Psoriasis is a complex long-lasting inflammatory skin disease with high prevalence and associated comorbidity. It is characterized by epidermal hyperplasia and dermal infiltration of immune cells. Here, we review the role of keratinocytes in the pathogenesis of psoriasis, focusing on factors relevant to genetics, cytokines and receptors, metabolism, cell signaling, transcription factors, non-coding RNAs, antimicrobial peptides, and proteins with other different functions. The critical role of keratinocytes in initiating and maintaining the inflammatory state suggests the great significance of targeting keratinocytes for the treatment of psoriasis. 

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Advances in the pathogenesis of psoriasis: from keratinocyte perspective

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Tuberculosis is an infectious disease with a major global impact, ranked in the top 10 mortality causes worldwide. In an immunocompetent individual, the host defence mechanisms control Mycobacterium tuberculosis infection and induce the latent form of the disease. However, in the presence of diseases or therapies, which exert an immunosuppressive effect, latent tuberculosis can be re-activated. Psoriasis is an immune-mediated, inflammatory disease, and its treatment has rapidly evolved over the last few years. It has long been recognized that the tumour necrosis factor (TNF)-α inhibitors are associated with increased risk of reactivation of latent tuberculosis infection. Thus, international guidelines have been suggesting tuberculosis screening before starting the treatment with all biological agents since then. In addition, the institution of chemoprophylaxis in the presence of latent tuberculosis and the annual screening for tuberculosis thereafter have also been indicated. However, anti-tuberculosis treatments can have significant side-effects and there are currently several contraindications to their use. The risk benefit of starting anti-tuberculous treatment should be carefully weighed up. The emergence of new biological drugs for the treatment of psoriasis, such as interleukin (IL)-17 and IL-23 inhibitors, has reignited the subject of tuberculosis reactivation as it is possible that IL-17 and 23 blockade do not carry the same risk of TB reactivation as TNF-α inhibitors. Although preclinical studies have shown that cytokines IL-17 and IL-23 have a possible role against infection with M. tuberculosis, data from clinical trials and post-marketing surveillance with drugs that inhibit these cytokines appear to suggest that they are not crucial to this response. In this article, we review the available data on tuberculosis reactivation after the treatment of psoriasis with IL-17 and IL-23 inhibitors, and its possible impact on the way we currently manage latent tuberculosis infection before or after starting treatment with these new drugs.

Risk of tuberculosis reactivation with interleukin (IL)-17 and IL-23 inhibitors in psoriasis - time for a paradigm change.

Unmet needs in the treatment of psoriasis call for novel therapeutic strategies. Pustular psoriasis and psoriatic arthritis often represent a therapeutic challenge. Focus on IL-36 cytokines offers an interesting approach, as the IL-36 axis has been appointed a critical driver of the autoinflammatory responses involved in pustular psoriasis. Two IL-36R blocking antibodies, imsidolimab and spesolimab, are currently undergoing phase II and III clinical trials, with promising results.

Exploring the Role of IL-36 Cytokines as a New Target in Psoriatic Disease

The interleukin-17 (IL-17) family consists of six family members (IL-17A-IL-17F) and all the corresponding receptors have been identified recently. This family is mainly involved in the host defense mechanisms against bacteria, fungi and helminth infection by inducing cytokines and chemokines, recruiting neutrophils, inducing anti-microbial proteins and modifying T-helper cell differentiation. IL-17A and some other family cytokines are also involved in the development of psoriasis, psoriatic arthritis and ankylosing spondylitis by inducing inflammatory cytokines and chemokines, and antibodies against IL-17A as well as the receptor IL-17RA are being successfully used for the treatment of these diseases. Involvement in the development of inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and tumors has also been suggested in animal disease models. In this review, we will briefly review the mechanisms by which IL-17 cytokines are involved in the development of these diseases and discuss possible treatment of inflammatory diseases by targeting IL-17 family members.

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Interleukin-17 family members in health and disease.

Psoriasis and psoriatic arthritis are chronic immune-mediated disorders with involvement of interleukin (IL)-17 cytokines in their pathogenesis. IL-17A has been considered to be the most biologically active, but IL-17F is also over-expressed in skin and synovial tissues of patients with these diseases. Many therapeutic advances have been made in the past years, but some needs remain unmet. Dual inhibitor and bispecific antibodies simultaneously targeting IL-17A and IL-17F could provide better disease control. Herein we review current evidence on bimekizumab and sonelokimab. The antigen-binding site of bimekizumab neutralizes both IL-17A and IL-17F; phase I, II, and III studies have demonstrated its efficacy and safety in psoriasis and psoriatic arthritis. Sonelokimab is a trivalent nanobody targeting IL-17A and IL-17F; phase I and II studies with this molecule have yielded promising results in psoriasis.

https://journals.sagepub.com/doi/pdf/10.1177/20406223211037846

Dual inhibition of IL-17A and IL-17F in psoriatic disease

Lentigo maligna (LM) is a type of melanoma in situ that has distinctive characteristics regarding epidemiology, risk factors and clinical features. In addition, LM has a potential to progress to an invasive tumor with potentially aggressive behavior: lentigo maligna melanoma (LMM). Overall, LM has a very good prognosis, whereas LMM has the same prognosis as other invasive melanomas with similar Breslow thickness. LM/LMM represents a challenging entity not only regarding the diagnosis but also regarding the management. Diagnostic criteria are not well established, and there is an overlap of clinical, dermoscopic and pathological features with other benign pigmented skin lesions such as lentigines, pigmented actinic keratoses or macular seborrheic keratoses. LM/LMM's common appearance within photodamaged skin makes lesion border identification difficult. Wide excisions are often required, but since LM/LMM typically appears on cosmetically sensitive areas such as the face, sometimes large excisions are not possible nor desirable. In this sense, specialized approaches have been developed such as margin-controlled surgery or image-guided treatment using reflectance confocal microscopy. Other treatments for LM such as cryosurgery, imiquimod, radiotherapy or photodynamic therapy have been proposed, although recurrence/persistence is common. The current manuscript reviews extensively the published data regarding the diagnosis, treatment and management of both complex entities LM and LMM.

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Lentigo Maligna: Clinical Presentation and Appropriate Management.

Introduction: Brodalumab is a newly developed targeted biologic agent for the treatment of psoriasis that blocks IL-17 receptor A.Areas covered: This review sought to provide a detailed overview on safety of brodalumab for the treatment of psoriasis. A PubMed search was conducted for relevant literature. Here we review the efficacy and safety data from key phase II, phase III and open-label extension clinical trials, as well as systematic reviews and meta-analyses.Expert opinion: The unique mechanism of action of brodalumab offers advantages on efficacy over other targeted treatments, with a quick onset of action and long-term maintenance of treatment response. Brodalumab has a favorable safety profile, similar to other IL-17 inhibitors. Infections, especially mucocutaneous candidiasis, must be monitored. Suicidal ideation was detected in brodalumab trials, although a causal relationship has not been revealed. Brodalumab is a highly efficacious and comparably safe therapeutic choice in patients with moderate to severe psoriasis, especially when rapid control of the disease is desired.

The safety of brodalumab for the treatment of psoriasis

The interleukin-1 (IL-1) family is involved in the correct functioning and regulation of the innate immune system, linking innate and adaptative immune responses. This complex family is composed by several cytokines, receptors, and co-receptors, all working in a balanced way to maintain homeostasis. Dysregulation of these processes results in tissue inflammation and is involved in the pathogenesis of common inflammatory dermatoses such as psoriasis, hidradenitis suppurativa, and atopic dermatitis. Therefore, therapeutic targeting of IL-1 pathways has been studied, and several monoclonal antibodies are currently being assessed in clinical trials. So far, promising results have been obtained with anti-IL-36R spesolimab and imsidolimab in pustular psoriasis, and their efficacy is being tested in other conditions.

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Helena Iznardo

Papers

Exploring the Role of IL-36 Cytokines as a New Target in Psoriatic Disease

Dual inhibition of IL-17A and IL-17F in psoriatic disease

Lentigo Maligna: Clinical Presentation and Appropriate Management.

The safety of brodalumab for the treatment of psoriasis

IL-1 Family Cytokines in Inflammatory Dermatoses: Pathogenetic Role and Potential Therapeutic Implications