TNF‐α and IL‐10 gene polymorphisms show a weak association with pemphigus vulgaris in the Slovak population

Backround Pemphigus vulgaris is a rare chronic autoimmune disease of skin and mucous membranes, with several cytokines participating in its development. The role of their gene polymorphisms in susceptibility to the disease is, however, not fully understood. Objective The aim of our case‐control study was to investigate whether some of 22 single nucleotide polymorphisms (SNPs) in 13 cytokine genes (IL‐1α, IL‐1β, IL‐1RI, IL‐1Ra, IL‐4Rα, IL‐12, IFN‐γ, TGF‐β1, TNF‐α, IL‐2, IL‐4, IL‐6 and IL‐10) are associated with pemphigus vulgaris in the Slovak population. Methods DNA samples were obtained from 34 pemphigus vulgaris patients and 140 healthy controls of Slovak origin. Cytokine gene SNPs were determined using the polymerase chain reaction with sequence‐specific primers (PCR‐SSP) method. Results We found a weak association between pemphigus vulgaris and polymorphic variants in TNF‐α and IL‐10 genes only, with haplotypes TNF‐α–308G/–238G and IL‐10 –1082A/–819C/–592C being significantly overrepresented in pemphigus vulgaris patients (TNF‐α GG: 94.12% vs. 82.86%, P = 0.0216; IL‐10 ACC: 44.12% vs. 30.00%, P = 0.0309). Conclusions Our preliminary results suggest that certain TNF‐α and IL‐10 gene polymorphisms might contribute to genetic susceptibility to pemphigus vulgaris; however, their overall impact on disease development will be rather limited.     

Asymmetric dimethylarginine but not osteoprotegerin correlates with disease severity in patients with moderate‐to‐severe psoriasis undergoing anti‐tumor necrosis factor‐α therapy

Patients with psoriasis, in particular those with severe disease, have an increased risk of cardiovascular (CV) events compared with the general population. The aim of the present study is to determine whether correlation between asymmetric dimethylarginine (ADMA) and osteoprotegerin (OPG), two biomarkers associated with CV disease, and disease severity may exist in patients with moderate‐to‐severe psoriasis. We also aimed to establish if baseline serum levels of these two biomarkers could correlate with the degree of change in the clinical parameters of disease severity following the use of anti‐tumor necrosis factor (TNF)‐α therapy in these patients. This was a prospective study on a series of consecutive non‐diabetic patients with moderate‐to‐severe psoriasis who completed 6 months of therapy with anti‐TNF‐α‐adalimumab. Patients with kidney disease, hypertension or body mass index of 35 kg/m² or more were excluded. Metabolic and clinical evaluation was performed immediately prior to the onset of treatment and at month 6. Twenty‐nine patients were assessed. Unlike OPG, a significant positive correlation between ADMA and resistin serum levels was found at the onset of adalimumab and also after 6 months of biologic therapy. We also observed a positive correlation between the percent of body surface area affected (BSA) and ADMA levels obtained before the onset of adalimumab and a negative correlation between baseline ADMA levels and a 6‐month BSA change compared with baseline results. In patients with moderate‐to‐severe psoriasis, ADMA levels correlate with clinical markers of disease severity.     

Humoral Hypercalcemia of Malignancy with Elevated Plasma PTHrP,TNFα and IL-6 in Cutaneous Squamous Cell Carcinoma

A case of humoral hypercalcemia of malignancy in cutaneous squamous cell carcinoma is reported. An 82-year-old male underwent surgery for cutaneous squamous cell carcinoma (SCC) of the left hand in 1992. He subsequently developed clouding of consciousness with remarkable hypercalcemia, a high parathyroid hormone related protein (PTHrP) level, and elevated plasma cytokine levels [tumor necrosis factor α (TNFα), interleukin-6 (IL-6)]. Diagnosis of humoral hypercalcemia of malignancy (HHM) was made on the basis of these findings. He died of renal insufficiency due to this hypercalcemia in spite of several replacement therapies and chemotherapies. The PTHrP might have derived from the SCC and have been responsible for the HHM in conjunction with IL-6 and TNFα.     

Serum and salivary desmoglein 1 and 3 enzyme‐linked immunosorbent assay in pemphigus vulgaris: correlation with phenotype and severity

Background To the best of our knowledge there is only one report about salivary desmoglein (Dsg) 1 and 3 enzyme‐linked immunosorbent assay (ELISA) in pemphigus vulgaris (PV), whereas several studies have been performed on serum. Aims To find the sensitivity of serum and salivary anti‐Dsg1 and 3 antibodies in the diagnosis of PV, and to determine the relationship between disease severity and phenotype with antibody levels. Methods Fifty new patients with PV were included in this study. The diagnosis of PV was confirmed by histopathology and direct immunofluorescence. Demographical data, disease severity and phenotypes were recorded on questionnaire sheets. Dsg1 and Dsg3 ELISA were performed on serum and salivary samples of patients and controls. Results Thirty‐seven patients had mucocutaneous phenotype; whereas mucosal dominant and cutaneous dominant phenotypes were seen in 11 and 2 patients respectively. The sensitivities of serum anti‐Dsg3 and anti‐Dsg1 were 94% and 72% respectively. The sensitivities of salivary anti‐Dsg3 and anti‐Dsg1 antibodies were accordingly 94% and 70%. Compared with mucosal phenotype, serum and salivary anti‐Dsg1 antibodies were significantly higher in the patients with mucocutaneous phenotype. Serum Dsg1 antibodies were related with cutaneous and serum Dsg3 antibodies with mucosal severity scores. Salivary Dsg1 antibodies were significantly correlated with mucosal severity (P = 0.00); however there was no correlation between this antibody and cutaneous severity (P = 0.07). Salivary Dsg3 antibodies were not correlated with mucosal severity (P = 0.16). Conclusion Saliva Dsg ELISA could be used for diagnosis of PV. Salivary Dsg1 antibodies had a significant correlation with mucosal severity.     

Impact of anti‐tumor necrosis factor‐α agents on serum levels of KL‐6 and surfactant protein‐D in patients with psoriasis

We longitudinally examined the influence of anti‐tumor necrosis factor (TNF)‐α treatment on serum levels of KL‐6 and surfactant protein‐D (SP‐D). The study group comprised 22 patients with psoriasis treated with infliximab or adalimumab and with no history of interstitial lung disease (ILD). KL‐6 and SP‐D levels were measured in serum samples. Twelve of the 22 patients (55%) showed at least a 20% increase in KL‐6 levels compared with baseline. Of these 12 patients, none exhibited any signs of ILD on chest computed tomography and nine who showed an increase in KL‐6 levels (75%) showed at least a 20% increase in SP‐D levels. Some patients showed simultaneous increases in KL‐6 and SP‐D levels after treatment with anti‐TNF‐α agents. Although these patients may have undetectable or subtle alveolar damage, careful observation is needed.     

Activation of the PI3K/AKT signalling pathway in non‐melanoma skin cancer is not mediated by oncogenic PIK3CA and AKT1 hotspot mutations

Please cite this paper as: Activation of the PI3K/AKT signalling pathway in non‐melanoma skin cancer is not mediated by oncogenic PIK3CA and AKT1 hotspot mutations. Experimental Dermatology 2010; 19 : e222–e227. Abstract: Non‐melanoma skin cancer represents the most frequent human cancer entity. Activation of the PI3K/AKT signalling pathway has been reported both in squamous cell carcinoma (SCC) of the skin and in basal cell carcinoma (BCC). In many cancers, including SCC of the head and neck, the oesophagus and the penis, activation of this pathway is mediated by oncogenic PIK3CA and AKT1 mutations. We therefore screened 61 non‐melanoma skin cancer samples (30 SCC and 31 BCC) for the presence of activating PIK3CA and AKT1 mutations. PIK3CA hotspot mutations were analysed using a highly sensitive SNaPshot assay, and exon 4 of AKT1 was sequenced directly. In addition, immunohistochemistry was performed for phosphorylated AKT protein. Immunohistochemical expression of pAkt was observed both in SCC and in BCC samples, indicating an activation of the PI3K/AKT pathway. Although SCC showed higher expression levels than BCC, this difference was not significant. However, none of the 61 non‐melanoma skin cancer samples revealed any PIK3CA and AKT1 hotspot mutations at the investigated loci. We conclude that PIK3CA and AKT1 hotspot mutations do not contribute to the activation of the PI3K/AKT signalling pathway in non‐melanoma skin cancer. The distinct PIK3CA mutation spectrum between SCC of the skin and SCC of other tissues may reflect the different carcinogens which are involved into the mutagenesis of these cancers. PIK3CA and AKT1 hotspot mutations are obviously not caused by UV light exposure, the main risk factor in non‐melanoma skin cancer.     

TNFα-induced activation of eosinophil oxidative metabolism and morphology - Comparison with IL-5*

Abstract Human dermal mast cells are capable of releasing cytokines, particularly preformed TNFα, upon appropriate stimulation. Masl cell activation in vivo was shown to be associated with an influx and activation of inflammatory cells, initially PMN “polymorphonuclear neutrophilic granulocytes” then eosinophils. In order to learn more about the mechanisms by which TNFα is capable of activating eosinophils, in the present study the effect of TNFα on morphology and function of highly purified normal eosinophils “≥95%” was examined. As estimated by transmission and scanning electron microscopy, TNFα-stimulated eosinophils appeared to be strictly adherent and flattened exhibiting a characteristic “hemispheric” shape. TNFα induced a dose-dependent, long-lasting production of reactive oxygen species as measured by lucigenin-dependent chemiluminescence (CL). even at a concentration of 0.001 U/ml. The maximal response upon stimulation with TNFα, however, was significantly lower than optimal effects induced by IL-5. TNFα-induced responses were completely inhibited by cytochalasin B and staurosporin, and partially blocked by pertussis toxin. Separation of eosinophils by discontinuous density gradients revealed the existence of at least two hypodense eosinophil populations with a distinct susceptibility to stimulation with TNFα. Based on functional assay systems, in contrast to a significant extracellular, only a small intracellular H₂O₂: production was detected. Accordingly, H₂O₂ production, detected by an ultrastructural technique, was observed only on the outer surface of the plasma membrane in the contact zones in between adjacent cells. Extracellular as well as intracellular production of H₂O₂; was completely inhibited by cytochalasin B. TNFα-induced activation of eosinophils is most probably mediated by binding to the 55 kD and the 75 kD TNF-receptor since both receptor molecules could be detected by FACS analysis and immune electron microscopy using receptor-specific antibodies. However, in contrast to its effect on eosinophil oxidative response, TNFα did not induce the release of significant concentrations of eosinophil cationic protein or eosinophil peroxidase in supernatants of cytokine-stimulated eosinophils, as detected by functional as well as immunological assay systems. These results clearly indicate that TNFα represents a potent eosinophil-activating cytokine which may be of relevance in the allergic inflammatory response.     

Drug‐induced lupus erythematosus with emphasis on skin manifestations and the role of anti‐TNFα agents

Drug‐induced lupus erythematosus (DILE) is a lupus‐like syndrome temporally related to continuous drug exposure which resolves upon drug discontinuation. There are currently no standard diagnostic criteria for DILE. Findings include skin manifestations, arthritis, serositis, anti‐nuclear and anti‐histone antibodies positivity. Similarly to idiopathic lupus erythematosus, DILE can be divided into systemic (SLE), subacute cutaneous (SCLE) and chronic cutaneous lupus (CCLE). Systemic DILE presents as a milder version of idiopathic SLE, and the drugs most frequently implicated are hydralazine, procainamide and quinidine. Anti‐TNFα therapies are the latest class of medications found to be associated, although rarely, with a “lupus‐like” syndrome, which is however clinically distinct from classical DILE. Drug‐induced SCLE is the most common form of DILE. It is very similar to idiopathic SCLE in terms of clinical and serologic characteristics. The most commonly implicated drugs are antihypertensive drugs and terbinafine, but in recent years also proton pump inhibitors and chemotherapeutic agents have been associated. Drug‐induced CCLE is very rare and usually caused by fluorouracil agents and NSAIDS, but some cases have induced by pantoprazole and anti‐TNFα agents.     

沉默信息调节因子1、3和缺氧诱导因子1α在皮肤鳞状细胞癌组织和细胞中的表达

目的:分析沉默信息调节因子1（Sirt1）、3（Sirt3）和缺氧诱导因子1α（HIF-1α）在皮肤鳞状细胞癌（CSCC）组织和细胞中的表达,探讨其在CSCC发生发展中的作用。方法:收集2019年1月至2020年12月就诊于宁夏医科大学总医院皮肤科、经病理活检确诊为高、中、低分化CSCC患者的病变组织和非癌症患者正常皮...     

Expression profiles of cortisol‐inactivating enzyme, 11β‐hydroxysteroid dehydrogenase‐2, in human epidermal tumors and its role in keratinocyte proliferation

The enzyme 11β‐hydroxysteroid dehydrogenase (11β‐HSD) catalyzes the interconversion between hormonally active cortisol and inactive cortisone within cells. There are two isozymes: 11β‐HSD1 activates cortisol from cortisone and 11β‐HSD2 inactivates cortisol to cortisone. 11β‐HSD1 was recently discovered in skin, and we subsequently found that the enzyme negatively regulates keratinocyte proliferation. We verified 11β‐HSD1 and 11β‐HSD2 expression in benign and malignant skin tumors and investigated the role of 11β‐HSD in skin tumor pathogenesis. Randomly selected formalin‐fixed sections of skin lesions of seborrheic keratosis (SK), squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) were stained with 11β‐HSD1 and 11β‐HSD2 antibodies, and 11β‐HSD expression was also evaluated in murine epidermis in which hyperproliferation was induced by 12‐O‐tetradecanoylphorbol‐13 acetate (TPA). We observed that 11β‐HSD1 expression was decreased in all SK, SCC, and BCC lesions compared with unaffected skin. Conversely, 11β‐HSD2 expression was increased in SK and BCC but not in SCC. Overexpression of 11β‐HSD2 in keratinocytes increased cell proliferation. In the murine model, 11β‐HSD1 expression was decreased in TPA‐treated hyperproliferative skin. Our findings suggest that 11β‐HSD1 expression is decreased in keratinocyte proliferative conditions, and 11β‐HSD2 expression is increased in basal cell proliferating conditions, such as BCC and SK. Assessing 11β‐HSD1 and 11β‐HSD2 expression could be a useful tool for diagnosing and characterizing skin tumors.     

Cutaneous polyarteritis nodosa in pediatric patients successfully treated with TNF‐α inhibitor and methotrexate: Case series and literature review

Cutaneous polyarteritis nodosa (CPAN) is a rare necrotizing vasculitis affecting small‐ to medium‐sized arteries. Reported treatments include oral corticosteroids alone or in combination with non‐steroidal antiinflammatory drugs, intravenous immunoglobulins, cyclophosphamide, azathioprine, colchicine, or dapsone. However, some patients with CPAN do not respond to such treatments and continue to experience exacerbations over prolonged periods. This series provides support for the use of TNF‐α inhibitors in the treatment of recalcitrant CPAN in pediatric patients.     

Cutaneous squamous cell carcinoma,thyroid cancer and Langerhans cell histiocytosis in a patient with X‐linked recessive Mendelian susceptibility to mycobacterial diseases with a nuclear factor‐κB essential modifier mutation

Nuclear factor (NF)‐κB essential modifier (NEMO), also known as IκB kinase subunit‐γ (IKKγ), is a pivotal molecule in the NF‐κB signaling pathway. Mutations of NEMO cause incontinentia pigmenti and X‐linked ectodermal dysplasia with immunodeficiency. Mendelian susceptibility to mycobacterial diseases (MSMD), which confers an almost selective predisposition to mycobacterial infection, is also caused by NEMO mutations. We herein report the first case of a patient with X‐linked recessive (XR) MSMD who developed cutaneous squamous cell carcinoma, thyroid cancer and Langerhans cell histiocytosis. The relationship between NEMO mutation and oncogenesis is discussed.