Does the effectiveness of biological medications in the treatment for psoriasis depend on the moment of starting therapy? A preliminary study.

Introduction: It is well known that biological medications acting on selected elements of the immune response are highly effective in psoriasis treatment. It is a common perception that psoriasis is a seasonal disorder with improvement in warmer months, however it has not been unequivocally confirmed. It is not known whether the time of year of starting systematic therapy for psoriasis influences treatment outcomes. Material and methods: Changes in psoriasis severity scores during treatment with biologics were investigated. The scores were recorded for 62 patients with moderate to severe psoriasis at the beginning, after 1, 4 and 7 months of the therapy. Patients were divided into two groups: those beginning the treatment in the cold period of the year (November-March) and in the warm period (May-September). The seasonal groups were also divided into subgroups according to the type of biologics used: interleukin inhibitors and tumor necrosis factor α (TNF-α) inhibitors. Results of the treatment were analysed using standard statistical tests of differences between samples. Results: After 1 and 4 months of the therapy, better efficacy of interleukin inhibitors was found in patients starting treatment in summer. The course of psoriasis improvement in patients taking TNF-α inhibitors resulted in consistent improvement regardless of the season. The outcome of the treatment after 7 months was similar for both seasonal groups and types of biologics used. Conclusions: Our understanding of the effectiveness of the treatments depending on the time of the year combined with the type of biologics used, may further improve results of the therapy.

Case report: Successful treatment with biologics in a pediatric patient with a severe inflammatory skin disease and novel CARD14 mutation.

CARD14 (caspase activation and recruitment domain) mutations have been associated with psoriasis vulgaris, psoriatic arthritis, generalized and palmoplantar pustular psoriasis, pityriasis rubra pilaris, and atopic dermatitis. We present a pediatric patient with a novel CARD14: c.394A > T/- (Ile123Phe) mutation, diagnosed with CARD14-associated papulosquamous eruption (CAPE), who was successfully treated with biological treatment.

Shift in skin microbiota of children with atopic dermatitis after topical gentian violet application.

Introduction: Increasing usage of antimicrobial agents may contribute to bacterial resistance in atopic dermatitis (AD). In this case an alternative topical treatment might be gentian violet (GV), suggested for its antibacterial and antifungal properties. Aim: To assess the microbial composition of lesional skin in children with AD and a control group aged 2-12 years, before and after 3 days of 2% aqueous GV application. Material and methods: Skin samples were taken from 30 AD patients and 30 healthy controls aged 2-12 years. The procedure was done two times - before and after 3 days of 2% aqueous GV application. The material was collected from skin lesions in the cubital fossa using 25 cm2 impression plates, containing CHROMagar Staph aureus and CHROMagar Malassezia. After the incubation period, the grown colonies were counted and identified by the Phoenix BD testing system. Results: The results revealed a statistically significant reduction in total counts of bacteria in both groups of children after GV application (p < 0.05). The significant decrease in the number was seen in Staphylococcus spp. (S. aureus, S. capitis, S. haemolyticus, S. cohnii) in AD patients. The number of Staphylococcus spp. was comparable in patients with AD after GV treatment and healthy patients before GV exposure (p = 1.000). Conclusions: Our study results show that GV does not damage the skin surface ecosystem and allows the reduction of excessive bacterial counts on eczematous lesions to a 'safe' level, similar to that of healthy children.

Promising Immune Treatment of Advanced Cutaneous Squamous Cell Carcinoma with Cemiplimab-Real-World Experience in the Global SARS-CoV-2 Pandemic.

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent non-melanoma skin cancer. The standard curative treatment is surgical resection, but the treatment of locally advanced and metastatic disease apart from radiotherapy is currently based on cemiplimab. Cemiplimab has demonstrated efficacy in the treatment of advanced and metastatic cSCC in clinical trials, although real-world data are still limited. We present four cases of cSCC, which showed a tremendous response to cemiplimab-one patient achieved complete response and three of them achieved partial response. Immunotherapy with cemiplimab, a recently approved PD1 inhibitor, is an important addition to the cutaneous oncology therapeutic options that may be considered in patients with advanced disease not amenable to surgery or radiotherapy. In all four cases, the patients postponed visits to the doctor because of the fear of SARS-CoV-2 infection or for administrative and organizational reasons declared difficult access to doctors caused by the pandemic.

The Kinetics of FMS-Related Tyrosine Kinase 3 Ligand (Flt-3L) during Chemoradiotherapy Suggests a Potential Gain from the Earlier Initiation of Immunotherapy.

The optimal sequence of chemoradiotherapy with immunotherapy is still not established. The patient's immune status may play a role in determining this order. We aim to determine the kinetics of a multi-potential haemopoietic factor FMS-related tyrosine kinase 3 ligand (Flt-3L) during chemoradiotherapy. Our pilot, a single arm prospective study, enrolled patients with rectal cancer who qualified for neoadjuvant chemoradiotherapy. Blood samples for Flt-3L were collected before and every second week of chemoradiotherapy for a complete blood count every week. The kinetics of Flt-3L were assessed using Friedman's ANOVA. A multiple factor analysis (MFA) was performed to find relevant factors affecting levels of serum Flt-3L during chemoradiotherapy. FactoMineR and factoextra R packages were used for analysis. In the 33 patients enrolled, the level of Flt-3L increased from the second week and remained elevated until the end of treatment (p < 0.01). All patients experienced Grade ≥2 lymphopenia with a nadir detected mostly in the 5/6th week. MFA revealed the spatial partitioning of patients among the first and second dimensions (explained by 38.49% and 23.14% variance). The distribution along these dimensions represents the magnitude of early changes of Flt-3L. Patients with the lowest values of Flt-3L change showed the highest lymphocyte nadirs and lowest dose/volume parameters of active bone marrow. Our hypothesis-generating study supports the concept of early initiation of immuno-therapy when the concentration of Flt-3L is high and no lymphopenia has yet occurred.

Risk Factors and Clinicopathological Features for Developing a Subsequent Primary Cutaneous Squamous and Basal Cell Carcinomas.

BACKGROUND: Patients with diagnosed keratinocyte carcinomas (KCs) have an increased risk of subsequent skin cancers development. Current studies indicate that patients with subsequent tumors should be followed up regularly. However, none of the studies indicate the connection between the specific subtypes and an increased risk for further KCs development. The study assesses the differences in the risk of developing a subsequent skin cancer after a previous diagnosis of KC, especially considering individual types of skin malignances, and identifies potential factors associated with an increased risk of new cutaneous tumor describing non-invasive diagnosis and monitoring. METHODS: Pathology and medical records were examined to identify the characteristics of patients with multiple KCs diagnosed between 1999 and 2019. RESULTS: The study group comprised 13,913 KCs occurring in 10,083 patients. Multiple KCs were observed in 2300 patients (22.8%). The analysis showed aggressive subtypes, multiple tumors, and male sex as significant prognostic factors. CONCLUSIONS: The most crucial risk factors for developing subsequent KC are being of a male gender, an aggressive tumor subtype, and previous history of multiple skin cancers. Basal cell carcinoma subtypes, such as infiltrative basosquamous, with aggressive growth patterns predispose not only to increased risk for the recurrence but are also expected to be at higher risk of subsequent KCs.

The role of inflammasomes in cutaneous pathology.

Inflammasomes are large intracellular multiprotein complexes, which constitute a novel part of the innate immune system. In response to danger signals from pathogens or other harmful agents, inflammasomes assemble resulting in production of the inflammatory cytokines. We discuss recent knowledge of the role of deregulated inflammasome activity in skin pathologies such as autoinflammatory diseases as well as common skin diseases such as psoriasis and atopic dermatitis. We also present an insight into the activation and effector mechanisms of inflammasomes in skin carcinogenesis. The complex influence of inflammasome on cutaneous disorders raises new challenges and opportunities for the treatment of skin diseases.

Impact of the COVID-19 Pandemic on Atopic Dermatitis Patients.

Atopic dermatitis (AD) can have a significantly negative impact on quality of life (QoL). The impact of coronavirus disease 2019 (COVID-19) on the AD population is not yet well established. The study comprised 195 patients with diagnosed AD who were asked about their cognitive and preventive behaviors regarding COVID-19 and the accessibility of medical support, including online consultations. Moreover, the patients responded to the self-reported Dermatology Life Quality Index (DLQI) and Hospital Anxiety and Depression Scale (HADS). Most of the patients were worried about being infected with COVID-19. Most of the patients believed that people suffering from skin disease were more prone to be infected with COVID-19 compared with the general population. Most the patients negatively assessed the availability of dermatological treatment during the pandemic. Furthermore, 66.1% of the patients declared using telemedicine. Nearly 50% of patients were discontented with telemedicine, and 1/3 of the patients did not mind the use of telemedicine. AD during the COVID-19 pandemic was associated with a lower overall health rating and life satisfaction and impaired QoL related to mental health in a Polish population. These results provide original information that can be applied in dermatologic patient screenings to evaluate the state of depression and anxiety during the epidemic period.

The role of heterodimer IL-17-A/F in atopic dermatitis.

Introduction: The importance of multifactorial dysregulation in immune response is well recognised in atopic dermatitis (AD). Th17 family cytokine IL-17 (IL-17A-F) is of significance in both acute and chronic phase of AD. Aim: We analysed the differences between serum levels of IL-17A/F and IL-17A, IL-17-F, IL-13, IL-4, association of rs2275913 IL-17A and rs763780 IL-17F gene polymorphisms in paediatric AD patients and control subjects. Material and methods: We assessed 30 children with AD and 30 healthy patients aged 2-12 years. Eczema Area and Severity Index, Investigator Global Assessment and Scoring Atopic Dermatitis scales were used to analyse the severity of skin lesions in AD patients. Genotyping was performed using PCR and the serum concentrations of IL-17A/F, IL-17A, IL-17F, while IL-13 and IL-4 interleukins were determined by enzyme-linked immuno-sorbent assays (ELISA). Results: The revised median assessment scoring in disease severity showed that the studied AD population had a moderate course of the disease. The obtained results indicated elevated plasma levels of IL-17A/F and IL-17-13 in AD patients with no statistically significance of IL-17A, IL-17F and IL-4 compared to controls. AD duration was positively correlated with IL-13 levels and negatively with IL-17A/F (p < 0.05). Moreover, there was no significant difference between case and control groups in the frequency of genotypes and alleles at rs2275913 IL-17A and rs763780 IL-17F polymorphisms (p > 0.05). Conclusions: This study demonstrates increased levels of IL-17A/F in atopic patients, which is positively correlated with severity of the disease and the early phase of the disease. These results highlight a functional role of this cytokine in the pathogenesis of AD in paediatric patients.

More Than Skin Deep - the Effects of Ultraviolet Radiation on Cathepsin K and Progerin Expression in Cultured Dermal Fibroblasts.

INTRODUCTION: Photoaging is a premature skin aging developing secondarily to the excessive exposure to ultraviolet radiation. Due to its complexity, an exact mechanism of photoaging has not been found yet; however, recent research has shown two new emerging players in this process - cathepsin K and progerin. AIM: To evaluate how different wavelengths of ultraviolet radiation (UVA, narrowband UVB and broadband UVB) influence cathepsin K and progerin protein and mRNA expression in dermal cultured fibroblasts. MATERIALS AND METHODS: Primary human dermal fibroblasts (Detroit 551, ATCC CCL-110) were cultured and irradiated with UVA, narrowband UVB (UVBnb) and broadband UVB (UVBwb). Fibroblasts were irradiated with 2 protocols: single high-dose exposure to UVR with protein/mRNA extraction immediately after exposure, 24 h after exposure and 48 h after exposure, and repeated (0 h, 24 h and 48 h) low-dose exposure to UVR with protein/mRNA extraction 48 h after first exposure. RESULTS: Single high doses of UVA, UVBwb and UVBnb resulted in decreased expression of cathepsin K and progerin protein/mRNA in all subsequent time points. Repeated exposure to low doses of UVA results in significant increase of progerin mRNA and significant decrease of progerin protein after 48 h, but repeated exposure to UVBwb and UVBnb resulted in decreased progerin mRNA and protein expression. Repeated exposure to UVA, UVBwb and UVBnb resulted in decreased cathepsin K protein and mRNA expression. CONCLUSION: The results suggest that there could be another progerin/cathepsin K regulatory pathway, which has not been described yet. Being contradictory with previous research, the influence of ultraviolet radiation on progerin and cathepsin K needs to be further elucidated.

COVID-19 in Patients with Atopic Dermatitis Treated with Dupilumab: Three Cases and a Literature Review.

There are limited clinical data on the impact of the SARS-CoV2 infection on patients with dermatological conditions treated with biologics. Dupilumab is a recombinant human IgG4 human monoclonal antibody that inhibits IL4 and IL13 signaling, and is used for moderate-severe atopic dermatitis treatment. We present three patients with atopic dermatitis (AD) treated with dupilumab who contracted COVID-19. In all patients, the infection had a mild course, and only in one, as documented by SCORAD, EASI, and DLQI scores, the condition of the skin deteriorated, and a prolonged positive PCR COVID-19 test was observed. The mechanism of dupilumab action and more evidence for IL13 importance in lung damage caused by SARS-CoV2 suggest a possible explanation for a mild-moderate course of the infection in treated AD patients. Based on current knowledge, there is evidence to continue dupilumab treatment in AD patients with mild-moderate COVID-19; however, careful assessment is needed for each patient.

Tumor of the Nose - A Rare Manifestation of a Metastatic Lung Cancer.

Lung cancer most often metastasizes to the central nervous system, bone and liver. Although metastases to the skin are quite rare, it is estimated that they may be the first clinical manifestation of this disease in 0.7%-12% of cases. Metastases to the skin are caused by adenocarcinoma (about 30%), squamous cell carcinoma (30%) and undifferentiated carcinoma (40%). Nasal tip metastases are extremely rare. They can be confused with more common skin problems, including non-melanoma skin cancers, rhinophyma, inflammatory tumors or infectious diseases. We report two patients with a tumor on the nose, which proved to be the first sign of the metastatic lung cancer.

Hippo Signaling Pathway as a New Potential Target in Non-Melanoma Skin Cancers: A Narrative Review.

Non-melanoma skin cancers (NMSCs), including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), are the most frequently diagnosed cancers in humans, however, their exact pathogenesis is not fully understood. In recent years, it has been hypothesized that the recently discovered Hippo pathway could play a detrimental role in cutaneous carcinogenesis, but no direct connections have been made. The Hippo pathway and its effector, YAP, are responsible for tissue growth by accelerating cell proliferation, however, YAP upregulation and overexpression have also been reported in numerous types of tumors. There is also evidence that disrupted YAP/Hippo signaling is responsible for cancer growth, invasion, and metastasis. In this short review, we will explore whether the Hippo pathway is an important regulator of skin carcinogenesis and if it could be a promising target for future therapies.

TaaI/Cdx-2 AA Variant of VDR Defines the Response to Phototherapy amongst Patients with Psoriasis.

1,25-dihydroxyvitamin-D3 plays a central role in the immune system via binding to the vitamin D receptor. VDR polymorphisms have been associated with multiple autoimmune disorders, including psoriasis. Until now, five VDR polymorphisms, FokI, ApaI, BsmI, TaqI and TaaI/Cdx2, have been studied in psoriasis, with contradicting results. Therefore, this study aimed to evaluate the association of VDR polymorphisms with susceptibility to psoriasis, effectiveness of NB-UVB phototherapy and concentration of proinflammatory cytokines and vitamin D amongst the Polish population. VDR polymorphisms were analyzed by PCR-RFLP or real-time PCR. We found that the frequency of the TaaI/Cdx-2 GG genotype was significantly higher in psoriasis patients and was associated with regulation of IL-17 and IL-23 concentration. Moreover, TaaI/Cdx-2 AA might have a significant effect on the response to phototherapy amongst patients with psoriasis. Our results suggest that VDR is a susceptibility factor for psoriasis development. Moreover, TaaI/Cdx-2 variants have a significant effect on the response to phototherapy amongst patients with psoriasis and regulation of inflammatory response via decrease of IL-17 and IL-23 level after UVB phototherapy in the Polish population. Results of our study provide some evidence in support of the hypothesis that the vitamin D signaling pathway may be of relevance for pathogenesis and treatment of psoriasis.

The Role of NLRP1, NLRP3, and AIM2 Inflammasomes in Psoriasis: Review.

Inflammasomes are high-molecular-weight protein complexes that may cleave the two main proinflammatory cytokines, pro-interleukin-1ß and pro-interleukin-18, into active forms, and contribute to psoriasis. Despite recent advances made in the pathogenesis of psoriasis, mainly studied as an autoimmune condition, activation of immune response triggers of psoriasis is still not completely understood. Recently, focus was placed on the role of inflammasomes in the pathogenesis of psoriasis. Multiple types of inhibitors and activators of various inflammasomes, inflammasome-related genes, and genetic susceptibility loci were recognized in psoriasis. In this systemic review, we collect recent and comprehensive evidence from the inflammasomes, NLRP1, NLRP3, and AIM2, in pathogenesis of psoriasis.

Alterations of the Skin and Gut Microbiome in Psoriasis and Psoriatic Arthritis.

Numerous scientific studies in recent years have shown significant skin and gut dysbiosis among patients with psoriasis. A significant decrease in microbiome alpha-diversity (abundance of different bacterial taxa measured in one sample) as well as beta-diversity (microbial diversity in different samples) was noted in psoriasis skin. It has been proven that the representation of Cutibacterium, Burkholderia spp., and Lactobacilli is decreased and Corynebacterium kroppenstedii, Corynebacterium simulans, Neisseria spp., and Finegoldia spp. increased in the psoriasis skin in comparison to healthy skin. Alterations in the gut microbiome in psoriasis are similar to those observed in patients with inflammatory bowel disease. In those two diseases, the F. prausnitzii, Bifidobacterium spp., Lactobacillus spp., Parabacteroides and Coprobacillus were underrepresented, while the abundance of Salmonella sp., Campylobacter sp., Helicobacter sp., Escherichia coli, Alcaligenes sp., and Mycobacterium sp. was increased. Several research studies provided evidence for the significant influence of psoriasis treatments on the skin and gut microbiome and a positive influence of orally administered probiotics on the course of this dermatosis. Further research is needed to determine the influence of the microbiome on the development of inflammatory skin diseases. The changes in microbiome under psoriasis treatment can serve as a potential biomarker of positive response to the administered therapy.

Ultraviolet Radiation and Chronic Inflammation-Molecules and Mechanisms Involved in Skin Carcinogenesis: A Narrative Review.

The process of skin carcinogenesis is still not fully understood. Both experimental and epidemiological evidence indicate that chronic inflammation is one of the hallmarks of microenvironmental-agent-mediated skin cancers and contributes to its development. Maintaining an inflammatory microenvironment is a condition leading to tumor formation. Multiple studies focus on the molecular pathways activating tumorigenesis by inflammation and indicate several biomarkers and factors that can improve diagnostic and prognostic processes in oncology and dermatology. Reactive oxygen species produced by ultraviolet radiation, oxidizers, or metabolic processes can damage cells and initiate pro-inflammatory cascades. Considering the potential role of inflammation in cancer development and metastasis, the identification of early mechanisms involved in carcinogenesis is crucial for clinical practice and scientific research. Moreover, it could lead to the progress of advanced skin cancer therapies. We focus on a comprehensive analysis of available evidence and on understanding how chronic inflammation and ultraviolet radiation can result in skin carcinogenesis. We present the inflammatory environment as complex molecular networks triggering tumorigenesis and constituting therapeutic targets.

AntiTNF-alpha therapy normalizes levels of lipids and adipokines in psoriatic patients in the real-life settings.

Studies have shown that the levels of pro-inflammatory adipokines in patients with psoriasis are higher than in general population. The aim of the study was to investigate the influence of 36-month therapy with TNF-α inhibitors (adalimumab, etanercept, infliximab) on the levels of adipokines (resistin, adiponectin, leptin) and lipids (TG, cholesterol, LDL, HDL) in 37 psoriasis patients and 30 healthy controls. The mean serum concentrations of adiponectin in patients from adalimumab, etanercept and infliximab group were similar to control group (p > 0.05, 142.71, 164.32, 129.35 and 174.44 µg/ml respectively). Resistin levels were higher in patients (p < 0.05, 4.48, 4.53 and 3.39 ng/ml respectively) than in controls (3.05 ng/ml). Mean leptin concentrations were significantly higher (p < 0.05) in the study group than in subjects without psoriasis (428.61, 523.24, 755.27 and 154.10 pg/ml respectively). A significant decrease in the mean resistin concentration was observed under the influence of biological therapy (p < 0.05). Decrease in serum leptin level was noted in etanercept and infliximab groups (p = 0.001 and p = 0.002 respectively). Improvement in all lipidogram parameters was noted in all examined groups (p < 0.05). Results may prove that biologic therapy affects the systemic inflammation associated with psoriasis and this effect persists with long-term therapy.