Interest in autoinflammatory diseases has grown in the last 10 years. Since they were first defined, more than 30 new genes associated with autoinflammatory diseases affecting different parts of the innate immune system have been identified. The first diseases to be included were hereditary periodic fever syndromes such as familial Mediterranean fever and TRAPS. Other periodic syndromes were soon added, including hereditary hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) and cryopyrin-associated periodic syndrome (CAPS). The concept of autoinflammation subsequently extended to various monogenic diseases, such as Blau syndrome, Majeed syndrome, deficiency of the interleukin 1 receptor antagonist (DIRA), pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome, as well as genetic disorders of uncertain origin, such as periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome, Behçet disease, Still disease, Crohn disease, and acquired autoinflammatory syndromes such as Schnitzler syndrome2,3. In clinical terms, autoinflammatory syndromes commonly present as follows: (1) neutrophilic urticarial dermatosis, as in CAPS; (2) pustules, abscesses, sinus tracts, or ulcers, and syndromic forms of hidradenitis (synovitis, acne, pustulosis, hyperostosis, osteitis [SAPHO], PAPA, pyogenic arthritis, pyoderma gangrenosum, acne vulgaris, and HS [PAPASH], and pyoderma gangrenosum, acne, and HS [PASH]); and (3) various types of rash such as panniculitis or livedo reticularis (chronic atypical dermatosis with lipodystrophy and elevated temperature [CANDLE], adenosine deaminase 2 [ADA2] deficiency).

Monogenic autoinflammatory diseases are rare, although some diseases have a probable polygenic autoinflammatory basis, such as acne, hidradenits suppurativa (HS), gout, and inflammatory bowel disease, as well as diseases with a clearly mixed pathogenesis (autoimmune and autoinflammatory), as is the case with Behçet disease and psoriasis.

In 2017, Akiyama et al.4 first proposed the term AiKD to describe the essential characteristics that differentiated these diseases from autoinflammatory diseases. Inflammation mainly affects the epidermis and upper dermis, leading to the presence of hyperkeratosis. In addition, all these diseases have primary genetic etiological and pathogenic factors associated with autoinflammation.

The concept of AiKD also includes diseases with autoinflammation and mixed autoimmune mechanisms. Similarly, a change occurred in the paradigm by which alteration of keratinization was assumed to be the first event and preceded inflammation, as is the case in acne or HS. In AiKD, inflammation is the first event, followed by aberrant, or defective, keratinization. Furthermore, given that some AiKDs, such as HS, were considered neutrophilic dermatoses, with a mainly autoinflammatory origin, the pathogenic mechanisms and clinical characteristics of AiKD and neutrophilic dermatosis might be considered to overlap.

While the pathogenic mechanisms of most AiKDs are not completely known, new data shed light on some of them (Fig. 2)5. First, loss-of-function mutations in IL36RN lead to positive regulation of IL-36 signaling. This in turn leads to secretion of chemokines/cytokines by keratinocytes. Positive regulation of the IL-36 signaling pathway eventually activates neutrophils and dendritic cells, thus leading to polarization of type 1 helper T cells (TH1) and TH17 cells. The pustular dermatoses associated with IL-36Ra are generalized pustular psoriasis (GPP) without psoriasis vulgaris lesions, impetigo herpetiformis, and acrodermatitis continua. Furthermore, some studies have confirmed the role of IL-36 in HS6. Second, the mutation in CARD14 hyperactivates nuclear factor κB (NF-κB; red arrows with asterisks), also leading to secretion of chemokines and cytokines—IL-36, IL-8, CXCL1, CXCL2, CCL20—in the keratinocyte and activation of neutrophils and dendritic cells in the dermis. Similarly, differentiated TH1 and TH17 cells produce TH1 cytokines, such as IL-17. GPP with psoriasis vulgaris and palmoplantar pustular psoriasis are pustular psoriasiform dermatoses mediated by CARD14 that present gain-of-function variants in CARD14, as is also the case in pityriasis rubra pilaris (PRP) type V. Third, mutations have been identified in NLRP1, an inflammasome sensor expressed mainly in human skin in patients with familial keratosis lichenoides chronica (KLC). NLRP1 includes alterations in caspase 1, an apoptosis-associated speck-like protein containing a CARD (ASC), IL-1β, and IL-184. Similarly, in some patients with HS, a role for NLRP1 dysfunction has been hypothesized. Fourth, in the case of patients with severe pustular psoriasis, such as GPP, mutations in AP1S3 have been less frequently reported. Adaptor protein complex 1 (AP-1) promotes vesicular trafficking between the trans-Golgi network and endosomes. Expression of AP1S3 is clearly elevated in keratinocytes, and its silencing interrupts endosomal translocation of the innate pattern recognition receptor TLR-3, resulting in markedly inhibited regulation of signaling. Furthermore, its inactivation interrupts keratinocyte autophagy, leading to abnormal accumulation of p62, an adaptor protein that mediates activation of NF-κB and results in positive signaling of IL-1 and overexpression of IL-36α7,8. In some patients with HS, functional mutations have been reported in genes encoding γ-secretase, including NCSTN, PSENEN, and PSEN1. These genetic abnormalities result in hyperkeratosis, dysregulated differentiation of the hair follicle, and formation of cysts via signaling of aberrant Notch. Furthermore, abnormalities have been shown in IL-1β, IL-36, caspase-1, and NLRP3, as has dysregulation of the TH17-Treg axis in samples from patients with HS9. Finally, loss of function mutations in EGFR were recently reported to be a potential cause of hyperkeratosis and autoinflammation owing to positive regulation of various inflammatory/innate immune response networks (Fig. 3)10.

Figure 2.

Pathogenic mechanisms and interaction between keratinocytes and immune cells in AiKD. Diseases associated with all the mechanisms are shown in red. GPP indicates generalized pustular psoriasis; HS, hidradenitis suppurativa; CLK, chronic lichenoid keratosis; PRP, pityriasis rubra pilaris.

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Figure 3.

Typical clinical appearance of autoinflammatory keratinization disease. A, Keratosis lichenoides chronica. B, Porokeratosis. C, Acrodermatitis continua of Hallopeau. D, Pustular psoriasis.

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Various strategies for the treatment of AiKDs have been based on the underlying autoinflammatory pathogenic mechanisms. Therefore, the approach used comprises treatments targeting the molecules responsible for alteration of the autoinflammatory cascade, namely, cytokines, their receptors, and signaling molecules. Given that the effectiveness of these treatments is promising, they are expected to generate new therapeutic options (Table 1).

In the first place, high levels of TNF-α make TNF inhibitors such as infliximab theoretically efficacious for control of the acute phase of the disease, especially in the case of GPP5. The anti-TNF agent adalimumab is the only biologic approved for HS.

Furthermore, the increased expression of IL-17A observed led to various trials with IL-17A antagonists (e.g., secukinumab, ixekizumab, and brodalumab), for which findings have been satisfactory. Cordoro et al.25 reported that inhibition of IL-17 in a patient with GPP and IL-36Ra deficiency had proven effective. Similarly, given that IL-1 participates in the pathogenesis of AiKD, therapy with an IL-1 receptor antagonist, anakinra, was successful in a patient with GPP caused by mutations in IL36RN and could be an option in patients with KLC and known activation of the inflammasome5. Surprisingly, a patient diagnosed with KLC did not respond to this approach, yet responded to efalizumab, an anti-CD11a antagonist that could act by modulating transit of T cells to the epidermis, with subsequent keratinocyte malfunction26. Unfortunately, efalizumab was withdrawn from the market and is no longer available.

High IL-36 and interferon levels in psoriasis vulgaris and GPP point to these molecules as a potential target. In fact, ongoing trials with new drugs, such as BI 655130 (spesolimab), a monoclonal antibody against the IL-36 receptor, have reduced the severity of GPP in the early phases. According to Bachelez et al.27, the efficacy of BI 655130 suggests that the IL-36 pathway itself could play a key role in pathogenesis, independently of the mutation in IL36RN. Also under study is ANB019, another humanized monoclonal antibody targeting the IL-36 receptor.

IL-12 and IL-23 are thought to be involved in the inflammatory cascades that trigger AiKD, including GPP (with mutations in IL36RN) and in PRP (with mutations in CARD14). In this sense, ustekinumab has proven efficacious in affected patients28,29. Arakawa et al.30 suggested that treatment with acitretin could support the efficacy of ustekinumab by suppressing the TH17 response via retinoid-related orphan receptors. This finding is not novel, since the early phases of HS were traditionally treated with antibiotics, classic immunosuppressants, and acitretin, with biologics being reserved for patients with active, severe disease. Similarly, if the endotypes of HS are considered, in the case of the inflammatory endotype, all interleukin blockers associated with inhibition of the TH17 response (including first- and second-line cytokines) and steroids could yield promising results13. Moreover, apremilast, a PDE-4 inhibitor, has proven effective in moderate disease. In contrast, with the follicular endotype, acitretin, tetracyclines, dapsone, and colchicine could initially prove more useful19,31,32. A recent study on the histologic progression of HS revealed epithelial tendrils, with formation and rupture of cysts. Treatments that inhibit the formation of these tendrils could prove successful33.

Campbell et al.34 reported that an optimized small-molecule antagonist, CCX624, targeting CCR6 and CXCR2 significantly diminished inflammatory T-cell, neutrophil, and dendritic cell infiltrates in skin treated with IL-36a and even proved to be more effective for reducing inflammatory symptoms than anti-IL-17RA monoclonal antibodies.

Papp et al.35 found that selective inhibition of tyrosine kinase 2 with the oral agent BMS-986165 could also prove useful in patients with GPP.

Neutrophils frequently participate in the inflammatory reaction induced in AiKDs, and some AiKDs have been classified as neutrophilic dermatoses (HS and pustular forms of psoriasis). Therefore, treatments such as dapsone and colchicine have proven useful in a specific subgroup of patients. Granulocyte and monocyte adsorption apheresis is expected to be effective in some cases of AiKD; in fact, it has been reported to be effective in patients diagnosed with refractory GPP36. Accordingly, the granulocyte colony-stimulating factor pathway is a key regulator of neutrophils, whose positive regulation and its effects seem to be very specific for HS lesions. Consequently, blocking the action of granulocyte colony-stimulating factor could prove to be a new therapeutic approach37.