The Use of JAK/STAT Inhibitors in Chronic Inflammatory Disorders.

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a critical role in orchestrating immune and inflammatory responses, and it is essential for a wide range of cellular processes, including differentiation, cell growth, and apoptosis. Over the years, this pathway has been heavily investigated due to its key role in the pathogeneses of several chronic inflammatory conditions, e.g., psoriasis, atopic dermatitis (AD), and inflammatory bowel diseases (IBDs). Nevertheless, the impact of this pathway on the pathogenesis of inflammatory conditions remains unclear. This review describes the role of the JAK/STAT signaling pathway in the pathogenesis of inflammatory diseases such as psoriasis (Pso), psoriatic arthritis (PsA), AD, and IBD with a focus on ulcerative colitis (UC) and briefly resumes the use of JAK inhibitors in their clinical management.

Loss of p53 activates thyroid hormone via type 2 deiodinase and enhances DNA damage.

The Thyroid Hormone (TH) activating enzyme, type 2 Deiodinase (D2), is functionally required to elevate the TH concentration during cancer progression to advanced stages. However, the mechanisms regulating D2 expression in cancer still remain poorly understood. Here, we show that the cell stress sensor and tumor suppressor p53 silences D2 expression, thereby lowering the intracellular THs availability. Conversely, even partial loss of p53 elevates D2/TH resulting in stimulation and increased fitness of tumor cells by boosting a significant transcriptional program leading to modulation of genes involved in DNA damage and repair and redox signaling. In vivo genetic deletion of D2 significantly reduces cancer progression and suggests that targeting THs may represent a general tool reducing invasiveness in p53-mutated neoplasms.

Irisin, a novel metabolic biomarker in hidradenitis suppurativa: correlation with clinical responsivity to anti-TNF-α therapy.

BACKGROUND: Suppurative hidradenitis (HS) is a chronic, inflammatory skin disease of the hair follicle unit. Adalimumab (ADA), an anti-tumor necrosis factor (TNF) alpha, is the only FDA-approved biologic available for the management of HS. TNF-α can also affect glucose and lipid metabolism, promoting insulin resistance and obesity by negatively regulating irisin, a new adipomyokine. METHODS: A total of 17 HS patients were enrolled in the study. Blood samples were collected from all patients at baseline and week-16. Plasma irisin levels were detected by ELISA assay. RESULTS: Plasma irisin levels were significantly increased after 16 weeks of ADA therapy in HS patients compared to baseline. Interestingly, plasma irisin levels correlated with clinical response. CONCLUSIONS: The link between skin inflammatory diseases and metabolic disorders has aroused great interest in order to research new biomarkers able to early identify metabolic comorbidities. Among these emerging biomarkers, irisin is one of the most recently discovered. We examined a group of patients affected by moderate-severe HS treated with anti-TNF-α, demonstrating for the first time how a therapy able to block an inflammatory cytokine can also affect the metabolic profile by modifying levels of irisin.

Antiflammatory activity and potential dermatological applications of characterized humic acids from a lignite and a green compost.

Long-term exposure to air pollution has been associated with the development of some inflammatory processes related to skin. The goal of modern medicine is the development of new products with antiflammatory action deriving from natural sources to improve environmental and economic sustainability. In this study, two different humic acids (HA) were isolated from from lignite (HA-LIG) and composted artichoke wastes (HA-CYN) and characterized by infrared spectrometry, NMR spectroscopy, thermochemolysis-GC/MS, and high-performance size-exclusion chromatography (HPSEC), while their antiflammatory activity was evaluated on HaCaT cells. Spectroscopic results showing the predominance of apolar aliphatic and aromatic components in HA-LIG, whereas HA-CYN revealed a presence of polysaccharides and polyphenolic lignin residues. The HA application on human keratinocyte pre-treated with Urban Dust revealed a general increase of viability suggesting a protective effect of humic matter due to the content of aromatic, phenolic and lignin components. Conversely, the gene expression of IL-6 and IL-1ß cytokines indicated a significant decrease after application of HA-LIG, thus exhibiting a greater antiflammatory power than HA-CYN. The specific combination of HA protective hydrophobic components, viable conformational arrangements, and content of bioactive molecules, suggests an innovative applicability of humic matter in dermatology as skin protectors from environmental irritants and as antiflammatory agents.

Eczematous drug eruption in patients with psoriasis under anti-interleukin-17A: does interleukin-22 play a key role?

BACKGROUND: Eczematous drug eruption (EDE) is a spongiotic skin reaction in response to systemic medications. To date, EDE has been described in patients treated with anti-interleukin (IL)-17A monoclonal antibodies with a prevalence of 2.2%-12.1%. AIM: To describe the clinical and histological features and the skin cytokine milieu in patients with EDE induced by anti-IL-17A biologics. METHODS: This was a prospective study, enrolling patients with psoriasis who developed EDE during treatment with two anti-IL-17 biologics, ixekizumab and secukinumab, from June 2019 to April 2021. Skin biopsies were taken from all patients: a 5-mm lesional biopsy (LB) and a 3-mm nonlesional biopsy (NLB). The LB sample was split into two parts, one for histological examination and the other for cytokine profile evaluation. RESULTS: During the study period, treatment with an anti-IL-17A drug was given to 289 patients of whom 8 (2.8%) developed EDE during the treatment. Histopathological evaluation suggested a diagnosis of spongiotic dermatitis in all eight patients. Cytokine gene expression showed a predominance of T helper (Th)2/Th22 cytokines in EDE lesions with a large increase in IL-4, IL-22 and S100A7 levels in both LB and NLB samples compared with healthy skin. IL-4, IL-22 and S100A7 were significantly higher in LB compared with NLB samples. IL-26 levels were also significantly increased in both LB and NLB compared with healthy skin, whereas low levels of IL-23A were found in both LB and NLB. CONCLUSION: Eczematous drug eruption skin lesions have mainly Th2/Th22 features, with IL-22 playing a major role in their pathogenesis. EDE seems to be the result of an imbalance towards a Th2/Th22 response, secondary to the blockade of IL-17A activity.

Safety concerns with current treatments for psoriasis in the elderly.

Introduction: The approach to manage psoriasis in the elderly (ages ≥65 years) patients can be challenging. They often suffer from multiple comorbidities and polypharmacy with possible adverse effects and undergo a progressive functional impairment of the immune system that increases susceptibility to infections as well as to auto-reactivity. Despite the increasing aging of the general population and although several therapies are currently available for psoriasis treatment, data regarding their use and tolerability in the elderly are quite limited.Areas covered: This review focuses on topical and systemic therapies that have been investigated in elderly patients in order to provide their safety profile in this population.Expert opinion: Conventional systemic therapies in elderly patients should be carefully dispensed and the correct dosage individually determined, taking into account the metabolism changes, organ impairment, comorbidities, concomitant medications, and contraindications. Apremilast, due to its satisfactory safety profile and low risk of drug interactions, results as an appropriate treatment option for elderly patients. Biologics (TNF-α, IL-12/23, IL-17, and IL-23 inhibitors) come out as safe and long-term options for the management of these patients resulting not associated with a higher risk of adverse events.

Psoriatic arthritis onset in psoriatic patients receiving UV phototherapy in Italy.

BACKGROUND: Psoriasis is a chronic, recurrent, and immune-mediated inflammatory disease that affects 2-3% of the world population. A substantial proportion of patients with psoriasis, approximately 40%, develop a form of inflammatory arthritis known as psoriatic arthritis (PsA), the arthritis follows the development of psoriasis, and it will develop simultaneously or possibly before the appearance of skin lesions. The presence of PsA indicates a need for more active intervention rather than purely topical therapies or UV-based therapies. The aim of this multicenter, retrospective, epidemiological study was to estimate the incidence of PsA in psoriatic patients receiving UV treatment as monotherapy. METHODS: A retrospective epidemiological study was performed in 8 dermatological reference center, located throughout Italy (2 from Northern, 3 from Center, 3 from Southern); a period of 1 year was considered. Data from the overall study population including 326 patients with a diagnosis of psoriasis were analyzed. Furthermore, data coming from follow-up visits, including screening for PsA onset through specific questionnaires were analyzed. RESULTS: PsA screening was positive in 27 patients (8.3%), whereas PsA diagnosis was confirmed by a rheumatologist in only 22/27 (81.5%) being therefore found in 22/326 (6.7%). Patients diagnosed with PsA had a statistically significantly higher abdominal circumference (96±15.3 vs. 88.9±18.3, P=0.048) and more commonly presented a positive past medical history for phototherapy (90.9% vs. 57.6% P=0.004). CONCLUSIONS: Our study showed that phototherapy is not able to prevent or slow down the risk of PsA development in psoriatic patients. PsA screening should be always carried out in those patients even if asymptomatic, especially in obese subjects which are at great risk to develop PsA due to their increased systemic inflammatory state.

Possible role of BMP-4 in the hyper-pigmentation of psoriatic plaques after anti-TNF-α treatment.

Psoriasis over-expresses several inflammatory mediators, which impacts the activity of melanocytes. Tyrosinase (Tyr) and microphthalmia-associated transcription factor (MITF) are the primary regulators of melanogenesis. Furthermore, bone morphogenetic proteins (BMPs) modulate various pathobiologic processes including inflammation, melanogenesis and melanomagenesis. To determine the association between psoriasis and melanogenesis, psoriatic lesional skin was screened through gene expression, immunohistochemistry, immunogold staining and melanin content assays. The present study detected a decreased expression of Tyr, MITF and BMP-4 in psoriatic lesional skin compared with healthy skin. Tyr, BMP-4 and melanin content were also evaluated in the psoriatic lesional skin of patients receiving adalimumab therapy, before and after 16 weeks of treatment. TNF-α blockade modulated the Tyr, BMP-4 and melanin content of the patient skin lesions, which supported the hypothesis that hyper-pigmentation may occur in areas of psoriatic plaque after biological treatment. The present study confirmed the influence of the psoriatic pro-inflammatory network on melanogenesis, exerting an inhibitory effect mediated by TNF-α. Furthermore, the results regarding BMP-4 in the present study add another important element to the mechanism of psoriasis.

Paraoxonases and psoriasis: negative imbalance of antioxidant endogenous mechanisms.

BACKGROUND: Numerous reports have shown that psoriasis patients are more exposed to lipoprotein peroxidation and to a decrease in the activity of paraoxonase (PON)1, an antioxidant and anti-inflammatory enzyme. Thus, it has been suggested that malfunction of the antioxidant system and an increased production of reactive oxygen species drive immune inflammatory events, that result in progressive skin cell damage in patients with psoriasis. The PON protein family, including PON1, PON2 and PON3, is one of the most important endogenous defense mechanisms against oxidative stress. In the present study, we investigated PON gene expression in psoriasis and in cutaneous oxidative stress. METHODS: The study population included 10 patients affected by moderate-to-severe plaque psoriasis and 15 healthy donors who have undergone to plastic surgery, were used as control. Skin punch biopsies of lesional and non lesional psoriatic skin were performed for analysis of PON2 and PON3 gene expression. In addition, oxidation assays in ex vivo full-thickness healthy skin organ cultures were performed. RESULTS: No significant differences were observed between PON2 and PON3 gene expression in psoriatic lesional and non lesional skin compared with healthy controls. H2O2 treatment induced a significant decrease of PON2 and PON3 expression in ex vivo full-thickness healthy skin organ cultures; conversely the pretreatment of samples with the antioxidant reagent N-acetyl-L-cysteine (NAC) induced a significant increase. Interestingly, no significant alterations were reported for PON2 and PON3 expression in ex vivo full-thickness healthy skin organ cultures stimulated with IL-17. CONCLUSIONS: Taken together our findings have revealed that a strong pro-oxidative activity is not effectively countered by antioxidant endogenous mechanisms both in psoriatic skin and in ex vivo experimental model.

Psoriasis, Cardiovascular Events, and Biologics: Lights and Shadows.

Nowadays, it is well established a link between psoriasis and cardiovascular (CV) diseases. A series of different overlapping mechanisms including inflammation, homeostasis dysregulation, and genetic susceptibility are thought to underlie this association. Advances in understanding the molecular patterns involved in the complex scenario of psoriasis have highlighted a tight correlation with atherosclerosis. Indeed, common profiles are shared in term of inflammatory cytokines and cell types. In the last decade, the management of psoriasis patients has been revolutionized with the introduction of biological therapies, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-12/23, and IL-17 inhibitors. In clinical setting, the effectiveness of these therapies as well as the incidence of CV events is related to the type of biologics. In particular, anti-TNF-α agents seem to reduce these events in psoriasis patients whereas anti-IL-12/23 agents related CV events reduction still remain to clarify. It has to be taken into account that IL-12/23 inhibitors have a shorter post-marketing surveillance period. An even more restricted observational time is available for anti-IL-17 agents. IL-17 is associated with psoriasis, vascular disease, and inflammation. However, IL-17 role in atherosclerosis is still debated, exerting both pro-atherogenic and anti-atherogenic effects depending on the specific context. In this review, we will discuss the differences between the onset of CV events in psoriasis patients, referred to specific biological therapy and the underlying immunological mechanism. Given the development of new therapeutic strategies, the investigation of these inhibitors impact on heart failure outcome is extremely important.

Chronic hand eczema: is IL-36α helpful in diagnosis and classification?

BACKGROUND: Chronic hand eczema (CHE) is not a homogenous disease, necessitating complex differential diagnostics. Interleukin (IL) -1 family members are significantly up-regulated in ACD and psoriasis patients skin. METHODS: The present study aims to deepen the knowledge about clinical assessment and characterization of patients affected by chronic hand dermatitis (CHD) as well as to investigate the role of possible biomarkers which may help in the diagnostic process. An observational case-control study was performed enrolling 30 CHD patients and 20 healthy controls. Each patient underwent detailed medical history, clinical examination, epicutaneous patch test, and lesional skin biopsies for histological and immunohistochemical analysis. RESULTS: Patient history, clinical examination and patch testing led us to a final CHD characterization in only 8/30 subjects (26.7%). In the remaining subjects, clinical and histological features suggested a diagnosis of psoriasis in 9/22 (30%) and idiopathic chronic hand eczema (CHE) in 13/22 (43.3%). Trying to find a possible marker for the latter dermatosis, we analyzed IL-1 family in all the recruited subjects. IL-1 members were increased in all conditions, but IL-36α was the only analyzed cytokine able to characterize patients who end up with a diagnosis of idiopathic CHE. CONCLUSIONS: In conclusion, we can assess that medical history and patch testing remain essential investigations in CHD patients even if not always sufficient to perform a final diagnosis. Moreover, IL-1 members are probably involved in CHE skin inflammation, with IL-36α being a possible future biomarker which might help in the complex diagnostic process of CHE.