Review article
Autoinflammatory keratinization diseases: An emerging concept encompassing various inflammatory keratinization disorders of the skin

https://doi.org/10.1016/j.jdermsci.2018.01.012Get rights and content

Highlights

Abstract

Classifying inflammatory skin diseases is challenging, especially for the expanding group of disorders triggered by genetic factors resulting in hyperactivated innate immunity that result in overlapping patterns of dermal and epidermal inflammation with hyperkeratosis. For such conditions, the umbrella term “autoinflammatory keratinization diseases” (AIKD) has been proposed. AIKD encompasses diseases with mixed pathomechanisms of autoinflammation and autoimmunity, and includes IL-36 receptor antagonist (IL-36Ra)-related pustulosis, CARD14-mediated pustular psoriasis, pityriasis rubra pilaris (PRP) type V, and familial keratosis lichenoides chronica (KLC). Mechanistically, the entities include generalized pustular psoriasis (GPP) without psoriasis vulgaris, impetigo herpetiformis and acrodermatitis continua, which are IL-36Ra-related pustuloses caused by loss-of-function mutations in IL36RN; GPP with psoriasis vulgaris and palmoplantar pustular psoriasis which are CARD14-mediated pustular psoriasiform dermatoses with gain-of-function variants of CARD14; PRP type V which is caused by gain-of-function mutations in CARD14; and, familial KLC in which mutations in NLRP1, an inflammasome sensor protein predominantly expressed in skin, have been identified. It is likely that further inflammatory keratinization disorders will also fall within the concept of AIKD, as elucidation of novel pathogenic mechanisms of inflammatory keratinization diseases emerges. A better understanding of the pathophysiology of AIKD is likely to lead to innovative, targeted therapies that benefit patients.

Introduction

Among the myriad diseases affecting the skin are a subset of disorders whose main pathobiology is inflammation, predominantly in the epidermis and the superficial dermis, that leads to hyperkeratosis, manifesting clinically as thickened scaly skin. These are designated as “inflammatory keratinization disorders”. The category includes many conditions that are poorly defined, although some, including psoriasis and lichen planus, are better categorized.

Nevertheless, the pathogenic mechanisms of most inflammatory keratinization disorders remain unresolved. However, new pathogenic mechanisms relating to autoinflammation have been demonstrated in some inflammatory keratinization disorders, providing unexpected mechanistic insights and new ideas for targeted therapies. In 2017, we proposed a new umbrella term, “autoinflammatory keratinization diseases” (AIKD), to encompass inflammatory keratinization disorders with autoinflammatory pathogenic mechanisms [1]. We herein summarize the concept of AIKD, review the diseases included in this disease subgrouping, and discuss the clinical value of grouping conditions as AIKD.

Section snippets

What are AIKD?

Our initial concept paper on AIKD defined the disease entities as having four inclusion criteria [1]: (1) the primary and main inflammation sites are the epidermis and the upper dermis; (2) the inflammation leads to hyperkeratosis, which is the main and characteristic phenotype of AIKD; (3) AIKD have primary genetic causative factors associated with the hyperactivation of innate immunity (autoinflammation), mainly in the epidermis and the upper dermis; (4) the spectrum of AIKD encompasses

IL-36RA-related pustulosis

In 2011, Marrakchi et al. [3] reported that IL36RN mutations leading to IL-36Ra deficiency were present in nine Tunisian families with recessively inherited familial generalized pustular psoriasis (GPP). IL36RN mutations were also reported as a genetic cause in three sporadic European GPP patients [4] and a Japanese GPP patient [5] (Fig. 1A, B). Subsequently, it was established that most sporadic GPP patients without preceding or concomitant psoriasis vulgaris (PV) skin lesions have IL36RN

CARD14-mediated pustular psoriasis

Psoriasis, one of the most common inflammatory keratinization disorders, is a chronic multifactorial inflammatory disease involving the skin, nails and joints [17]. The most common plaque-type psoriasis is psoriasis vulgaris (PV). Various inflammatory keratinization disorders such as psoriatic arthritis, GPP and palmoplantar pustular psoriasis (palmoplantar pustulosis) are known to be psoriasis-related diseases [18]. Recently, Arakawa et al. [19] demonstrated that melanocyte antigens can

Pityriasis rubra pilaris (PRP)

In addition, the concept of AIKD can also be applied to CARD14 mutation-driven inflammatory keratinization diseases, such as PRP type V. PRP is an inflammatory keratinization disease that shows general follicular plugging and perifollicular erythema with confluent configurations [31]. Pityriasis capitis and palmoplantar keratoderma are also seen in PRP [31]. In 1980, PRP was classified into five subgroups, types I–V, based on clinical criteria (age of onset, distribution of lesions, disease

Familial keratosis lichenoides chronica (KLC)

KLC is an infrequently seen inflammatory keratinization disorder. Kaposi first described KLC in 1895, but the term KLC was formally proposed by Margolis in 1972 [38]. Patients with KLC show multiple small papules with confluent, linear and reticulate configurations on the trunk and extremities. KLC patients may also have seborrheic dermatitis-like eruptions on the face, palmoplantar keratoderma and hypertrophic nail deformities. These skin lesions are usually asymptomatic, but typically show

Therapies based on the pathomechanisms of AIKD

Recently, various therapies based on the pathomechanisms of AIKD have achieved sufficient efficacy in several kinds of AIKD.

Neutrophils are thought to be frequently involved in the inflammatory reaction induced in AIKD (Fig. 2). Thus, granulocyte and monocyte adsorption apheresis is expected to be effective for AIKD cases. Indeed, the treatment efficacy of granulocyte and monocyte adsorption apheresis was reported in a GPP case that resulted from an IL36RN mutation [45].

Concerning molecularly

Conclusions and future perspectives

In 2017, the disease terminology AIKD was proposed for inflammatory keratinization disorders with autoinflammatory mechanisms as their main etiology (Fig. 2) [1]. The clinical entity of AIKD contains certain PRP type V, KLC, and subgroups of psoriasis-related diseases as described above (Table 2).

The data summarized indicate that certain subsets of psoriasis and diseases related to it have genetic causes and predisposing factors associated with autoinflammatory mechanisms, such as CARD14

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

This work was supported by funding from Advanced Research and Development Programs for Medical Innovation (AMED-CREST: JP17gm0910002) to M.A. from Japan Agency for Medical Research and Development (AMED), and by a Grant-in-Aid for Scientific Research (B)15H04887 to M.A. from the Japan Society for the Promotion of Science (JSPS).

Masashi Akiyama (M.D., Ph.D.) is a Professor and Chairman of the Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan from 2010. He received the M.D. in 1986 and Ph.D. in 1991 from Keio University, Tokyo, Japan. He was assigned as a Senior Research Fellow at University of Washington, Seattle (1992–1994) and an Associate Professor at Teikyo University Ichihara Hospital, Chiba, Japan (1999–2001). He served as an Assistant Professor (2001–2007) and an Associate

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