Dermatologica Sinica

: 2022  |  Volume : 40  |  Issue : 4  |  Page : 197--203

Autoinflammatory keratinization diseases: The concept, diseases involved, and pathogeneses

Masashi Akiyama 
 Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Correspondence Address:
Prof. Masashi Akiyama
Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550


As predisposing factors and pathogenic mechanisms of inflammatory keratinization disorders of the skin have become increasingly elucidated in recent years, a number of inflammatory keratinization disorders are now known to have the excessive activation of innate immunity as their pathogenesis. Autoinflammation-associated pathogeneses have been clarified in patients with generalized pustular psoriasis (GPP), pityriasis rubra pilaris (PRP) type V, and familial keratosis lichenoides chronica (KLC). Thus, based on these findings, in 2017, we proposed the clinical entity “autoinflammatory keratinization disease (AiKD),” which comprehensively includes inflammatory keratinization disorders with pathogenic mechanisms related to autoinflammation (the excessive activation of innate immunity). In 2017, GPP and associated diseases, PRP type V, and familial KLC came to be considered as AiKDs. In addition to these diseases, hidradenitis suppurative, porokeratosis, keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome, and AiKDs with hepatitis and autism have been newly recognized as AiKDs. The concept of AiKD may contribute to the selection of novel treatment methods. For example, recognizing hidradenitis suppurativa precisely as an AiKD has resulted in the application of adalimumab, an anti-tumor necrosis factor alpha antibody, as a treatment. The concept of AiKD is thought to be useful toward our accurate understanding of the pathogeneses of inflammatory keratinization disorders and our choice of appropriate treatment methods. As the pathogenic mechanisms of inflammatory keratinization disorders are further elucidated, it is presumed that the number of keratinization diseases whose pathogeneses are associated with autoinflammation will increase and that the number of diseases recognized as AiKDs will grow more and more.

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Akiyama M. Autoinflammatory keratinization diseases: The concept, diseases involved, and pathogeneses.Dermatol Sin 2022;40:197-203

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Akiyama M. Autoinflammatory keratinization diseases: The concept, diseases involved, and pathogeneses. Dermatol Sin [serial online] 2022 [cited 2023 Feb 2 ];40:197-203
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Autoinflammatory diseases and autoinflammatory syndromes that have autoinflammation (the excessive activation of innate immunity by genetic factors) as pathogenic mechanisms are well-known.[1] Systemic autoinflammatory diseases include a number of disorders, i.e., cryopyrin-associated periodic syndrome, familial Mediterranean fever (FMF), and tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS).[1] Systemic autoinflammatory diseases are generally monogenic disorders that result from the upregulation of innate immunity, have repeated bouts of fever, and affect multiple organs including the skin.[2] Unlike in systemic autoimmune diseases, however, in systemic autoinflammatory diseases, neither the antigen-specific loss of immune tolerance nor significant B-cell/T-cell hyperactivation is observed. Instead, innate immune responses, including neutrophil infiltration, play important roles in the pathogenesis.[2]

In contrast, in a group of disorders called inflammatory keratinization diseases, inflammation of the epidermis and the superficial dermis results in hyperkeratosis. Inflammatory keratinization diseases comprise various disorders, including a number of common diseases such as psoriasis and lichen planus. The etiology and predisposing factors of many inflammatory keratinization diseases have been unclear for a long time, even for common diseases. Due to recent remarkable advances in molecular genetic research technology, such as whole-exome and whole-genome sequencing using next-generation sequencers, the pathogenic factors and etiologies of inflammatory keratinization diseases have been clarified.[3],[4],[5],[6],[7],[8],[9],[10],[11] Among inflammatory keratinization diseases, many disorders have been shown to have etiological and pathogenic factors associated with autoinflammation, i.e., excessive activation of the innate immune system due to genetic predisposing factors.[12]

In fact, over the last decade, gain-of-function variants of CARD14 and loss-of-function variants of IL36RN have been found as pathogenic factors in pustular psoriasis and related diseases.[13] In addition, gain-of-function variants of CARD14 have been reported as predisposing factors for pityriasis rubra pilaris (PRP) type V.[14] NLRP1 variants are now known to be the causes of familial cases of keratosis lichenoides chronica (KLC).[15] All these genes encode important players in innate immune responses in the epidermis. The CARD14 protein, which is encoded by CARD14, activates NFkB, leading to downstream inflammatory responses in epidermal keratinocytes.[5] The Interleukin (IL)-36 receptor antagonist, which is encoded by IL36RN, inhibits the binding of IL-36 (an IL-1 family cytokine) to the IL-36 receptor and regulates IL-36 signaling and inflammatory reactions.[16] NLR family pyrin domain-containing protein 1 (NLRP1), which is encoded by NLRP1, is an inflammasome sensor found mainly in keratinocytes, and the activation of NLRP1 inflammasomes results in the secretion of IL-1β and IL-18 from keratinocytes and downstream inflammatory responses.[15] These causative molecules are closely associated with innate immune responses, which indicates that autoinflammation plays an important role in the pathogeneses of these inflammatory keratinization diseases.[12]

Based on a series of new data, in 2017, we proposed the novel concept of “autoinflammatory keratinization disease (AiKD),” which comprehensively includes various inflammatory keratinization diseases whose pathogenic mechanism is autoinflammation.[17],[18] At present, the disease concept AiKD includes pustular psoriasis and related diseases, PRP type V, familial KLC, hidradenitis suppurativa, porokeratosis, and others [Table 1].[12],[19],[20] All these diseases have long been known, but under the new disease concept of AiKD, it may be possible to understand their genetic predisposing factors and pathogenic mechanisms more accurately. Such a correct understanding of disease pathogeneses is expected to lead to the development of new treatment methods that target the key molecules or pathways in the pathogeneses of AiKDs.[12] For example, biologics targeting the IL-36 pathway and inhibitors of NFkB activation by CARD14 might be promising candidate therapeutic agents for pustular psoriasis and related AiKDs.{Table 1}

 Autoinflammatory Keratinization Disease as a New Disease Concept

AiKD is defined by four important characters.[17],[18] (1) The primary pathogenic process is inflammation in the epidermis and the superficial dermis. (2) The inflammation in the epidermis and the superficial dermis leads to hyperkeratosis. (3) An AiKD predisposing factor is a genetic abnormality that induces autoinflammation in the epidermis and the superficial dermis. (4) For inflammation that is related to the pathogenesis, not only does autoinflammation play a role, but also do autoimmune mechanisms, even though the primary and main pathogenic mechanism is autoinflammation.[17],[18]

As I note above, diseases known as AiKDs include pustular psoriasis and related diseases, hidradenitis suppurativa, palmoplantar pustular psoriasis, PRP type V, familial KLC, porokeratosis, keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome, and AiKDs with hepatitis and autism [Table 1].[11],[12],[19],[20] The number of diseases included in the concept of AiKD is expected to increase as the pathogenic mechanisms and pathophysiologies of many inflammatory keratinization disorders are elucidated.[12] With the new disease concept of AiKD, a correct understanding of the pathogenic mechanism and pathophysiology of each disease will greatly contribute to the accurate diagnosis and appropriate treatment of each disease.[11],[12],[17],[18],[19],[20]

 Comprehensive Disease Group of Autoinflammatory Keratinization Diseases

As mentioned above, various inflammatory keratinization disorders are included in the disease concept of AiKD, and the number of diseases included in AiKD is increasing. The predisposing factors, pathogenic mechanisms, and pathophysiologies of these diseases are extremely diverse. The following is an overview of each disease included in AiKD to date.

Pustular psoriasis and related diseases

Pustular psoriasis is a form of psoriasis that features sterile pustules. It is divided into generalized types, in which the skin lesions are found over almost the entire body, and localized types.[13] Generalized pustular psoriasis (GPP) consists of acute GPP (von Zumbusch), infantile GPP, impetigo herpetiformis (GPP triggered by pregnancy), generalized acrodermatitis continua of Hallopeau, and annular pustular psoriasis.[21] The localized types consist of acrodermatitis continua of Hallopeau and palmoplantar pustular psoriasis (PPPP).[21] All these subtypes of pustular psoriasis are considered to be AiKDs.[13] Among GPP cases, most early-onset GPP patients without psoriasis vulgaris have IL36RN variants as genetic predisposing factors [Figure 1]a.[22],[23] In addition to IL36RN, four other genes (CARD14, adaptor-related protein complex 1, which is the sigma-3 subunit [AP1S3], MPO, and serine protease inhibitor A3 [SERPINA3]) have been identified as being associated with pustular psoriasis.[13]{Figure 1}

IL36RN is a gene that encodes the IL-36 receptor antagonist. The IL-36 receptor antagonist is mainly produced by epidermal keratinocytes, and it competitively inhibits the binding of IL-36α, β, and γ, which are cytokines in the IL-1 family, to the IL-36 receptor.[16] IL-36α, β and γ produced in the TNF-α and IL-17A inflammatory pathways bind to the IL-36 receptor, activate NFkB, and up-regulate cytokine/chemokine secretion in the epidermis of pustular psoriasis, leading to inflammation in the epidermis and superficial dermis.[24] The IL-36 receptor antagonist suppresses the amplification of the inflammatory response by competitively inhibiting the IL-36 pathway. Deficiency of the IL-36 receptor antagonist due to loss-of-function variants in IL36RN results in insufficient suppression of IL-36-driven inflammation and the inflammation is excessively enhanced.[4] Excessive inflammation caused by deficiency of the IL-36 receptor antagonist is the primary pathogenic mechanism in cases of GPP and related diseases with variants of IL36RN.[22]

CARD14 encodes the CARD14 protein, which is responsible for the activation of NFkB signals in epidermal keratinocytes.[5] Therefore, in cases of GPP and PPPP with CARD14 gain-of-function variants, the CARD14 variants activate NFkB excessively and cause inflammation in the pustular psoriatic skin lesions.[25] Interestingly, it was reported that loss-of-function mutations in CARD14 are associated with a severe variant of atopic dermatitis.[26]

AP1S3 encodes AP1S3, and AP1S3 variants have been detected in all subtypes of pustular psoriasis.[7],[27],[28],[29] AP1S3 participates in the formation of adaptor-related protein complex 1 (AP-1). AP-1 traffics various molecules between the trans-Golgi network and the endosomes. Silencing of AP1S3 was reported to disrupt the endosomal translocation of Toll-like receptor 3 (TLR-3) and to affect the homeostasis of the TLR system in keratinocytes.[7] In addition, the loss of function of AP1S3 was demonstrated to cause defective autophagy and the abnormal accumulation of p62, resulting in excessive NFkB activation and the subsequent upregulation of IL-1 signaling and IL-36 α production in the skin.[27]

Furthermore, it was reported that deficiency of the neutrophilic heme-containing enzyme myeloperoxidase (MPO), encoded by MPO, is associated with the occurrence of GPP.[8],[9] The neutrophil serine proteases cathepsin G (CTSG), elastase (NE), and proteinase 3, and the monocytic protease cathepsin S are known to proteolyze and activate IL-36 precursors. MPO deficiency in neutrophils leads to the increased activity of neutrophil serine proteases, the reduced formation of neutrophil extracellular traps, and the predominance of soluble neutrophil proteases, resulting in the hyperactivation of IL-36 cytokines.[8] In addition, the efferocytosis of neutrophils is impaired by MPO deficiency, leading to the prolonged persistence of infiltrating neutrophils in skin inflammation.[8]

Furthermore, loss-of-function variants in SERPINA3, which encodes SERPINA3, were suggested to be a predisposing factor for GPP in 2020.[10]

SERPINA3 inhibits several neutrophilic proteases, especially CTSG, which activate IL-36 cytokines. Thus, SERPINA3 loss-of-function variants are considered to have reduced inhibitory effects on serine proteases, such as CTSG, leading to the hyperactivation of IL-36 cytokines.[10]

Pityriasis rubra pilaris

PRP, like pustular psoriasis, has long been well-known as an inflammatory keratinization disorder. In PRP, scales and hyperkeratotic papules are seen on the trunk and the extensor sides of the limbs [Figure 1]b. Many of the hyperkeratotic papules are found on reddish plaques and may have a crater-like appearance. Hyperkeratosis with erythema on the palms is also commonly seen. Currently, PRP is classified into six types, from type I to type VI, according to the age of onset, clinical picture, and course.[30],[31] Type V develops at a young age, progresses chronically, and never improves during the entire life. Many cases of this type have CARD14 variants as a genetic cause, and PRP of this type is considered to be an AiKD.[14],[17] Patients with other types also have CARD14 variants as a disease-predisposing factor, although the frequency is lower than that of type V cases.[14] In PRP cases with CARD14 variants as a disease-predisposing factor, the gain-of-function variants of CARD14 hyperactivate NFkB in epidermal keratinocytes and cause autoinflammation in the skin. Cases of PRP, or at least PRP cases with gain-of-function CARD14 variants, are thought to be AiKD.[14],[17]

Hidradenitis suppurativa

In hidradenitis suppurativa, chronic and recurrent multiple abscesses and pustular drainage are found, mainly in the inguinal region, buttocks, vulva, and axillae [Figure 1]c.[32],[33] Previously, the condition was thought to be an infectious disease. However, in recent years, it has been considered to be an AiKD.[34] Among hidradenitis suppurativa cases, familial cases show a stronger tendency to have the characteristics of AiKDs.[34] In some cases of hidradenitis suppurativa, mutations have been identified in the genes that encode proteins which form the γ -secretase complex: NCSTN, PSENEN, and PSEN1.[34] In patients with mutations in these genes, hyperkeratosis of the hair follicle epithelium is observed, resulting in hair follicle obstruction and keratin plug formation. Hair follicle obstruction and keratin plug formation are important processes in the pathogenic mechanisms of hidradenitis suppurativa.[34],[35] In addition, the increased production of TNF, caspase-1, IL-1, and IL-17 has also been observed in the affected skin.[34] In addition, hidradenitis suppurativa-like lesions are seen as a symptom in various autoinflammatory diseases or syndromes, such as FMF, pyogenic arthritis, pyoderma gangrenosum, acne syndrome, pyoderma gangrenosum, acne, hidradenitis suppurativa syndrome, and Majeed syndrome. In these autoinflammatory diseases/syndromes, excessive activation of innate immunity in the skin is presumed to be the pathogenic mechanism of the hidradenitis suppurativa-like skin lesions.[34]

Furthermore, variants of various autoinflammation-related genes (NOD2, LPIN2, NLRP3, NLRP12, PSMB8, MVK, and IL1RN) have been found in cases of hidradenitis suppurativa.[34] In addition, some autoinflammatory diseases or syndromes are known to show hidradenitis suppurativa-like symptoms.[34] These findings uniformly indicate that autoinflammatory mechanisms are important in the pathogenesis of hidradenitis suppurativa. Adalimumab is a monoclonal anti-TNFα antibody that has been used to treat pustular psoriasis, an AiKD. In recent years, adalimumab has been used for patients with hidradenitis suppurativa.[36],[37] The efficacy of adalimumab in cases of hidradenitis suppurativa might support the idea that hidradenitis suppurativa is an AiKD.


Porokeratosis has long been recognized as a disease. Porokeratotic lesions are chronic, brown, round or oval, keratotic plaques with ridge-like hyperkeratotic borders.[38] In general, there are no subjective symptoms in porokeratosis, although there are cases with strong inflammatory symptoms, i.e., eruptive pruritic papular porokeratosis [Figure 1]d.[39] The ridge-like hyperkeratosis on the margin of individual plaques is histopathologically a column of parakeratotic cells (cornoid lamella), which is a characteristic finding of this disease. Historically, mainly according to the clinical picture, cases of porokeratosis are classified into various subtypes, including the classic type, disseminated superficial porokeratosis, and disseminated superficial actinic porokeratosis.[38] Some families with familial porokeratosis show autosomal dominant inheritance. Mutations in four genes (MVD, MVK, PMVK, and FDPS) that encode enzymes in the mevalonate pathway have been reported as predisposing factors for porokeratosis.[6],[40] Thus, porokeratosis is recognized as an AiKD due to the variants in the genes.[41] Although porokeratosis has long been documented, it is an example of a disease that has been newly understood as an AiKD through the clarification of predisposing factors and pathophysiology.

Familial keratosis lichenoides chronica

KLC has long been known, despite being very rare. Hyperkeratotic papules and nodules frequently occur on the trunk and extensor sides of the extremities, and seborrheic dermatitis-like eruptions on the face, keratinization of the palms and feet, and thickening of the nails are observed.[42] Histopathologically, biopsy samples from the skin lesions show a lichenoid tissue reaction.[42] Most reported cases of KLC have no family history, but familial cases have also been reported. In 2016, it became clear that the etiology of familial KLC (FKLC) is a gain-of-function variant in NLRP1.[15] The molecule encoded by NLRP1, which is NLR family pyrin domain-containing protein 1 (NLRP1), is an inflammasome sensor.[15] The NLRP1 variant, which is the cause of FKLC, is a gain-of-function variant, and it overactivates the inflammasome.[15] Overactivation of inflammasomes in epidermal cells induces increased secretion of IL-1β and causes inflammation in the epidermis and superficial dermis.[15],[43] Thus, the pathogenic mechanism of FKLC is autoinflammation in the epidermis and superficial dermis due to the gain-of-function variant of NLRP1, and FKLC that results from the NLRP1 variant is an AiKD.[17],[18]

Keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome

In KLICK syndrome, hyperkeratosis and scales are found over large areas of the body, including on the palms and soles, and there are hyperkeratotic papules that show linear arrangements on the wrists and the cubital fossa.[44] Hyperkeratotic plaques are also seen on the neck and the axillae. Histopathologically, acanthosis and hyperkeratosis in the epidermis with inflammatory cell infiltration are observed in the lesional skin.[44] The etiology of KLICK syndrome is a homozygous single-nucleotide deletion in the 5'UTR of the proteasome maturation protein (POMP) gene.[3] POMP, which is encoded by POMP, is an important chaperone for proteasome maturation, and proteasome maturation deficiency due to POMP dysfunction enhances ER stress and induces unfolded protein response.[3],[45],[46] Based on the pathogenetic mechanism whereby the autoinflammation causes hyperkeratosis, KLICK syndrome is considered to be an AiKD.[19] Interestingly, heterozygous frameshift variants the penultimate exon of POMP are known to be the cause of proteasome-associated autoinflammatory syndrome-2, also known as POMP-related autoinflammation and immune dysregulation disease, which is a systemic autoinflammatory disease.[46],[47]

Autoinflammatory keratinization disease with hepatitis and autism

Very recently, a JAK1 gain-of-function mutation was identified in a unique AiKD patient with severe early-onset hepatitis and autism.[11] The female patient showed dry skin and mild erythema from birth and was diagnosed with atopic dermatitis. At the age of 8 years, she had scaly erythema on the trunk [Figure 1]. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is a major transduction pathway of cytokine inflammatory signals.[48] JAK1, which is encoded by JAK1, is important for the signaling of various cytokines, including IL-6 and interferons.[48] Recently, heterozygous mutations in JAK1 were reported to cause an autosomal dominant disorder of multi-organ immune dysregulation.[49],[50] Clinicopathological observations of AiKD patients with hepatitis and autism, and functional analyses of mice with the causative JAK1 mutation knocked in revealed that the gain-of-function mutation in JAK1 causes the hyperactivation of JAK-STAT signaling pathways, resulting in AiKD with hepatitis and autism.[11]

 Treatments for Autoinflammatory Keratinization Diseases

The anti-TNF-α monoclonal antibody adalimumab is a biologic that can be used to treat pustular psoriasis, a typical AiKD. Adalimumab has recently been approved for health insurance coverage in Japan as a treatment for hidradenitis suppurativa. Likewise, for various other AiKDs, the development of new therapeutic strategies and drug repurposing is expected based on the recognition that autoinflammation is greatly involved in the pathogenic mechanisms of each AiKD [Table 2].[11],[13],[14],[15],[19],[34],[41] In a number of AiKDs, an accurate pathophysiological understanding is expected to contribute to the establishment of epoch-making treatment strategies.{Table 2}

It is important to accurately recognize the pathophysiologies of AiKDs and to understand the causative factors in terms of the overactivation of innate immunity that results from genetic factors [Figure 2]. Such an understanding is expected to lead to the development of novel effective treatments based on disease pathogeneses, such as molecular target drugs for pathogenic molecules and biologics and immunosuppressive drugs for controlling systemic autoinflammation. Furthermore, the precise elucidation of AiKD pathomechanisms may result in drug repurposing and the development of precision medicines for AiKD patients. With increases in the number of diseases included in AiKD, we can expect increases in the number of diseases and patients for which appropriate and effective treatments targeting autoinflammatory pathogenetic pathways are innovated.[12]{Figure 2}


Inflammatory keratinization diseases that have autoinflammation as their driving inflammatory pathways are regarded as “AiKDs,”[17] and their pathogenic mechanisms are recognized as “the overactivation of innate immunity by genetic factors.”[18] Understanding the pathophysiologies of AiKDs precisely is expected to lead to the development of new treatment methods, the repurposing of existing drugs, and the establishment of precision medicines.[12] As new therapeutic strategies, drugs targeting pathogenic molecules, biologics, and immunosuppressive drugs that control systemic autoinflammation will come into view. The use of adalimumab to treat hidradenitis suppurativa is a good example of the accurate recognition of a disease as an AiKD leading to the selection of a new treatment method.[12] With regard to various other AiKDs, development is expected of new therapeutic methods and the repurposing of drugs that target the molecule and significant inflammatory pathway that is important in each AiKD.

In the future, the etiology, pathogenetic mechanisms, and pathophysiologies of many inflammatory keratinization diseases with unknown etiologies and causative factors will be clarified, and some of these will be recognized as AiKDs. As the number of diseases included in AiKDs increases in the future, I hope that appropriate and effective therapeutic agents and treatment methods will be innovated that are derived from an accurate understanding of AiKD etiologies and pathophysiologies.


I thank Dr. Takuya Takeichi for providing the patients' photos for the figure with patient's consent.

Financial support and sponsorship

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: 20FC1052).

Conflicts of interest

Prof. Masashi Akiyama, an editorial board member at Dermatologica Sinica, had no role in the peer review process of or decision to publish this article. Prof. Masashi Akiyama has received research grants from Boehringer Ingelheim, Novartis Japan, and Maruho. The author has received payment for lectures from Maruho and Sanofi.


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