by autoinflammation.^21,22 AiKDs initially included pustular psoriasis and related diseases, PRP type V, and familial KLC during its proposal.²¹ To date, hidradenitis suppurativa, porokeratosis, keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome, and AiKDs associated with epidermal growth factor receptor (EGFR) deficiency or with hepatitis and autism have been added to AiKDs (Table 1).^{16,17,20,22-26} Accurately understanding that the disease pathomechanisms included in AiKDs are autoinflammatory is of great significance. Such an understanding of disease etiology promises to contribute to novel therapeutic innovation targeting essential molecules or inflammatory pathways in AiKD pathogenic mechanisms.^20,26,27 For example, biologics focusing on the IL-36 axis are promising novel therapeutic agents for pustular psoriasis and related disorders.

Table 1.

Diseases classified as AiKDs, with their predisposing factors and mechanisms of pathogenesis (adopted and modified from References No. 17, 20, 22 and 26)

Disease	Genetic causative or predisposing factor	Pathogenetic mechanism
Pustular psoriasis and related conditions
Generalized pustular psoriasis (GPP) (including impetigo herpetiformis)	1) IL36RN loss-of-function variants	a) hyperactivation of the IL-36 pathway
	2) CARD14 gain-of-function variants	b) upregulation of CARD14-NFκB signaling
	3) AP1S3 loss-of-function variants	c) deficient AP1 endosomal translocation, defective autophagy
	4) MPO loss-of-function variants	d) hyperactivation of the IL-36 pathway, defective efferocytosis of neutrophils
	5) SERPINA3 loss-of-function variants	e) hyperactivation of the IL-36 pathway
	6) BTN3A3 loss-of-function variant(s)	f) disturbed IL-1/IL-36 axis (?), upregulation of the TNF-α pathway (?)
acrodermatitis continua	1) – 4) above	a) – d) above
palmoplantar pustular psoriasis (palmoplantar pustulosis)	1) – 3) above	a) – c) above
Pityriasis rubra pilaris (PRP) (mainly type V)	CARD14 gain-of-function variants	upregulation of CARD14-NFκB signaling
Porokeratosis	loss-of-function variants in the mevalonate pathway-related genes MVK, MVD, PMVK and FDPS	disturbed mevalonate-isoprenylated protein pathway
Hidradenitis suppurativa	1) loss-of-function variants in the γ-secretase genes NCSTN, PSENEN and PSEN1	a) deficient γ-secretase, downregulated Notch signaling
	2) variants in NOD2, LPIN2, NLRP3, NLRP12, PSMB8, MVK, IL1RN	b) other autoinflammatory pathways
Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome	a single-nucleotide deletion in the 5′UTR of POMP (dysfunction of POMP)	proteasome maturation deficiency, ER stress and UPR
Familial keratosis lichenoides chronica	NLRP1 gain-of-function variants (unknown)	hyperactivation of the NLRP1 inflammasome pathway
AiKD with EGFR deficiency	EGFR loss-of-function variants	hyperactivation of PLA2, NFκB, and JNK1 signaling
AiKD with hepatitis and autism	JAK1 gain-of-function variants	hyperactivation of JAK1-STAT signaling

AiKDs are characterized by four significant attributes.^21,22 (1) The primary etiological event is epidermal and superficial dermal inflammation. (2) This inflammation causes hyperkeratosis. (3) Genetic causative factors of AiKDs provoke innate immunity hyperactivation, causing epidermal and superficial dermal autoinflammation. (4) The main pathogenic mechanism of inflammation in AiKDs is autoinflammation, but autoimmune reactions sometimes play a crucial role.^21,22 Psoriasis vulgaris has both autoinflammatory and autoimmune pathogeneses. Thus, psoriasis vulgaris might well be included in AiKDs.²⁰ However, several patients have psoriasis vulgaris, but only a minority of whom have been revealed to have genetic predisposing factors. Hence, I have intentionally excluded psoriasis vulgaris. In the future, we cannot exclude the possibility of considering psoriasis vulgaris as an AiKD if a majority of patients with psoriasis vulgaris are demonstrated to have distinct genetic predisposing factors.

As previously described above, AiKDs included pustular psoriasis and associated disorders, PRP type V, hidradenitis suppurativa, porokeratosis, familial KLC, KLICK syndrome, and AiKDs associated with EGFR deficiency or with hepatitis and autism (Table 1, Figure 1).^{16,17,20,22-26} Disorders and conditions contained in the AiKD category are anticipated to grow in number in recent years, with the clarification of the pathogeneses of inflammatory keratinization diseases.²⁰ The unique concept of AiKDs is expected to help precisely understand the pathogenesis of inflammatory keratinization disorders due to autoinflammation, causing novel treatment strategy innovation.^{16,20,21-24,26}

Fig. 1.

Clinical features of patients with representative AiKDs

Fig. 1a: Pustular psoriasis characterized by irregularly shaped confluent erythema with multiple pustules on the leg of a patient with DITRA with a heterozygous IL36RN loss-of-function variant.

Fig. 1b: PRP type V characterized by keratotic papules and erythema on the trunk and arm of a patient carrying a heterozygous CARD14 gain-of-function variant.

Fig. 1c: Porokeratosis (eruptive pruritic papular porokeratosis) characterized by inflammation at the typical disseminated superficial porokeratotic lesions and erythema expanding to the surrounding areas on the left thigh of a patient with eruptive pruritic papular porokeratosis carrying an MVD germline variant.

Diseases included in AiKDs may be categorized into those that are purely genetic, such as KLICK syndrome, and those that have germline mutations associated with only some patients, such as generalized pustular psoriasis (GPP). However, distinguishing between them might be difficult because it may become clear in the future that a considerable number of patients do have genetic causative variants even in diseases in which genetic factors are not known to play a crucial role in the majority of patients. Thus, categorizing AiKDs into purely genetic ones versus partly genetic ones might be premature.

Researchers have elucidated only a few AiKDs for which the immune cells associated with innate immunity play important roles in pathogenesis. Neutrophils have played crucial roles in the pathogenesis of skin lesions in GPP and hidradenitis suppurativa.^17,28 However, neither γδ T cells nor natural killer (NK) cells have been reported to play crucial roles in AiKD pathogeneses.

DISEASES INCLUDED IN AiKDs AND THEIR PATHOGENESIS

At present, AiKDs included many inflammatory keratinization diseases, and the number of disorders and conditions considered to be AiKDs remains increasing. The genetic causative factors and pathomechanisms of the disorders included in AiKDs widely vary, although they share autoinflammation as the main pathogenic mechanism. The diseases currently classified in AiKDs are summarized below.

Pustular psoriasis and related conditions

Pustular psoriasis is considered a subtype of psoriasis and is characterized by sterile pustules. Pustular psoriasis is divided into generalized and localized types.¹⁷ The generalized types are characterized by skin lesions seen almost in the entire body. The GPP types include acute GPP (von Zumbusch), infantile GPP, impetigo herpetiformis (GPP caused by pregnancy), generalized acrodermatitis continua of Hallopeau, and annular pustular psoriasis.²⁹ Localized types are characterized by skin lesions seen only in limited areas, such as the tips of the extremities and the palms and soles. The localized types include acrodermatitis continua of Hallopeau and palmoplantar pustular psoriasis.²⁹ In general, all pustular psoriasis subtypes are included in AiKDs.¹⁷ In particular, GPP is considered a representative AiKD.³⁰ Patients with early-onset GPP without plaque psoriasis typically have IL36RN loss-of-function mutations as genetic causative factors (Figure 1a).^31,32

IL36RN encodes the IL-36 receptor antagonist. Epidermal keratinocytes mainly produce the IL-36 receptor antagonist, which competitively prevents the binding of IL-36α, β, and γ to the IL-36 receptor.¹⁸ TNF-α and IL-17 inflammatory pathways induce IL-36α, β, and γ production. IL-36α, β, and γ bind to IL-36 receptors, which activates NFκB, thereby increasing cytokine/chemokine production and lesional epidermal inflammation of pustular psoriasis (Figure 2a).³³ IL-36 receptor antagonists competitively inhibit IL-36 signaling and repress the IL-36-induced inflammation amplification. IL-36 pathway-induced inflammation is exacerbated in patients with impaired IL-36 signaling inhibition due to loss-of-function variants in IL36RN.⁵ Intensive inflammatory responses due to IL-36 receptor antagonist malfunction are the major pathogenic mechanisms in patients with pustular psoriasis harboring loss-of-function variants in IL36RN.

Fig. 2.

Genetic causative defects and pathogenic pathways/mechanisms of autoinflammatory keratinization diseases (AiKDs) (adopted and modified from References No. 17, 21, 22, and 26)

Fig. 2a: IL36RN loss-of-function variants in pustular psoriasis characterized by excessive IL-36 signaling due to IL-36 receptor antagonist deficiency causing autoinflammation in the skin.

Fig. 2b:CARD14 gain-of-function variants in pustular psoriasis and PRP type V characterized by CARD14 gain-of-function variants overactivating the CARD14-NFκB pathway and causing cutaneous inflammation.

Fig. 2c:POMP mutation (1-bp deletion in the 5′UTR) in KLICK syndrome characterized by POMP deficiency causing proteasome insufficiency and ER stress, thereby hyperactivating UPR and autoinflammation in the skin.

Fig. 2d:NLRP1 gain-of-function variants in familial KLC characterized by the aberrant NLRP1 inflammasome activation causing the upregulated IL-1β and IL-18 secretion, resulting in skin autoinflammation.

Fig. 2e:EGFR loss-of-function variants in AiKD with epidermal growth factor (EGFR) deficiency characterized by EGFR deficiency causing phospholipase A2 (PLA2), NFκB, and JNK1 upregulation, resulting in skin inflammation.

Fig. 2f: A JAK1 gain-of-function variant in AiKD with hepatitis and autism characterized by the hyperactivated JAK1-STAT pathway increasing chemokine and cytokine secretion.

Red up arrows: upregulation.

⊥: inhibition.

Stephenson et al³⁴ proposed the 15-item DITRA/Autoinflammatory Diseases Activity Index (DITRA/AIDAI), which consists of the AIDAI³⁵ plus three additional skin-focused items: skin rash (pustular), skin rash (plaque type with keratinization), and geographic tongue, to score the severity of deficiency of IL-36 receptor antagonist (DITRA)/AiKDs due to IL36RN variants.

Variants in five other genes, including CARD14, AP1S3, MPO, SERPINA3, and BTN3A3, in addition to IL36RN variants, have been recognized as predisposing factors for pustular psoriasis.^17,36

CARD14, which is encoded by CARD14, works in NFκB signaling activation in epidermal keratinocytes.⁶ Thus, variant CARD14 hyperactivates NFκB in keratinocytes and induces skin lesion inflammation in patients with GPP and palmoplantar pustular psoriasis due to CARD14 gain-of-function variants (Figure 2b).³⁷

AP1S3 encodes adapter-related protein complex 1 subunit sigma 3 (AP1S3), and AP1S3 variants have been identified in patients with all types of pustular psoriasis.^8,38-40 AP1S3 is involved in adapter-related protein complex 1 (AP-1) formation. AP-1 participates in clathrin-mediated vesicular transport from the Golgi or endosomes. AP1S3 silencing reportedly disturbs the endosomal translocation of Toll-like receptor 3, thereby affecting the homeostasis of the Toll-like receptor system in keratinocytes.⁸ Furthermore, AP1S3 loss-of-function was reported to cause defects in autophagy and the aberrant p62 accumulation, causing NFκB hyperactivation and IL-1 signaling upregulation and excessive IL-36α production in the skin.³⁸

Additionally, defects in the neutrophil heme-containing enzyme myeloperoxidase, which is encoded by MPO, have been associated with GPP development.^13,14

Neutrophil elastase, cathepsin G, and proteinase 3, which are neutrophil serine proteases, and monocyte protease cathepsin S cleave IL-36 precursors, causing the formation of active IL-36 forms. Defective myeloperoxidase activity in neutrophils causes the upregulated activity of neutrophil serine proteases, the decreased neutrophil extracellular trap formation, and an abundance of soluble neutrophil proteases, causing the excessive IL-36 cytokine activity.¹³ Furthermore, myeloperoxidase deficiency disturbs neutrophil efferocytosis, thereby extending the persistence of infiltrating neutrophils at inflammation sites in the skin.¹³

Additionally, in 2020, loss-of-function variants in SERPINA3, which encodes serine protease inhibitor A3 (SERPINA3), were reported as predisposing factors for GPP.¹⁵ The loss of SERPINA3 function is believed to cause the IL-36 pathway upregulation because SERPINA3 reduces the activity of various neutrophilic proteases that activate IL-36.¹⁵

In 2023, gene burden testing indicated that BTN3A3 correlates with GPP.³⁶ Further studies revealed the significant association between one loss-of-function variant, c.513G>A (p.Trp171*), in BTN3A3 and GPP.³⁶ BTN3A3 is a member of the butyrophilin (BTN) 3 subfamily, and its function remains to be elucidated. Zhang et al³⁶ indicated that BTN3A3 expression is related to inflammatory imbalances in patients with GPP and demonstrated that BTN3A3 deficiency in HaCaT cells significantly suppresses IL36RN mRNA expression.

Pityriasis rubra pilaris

PRP is commonly recognized as an inflammatory keratinization disease characterized by keratotic papules and scales primarily on the trunk and the extensor sides of the extremities (Figure 1b). Hyperkeratosis and erythema are often observed on the palms. At present, PRP is categorized into six types following onset age, clinical presentation, and disease course.^41,42 PRP type V has its onset in infancy or early childhood and has a chronic disease course without improvement for a lifetime. Many patients with PRP type V have CARD14 variants as a genetic predisposing factor, and PRP type V is believed to be an AiKD.^11,21 CARD14 gain-of-function variants activate NFκB excessively in keratinocytes in patients with PRP, causing autoinflammation in the epidermis and the superficial dermis (Figure 2b). PRP caused by gain-of-function CARD14 variants is considered an AiKD.^11,21

Porokeratosis

Porokeratosis is a keratinization disease characterized histopathologically by the presence of cornoid lamellae, which are towering columns of parakeratotic cells in the stratum corneum from the spinous cell layers, at the margin of brown keratotic plaques and macules.⁴³ Porokeratosis has been historically categorized following the clinical features into various subtypes, including classic porokeratosis (porokeratosis of Mibelli), superficial disseminated porokeratosis, and superficial disseminated actinic porokeratosis.⁴³ Porokeratosis lesions are usually asymptomatic, but they can be accompanied by intense inflammation such as in eruptive pruritic popular porokeratosis (Figure 1c).⁴⁴ Some familial cases of porokeratosis have exhibited autosomal dominant inheritance. Variants in four genes (MVD, MVK, PMVK, and FDPS) that encode enzymes involved in the mevalonate pathway have been described as disease-related genes for porokeratosis.^7,45 Porokeratosis has been considered an AiKD caused by variants in mevalonate pathway genes.⁴⁶ Abnormal epidermal morphology was reported in Mvda-deficient zebrafish (Mvda being the zebrafish homolog to human MVD).⁴⁷ Furthermore, peripheral T-cell subset alterations and proinflammatory cytokine dysregulated production by T cells are found in patients with porokeratosis who harbor MVD variants as well as those with MVK variants.⁴⁸ These findings might help elucidate the pathogenesis of porokeratosis as an AiKD.⁴⁸

Hidradenitis suppurativa

Hidradenitis suppurativa is characterized by chronic, recurrent, intractable multiple abscesses and pustular drainage, primarily in the groins, axillae, buttocks, and vulva.^49,50 It had been considered an infectious disorder but has recently been recognized as an AiKD.^12,51-53 Familial cases of hidradenitis suppurativa exhibit a more robust tendency to possess AiKD characteristics than nonfamilial cases.⁵¹ Some hidradenitis suppurativa cases demonstrated variants in genes that encode NCSTN, PSENEN, and PSEN1, which are the proteins that form the γ-secretase complex.⁵¹ Hair follicle epithelial hyperkeratosis is seen in hidradenitis suppurativa cases with variants in these genes, thereby occluding hair follicles and plugging keratin. Such occlusion and plugging are major steps in hidradenitis suppurativa pathogenesis.^12,51 Notch1 and Notch2 signaling dysfunction was indicated in the skin lesions of patients with hidradenitis suppurativa with variants in γ-secretase complex genes.^53,54

Some patients with various systemic autoinflammatory diseases/syndromes, including familial Mediterranean fever, arthritis suppurativa, pyoderma gangrenosum, acne (PAPA) syndrome, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PASH) syndrome, demonstrated hidradenitis suppurativa-like cutaneous symptoms. Innate immunity hyperactivation in the skin is assumed to be the pathogenesis of hidradenitis suppurativa-like cutaneous symptoms in systemic autoinflammatory diseases and syndromes,⁵¹ and these hidradenitis suppurativa-like cutaneous symptoms indicate the significance of autoinflammatory pathomechanisms in hidradenitis suppurativa.

Additionally, patients with hidradenitis suppurativa have demonstrated variants in several autoinflammation-related genes (NOD2, LPIN2, NLRP3, NLRP12, PSMB8, MVK, and IL1RN).⁵¹ Recently, patients with biallelic MVK variants have shown both hidradenitis suppurativa and hyper-IgD syndrome (an autoinflammatory syndrome).⁵⁵ These cases further support the idea that hidradenitis suppurativa should be included in the AiKDs. Adalimumab, which is a monoclonal anti-TNFα antibody used to treat pustular psoriasis, has recently been used in patients with hidradenitis suppurativa, considering the pathogenesis of hidradenitis suppurativa as an AiKD.^56,57 Additionally, brodalumab, which is an IL-17 receptor A antibody, was reported to be effective for hidradenitis suppurativa as an AiKD.⁵⁸

KLICK syndrome

KLICK syndrome is a very rare inflammatory keratinization disease. Patients present hyperkeratosis and scaling over wide body surface areas, including the palmoplantar areas.⁵⁹ Linearly arranged hyperkeratotic papules are seen on the cubital fossae and the wrists while hyperkeratotic plaques on the axillae and the neck.⁵⁹ Hyperkeratosis, acanthosis with papillomatosis, and hypergranulosis are histopathologically seen in the lesional epidermis, and nonspecific inflammatory cell infiltration is observed in the dermis of the skin lesions.⁵⁹ A homozygous single-nucleotide deletion in the 5′UTR of POMP, which encodes proteasome maturation protein (POMP), which is a key chaperone for proteasome maturation, causes KLICK syndrome.⁴ Deficiency in such maturation caused by POMP dysfunction boosts endoplasmic reticulum stress and provokes unfolded protein response (Figure 2c).^4,60,61 KLICK syndrome is thought to be an AiKD, considering the pathomechanism by which autoinflammation causes hyperkeratosis.²³ Notably, heterozygous frameshift variants in the penultimate exon of POMP have been reported to cause a systemic autoinflammatory disease called proteasome-associated autoinflammatory syndrome 2 (PRAAS2), which is also known as POMP-related autoinflammation and immune dysregulation disease.^61,62

KLC

KLC is a rare inflammatory keratinization disorder. Patients show multiple keratotic papules and nodules on the extensor sides of the extremities and the trunk. Patients with KLC show seborrheic dermatitis-like lesions on the face, hyperkeratotic lesions on the palms and the soles, and thickening deformities of the nails.⁶³ Lichenoid tissue reaction is histopathologically observed in the skin lesions.⁶³ Patients with KLC with a family history have occasionally been reported. An NLRP1 gain-of-function variant, which encodes NLR family pyrin domain-containing protein 1 (NLRP1), had been a genetic causative factor in familial KLC in 2016.¹⁰ NLRP1 is an inflammasome sensor, and the causal NLRP1 variant excessively activates NLRP1 inflammasomes, primarily in keratinocytes.¹⁰ NLRP1 inflammasome activation in the epidermis in increased IL-1β secretion causes epidermal and superficial dermal autoinflammation (Figure 2d).^10,64 Thus, familial KLC caused by NLRP1 gain-of-function variants is considered an AiKD.^21,22

AiKDs with epidermal growth factor deficiency

We indicated skin inflammatory symptoms due to germline EGFR variants to be included in AiKDs.²⁵ Several facts indicated that inflammatory skin symptoms caused by EGFR variants demonstrate characteristic AiKD features. Hyperkeratosis was clinically and histopathologically seen in the skin lesions of a patient with a homozygous loss-of-function variant who demonstrated neonatal inflammatory skin and bowel disease⁹ and in patients with fatal neonatal nephrocutaneous syndrome caused by EGFR variants.⁶⁵ The majority of patients carrying EGFR variants demonstrated ichthyosiform skin desquamation, which is a characteristic of AiKDs. Furthermore, the patient with neonatal inflammatory skin and bowel disease had neutrophilic infiltration in the follicular epithelium, causing folliculitis.⁹ The patient’s skin mRNA expression patterns revealed the upregulation of inflammatory and innate immune response pathways, especially NF-κB, c-Jun N-terminal kinase 1 (JNK1), and phospholipase A2.⁹ EGFR-ablated mice demonstrated the overexpression of the cytokines/chemokines CCL5, CCL11, CCL2, CCL22, IL-1β and TNF-α in the skin.⁶⁶ These data indicated patients with EGFR loss-of-function variants and skin symptoms to be having an AiKD (Figure 2e).

AiKDs with hepatitis and autism

A unique AiKD case suffering from severe early-onset hepatitis and autism has been reported with a JAK1 gain-of-function variant.¹⁶ The female patient presented with mild erythema and dry skin over a wide body area since birth, and she had erythema on the cheeks and ichthyotic lesions on the trunk at 8 years of age. Janus kinase 1 (JAK1), which is encoded by JAK1, plays crucial roles in various cytokine signaling, such as IL-6 and interferons.⁶⁷ Indeed, heterozygous JAK1 variants had been associated with a disease characterized by multiorgan immune dysregulation.^68,69 Thus, the heterozygous gain-of-function variant in JAK1 is considered to cause multiorgan immune dysregulation, causing the unique AiKD: AiKD with hepatitis and autism, in AiKD with hepatitis and autism due to a JAK1 variant (Figure 2f).¹⁶

TREATMENTS FOR AiKDs

Novel therapeutic strategies and new drugs that target key molecules and pathways in the autoinflammatory pathomechanisms of AiKD have already been developed or are expected to be innovated by precisely elucidating the autoinflammation-related pathogenetic mechanisms of various AiKDs.²⁶ Additionally, the repurposing of drugs already used for other inflammatory diseases as novel AiKD treatments is thought to be a promising strategy for innovative AiKD medications.

Treatments targeting the IL-36 pathway

GPP is representative of AiKD, and IL36RN variants are known as a significant predisposing factor for GPP. The IL-36 pathway is thought to be crucial in GPP pathogenesis. Thus, the IL-36 pathway is a promising target for novel treatments.²⁸ Individuals carrying loss-of-function variants in IL1RL2, which encodes the IL-36 receptor interleukin-1 receptor-like 2 (IL1RL2), were investigated in terms of safety.⁷⁰ Individuals with abolished IL-36 receptor functions demonstrated no immune function deficits. Therefore, IL-36 signal inhibition did not significantly disturb the host defense, and such inhibition was considered a possibly safe treatment.⁷⁰ Two biologics against the IL-36 receptor, including spesolimab (BI655130) and imsidrimab (ANB019), demonstrated potential as a treatment for several diseases. The Food and Drug Administration in the USA and Japan has recently approved spesolimab as a GPP treatment.

Spesolimab is a biologic that acts against the IL-36 receptor and blocks the IL-36 pathway,⁷¹ thereby reducing T-cell stimulation and proinflammatory process inhibition. Additionally, spesolimab has been assumed to, directly and indirectly, reduce several IL-36 family members and other cytokines production, including IL-17C, thereby contributing to Th cell activity suppression.⁷² A phase I, open-label, proof-of-concept study of spesolimab revealed that adult patients with biologic-naïve GPP with moderate flares demonstrated rapid improvement in skin symptoms after a single intravenous administration of 10 mg/kg of spesolimab.⁷³ Spesolimab had good efficacy in patients with GPP with or without GPP-associated IL36RN-variants.⁷³ These results verify the significant involvement of the IL-36 axis in GPP pathogenesis among patients without IL-36 receptor antagonist deficiency. A phase II study revealed that a single dose of 900 mg of intravenous spesolimab met the primary endpoint of “GPP Physician Global Assessment (GPPGA) pustule subscore 0 (no pustules visible)” and the secondary endpoint of “GPPGA total score 0 or 1 (clear or nearly clear skin)” 1 week after administration.^74,75

Hidradenitis suppurativa might be the next indication for “trunk” molecule IL-36-targeted therapies among AiKDs.²⁸ The greatly upregulated IL-36α, β, and γ expression has been observed in the skin lesions and sera of patients with hidradenitis suppurativa.^76-78 IL-36γ activates NFκB in keratinocytes, causing IL-8 secretion and neutrophil recruitment into the hidradenitis suppurativa lesions.⁷⁸ Furthermore, IL-36 has upregulated the granulocyte colony-stimulating factor levels, thereby recruiting and extending the survival of neutrophils in the lesions of hidradenitis suppurativa.⁷⁹ These data indicate the involvement of IL-36 in keratinocytes and immune cell interactions, especially neutrophils, thereby participating in the hidradenitis suppurativa pathogenesis.⁷⁸ Therefore, the NIH site ClinicalTrials.gov revealed clinical trials of spesolimab for hidradenitis suppurativa.

Imsidolimab is another IL-36 receptor antagonist that exhibited a sufficient safety profile in a phase I study (https://www2.anaptysbio.com/wp-content/uploads/ANB019-Phase-1-Study-Poster-EAACI-2018.pdf). Several phase II clinical trials of imsidolimab for the AiKDs GPP and hidradenitis suppurativa are found on the same NIH site: ClinicalTrials.gov (NCT03619902; NCT04856930; NCT05352893; NCT05366855).

Treatment target pathways other than the IL-36 axis

Various autoinflammation-related genes/molecules and pathways, in addition to the IL-36 pathway, are thought to play important roles in various AiKD pathogeneses. Understanding the genetic predisposing factors, disease-related genes/molecules, and pathways that induce innate immunity hyperactivation and precisely recognizing AiKD pathophysiology are essential for novel therapeutic strategy innovation. The precise elucidation of AiKD pathogeneses is expected to contribute to drug repurposing and the establishment of precision medicines for patients with AiKDs. One good example is the repurposing of adalimumab, which is an anti-TNF-α biologic for psoriases, including pustular psoriasis, which is a representative AiKD, as a treatment for hidradenitis suppurativa, which is another AiKD. In Japan, adalimumab has been approved for hidradenitis suppurativa. Furthermore, JAK inhibitors, as drugs that target disease-related molecules, might be effective against AiKD with hepatitis and autism caused by a JAK1 gain-of-function variant.¹⁶ Excellent etiological treatment strategies targeting disease-related molecules and pathways of autoinflammation are expected to be established for more diseases and greater numbers of patients as more inflammatory keratinization disorders are recognized as AiKDs.²⁰

CONCLUSION

Inflammatory keratinization disorders, with autoinflammation as the main inflammatory pathway, are considered AiKDs,²¹ and their mechanisms of pathogenesis involve innate immunity hyperactivation by disease-related gene variants.²² The accurate recognition of the pathogenesis and pathophysiology of each AiKD is expected to contribute to novel therapeutic strategy innovation, drug repurposing, and precision medicine establishment for various AiKDs.²⁰ The systemic administration of drugs targeting disease-related molecules, biologics for disease-related immune pathways, and immunosuppressants will be considered novel AiKD treatments.

The etiological mechanisms of various inflammatory keratinization disorders with unknown pathogeneses are expected to be identified. Some of the inflammatory keratinization disorders with newly clarified etiologies will probably be included in AiKDs. Thus, an increased number of disorders is expected to be realized as AiKDs. I hope that safe, novel, and effective treatment methods will be established for many AiKDs based on a precise and detailed recognition of pathogenetic autoinflammation mechanisms.

ACKNOWLEDGEMENTS

I thank Dr Takuya Takeichi for providing me with the patients’ photos for the figure.

The author is supported by Grant-in-Aid for Scientific Research (B) 21H02941 from the Japan Society for the Promotion of Science (JSPS) and by a grant from the Ministry of Health, Labor and Welfare of Japan (Health and Labor Sciences Research Grant for Research on Intractable Diseases: 23FC1039).

DISCLOSURE STATEMENT

The author has received research grants from Boehringer Ingelheim, Novartis Japan, and Maruho. The author has received payment for lectures from Maruho, Sanofi, and Boehringer Ingelheim.

Abbreviations

AiKDs

autoinflammatory keratinization diseases

EGFR

epidermal growth factor receptor

GPP

generalized pustular psoriasis

KLC

keratosis lichenoides chronica

KLICK

keratosis linearis with ichthyosis congenita and sclerosing keratoderma

NLRP1

NLR family pyrin domain-containing protein 1

POMP

proteasome maturation protein

PRP

pityriasis rubra pilaris

TNF

tumor necrosis factor