Imsidolimab, an anti-interleukin-36 receptor monoclonal antibody, for the treatment of generalized pustular psoriasis: results from the phase II GALLOP trial.

BACKGROUND: Generalized pustular psoriasis (GPP) is a systemic inflammatory disease that can be severe, debilitating and life threatening. Uncontrolled activation of interleukin (IL)-36 proinflammatory activity may underlie the pathogenesis of GPP. Currently, GPP-specific treatment options are limited. OBJECTIVES: To evaluate the efficacy and safety of the anti-IL-36 receptor antibody imsidolimab in patients with GPP. METHODS: In an open-label, single-arm, multiple-dose study, patients with GPP were treated with imsidolimab to assess clinical efficacy, tolerability and safety. Patients received an intravenous dose of imsidolimab 750 mg on day 1, followed by three subcutaneous doses of imsidolimab 100 mg administered on days 29, 57 and 85. The primary efficacy endpoint was the proportion of patients who achieved a clinical response at weeks 4 and 16 following treatment with imsidolimab, as measured by the Clinical Global Impression scale. RESULTS: Eight patients were enrolled and six completed the study. Responses were observed as early as day 3, most rapidly for pustulation relative to other manifestations of GPP, with continued and consistent improvement across multiple efficacy assessments at day 8, day 29 and through day 113. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity. No patient discontinued the study owing to a nonserious TEAE. Two patients experienced serious adverse events (SAEs); no deaths were reported. CONCLUSIONS: Imsidolimab demonstrated a rapid and sustained resolution of symptoms and pustular eruptions in patients with GPP. It was generally well tolerated, with an acceptable safety profile, and is advancing to phase III trials. These data support the targeting of IL-36 signalling with a specific antibody - imsidolimab - as a therapeutic option for this severely debilitating condition.

The Role of Mast Cells in the Induction and Maintenance of Inflammation in Selected Skin Diseases.

Under physiological conditions, skin mast cells play an important role as guardians that quickly react to stimuli that disturb homeostasis. These cells efficiently support, fight infection, and heal the injured tissue. The substances secreted by mast cells allow for communication inside the body, including the immune, nervous, and blood systems. Pathologically non-cancerous mast cells participate in allergic processes but also may promote the development of autoinflammatory or neoplastic disease. In this article, we review the current literature regarding the role of mast cells in autoinflammatory, allergic, neoplastic skin disease, as well as the importance of these cells in systemic diseases with a pronounced course with skin symptoms.

mRNA expression of caspase 14 in skin epithelial malignancies.

Introduction: The skin is the largest organ in the human body and it is also a complex organ. Its protective function is properly maintained due to its continuous renewal. Malignancies develop when the balance between proliferation and cell death is dysregulated in skin cells. Skin epithelial cancers are the most common neoplasms in humans. Although caspases are proteins which regulate the cell cycle and cell death, caspase 14 is a unique representative of the caspase family which does not participate in apoptosis. The detailed role of caspase 14 in skin epithelial malignancies has not been elucidated. Material and methods: We performed a prospective study aimed at the analysis of the mRNA expression of caspase 14 in groups of skin epithelial malignancies. We enrolled 56 patients (control group n = 21, study group n = 35). The mRNA expression of caspase 14 was lower in the non-lesional skin of patients with basal cell cancer or squamous cell cancer compared to a combined group of non-lesional samples from actinic keratosis patients and the control group. Results: The prognostic potential of caspase 14 mRNA is suggested when trying to identify patients predisposed to skin cancer. Moreover, the expression level was lower in combined groups of non-lesional skin obtained from patients with basal cell cancer (BCC)/squamous cell cancer (SCC) in comparison with lesional samples obtained from patients with BCC/SCC. Conclusions: We present primary results of a pilot study and define further goals for research continuation.

Cyclosporine-induced gingival overgrowth-Review.

Drug-induced gingival overgrowth (DIGO) is an undesirable effect resulting from the therapy of one of the three groups of drugs: phenytoin, calcium channel blockers, and cyclosporine A (CsA). It is caused by a fibrous overgrowth leading to gingivitis, periodontitis, and even tooth loss. Possible consequences include tooth decay worsening, pain and difficulty in eating, bleeding gums, and bad breath. The pathomechanism of the hypertrophy is unknown, but there is a correlation between insufficient oral hygiene and the severity of this phenomenon. The gender and age predilection of gingival hyperplasia as a result of CsA therapy is also noticeable. It is most common in children and adolescents of the male sex. The beneficial effect of the removal of tartar and local irritants in reducing the above symptoms has been demonstrated. One of the treatments for DIGO is conventional gingivectomy. The paper is a review article about cyclosporine-induced gingival hyperplasia.

Etiopathogenesis of dermatitis herpetiformis.

Dermatitis herpetiformis is a rare chronic, autoimmune bullous disease linked to gluten sensitivity with intense pruritus and characteristic skin eruptions. Etiopathogenesis is complex and not fully understood. It is currently considered to be a specific cutaneous manifestation of celiac disease. Genetic, environmental and immunological factors influence both conditions. Exposure to gluten is the starting point of an inflammatory cascade leading to the formation of circulating IgA antibodies against tissue transglutaminase and skin immune IgA deposition followed by skin lesions. Binding of the immune complex deposits of IgA transglutaminases and epidermal antibodies with enzymes in the papillary dermis stimulates complement activation, neutrophil influx, proinflammatory cytokine release and overproduction of matrix metalloproteinases. We have collected current knowledge of the pathogenesis of dermatitis herpetiformis.

The effect of therapy on TRM in psoriatic lesions.

Introduction: The course of psoriasis is associated with recurrence of the lesions at the same location despite effective treatment. It is due to the presence of TRM (tissue-resident memory cells) in the seemingly healthy skin, which may initiate an inflammatory cascade. Aim: The assessment of TRM in psoriatic lesions prior to and after 12 weeks of systemic therapy with methotrexate (MTX) or secukinumab (SEC) or ixekizumab (IXE) or adalimumab (ADA). Material and methods: TRM markers (CD4, CD8, CD103, CD69, CD49, CXCR6) and the tissue expression of cytokines (IL-17, IL-22) in the psoriatic lesions obtained from 13 patients compared to 10 healthy skin samples were evaluated with immunohistochemistry. Biopsy specimens were collected three times from the same psoriatic plaque before and after 4 and 12 weeks of therapy. Results: The expression of TRM markers in the lesions decreased at three time points (W0, W4, W12), revealing the diminished intensity of fluorescence over time with each therapy. The most rapid response was observed with anti-IL-17 therapy at W4 of treatment, while with MTX and ADA at W12. Conclusions: The decreased expression of TRM markers occurring predominantly in the lesional dermis and not in the epidermis over 12 weeks of observation may be due to the poorer penetration of systemic drugs to the epidermis, or the process of psoriatic lesion regression in the epidermis is secondary to the reduction of inflammation in the skin, or TRM in the epidermis may be more resistant to therapy.

Assessment of stem cell factor expression and its c-KIT receptor in patients with vitiligo.

Introduction: Melanocytes show antigen expressions characteristic for the immune response effector cells, and the immune reactions in the skin, especially those with inflammation background, significantly affect the function of melanocytes. Among the cytokines produced by keratinocytes, the stem cell factor (SCF) plays a leading role in stimulating melanogenesis. Aim: To compare the expression level of stem cell factor (mSCF, pSCF) and the c-Kit receptor in the centre of the vitiligo patch and in the area of healthy skin adjacent to the vitiligo patch. Material and methods: The research material consisted of skin samples from a vitiligo lesion and from non-lesional skin adjacent to the vitiligo patch. Real Time PCR analysis (Applied Biosystems 7900HT) was performed to determine the expression level of the studied genes. Results: The studies showed a statistically significant increase in the amount of mSCF within the vitiligo patch compared to both healthy skin of patients with vitiligo and controls. In patients with vitiligo, c-Kit receptor expression was significantly decreased in the area of the lesional skin compared to the healthy skin of the same patient and the skin of the control group. Conclusions: The membrane-bound form of the SCF is overexpressed within the vitiligo skin, which may indicate the participation of mSCF in the stimulation of melanogenesis in response to melanocyte damage. Decreased expression of C-Kit receptor by melanocytes in the vitiligo patch disrupts the ligand-receptor interaction and may therefore be related to melanocytes dysfunction and/or loss.

D-chiro-inositol as a treatment in plaque psoriasis: A randomized placebo-controlled clinical trial.

Cyclitols are widely available natural sugars which do not exert toxic effects. Their anti-inflammatory and antioxidant properties may be used in the treatment of psoriasis. The aim of this placebo-controlled, double-blind study was to evaluate the clinical effects of D-chiro-inositol (DCI) in mild plaque psoriasis (46 psoriatic patients and 10 healthy volunteers). Three stable psoriatic plaques were selected for evaluation in every patient. Different samples were applied on each lesion twice a day: vehiculum without an active agent, containing 1% DCI and 0.25% DCI. The lesions were assessed using the PSI, VAS scale, and the objective measurement of hydration, transepidermal water loss (TEWL), elasticity, and thickness (DermaLab Combo) at 0, 3, and 6 weeks. PSI and VAS were improved in all groups without significant statistical differences. 1% DCI sample presented the highest statistically significant increase in the hydration of 50%, but it was still significantly lower than in healthy controls. TEWL increased for 1% DCI, which was a statistically significant difference compared to 0.25% DCI and still higher than in controls. An improvement in elasticity was observed in all lesions-it was statistically significant for 1% DCI. The thickness of the lesion decreased for 1% DCI, but the change was not statistically significant. Subepidermal low-echogenic band showed a decreasing tendency in all groups, but it was not statistically significant. Favorable 1% DCI sample results indicate that it may be used as an adjuvant to the local treatment of psoriasis.

Psychological Stress, Mast Cells, and Psoriasis-Is There Any Relationship?

Psoriasis vulgaris is a common inflammatory skin disease with still unknown pathogenesis. In recent years, genetic and environmental factors have been mentioned as the main causes. Among environmental factors, many researchers are trying to investigate the role of mental health and its importance in the development of many diseases. In the pathophysiology of psoriasis, the role of the interaction between the nervous, endocrine, and immune systems are often emphasized. So far, no one has clearly indicated where the pathological process begins. One of the hypotheses is that chronic stress influences the formation of hormonal changes (lowering the systemic cortisol level), which favors the processes of autoimmunity. In inflammatory skin conditions, mast cells (MCs) are localized close to blood vessels and peripheral nerves, where they probably play an important role in the response to environmental stimuli and emotional stress. They are usually connected with a fast immune response, not only in allergies but also a protective response to microbial antigens. Among many cells of the immune system, MCs have receptors for the hormones of the hypothalamic-pituitary-adrenal (HPA) axis on their surface. In this review, we will try to take a closer look at the role of MCs in the pathophysiology of psoriasis. This knowledge may give the opportunity to search for therapeutic solutions.

Caspase-14-From Biomolecular Basics to Clinical Approach. A Review of Available Data.

Caspase-14 is a unique member of the caspase family-a family of molecules participating in apoptosis. However, it does not affect this process but regulates another form of programmed cell death-cornification, which is characteristic of the epidermis. Therefore, it plays a crucial role in the formation of the skin barrier. The cell death cycle has been a subject of interest for researchers for decades, so a lot of research has been done to expand the understanding of caspase-14, its role in cell homeostasis and processes affecting its expression and activation. Conversely, it is also an interesting target for clinical researchers searching for its role in the physiology of healthy individuals and its pathophysiology in particular diseases. A summary was done in 2008 by Denecker et al., concentrating mostly on the biotechnological aspects of the molecule and its physiological role. However, a lot of new data have been reported, and some more practical and clinical research has been conducted since then. The majority of studies tackled the issue of clinical data presenting the role of caspase in the etiopathology of many diseases such as retinal dysfunctions, multiple malignancies, and skin conditions. This review summarizes the available knowledge on the molecular and, more interestingly, the clinical aspects of caspase-14. It also presents how theoretical science may pave the way for medical research. Methods: The authors analyzed publications available on PubMed until 21 March 2021, using the search term "caspase 14".

The Role of Chemokines in Psoriasis-An Overview.

By participating in both the recruitment and activation of T lymphocytes, macrophages and neutrophils at the site of psoriatic inflammation, chemokines play an important role in the pathogenesis of psoriasis and, crucially, may be one indicator of the response to the systemic treatment of the disease. As a result of their major involvement in both physiological and pathological processes, both chemokines and their receptors have been identified as possible therapeutic targets. Due to their presence in the inflammatory process, they play a role in the pathogenesis of diseases that often coexist with psoriasis, such as atherosclerosis and psoriatic arthritis. Chemokines, cytokines and adhesion molecules may be biological markers of disease severity in psoriasis. However, the mechanism of inflammation in psoriasis is too complex to select only one marker to monitor the disease process and improvement after treatment. The aim of this review was to summarize previous reports on the role of chemokines in the pathogenesis of psoriasis, its treatment and comorbidities.

Adalimumab and methotrexate affect the concentrations of regulatory cytokines (interleukin-10, transforming growth factor-ß1, and interleukin-35) in patients with plaque psoriasis.

Dysfunctional regulatory T lymphocytes are important for the pathogenesis of psoriasis and atherosclerosis. We analyzed the severity of atherosclerosis and the concentration of regulatory cytokines in patients with psoriasis who were administered methotrexate or adalimumab for 12 weeks. We included 34 patients with psoriasis (17 each, administered methotrexate or adalimumab) and eight healthy volunteers. BMI, psoriasis area and severity index (PASI), body surface area (BSA), and at least 75% and 90% improvements in PASI were observed. The 10-year risk of fatal cardiovascular disease was estimated using Systematic Coronary Risk Evaluation charts. The plasma interleukin (IL)-10, IL-35, and transforming growth factor ß1 (TGF-ß1) levels were determined using enzyme-linked immunosorbent assay before and after the 12-week treatment regimen. PASI (P = .0006) and BSA (P = .0001) were positively correlated with the BMI, IL-35 (-0.38), and IL-10 (0.48) levels. Baseline IL-35 concentrations were the highest in healthy volunteers; the IL-10 and TGF-ß1 level were the highest in the methotrexate group. IL-10 concentration decreased in both treatment groups (P = .02 for the methotrexate and P = .09 for adalimumab group), and IL-35 decreased in the adalimumab group (P = .019), consistent with skin lesion recovery. Thus, this study demonstrates the dysregulated secretion of regulatory cytokines in psoriatic patients under systemic treatment.

Pyoderma gangrenosum-like lesions provocated by botulinum injections.

Botulinum toxin (BoNT) is a valuable therapeutic tool with several medical indications and the most popular of all cosmetic procedures worldwide. This is the reason for the growing number of unregistered products that may be the reason for adverse reactions. We present a case of a 51-year-old woman, who developed a pyoderma gangrenosum-like reaction at injection sites after the administration of an unregistered BoNT product by a beautician. The clinical course, the morphology of the lesions, the result of histopathological biopsy, and the response to the treatment meets the criteria for diagnosis of pyoderma gangrenosum. The case presented by us is the first adverse reaction of this type after BoNT administration.

The Role of TRM Cells in the Pathogenesis of Vitiligo-A Review of the Current State-Of-The-Art.

Vitiligo is the most common hypopigmentation disease affecting both the skin and mucous membranes. The pathogenesis of this disorder is complex and involves the influence of genetic and environmental factors, oxidative stress, and autoimmune responses. Recent studies have indicated that skin lesions observed in vitiligo tend to recur in the same places where they were found before treatment. This phenomenon is explained by the presence of recently discovered tissue-resident memory T cells (TRM), whose primary function is to provide antiviral and antibacterial protection in non-lymphoid tissues. TRM cells show the presence of CD49a, CD69, and CD103 markers on their surface, although not all of them express these particles. Due to their ability to produce and secrete perforin, IFN-γ, and granzyme B, TRM cells demonstrate a cytotoxic effect on melanocytes, thus inducing depigmented lesions in the course of the vitiligo. It has been proved that the occurrence of TRM cells largely depends on IL-15, which promotes the TRM function ex vivo. The findings above, as well as their reference to the pathogenesis of autoimmune skin diseases will have a considerable influence on the development of new therapeutic strategies in the near future. This article presents an up-to-date review of information regarding the role of TRM cells in the development and progression of vitiligo.

Immunological Memory of Psoriatic Lesions.

The natural course of psoriasis is the appearance of new lesions in the place of previous ones, which disappeared after a successful therapy. Recent studies of psoriasis etiopathogenesis showed that after psoriatic plaques have disappeared, in healthy skin we can still find a trace of inflammation in the form of tissue resident memory cells (TRM). They are originally responsible for protection against viral and bacterial infections in non-lymphatic tissues. In psoriatic inflammation, they are characterized by heterogeneity depending on their origin. CD8+ T cells TRM are abundantly present in psoriatic epidermis, while CD4+ TRM preferentially populate the dermis. In psoriasis, epidermal CD8+ TRM cells express CLA, CCR6, CD103 and IL-23R antigen and produce IL-17A during ex vivo stimulation. However, CD4+ CD103+ TRM can also colonize the epidermis and produce IL-22 during stimulation. Besides T cells, Th22 and epidermal DCs proved that epidermal cells in healed skin were still present and functioning after several years of disease remission. It explains the clinical phenomenon of the tendency of psoriatic lesions to relapse in the same location and it allows to develop new therapeutic strategies in the future.

Methotrexate and Adalimumab Decrease the Serum Levels of Cardiovascular Disease Biomarkers (VCAM-1 and E-Selectin) in Plaque Psoriasis.

Background and objectives: The shared pathogenesis of psoriasis and atherosclerosis may be determined by assaying the levels of endothelial activation molecules. This study aimed at evaluating vascular cell adhesion molecule 1 (VCAM-1) and E-selectin serum concentrations, and atherosclerosis severity in patients with plaque psoriasis. It also aimed to determine the effects of methotrexate/adalimumab treatment for 12 weeks on the plasma levels of the aforementioned molecules. Materials and Methods: The study included 34 psoriasis patients (17 treated with methotrexate and 17 treated with adalimumab) and eight controls. The 10-year risk of a fatal cardiovascular disease, body mass index, Psoriasis Area and Severity Index, and body surface area were calculated for each subject. VCAM-1 and E-selectin levels were determined via an enzyme-linked immunosorbent assay at baseline and after 12 weeks. Results: Baseline E-selectin and VCAM-1 levels were higher in the adalimumab group than in the methotrexate and control groups. VCAM-1 levels decreased in the adalimumab (p = 0.02) and methotrexate groups (p = 0.008), while E-selectin levels decreased in the methotrexate group (p = 0.004). Conclusions: The results indicate a correlation between systemic psoriasis treatment and E-selectin and VCAM-1 plasma concentrations, which may be associated with the risk of cardiovascular disease development.

Effect of methotrexate treatment on the expression of epidermal-fatty acid-binding protein (E-FABP) and apolipoproteins in patients with psoriasis.

INTRODUCTION: Epidermal-fatty acid-binding protein (E-FABP) is a marker of transiently amplifying cells which are formed from stem cells in epidermis. Their role is an uptake of fatty acids and metabolism. Psoriatic keratinocytes overexpress E-FABPs, which leads to acanthosis and may explain the lipid's disturbances in psoriasis. AIM: Assessment of FABP and apolipoprotein expression in patients treated with methotrexate (MTX). MATERIAL AND METHODS: FABP expression in the lesional and perilesional psoriatic skin from 11 male patients compared to 5 healthy skin samples were evaluated by immunohistochemistry. FABP, apolipoprotein A1 (ApoA1) and B (ApoB) serum levels were assessed by ELISA. These parameters were evaluated before and after treatment with subcutaneous MTX (15 mg/wk for 12 weeks). RESULTS: Expression of E-FABP was lower in the control group than in the lesional and perilesional psoriatic skin, before and after treatment. After treatment the expression decreased in the lesional and perilesional skin. Serum E-FABP was higher in the control group (482.855 ±240.550 pg/ml) compared to patients, but not statistically significantly. After MTX treatment, a statistically significant reduction was observed in psoriatic patients. ApoA1 levels did not differ in the control and patients groups, both before and after treatment. In contrast, ApoB levels did not differ statistically between the control group (1447.126 ±311.11 ng/ml) and patients before treatment, while they were the lowest after treatment (1081.67 ±117.83 ng/ml vs. 808.306 ±103.72 ng/ml; p < 0.01). CONCLUSIONS: Our study confirms the beneficial effect of MTX, not only as an anti-proliferative effect, but also reducing the cardiovascular risk by decreasing atherogenic ApoB.

Prevalence and severity of fatigue in psoriasis and psoriatic arthritis.

INTRODUCTION: Fatigue is an important and underrated symptom of many chronic diseases. AIM: The evaluation of incidence and severity of fatigue as well as the influence of selected factors on fatigue in patients with psoriasis and psoriatic arthritis (PsA). MATERIAL AND METHODS: The study included 60 patients with PsA, 58 patients with psoriasis and 61 persons in the control group aged 35-70 years. Assessment of fatigue was conducted using a fatigue subscale from the FACIT-F questionnaire. Severity of skin lesions and arthritis was determined with PASI and DAS28, respectively, as well as the number of painful and swollen joints, severity of pain and inflammatory markers. RESULTS: Severe fatigue occurred in 17%, 28%, and 1.6% of patients with psoriasis, PsA and the control group, respectively. Severity of fatigue was significantly higher in patients with PsA as compared to patients with psoriasis (p < 0.0001). In patients with psoriasis and PsA, it decreased along with the duration of psoriasis (r = 0.291, p < 0.05 vs. r = 0.382, p < 0.05, respectively). No significant correlation was found between the duration of PsA and fatigue. After using the linear regression model, severity of fatigue in psoriasis was correlated with the age of patients and the duration of psoriasis, while in PsA, with the duration of psoriasis, PASI, DAS28, CRP and the number of painful joints. CONCLUSIONS: The results of this study may indicate the need for routine fatigue examination among people with psoriasis and psoriatic arthritis.

Serum sickness disease in a patient with alopecia areata and Meniere' disease after PRP procedure.

BACKGROUND: Platelet rich plasma procedure (PRP) is considered to be one of the safest aesthetic procedures. Adverse reactions after PRP administration are extreme rare. PURPOSE: We present the patient with serum sickness disease (SSD) after PRP procedure. OBJECTIVE AND METHODS: 41 years old female suffers from alopecia areata for 5 years with frequent relapses and she has been suffering from Menier's disease recurrent symptoms for 6 years. The patient developed SSD after third PRP rejuvenating procedure and she has also noticed new alopecia areata lesions, but without Menier's disease symptoms. After SSD, 4 months later, she developed severe symptoms of Menier's disease with an episode of sudden sensorineural hearing loss. It alleviated only after intravenous administration of methylprednisolone. In our opinion, significant contraindication of PRP procedure is an autoimmune disease in the active phase.

Secondary failure of TNF-α inhibitors in clinical practice.

Tumor necrosis factor alpha (TNF-α) is a leading inflammatory cytokine that plays a pivotal role in the pathogenesis of psoriasis. In case of a severe course of psoriasis and moderate-to-severe disease in which traditional systemic treatments are ineffective or contraindicated, TNF-α inhibitors (iTNF-α) are used. This class of drugs includes monoclonal antibodies and a fusion protein (etanercept) and can induce a humoral or cell-mediated immune response, leading to formation of anti-drug antibodies (ADAs). The immunogenicity may affect iTNF-α drug pharmacokinetics, which would lead to hampering the clinical response (secondary drug failure), so a need to increase the drug dose arises. Antibodies against monoclonal antibodies (adalimumab, infliximab) have been associated with diminished clinical response, while against etanercept are non-neutralizing and appear to have no significant effect on clinical response and treatment safety. Switching of biologic agents may be one strategy in ADA-associated secondary failure of iTNF-α. However researches are needed to identify risk factors for ADA development and investigate management strategies for optimized treatment response. The authors reviewed the literature on the effectiveness of iTNF-α and pointed out the prevention of secondary failure in clinical practice.