The effectiveness of omalizumab therapy in patients with chronic spontaneous urticaria: the experience of a single-centre study in Poland.

Introduction: Omalizumab, which is a recombinant, humanised anti-immunoglobulin-E antibody, is the only approved drug for antihistamine refractory chronic spontaneous urticaria (CSU). It has been reported that it is an effective and safe drug, but the data about long-term effectiveness are still lacking. Aim: To perform a retrospective analysis of the patients with CSU treated with omalizumab at the dermatology department to assess effectiveness of omalizumab therapy in the single centre in Poland. Material and methods: A two-and-a-half-year retrospective analysis of patients with CSU undergoing the therapy with omalizumab was conducted. Patients' data were analysed for many factors such as age, gender, severity indexes (UAS7, DLQI), duration and effects of the treatment used. Results: Sixty-one patients with CSU have been treated with omalizumab in the drug program. The number of female patients - 42 (68.9%) significantly dominated over the number of male patients - 19 (31.1%). The mean UAS7 during the first course of treatment declined from 33.2 to 2.8, during the second from 30.9 to 1.7 and during the third 32.7 to 2.5. In case of DLQI the mean scores decrease from 18 to 2.1 in the first cycle, from 16.9 to 1.9 in the second and from 18.6 to 1.1 in the third. Conclusions: Our study confirmed that omalizumab is an effective medicine in a long-term treatment which improves a physical as well as psychological condition of the patients with antihistamine-resistant CSU. To our knowledge, it is the first study in Poland that presents omalizumab effectiveness during three courses of treatment.

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.

Interleukin 22 and 6 serum concentrations decrease under long-term biologic therapy in psoriasis.

INTRODUCTION: Psoriasis, affecting approximately 2% of the worldwide population, is a chronic, inflammatory skin disease in which overexpression of proinflammatory cytokines is observed. Most of the available data on the influence of antipsoriatic therapy on the cytokine serum concentration are inconsistent and based on short-term observations. AIM: To evaluate the influence of long-term biologic therapy with tumor necrosis factor α (TNF-α) blockers (adalimumab, etanercept, infliximab) and IL-12/23 inhibitor (ustekinumab) on the level of IL-6, IL-22 in the sera of patients with psoriasis. MATERIAL AND METHODS: Blood samples were collected from 42 psoriatic patients in order to determine IL-6 and IL-22 serum concentrations prior to and at the 3rd, 12th, 24th and 36th month of biologic therapy. Psoriasis Activity and Severity Index (PASI) was assessed at the same time points. The control group consisted of 30 sex- and age-matched healthy volunteers. RESULTS: Mean PASI index at baseline was 14.49 ±3.69 and decreased significantly until the end of the observation. Mean IL-6 serum concentration decreased significantly in all study groups (p < 0.05). A statistically significant decrease in IL-22 concentrations was demonstrated during the treatment with adalimumab and infliximab but not etanercept or ustekinumab. CONCLUSIONS: According to obtained results, IL-6 and IL-22 serum concentration may be an accurate marker of response to antipsoriatic therapy, even though not correlated with PASI index. Biologic therapy in psoriasis allows for long-term clinical improvement expressed not only by the remission of skin lesions, but also by lowering serum concentrations of pro-inflammatory interleukins.

Ingenol mebutate treatment in actinic keratosis - clinical effectiveness and potential side effects.

INTRODUCTION: Actinic keratosis is a common skin disease that occurs in response to prolonged exposure to ultraviolet radiation. This problem affects up to 60% of the population over 40 years of age. Actinic keratosis is considered to be a precancerous lesion leading to squamous cell carcinoma (SCC). The new therapeutic option for the treatment of actinic keratosis is ingenol mebutate gel (0.015%, 0.05%). AIM: Retrospective evaluation of response and potential side effects of ingenol mebutate treatment in clinical practice. MATERIAL AND METHODS: Eight patients with actinic keratosis lesions on the face or scalp self-applied a 0.015% gel for 3 consecutive days on the 25 cm2 marked area. They were assessed at baseline and on day 4, 7, 14 and 57. RESULTS: All patients on day 57 presented a complete absence of AK lesions in the area of ingenol mebutate application. No adverse events were observed. CONCLUSIONS: Our study shows that ingenol mebutate is highly efficacious field treatment for actinic keratosis.

Omalizumab for urticaria treatment in clinical practice: a case series.

INTRODUCTION: Omalizumab (Xolair) originally intended to reduce symptoms of moderate to severe asthma uncontrollable with steroids is the first monoclonal antibody approved for treatment of chronic spontaneous urticaria in 2014. AIM: To evaluate response and potential side effects to omalizumab treatment in clinical practice. MATERIAL AND METHODS: Eleven patients (6 males and 5 females) were recruited into the study. All participants signed written informed consent before enrollment to the study. At the beginning they were receiving 300 mg of omalizumab in a subcutaneous injection every 4 weeks in an outpatient clinic. Five the clinical response was sufficient, the dose of omalizumab was decreased to 150 mg. We evaluated response to the treatment using the Urticaria Activity Score in the last 7 days and the Urticaria Control Test at certain time points. RESULTS: Nine out of 11 patients achieved complete syndrome resolution. Five patients achieved clinical remission after the first dose of omalizumab. Mean time to remission was 9.3 weeks. During the study, no side effects were observed. CONCLUSIONS: Omalizumab appears to be a safe drug, which in a quick and effective way inducts remission in patients who have not responded to previous treatment.

Can biologic treatment induce cutaneous focal mucinosis?

Skin mucinosis is a rare skin disease which clinically manifests as firm papules and waxy nodules. We report a case of a 66-year-old female psoriatic patient who developed skin mucinosis during biological therapy. Because of a previous lack of response to the local and conventional systemic treatment of psoriasis, the patient received biological therapy (infliximab from June 2008 to May 2009 - initial clinical improvement and loss of treatment effectiveness in the 36(th) week of the therapy; adalimumab from June 2009 to January 2010 - lack effectiveness; ustekinumab from March 2012 to the present). Throughout 2 months we observed a manifestation of the skin mucinosis as well-demarcated, yellow and brown, papulo-nodular lesions of 5-10 mm in diameter, localized on the back. Histopathological examination with alcian blue staining demonstrated mucin deposits in the dermis. On the basis of clinical and histopathological findings, the diagnosis of cutaneous focal mucinosis was established. We present the case because of the extremely rare occurrence of the disease. Scarce literature and data suggest that there is an association between focal mucinosis and thyroid dysfunction, as well as possible adverse effects of biological therapy with TNF-α antagonists.

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.

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.

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.

Sonic hedgehog pathway dysregulation in skin basal-cell carcinoma of a Polish population.

Sonic hedgehog (Shh) pathway impairment plays a key role in the pathogenesis of basal-cell carcinomas (BCC), the most frequent skin tumor among Caucasians. Shh, Smo, and Gli2 family proteins are necessary for adequate and controlled cell proliferation. The aim of this study was to evaluate Shh, Smo, and Smo expression in BCC skin biopsies taken from sun-exposed areas. 41 BCC skin biopsies and 22 healthy skin specimens (the control group) taken from the same areas served as material for the study. All specimens were immunohistochemically stained with monoclonal antibodies directed against the chosen proteins. Shh and Smo expression (cytoplasmic pattern) were recorded semiquantitatively using a four-grade score (0-3). Gli2 expression (nuclear pattern) was determined using an image analysis system (semiautomatic function). The immunoexpression of the Shh and Smo proteins significantly increased in the BCC group, as compared with the normal controls (for Shh, the mean intensity was 1.67 in BCC vs. 1.17 in the control group, p < 0.001; for Smo, the mean intensity was 1.46 in BCC vs. 0.99 in the control group, p < 0.001). The staining for Gli2 in the BCC group was completely negative, but indicated the presence of Gli2 in the control patients (1.15 Gli2+ cells/100 cells). Sonic hedgehog pathway dysregulation may play an important role in skin cancerogenesis leading to BCC development.