The potential role of serum polyclonal free light chains as markers of immune activation in psoriatic patients.

BACKGROUND: Polyclonal free light chains (FLCs) of immunoglobulins include κ and λ chains and represent a sensitive marker of activation and/or dysfunction of the immune system. OBJECTIVES: The aim of this study was to investigate the role of FLCs as markers of immune activation in the management of psoriatic patients treated with biologics. MATERIALS & METHODS: The overall study population included 45 patients affected by mild-to-severe psoriasis with either ongoing biological treatment or without any current systemic therapy. Peripheral blood samples were taken from all patients and 10 healthy subjects in order to determine immunoglobulins, light chains and FLCs by quantitative nephelometric assay. Moreover, antinuclear antibodies (ANA) were detected by immunofluorescence. RESULTS: Psoriatic patients showed significant increased levels of κ and λ FLCs compared to healthy controls. Interestingly, κ and λ FLCs values were significantly increased only in psoriatic patients with ongoing biological treatment and, in particular, in responder subjects. Furthermore, both κ and λ FLCs significantly correlated with duration of therapy. For patients with FLC levels above normal range and under biological treatment for more than 12 months, the odds of being ANA+ was greater relative to patients with FLC levels above normal range but under biological treatment for less than 12 months. CONCLUSIONS: Increased FLC levels may represent a marker of immune reactivation in psoriatic patients treated with biologic agents. We suggest that determining FLC levels has clinical relevance, with a cost/benefit ratio justifying such evaluation in the clinical management of psoriasis.

A Familial Novel Putative-Pathogenic Mutation Identified in Plaque-Psoriasis by a Multigene Panel Analysis.

Psoriasis is a chronic multifactorial skin disorder with an immune basis. It is characterized by patches of skin that are usually red, flaky and crusty, and that often release silvery scales. The patches appear predominantly on the elbows, knees, scalp and lower back, although they may also appear on other body areas and severity may be variable. The majority of patients (about 90%) present small patches known as "plaque psoriasis". The roles of environmental triggers such as stress, mechanical trauma and streptococcal infections are well described in psoriasis onset, but much effort is still needed to unravel the genetic component. The principal aim of this study was to use a next-generation sequencing technologies-based approach together with a 96 customized multigene panel in the attempt to determine if there are germline alterations that can explain the onset of the disease, and thus to find associations between genotypes and phenotypes. To this aim, we analyzed a family in which the mother showed mild psoriasis, and her 31-year-old daughter had suffered from psoriasis for several years, whereas an unaffected sister served as a negative control. We found variants already associated directly to psoriasis in the TRAF3IP2 gene, and interestingly we found a missense variant in the NAT9 gene. The use of multigene panels in such a complex pathology such as psoriasis can be of great help in identifying new susceptibility genes, and in being able to make early diagnoses especially in families with affected subjects.

New Perspectives in the Management of Chronic Hand Eczema: Lessons from Pathogenesis.

Chronic hand eczema (CHE) is a common inflammatory skin condition that significantly impacts the quality of life. From work-related disabilities to social embarrassment, pain, and financial costs, the burden on society is substantial. Managing this condition presents challenges such as long-term treatment, poor patient compliance, therapy side effects, and economic feasibility. As a result, significant efforts have been made in this field in recent years. Specifically, the broader understanding of CHE pathogenesis has led to the development of new drugs, both topical and systemic. The aim of this narrative review is to summarize the current available data on hand eczema pathophysiology and explore the resulting developments in drugs for its treatment. A comprehensive search on PubMed and the other main scientific databases was conducted using keywords related to CHE and its pathogenesis. The most relevant pathways targeted by therapies include the JAK-STAT cascade, IL-4, and IL-13 axis, phosphodiesterase 4 enzyme, and chemo-attractant cytokines. In the near future, physicians will have a plethora of therapeutic alternatives. Consequently, they should be well-trained not only in how to use these alternatives but also how to combine these treatments to address the ongoing challenges related to efficacy, tolerability, and safety.

Beneficial effects of Rocchetta® oligomineral water in HaCaT keratinocytes after ultraviolet-B irradiation.

BACKGROUND: Several reports have previously suggested that oligomineral water may have a beneficial immunomodulatory role in skin physiology. However, molecular, and cellular mechanisms through which oligo-elements act in cutaneous trophism have not yet been fully clarified. Among the external stimuli that affect the skin, ultraviolet (UV) radiation, which is frequently encountered in everyday life, is a major environmental factor of skin damage. Keratinocytes are the major target of UV, and they play a key role in a first line of body defenses. Accumulating evidence suggests that UVB irradiation induces nuclear DNA damage, membrane destruction, resulting in apoptosis and skin inflammation. The aim of this study was to investigate the anti-inflammatory, antioxidant, antiapoptotic effects of Rocchetta® oligomineral (Co.Ge.Di. International SpA, Rome, Italy) water in UVB-irradiated immortalized human keratinocytes. METHODS: HaCaT UVB-irradiated was cultured with increasing concentrations of Rocchetta® oligomineral water. To evaluate the anti-inflammatory properties gene expression of TNF, IL1ß, IL6, COX2 and Caspase1 was performed. Moreover, the antiapoptotic effects were evaluated through gene expression of GADD45, Caspase3 and RIPK3. Finally, we evaluated the antioxidant activity of Rocchetta® oligomineral water by measuring total ROS/RNS and superoxide production as markers of oxidative stress after UVB irradiation. RESULTS: Our findings have shown that Rocchetta® oligomineral water is well tolerated by the cells and displays anti-inflammatory, antioxidant and antiapoptotic proprieties when used prior keratinocyte UVB irradiation. CONCLUSIONS: Our results highlight a possible protective role of Rocchetta oligomineral water in modulating the cutaneous inflammatory response to external triggers and injuries.

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.

Anti-IL-17 therapy rapidly decreases osteoclast activity in psoriatic patients: a novel quality in addition to its efficacy and safety.

BACKGROUND: Psoriasis is a chronic, immune-mediated, inflammatory skin disease where interleukin-17 plays an important role in the underlying pathogenesis. IL-17A is a key driver of pro-osteoclastogenic process, that is abnormal in psoriatic patients. Aim of this study was to investigate in vivo the capability of secukinumab to influence the osteoclastogenesis in psoriatic patients reporting also our experience regarding the effectiveness and safety profile of this biological treatment. METHODS: Efficacy and tolerability of secukinumab were evaluated after the induction period and 12 weeks. Moreover, to investigate how the cutaneous clinical improvement impacted also on the osteoclastogenic profile of psoriatic patients, the osteoclastogenic assay was performed in 5 secukinumab-treated psoriatic patients, not including psoriatic arthritis, before and after 5 weeks of therapy. RESULTS: In line with clinical trials, our results confirmed the efficacy, speed of achievement and safety of secukinumab for the treatment of psoriatic patients. CONCLUSIONS: Moreover, in our experiments secukinumab has demonstrated speed of action also on osteoclastogenic process, reducing the number and activity of osteoclasts only after five weeks of treatment.

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.

Milk thistle and olive extract: old substances with a new mission against sun-induced skin damage.

BACKGROUND: Natural antioxidants represent an effective option in the prevention and/or improvement of ultraviolet radiations (UVR)-induced/aggravated skin conditions. UVR cause DNA damage in keratinocytes, directly, in the form of cyclobutane pyrimidine dimers (CPDs), or indirectly, through oxidative stress production. Failure of the repair system can result in genetic mutations primarily responsible for the initiation of NMSCs. The aim of our study was to evaluate the in vitro protective effect of milk thistle and olive purified extracts on cultured keratinocytes after solar simulator irradiations (SSR). METHODS: Immortalized keratinocytes were pre-incubated with different concentrations of milk thistle and olive purified extracts, and irradiated with increasing doses of SSR. Thereafter, CPDs and p53 expression were evaluated to assess DNA damage, whereas cellular antioxidants consumption and lipid membranes peroxidation were measured to analyze oxidative stress. RESULTS: The study substances were well tolerated by cells and displayed good cytoprotective and antioxidant activities, being milk thistle dry extract more effective in limiting the direct DNA damage, and olive extract particularly able to reduce lipid membrane peroxidation and to increase cellular antioxidants. CONCLUSIONS: Both study substances can be defined as safe compounds, showing differential cytoprotective and antioxidant activities and might represent interesting options for NMSCs chemoprevention.

Exploring Anti-Fungal, Anti-Microbial and Anti-Inflammatory Properties of a Topical Non-Steroidal Barrier Cream in Face and Chest Seborrheic Dermatitis.

INTRODUCTION: The pathogenesis of seborrheic dermatitis (SD) is multifactorial and traditional treatments may not target all aspects of it. The aim of this study was to evaluate short-term anti-fungal, anti-microbial, anti-inflammatory and anti-pruritus properties of a novel non-steroidal cream (NSC) containing piroctone olamine, zinc salt of L-pyrrolidone carboxylate (PCA), hydroxyphenyl propamidobenzoic acid, biosaccharide gum-2 and stearyl glycyrrhetinate in patients with face and chest SD. METHODS: Twelve male subjects affected by SD, presenting face and chest manifestations, were enrolled. Patients were instructed to apply NSC twice a day, performing regular visits at baseline (W0), after 7 (W1) and 14 (W2) days of treatment. A limitation of the study was that no control group treated with the vehicle without active ingredients was enrolled. To evaluate the efficacy of the NSC, investigator's assessments were represented by scoring index (SI) and investigator's global assessment score (IGA). In order to assess NSC anti-fungal and anti-microbial effects, skin scale scrapings were collected and used for Malassezia furfur (MF) and Staphylococcus epidermidis (SE) cultures. In parallel, in order to assess NSC anti-inflammatory effects, gene expression of IL-1α, IL-1ß, IL-6, IL-8, and TNF-α was assessed. In addition, anti-pruritus effects were also evaluated through gene expression of cathepsin S and L-histidine decarboxylase. RESULTS: SI mean scores significantly decreased at W1 and, to a greater extent, at W2 compared with W0. The IGA score registered an important improvement efficacy both for face and chest, from W1 to W2. MF and SE growth was already inhibited at W1, with a more pronounced decrease at W2. Gene expression of all analyzed mediators was significantly reduced at W1 compared to W0. CONCLUSION: In conclusion, our assessment is that NSC is an effective and well tolerated treatment option for SD with anti-fungal, anti-microbial and anti-inflammatory properties. TRIAL REGISTRATION: ISRCTN registry, ISRCTN77871064 (retrospectively registered October 17, 2019). EudraCT number, 2019-003813-32. FUNDING: ISDIN.

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.

The anti-inflammatory and antioxidant properties of 1,2-decanediol and willow bark extract in lipopolysaccharide-stimulated keratinocytes.

BACKGROUND: 1,2-Decanediol (S-Mal) is an organic compound belonging to the 1,2-alkanediol family, with two hydroxyl groups located on the first and second carbon of the alkane chain, probably responsible for the enhanced anti-bacterial efficacy. The willow bark total extract (W-Mal) has been used since thousands of years as an herbal remedy for its antipyretic, analgesic, anti-inflammatory and anti-microbial activities. S-Mal is used in cosmetic preparations, whether W-Mal can be topically or systemically administered. Aim of our study was to evaluate in vitro the anti-inflammatory and antioxidant properties of S-Mal and W-Mal, singularly or in combination, in LPS-stimulated keratinocytes. METHODS: The possible toxic effect of S-Mal and W-Mal was assessed through analysis of cell viability 24 hours after treatment. The anti-inflammatory and antioxidant activities were evaluated by measuring IL-8, TNF-α and IL-1ß production as well as cellular antioxidants (GSH and NADPH) consumption, 24 and 48 hours, respectively, after LPS stimulation. RESULTS: Both substances resulted able to: 1) increase cell viability (P<0.05); 2) decrease the release of inflammatory mediators (IL-8, TNF-α and IL-1ß) (P<0.05 - P<0.001); and 3) limit the depletion of cellular antioxidants (GSH and NADPH) (P<0.001). CONCLUSIONS: S-Mal and W-Mal have shown a potential cytoprotective activity when used together, and good anti-inflammatory and antioxidant effects when used either singularly or in combination. In light of our results, S-Mal and W-Mal could represent effective and safe options in the management of bacterial-induced or aggravated skin conditions.

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.

Human Microbiome: Composition and Role in Inflammatory Skin Diseases.

This review focuses on recent evidences about human microbiome composition and functions, exploring the potential implication of its impairment in some diffuse and invalidating inflammatory skin diseases, such as atopic dermatitis, psoriasis, hidradenitis suppurativa and acne. We analysed current scientific literature, focusing on the current evidences about gut and skin microbiome composition and the complex dialogue between microbes and the host. Finally, we examined the consequences of this dialogue for health and skin diseases. This review highlights how human microbes interact with different anatomic niches modifying the state of immune activation, skin barrier status, microbe-host and microbe-microbe interactions. It also shows as most of the factors affecting gut and skin microorganisms' activity have demonstrated to be effective also in modulating chronic inflammatory skin diseases. More and more evidences demonstrate that human microbiome plays a key role in human health and diseases. It is to be expected that these new insights will translate into diagnostic, therapeutic and preventive measures in the context of personalized/precision medicine.

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.

IL-26 in allergic contact dermatitis: Resource in a state of readiness.

In this study, we investigated the role of IL-26 in allergic contact dermatitis (ACD), highlighting its' contribute in the cytotoxic mechanism responsible for the tissue injury. IL-26 is a signature Th17 cytokine, and immune cells are its predominant sources. Recently, it has shown that Th17 cell-derived-IL-26 functions like an antimicrobial peptide. Here, we hypothesized that IL-26 could be involved in cytotoxicity mechanism that underlies ACD. Indeed, we have attributed a role to IL-26 in this context, through PBMC cytotoxicity assays vs HaCat. To demonstrate that IL-26 was effectively involved in this activity, we performed the assay using transfected ACD PBMCs by siRNA for IL-26. Indeed, we demonstrated that these cells were less able to kill keratinocytes compared with ACD PBMCs (P < .01). In conclusion, our findings support the idea that this emergent cytokine, IL-26, is implicated in the killing mechanisms of KC observed during ACD.

Biologics that inhibit the Th17 pathway and related cytokines to treat inflammatory disorders.

INTRODUCTION: Advances in the understanding of TNF-α and IL-17 synergistic functions have recently led to the concept that patients who do not respond or who respond inadequately to TNF-α inhibitors may have IL-17-driven diseases, opening up the way for a new class of therapeutic development: Th17-inhibitors. Areas covered: In this review, the authors discuss the central role that the IL-23/Th17 axis plays in the pathogenesis of several inflammatory diseases, such as psoriasis, highlighting its position as a relevant therapeutic target. In particular, the authors start by giving a brief historical excursus on biologic agent development up until the success of TNF-α inhibitors, and continue with an overview of IL12/23 pathway inhibition. Next, they describe Th17 cell biology, focusing on the role of IL-17 in host defense and in human immune-inflammatory diseases, discussing the use and side effects of IL-17 inhibitors. Expert opinion: The IL-23/Th17 signaling pathway plays a central role in the pathogenesis of several inflammatory diseases, such as psoriasis. Recent data has demonstrated that biologics neutralizing IL-17 (ixekizumab, secukinumab) or its receptor (brodalumab) are highly effective with a positive safety profile in treating moderate to severe psoriasis, offering new treatment possibilities, especially for patients who do not respond adequately to anti-TNF-α therapies.