EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update.

OBJECTIVE: New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the pharmacological treatment of PsA. METHODS: Following EULAR standardised operating procedures, the process included a systematic literature review and a consensus meeting of 36 international experts in April 2023. Levels of evidence and grades of recommendations were determined. RESULTS: The updated recommendations comprise 7 overarching principles and 11 recommendations, and provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs should be used in monotherapy only for mild PsA and in the short term; oral glucocorticoids are not recommended. In patients with peripheral arthritis, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended and methotrexate preferred. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drug (bDMARD) should be initiated, without preference among modes of action. Relevant skin psoriasis should orient towards bDMARDs targeting interleukin (IL)-23p40, IL-23p19, IL-17A and IL-17A/F inhibitors. In case of predominant axial or entheseal disease, an algorithm is also proposed. Use of Janus kinase inhibitors is proposed primarily after bDMARD failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. Inflammatory bowel disease and uveitis, if present, should influence drug choices, with monoclonal tumour necrosis factor inhibitors proposed. Drug switches and tapering in sustained remission are also addressed. CONCLUSION: These updated recommendations integrate all currently available drugs in a practical and progressive approach, which will be helpful in the pharmacological management of PsA.

Efficacy and safety of pharmacological treatment of psoriatic arthritis: a systematic literature research informing the 2023 update of the EULAR recommendations for the management of psoriatic arthritis.

OBJECTIVES: To obtain an overview of recent evidence on efficacy and safety of pharmacological treatments in psoriatic arthritis (PsA). METHODS: This systematic literature research (SLR) investigated the efficacy and safety of conventional synthetic (cs), biological (b) and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs) in patients with PsA. A systematic database search using Medline, EMBASE, Cochrane CENTRAL was conducted to identify relevant articles published since the previous update in 2019 until 28 December 2022. Efficacy was assessed in trials while for safety observational data were also considered. Adverse events of special interest were infections (including herpes zoster, influenza and tuberculosis), malignancies, major adverse cardiovascular events, venous thromboembolisms, liver disease, laboratory changes and psychiatric adverse events. No meta-analyses were performed. RESULTS: For efficacy, of 3946 articles screened, 38 articles (30 trials) were analysed. The compounds investigated included csDMARDs (leflunomide, methotrexate), bDMARDs inhibiting IL17 (bimekizumab, brodalumab, ixekizumab, izokibep, secukinumab,), IL-23 (guselkumab, risankizumab, tildrakizumab), IL-12/23 (ustekinumab) as well as TNF (adalimumab, certolizumab-pegol, etanercept, infliximab, golimumab) and Janus Kinase inhibitors (JAKi) (brepocitinib, deucravacitinib, tofacitinib, upadacitinib). The compounds investigated were efficacious in improving signs and symptoms of PsA, improving physical functioning and quality of life. For safety, 2055 abstracts were screened, and 24 articles analysed: 15 observational studies and 9 long-term follow-ups of trials, assessing glucocorticoids, TNFi, IL-17i, JAKi, IL-12/23i and PDE4i (apremilast). Safety indicators were generally coherent with the previous SLR in 2019. CONCLUSION: The results of this SLR informed the task force responsible for the 2023 update of the European Alliance of Associations for Rheumatology recommendations for pharmacological management of PsA.

Sex differences in adverse events from systemic treatments for psoriasis: A decade of insights from the Swiss Psoriasis Registry (SDNTT).

BACKGROUND: Psoriasis is a disease that often requires prolonged systemic treatment. It is important to determine the safety of available therapies. There is currently little insight into sex-specific differences in the safety of systemic psoriasis therapies. OBJECTIVES: To examine the real-world, long-term safety of systemic psoriasis therapies with sex stratification in drug-related adverse events (ADRs). METHODS: Ten-year data from adults with moderate-to-severe psoriasis requiring systemic treatment (conventional systemic therapies [CST], biologics) were obtained from the Swiss psoriasis registry (SDNTT). ADRs were categorized according to the international terminology Medical Dictionary for Regulatory Activities (MedDRA). Safety was assessed by calculating event rates per 100 patient-years (PY). We used descriptive statistics for patient and disease characteristics, and binomial and t-tests to compare treatment groups and sex. RESULTS: In total, 791 patients (290 females) were included with a mean age of 46 years. 358 (45%) received CSTs and 433 (55%) biologics; both groups had similar baseline characteristics except for more joint involvement in patients using biologics (26.86% vs. 14.8%, p < 0.0001). CSTs were associated with a 2.2-fold higher ADR rate (40.43/100 PY vs. 18.22/100 PY, p < 0.0001) and an 8.0-fold higher drug-related discontinuation rate than biologics (0.16/PY vs. 0.02/PY, p < 0.0001). Trends showed non-significant higher serious adverse event rates per 100 PY for biologics (8.19, CI 6.87-9.68) compared to CSTs (7.08, CI 5.39-9.13) (p = 0.3922). Sex stratification revealed a significantly higher overall ADR rate for all treatments in females (1.8-fold for CSTs [57.30/100 PY vs. 31.69/100 PY] and 2.0-fold for biologics [27.36/100 PY vs. 13.9/100 PY], p < 0.0001), and drug-related discontinuation rates for most CSTs in females. CONCLUSION: Females were associated with a significantly higher rate of ADRs and drug-related discontinuation rates. Sex stratification should be taken into consideration when designing studies in the patient-tailored management of psoriasis.

Full-body blue light irradiation as treatment for atopic dermatitis: a randomized sham-controlled clinical trial (AD-Blue).

BACKGROUND: Visible blue light (wavelength 400-495 nm) is a promising new treatment option for both psoriasis and atopic dermatitis (AD). Whilst previous clinical trials featured various devices and blue light at a variety of wavelengths, none of these interventions were challenged in objective clinical criteria. PATIENTS AND METHODS: Eighty-seven patients diagnosed with AD were enrolled in AD-Blue, an international, prospective, double-blinded, three-armed (415 nm vs. 450 nm vs. sham control), randomized trial designed to investigate the safety and efficacy of prototype full-body blue light devices. RESULTS: Full-body irradiation with 450 nm blue light but not 415 nm had a significant impact on itch (Itch-VAS, -1.6 ± 2.3; p  =  0.023 vs. sham irradiation). PO-SCORAD values also decreased significantly in response to irradiation at 415 nm (-11.5 ± 18.4; p = 0.028 vs. sham irradiation). None of the other outcome measures (EASI, SCORAD, IGA, DLQI) changed significantly. No safety signals were observed. Evaluation of skin transcriptomes, cytokine levels in serum, and ELISpots from peripheral blood mononuclear cells isolated from a subset of patients revealed moderate decreases in IL-31 in response to irradiation with blue light. CONCLUSIONS: Despite its favorable safety profile and moderate reductions in itch and IL-31 levels, full-body blue light irradiation did not lead to an amelioration of any of the objective measures of AD.

EULAR points to consider for the definition of clinical and imaging features suspicious for progression from psoriasis to psoriatic arthritis.

BACKGROUND: The transition from psoriasis (PsO) to psoriatic arthritis (PsA) and the early diagnosis of PsA is of considerable scientific and clinical interest for the prevention and interception of PsA. OBJECTIVE: To formulate EULAR points to consider (PtC) for the development of data-driven guidance and consensus for clinical trials and clinical practice in the field of prevention or interception of PsA and for clinical management of people with PsO at risk for PsA development. METHODS: A multidisciplinary EULAR task force of 30 members from 13 European countries was established, and the EULAR standardised operating procedures for development for PtC were followed. Two systematic literature reviews were conducted to support the task force in formulating the PtC. Furthermore, the task force proposed nomenclature for the stages before PsA, through a nominal group process to be used in clinical trials. RESULTS: Nomenclature for the stages preceding PsA onset, 5 overarching principles and 10 PtC were formulated. Nomenclature was proposed for three stages towards PsA development, namely people with PsO at higher risk of PsA, subclinical PsA and clinical PsA. The latter stage was defined as PsO and associated synovitis and it could be used as an outcome measure for clinical trials evaluating the transition from PsO to PsA. The overarching principles address the nature of PsA at its onset and underline the importance of collaboration of rheumatologists and dermatologists for strategies for prevention/interception of PsA. The 10 PtC highlight arthralgia and imaging abnormalities as key elements of subclinical PsA that can be used as potential short-term predictors of PsA development and useful items to design clinical trials for PsA interception. Traditional risk factors for PsA development (ie, PsO severity, obesity and nail involvement) may represent more long-term disease predictors and be less robust for short-term trials concerning the transition from PsO to PsA. CONCLUSION: These PtC are helpful to define the clinical and imaging features of people with PsO suspicious to progress to PsA. This information will be helpful for identification of those who could benefit from a therapeutic intervention to attenuate, delay or prevent PsA development.

Revisiting the interleukin 17 family of cytokines in psoriasis: pathogenesis and potential targets for innovative therapies.

Psoriasis is a common chronic inflammatory skin disease, associated with substantial comorbidity. TH17 lymphocytes, differentiating under the influence of dendritic cell-derived IL-23, and mediating their effects via IL-17A, are believed to be central effector cells in psoriasis. This concept is underlined by the unprecedented efficacy of therapeutics targeting this pathogenetic axis. In recent years, numerous observations made it necessary to revisit and refine this simple "linear" pathogenetic model. It became evident that IL-23 independent cells exist that produce IL-17A, that IL-17 homologues may exhibit synergistic biological effects, and that the blockade of IL-17A alone is clinically less effective compared to the inhibition of several IL-17 homologues. In this review, we will summarize the current knowledge around IL-17A and its five currently known homologues, namely IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25) and IL-17F, in relation to skin inflammation in general and psoriasis in particular. We will also re-visit the above-mentioned observations and integrate them into a more comprehensive pathogenetic model. This may help to appreciate current as well as developing anti-psoriatic therapies and to prioritize the selection of future drugs' mode(s) of action.

Inflammation modulates intercellular adhesion and mechanotransduction in human epidermis via ROCK2.

Aberrant mechanotransduction and compromised epithelial barrier function are associated with numerous human pathologies including inflammatory skin disorders. However, the cytoskeletal mechanisms regulating inflammatory responses in the epidermis are not well understood. Here we addressed this question by inducing a psoriatic phenotype in human keratinocytes and reconstructed human epidermis using a cytokine stimulation model. We show that the inflammation upregulates the Rho-myosin II pathway and destabilizes adherens junctions (AJs) promoting YAP nuclear entry. The integrity of cell-cell adhesion but not the myosin II contractility per se is the determinative factor for the YAP regulation in epidermal keratinocytes. The inflammation-induced disruption of AJs, increased paracellular permeability, and YAP nuclear translocation are regulated by ROCK2, independently from myosin II activation. Using a specific inhibitor KD025, we show that ROCK2 executes its effects via cytoskeletal and transcription-dependent mechanisms to shape the inflammatory response in the epidermis.

Adipose-Derived Stromal Cells within a Gelatin Matrix Acquire Enhanced Regenerative and Angiogenic Properties: A Pre-Clinical Study for Application to Chronic Wounds.

This study evaluates the influence of a gelatin sponge on adipose-derived stromal cells (ASC). Transcriptomic data revealed that, compared to ASC in a monolayer, a cross-linked porcine gelatin sponge strongly influences the transcriptome of ASC. Wound healing genes were massively regulated, notably with the inflammatory and angiogenic factors. Proteomics on conditioned media showed that gelatin also acted as a concentrator and reservoir of the regenerative ASC secretome. This secretome promoted fibroblast survival and epithelialization, and significantly increased the migration and tubular assembly of endothelial cells within fibronectin. ASC in gelatin on a chick chorioallantoic membrane were more connected to vessels than an empty sponge, confirming an increased angiogenesis in vivo. No tumor formation was observed in immunodeficient nude mice to which an ASC gelatin sponge was transplanted subcutaneously. Finally, ASC in a gelatin sponge prepared from outbred rats accelerated closure and re-vascularization of ischemic wounds in the footpads of rats. In conclusion, we provide here preclinical evidence that a cross-linked porcine gelatin sponge is an optimal carrier to concentrate and increase the regenerative activity of ASC, notably angiogenic. This formulation of ASC represents an optimal, convenient and clinically compliant option for the delivery of ASC on ischemic wounds.

Multidomain Efficacy and Safety of Guselkumab Through 1 Year in Patients With Active Psoriatic Arthritis With and Without Prior Tumor Necrosis Factor Inhibitor Experience: Analysis of the Phase 3, Randomized, Placebo-Controlled DISCOVER-1 Study.

OBJECTIVE: To evaluate efficacy and safety of the interleukin-23p19-subunit inhibitor, guselkumab, in DISCOVER-1 patients with active psoriatic arthritis (PsA) by prior use of tumor necrosis factor inhibitor (TNFi). METHODS: The phase 3, randomized, placebo-controlled DISCOVER-1 study enrolled patients with active PsA (swollen joint count ≥3, tender joint count ≥3, and C-reactive protein level ≥ 0.3 mg/dl) despite standard therapies; approximately one-third could have received two or fewer prior TNFi. Patients were randomized to 100 mg of guselkumab every 4 weeks (Q4W); 100 mg of guselkumab at week 0, at week 4, and every 8 weeks (Q8W); or placebo with crossover to guselkumab Q4W at week 24. Efficacy end points of ≥20% and ≥50% improvement in individual American College of Rheumatology (ACR) criteria and achieving the minimal disease activity (MDA) components were summarized by prior TNFi status. RESULTS: In DISCOVER-1, 118 (31%) patients previously received one or two TNFi. As previously reported, rates for acheiving ≥20% improvement in the composite ACR response at week 24 and week 52 were similar in TNFi-naive and TNFi-experienced patients randomized to guselkumab Q4W (76% and 68%, respectively) and Q8W (61% and 58%, respectively). Similar trends were observed for response rates of ≥20% and ≥50% improvement in individual ACR criteria and for achieving individual MDA components at week 24; TNFi-naive patients were more likely to achieve end points related to physical function and pain than TNFi-experienced patients. Overall, response rates were maintained or increased through week 52 regardless of prior TNFi use. Through week 60 in guselkumab-treated TNFi-naive and TNFi-experienced patients, 62% and 64%, respectively, reported one or more adverse events (AEs); 4% and 6% had serious AEs, respectively. CONCLUSION: Through 1 year, 100 mg of guselkumab Q4W and Q8W provided sustained improvements across multiple domains in both TNFi-naive and TNFi-experienced patients with active PsA.

Safety of Guselkumab With and Without Prior Tumor Necrosis Factor Inhibitor Treatment: Pooled Results Across 4 Studies in Patients With Psoriatic Arthritis.

OBJECTIVE: Assess pooled safety results through the end of the phase II/III studies of guselkumab (GUS; ≤ 2 years) in tumor necrosis factor inhibitor (TNFi)-naïve and -experienced patients with psoriatic arthritis (PsA). METHODS: Data were pooled from the Phase 2 and DISCOVER-1 (both TNFi-naïve and -experienced), DISCOVER-2 (TNFi-naïve), and COSMOS (TNFi-experienced) studies. Patients with active PsA were randomized to GUS 100 mg every 4 or 8 weeks (Q4W + Q8W = Combined GUS) or placebo (PBO) with crossover to GUS Q4W or Q8W at week 24. Time-adjusted adverse event (AE) rates (events/100 patient-years [PY]) and clinical laboratory findings were assessed during the PBO-controlled period and through end of study (≤ 2 years). RESULTS: Of 1554 randomized patients (n = 373 [GUS Q4W], 664 [GUS Q8W], and 517 [PBO]), 1138 (73.23%) were TNFi-naïve and 416 (26.77%) were TNFi-experienced. Respective AE rates through week 24 were 220.8/100 PY (TNFi-naïve) and 251.6/100 PY (TNFi-experienced) in the Combined GUS group and 196.1/100 PY (TNFi-naïve) and 303.0/100 PY (TNFi-experienced) in the PBO group. Among all GUS-treated patients (including those who crossed over from PBO), low AE rates were maintained during long-term evaluation in both TNFi-naïve (139.7/100 PY) and TNFi-experienced (174.0/100 PY) patients. Rates/100 PY of AEs leading to treatment discontinuation, serious AEs, and other AEs of interest, as well as occurrence of elevated hepatic transaminase levels and decreased neutrophil counts were consistent between PBO and GUS-treated patients through week 24 regardless of prior TNFi use and remained low through the end of the studies. CONCLUSION: The safety profile of GUS in TNFi-experienced patients was consistent with that in TNFi-naïve patients, which remained favorable for up to 2 years. [ClinicalTrials.gov: Phase 2 (NCT02319759), DISCOVER-1 (NCT03162796), DISCOVER-2 (NCT03158285), and COSMOS (NCT03796858)].

Adipose-Derived Stromal Cells for Chronic Wounds: Scientific Evidence and Roadmap Toward Clinical Practice.

Chronic wounds, ie, non-healing ulcers, have a prevalence of ~1% in the general population. Chronic wounds strongly affect the quality of life and generate considerable medical costs. A fraction of chronic wounds will heal within months of appropriate treatment; however, a significant fraction of patients will develop therapy-refractory chronic wounds, leading to chronic pain, infection, and amputation. Given the paucity of therapeutic options for refractory wounds, cell therapy and in particular the use of adipose-derived stromal cells (ASC) has emerged as a promising concept. ASC can be used as autologous or allogeneic cells. They can be delivered in suspension or in 3D cultures within scaffolds. ASC can be used without further processing (stromal vascular fraction of the adipose tissue) or can be expanded in vitro. ASC-derived non-cellular components, such as conditioned media or exosomes, have also been investigated. Many in vitro and preclinical studies in animals have demonstrated the ASC efficacy on wounds. ASC efficiency appears to occurs mainly through their regenerative secretome. Hitherto, the majority of clinical trials focused mainly on safety issues. However more recently, a small number of randomized, well-controlled trials provided first convincing evidences for a clinical efficacy of ASC-based chronic wound therapies in humans. This brief review summarizes the current knowledge on the mechanism of action, delivery and efficacy of ASC in chronic wound therapy. It also discusses the scientific and pharmaceutical challenges to be solved before ASC-based wound therapy enters clinical reality.

Elevating the Standard of Care for Patients with Psoriasis: 'Calls to Action' from Epicensus, a Multistakeholder Pan-European Initiative.

INTRODUCTION: Despite advances in treatment options and the management of patients with psoriasis, considerable unmet needs remain. Our objective was to identify ways to elevate the standard of care for patients with psoriasis by combining the perspectives of three important stakeholders: patients, clinicians and payors, and define 'Calls to Action' designed to achieve the identified changes. METHODS: Eight themes relevant to elevating the standard of care were identified from an insights-gathering questionnaire completed by all three stakeholder groups. A modified Delphi exercise gained consensus on statements informed by the insights. Statements were then used to inspire 'Calls to Action' - practical steps that could be taken to realise the desired changes and elevate the standard of care. RESULTS: In total, 18 European experts (10 dermatologists, 3 payors and 5 patient representatives) took part in the Delphi process. Consensus was reached on statements relating to all eight themes: improve healthcare systems to better support multidisciplinary team working and digital services, real-world data generation and optimal use, improve patient access, elevate quality-of-life measures as the most important outcomes, involve patients in patient-centred and personalised approaches to care, improve the relevance and reach of guidelines, education, and multistakeholder engagement. 'Calls to Action' common to all three stakeholder groups recognised the need to capitalise on the shift to digital healthcare, the need for consistent input into registries to generate real-world evidence to support guideline development, and the necessity of educating patients on the benefits of reporting outcomes to generate real-world data. The enormous quality-of-life burden and psychological impact of psoriasis, as well as the clinical needs of patients must be better understood, including by healthcare commissioners, so that funding priorities are assessed appropriately. CONCLUSION: This unique initiative identified a practical 'Call-to-Action Framework' which, if implemented, could help improve the standard of care for patients with psoriasis.

Despite improvements in the management of psoriasis, there is room for the standard of care for patients to be improved further. The aim of the 'Epicensus' programme is to help realise improvements by bringing together three important stakeholder groups involved in the care of patients with psoriasis: dermatologists, payors and patient representatives. First, unmet needs were explored with these stakeholders and eight themes for change were identified: 1) improve healthcare systems to better support multidisciplinary team working and digital services; 2) optimise real-world data generation and use; 3) improve patient access; 4) elevate quality-of-life measures as the most important outcomes; 5) involve patients in people-centred and personalised approaches to care; 6) improve the relevance and reach of guidelines; 7) education; 8) multistakeholder engagement. Next, a panel of experts representing the three stakeholder groups took part in a consensus process (Delphi) to reach agreement on statements relating to each of the eight themes. The statements describe current problems and what needs to be changed to raise the standard of care for patients with psoriasis. Some of the problems identified are similar to those that existed a decade ago, showing that simply recognising what needs to change is not enough to bring about improvements: action must be taken. Therefore, the Epicensus participants met to produce specific 'Calls to Action'­ practical steps described in this publication that, if put into practice, should contribute to an improvement in the standard of care for patients with psoriasis.

Comparative effectiveness of guselkumab in psoriatic arthritis: updates to a systematic literature review and network meta-analysis.

OBJECTIVE: The IL-23 p19-subunit inhibitor guselkumab has been previously compared with other targeted therapies for PsA through network meta-analysis (NMA). The objective of this NMA update was to include new guselkumab COSMOS trial data, and two key comparators: the IL-23 inhibitor risankizumab and the Janus kinase (JAK) inhibitor upadacitinib. MATERIAL AND METHODS: A systematic literature review was conducted to identify randomized controlled trials up to February 2021. A hand-search identified newer agents up to July 2021. Bayesian NMAs were performed to compare treatments on ACR response, Psoriasis Area and Severity Index (PASI) response, modified van der Heijde-Sharp (vdH-S) score, and serious adverse events (SAEs). RESULTS: For ACR 20, guselkumab 100 mg every 8 weeks (Q8W) and every 4 weeks (Q4W) were comparable (i.e. overlap in credible intervals) to most other agents, including risankizumab, upadacitinib, subcutaneous TNF inhibitors and most IL-17A inhibitors. For PASI 90, guselkumab Q8W and Q4W were better than multiple agents, including subcutaneous TNF and JAK inhibitors. For vdH-S, guselkumab Q8W was similar to risankizumab, while guselkumab Q4W was better; both doses were comparable to most other agents. Most agents had comparable SAEs. CONCLUSIONS: Guselkumab demonstrates better skin efficacy than most other targeted PsA therapies, including upadacitinib. For vdH-S, both guselkumab doses are comparable to most treatments, with both doses ranking higher than most, including upadacitinib and risankizumab. Both guselkumab doses demonstrate comparable ACR responses to most other agents, including upadacitinib and risankizumab, and rank favourably in the network for SAEs.

Pathogenesis-oriented therapy of psoriasis using biologics.

INTRODUCTION: Psoriasis is currently regarded an immune-mediated inflammatory disease. The central pathogenic axis comprises interleukin-23, TH17-lymphocytes differentiating under its influence, and interleukin-17A as a key effector cytokine of these T-lymphocytes. All of these can selectively be targeted using biological therapies, thus potentially increasing efficacy and reducing adverse events when compared to conventional systemic therapeutics. AREAS COVERED: We review the current concept of psoriasis as an immune-mediated inflammatory disease, assessing the evidence for a role of elements of the innate and adaptive immune system. We then correlate the pharmacological effects of biologics in psoriasis in light of the known physiologic as well as pathophysiological role of the respective targets. This is done on the basis of an extensive literature search of publications since 2018 which describe the role of the above-mentioned elements in health and disease or the effects of blocking these as an attempt to treat psoriasis. EXPERT OPINION: Biologics targeting the above-mentioned central pathogenic axis provide a particularly effective and safe way to treat psoriasis. Given the impact of comorbidities on therapeutic decision-making, and the efficacy of some biologics also on certain comorbidities, these drugs represent a first step toward personalized medicine in the management of psoriasis.

IL-38 orchestrates proliferation and differentiation in human keratinocytes.

Interleukin (IL)-38 is a member of the IL-1 cytokine family with reported anti-inflammatory activity. The highest constitutive IL-38 expression is detected in the skin, where it is mainly produced by differentiating keratinocytes. However, little data are available regarding its biological functions. In this study, we investigated the role of IL-38 in skin physiology. We demonstrate here that dermal fibroblasts and epithelial cells of skin appendages, such as eccrine sweat glands and sebaceous glands, also express IL-38. Next, using two- and three-dimensional cell cultures, we show that endogenous expression of IL-38 correlates with keratinocyte differentiation and its ectopic overexpression inhibits keratinocyte proliferation and enhances differentiation. Accordingly, immunohistochemical analysis revealed downregulation of IL-38 in skin pathologies characterized by keratinocyte hyperproliferation, such as psoriasis and basal or squamous cell carcinoma. Finally, intracellular IL-38 can shuttle between the nucleus and the cytoplasm and its overexpression modulates the activity of the transcription regulators YAP and ID1. Our results indicate that IL-38 can act independently from immune system activation and suggest that it may affect the epidermis directly by decreasing proliferation and promoting differentiation of keratinocytes. These data suggest an important role of keratinocyte-derived IL-38 in skin homeostasis and pathologies characterized by epidermal alterations.

Mechanotransduction in Skin Inflammation.

In the process of mechanotransduction, the cells in the body perceive and interpret mechanical stimuli to maintain tissue homeostasis and respond to the environmental changes. Increasing evidence points towards dysregulated mechanotransduction as a pathologically relevant factor in human diseases, including inflammatory conditions. Skin is the organ that constantly undergoes considerable mechanical stresses, and the ability of mechanical factors to provoke inflammatory processes in the skin has long been known, with the Koebner phenomenon being an example. However, the molecular mechanisms and key factors linking mechanotransduction and cutaneous inflammation remain understudied. In this review, we outline the key players in the tissue's mechanical homeostasis, the available data, and the gaps in our current understanding of their aberrant regulation in chronic cutaneous inflammation. We mainly focus on psoriasis as one of the most studied skin inflammatory diseases; we also discuss mechanotransduction in the context of skin fibrosis as a result of chronic inflammation. Even though the role of mechanotransduction in inflammation of the simple epithelia of internal organs is being actively studied, we conclude that the mechanoregulation in the stratified epidermis of the skin requires more attention in future translational research.