Digital Image Analysis-Based Evaluation of Claudin-1 and Claudin-7 Delocalization in Cutaneous Squamous Cell Carcinoma and in Its Precancerous State.

Accumulating evidence has revealed that delocalization of the transmembrane proteins, Claudin-1 and Claudin-7, to the cytoplasm and/or nucleus occurs in various tumors. However, their subcellular distribution in terms of the membrane, cytoplasm, and nucleus and relationship with signaling pathways have not been elucidated during carcinogenesis. We first determined the expression of these proteins in the membrane, cytoplasm, and nucleus using ImageJ software and automatically collected the immunohistochemical quantification of dysplasia (actinic keratosis (AK)), carcinoma in situ (CIS; Bowen's disease (BD)), and invasive cutaneous squamous cell carcinoma (SCC) for digital image analysis (DIA). The activity of p-ERK, p-AKT, and p-mTOR and their correlation with subcellular Claudin-1 and Claudin-7 were also performed. Finally, we validated Claudin-1 and Claudin-7 delocalization at the cytoplasm and nucleus in cultured human normal keratinocytes and cutaneous SCC cells. Claudin-1 and Claudin-7 were delocalized as revealed by membranous, cytoplasmic, and nuclear staining in sun-exposed skin, AK, BD, and SCC. In BD, both membranous and cytoplasmic Claudin-1 (nuclear Claudin-1 decrease but no significant difference) were higher than AK, while Claudin-7 almost had the opposite situation. In SCC, cytoplasmic and nuclear Claudin-1 (membranous Claudin-1 no significant difference) was lower than in AK and sun-exposed skin, while Claudin-7 had higher membranous and cytoplasmic but lower nuclear expression. Moreover, p-AKT and p-mTOR (but not p-ERK) were downregulated in the SCC. Subcellular Claudin-1 and Claudin-7 were not only correlated with each other, but also correlated with p-ERK in BD and p-AKT and p-mTOR in SCC. Together, these results imply the delocalization of Claudin-1 and Claudin-7 and their correlation with MAPK/ERK and PI3K-AKT-mTOR signaling pathways in tumorigenesis and infiltration in cutaneous SCC.

Evaluation of Serum Proinflammatory Cytokine IL-17A and Tight Junction Protein Claudin-1 in Psoriasis.

Objective: This study aimed to estimate serum IL-17A and Claudin-1 levels, investigate their correlation, and evaluate their diagnostic significance as potential blood-based biomarkers in psoriasis. Methods: Serum IL-17A and Claudin-1 concentrations were determined using enzyme-linked immunosorbent assay (ELISA). Statistical analyses were performed to determine differences in serum levels of IL-17A and Claudin-1, their bivariable correlation with psoriasis severity, as Psoriasis Area Severity Index (PASI), and their predictive abilities using receiver operating characteristic (ROC) curves. Results: Significantly higher IL-17A and lower Claudin-1 levels were found in psoriasis (p < 0.05). PASI did not correlate significantly with either IL-17A or Claudin-1 in psoriasis and their subtypes. The only significant correlation between serum IL-17A and Claudin-1 was shown in late-onset psoriasis (r = 0.630, p = 0.028). ROC curve analysis indicated the serum IL-17A, serum Claudin-1, and combination of IL-17A and serum Claudin-1 for predicting psoriasis with the areas under the curve (AUC) of 0.951 (p < 0.0001), 0.709 (p = 0.0119), and 0.949 (p < 0.0001), respectively. Moreover, the potential role in distinguishing between early-onset and late-onset psoriasis: we obtained serum IL-17A, serum Claudin-1, and their combination AUC of 0.590 (p = 0.3126), 0.741 (p = 0.0045), and 0.741 (p = 0.0067), respectively. However, none of the serum IL-17A, serum Claudin-1, and their combination was well-performed discriminating mild psoriasis from moderate-to-severe psoriasis with AUC of 0.553 (p = 0.5596), 0.518 (p = 0.8539), and 0.559 (p = 0.5225), respectively. Conclusion: These preliminary results suggest that the serum Claudin-1 as a potential biomarker and the relationship and possible regulatory interactions between IL-17A and Claudin-1 in psoriasis are distinguishable by age of onset.

Effect of minocycline hydrochloride combined with photodynamic therapy on skin barrier function of patients with acne.

OBJECTIVE: The aim of this study is to evaluate the effects of minocycline hydrochloride combined with photodynamic therapy on skin barrier function of patients with acne. METHODS: Eighty-eight acne patients admitted to our hospital were randomized into research group (n=44, photodynamic therapy on the basis of minocycline hydrochloride) and control group (n=44, minocycline hydrochloride). The clinical efficacy, skin barrier function indexes (transdermal water loss (TEWL), stratum corneum water content, pH value), scores of GAGS and Acne-QOL, cosmetic satisfaction and adverse reaction rates of the two groups were compared. RESULTS: The total effective rate of research group was higher than that of control group (P<0.05). After treatment, TEWL, cuticle water content and pH value were improved compared with those before treatment, and the research group was superior to the control group (all P<0.05). After treatment, the GAGS scores of both groups were lower than those before treatment, and the research group was lower than that of the control group (all P<0.05). The cosmetic satisfaction in the research group was higher than that in the control group (P<0.05). There was no marked difference in the incidence of adverse reactions between the two groups (P>0.05). After treatment, the quality of life scores of patients were higher than before treatment, and the research group was higher than that of the control group (all P<0.05). CONCLUSION: Minocycline hydrochloride combined with photodynamic therapy can effectively improve the skin barrier function of patients, relieve clinical symptoms, and enhance the overall efficacy and quality of life. It is also safe and patients are highly satisfied with the cosmetic effect.

Real-World Experience on Omalizumab Treatment for Patients with Normocomplementemic Urticarial Vasculitis.

BACKGROUND: Urticarial vasculitis is a small vessel vasculitis characterized by long-lasting wheals. It was suggested omalizumab is well tolerated and effective in patients with hypocomplementaemic urticarial vasculitis. OBJECTIVE: To evaluate the clinical response and safety of omalizumab for treating patients with normocomplementaemic urticarial vasculitis (NUV) in real-world setting. METHODS: We collected data from a single-center. This study included patients with NUV who was received omalizumab therapy. During a 24-week study period, the clinical efficacy was evaluated by patient's self-assessment instrument urticarial vasculitis activity score and Dermatology Life Quality Index. RESULTS: Five patients with NUV were enrolled. Three patients received 6 doses of 150 or 300 mg omalizumab subcutaneously every 4 weeks. At 24-week follow-up, it was revealed improvement of clinical manifestations and reduction of urticarial vasculitis activity score and Dermatology Life Quality Index. At 24-week visit, mild wheals recurred in one patient who was only administrated with omalizumab for 4 times. One patient did not response to omalizumab therapy. No adverse events were recorded in the 5 patients. CONCLUSION: Omalizumab may be a potential choice in the treatment of patients with NUV in the real-world life.

Elevated carcinoembryonic antigen predicts rapidly progressive interstitial lung disease in clinically amyopathic dermatomyositis.

OBJECTIVES: The present study aimed to determine the correlation between serum carcinoembryonic antigen (CEA) level and the severity of interstitial lung disease (ILD) in clinically amyopathic DM (CADM) patients. METHODS: We performed a retrospective study including 41 Chinese CADM patients without malignancy. Serum CEA levels, clinical and laboratory findings were collected. Association tests between CEA levels and disease activity parameters were performed. RESULTS: Among the 41 patients, 16 (39.0%) developed rapidly progressive (RP)-ILD; of them, 14 (87.5%) had elevated serum CEA levels. Multivariate logistic regression analysis indicated that an elevated serum CEA level was an independent risk factor for RP-ILD. The incidence of elevated CEA level was significantly higher in patients with RP-ILD than in those without RP-ILD (87.5 vs 16.0%, P < 0.001). Furthermore, CEA levels were higher in patients with CADM with RP-ILD [26.87 (6.71) µg/l] than in those without RP-ILD [3.23 (0.64) µg/l] (P < 0.001). CEA levels in CADM patients were associated with the ferritin, alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase levels, and CT scores of the lungs. Also, elevated CEA levels are related to the organizing pneumonia pattern and lower lung zone consolidation in high-resolution CT. Moreover, the cumulative survival rate was significantly lower (68.4 vs 31.6%, P < 0.001) in the group with a CEA level >8.75 µg/l than that in the group with a CEA level <8.75 µg/l. CONCLUSIONS: An elevated serum CEA level is common in patients with CADM, and a higher serum CEA level is a powerful indicator of RP-ILD and poor prognosis in those patients.

Insights Into the Characteristics of Sweet Syndrome in Patients With and Without Hematologic Malignancy.

Background: Sweet syndrome is a neutrophilic dermatosis that could be associated with malignancy, especially hematologic malignancy. Few studies have systematically elaborated on this disorder and its features related with hematologic malignancy. Objective: This study aimed to describe the clinicopathological characteristics, treatment, and outcome of Sweet syndrome and to evaluate patient characteristics associated with hematologic malignancy. Methods: We retrospectively reviewed patients with Sweet syndrome at the Department of Dermatology, the First Affiliated Hospital of Zhejiang University from October 2010 to February 2019. Results: The study included 37 patients (16 men and 21 women), with a mean age of 53 years. Ten patients (27%) were classified as having malignancy-associated Sweet syndrome: nine with a hematologic malignancy including acute myeloid leukemia (4/9, 44%), myelodysplastic syndrome (4/9, 44%), and multiple myeloma (1/9, 11%) and one with a solid tumor diagnosed with liver carcinoma. The mean hemoglobin and platelet levels (P = 0.007 and P = 0.013, respectively), were significantly lower in patients with hematologic malignancy than in those with Sweet syndrome only. No significant difference in histopathology was found between patients with and without hematologic malignancy. Systemic corticosteroids were the most frequently used treatment (24/37, 65%). Higher mortality was found in patients with hematologic malignancy. Conclusion: It is important to assess Sweet syndrome patients who have laboratory evidence of lower hemoglobin and platelet levels for a hematologic malignancy.

Biologic TNF-alpha inhibitors in the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis: a systemic review.

Background: Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) is one of severe cutaneous adverse reactions with low morbidity but high mortality. Different systemic immunomodulating treatments are proposed but still remain controversial. Tumor necrosis factor (TNF)-alpha is long thought to be a vital mediator of epithelial cell death in SJS-TEN, indicating a potential target for therapy.Objective: The aim of this systemic review is to evaluate the efficacy and safety of biologic TNF-alpha inhibitors in the treatment of SJS-TEN.Methods: We reviewed the published literature by searching from PubMed, EMBASE, Web of Science and ClinicalTrial.gov. A total of 27 articles fulfilling our inclusion criteria were found and analyzed.Results: There were 21 case reports, four case series and two randomized controlled trials (RCTs) on the biologic TNF-alpha inhibitors for SJS-TEN therapy, comprising 91 patients. TNF-alpha inhibitors were used as monotherapy, second-line therapy or combination therapy. Among them, 79 patients (86.8%) responded well and discharged with few side effects and complications.Conclusions: Biologic TNF-alpha inhibitors are a safe and effective treatment for SJS-TEN. But further, larger RCTs need to be conducted to provide more evidence for clinical application.

Autoinflammatory Pathogenesis and Targeted Therapy for Adult-Onset Still's Disease.

Adult-onset Still's disease (AOSD) is a rare multisystem autoinflammatory disorder of unknown etiology. AOSD is generally characterized by high spiking fever, arthralgia or arthritis, skin rash, leukocytosis, and hyperferritinemia. Traditionally, AOSD has been treated with non-steroidal anti-inflammatory drugs, corticosteroids, and immunosuppressants. An increasing number of studies have shown that proinflammatory cytokines, such as interleukin-1ß, -18, -6, and tumor necrosis factor-α, play key roles in AOSD and may serve as therapeutic targets. In the current review, we provided insights into the roles of these cytokines in the pathogenesis of AOSD and also provided a commentary on the clinical studies of biologic therapy against AOSD.

Association between serum ferritin and the severity of drug eruptions.

BACKGROUND: Early recognition and treatment for severe drug eruption are important in improving clinical outcomes. A few studies have reported laboratory parameters to evaluate the severity of drug eruptions. This study aimed to determine the association between serum ferritin and the severity of drug eruptions. METHODS: We retrospectively reviewed patients diagnosed with drug eruptions in our hospital from 2013 to 2018. RESULTS: We identified 85 patients (mean age 53.4 years), 20 in the severe cutaneous adverse drug reactions (SCADRs) group and 65 in the non-SCADRs group. Serum ferritin level was higher in the SCADRs group compared with that in the CADRs group (P<.001). Serum ferritin was positively associated with peripheral white blood cell count, aspartate aminotransferase level, alanine aminotransferase level, blood glucose level, blood creatinine level, and body temperature. Receiver operating characteristic (ROC) analysis revealed a good diagnostic value of ferritin (area under the curve [AUC]:0.87, 95% confidence interval [CI]:0.78-0.96) with a sensitivity of 80% and a specificity of 87.7% at a cutoff value of 416.15 ng/mL. CONCLUSIONS: Serum ferritin is significantly associated with the severity of CADRs and hence might be potentially used to evaluate the severity of CADRs.

Adult-Onset Still Disease Presenting With Dermatomyositis-Like Persistent Pruritic Lesions.

Adult-onset Still disease (AOSD) is a rare autoinflammatory condition. The presence of an evanescent, salmon-pink, nonpruritic rash is one of the major diagnostic criteria for the disease. The rash occurs with fever and subsides with defervescence. The presence of dyskeratotic keratinocytes in the upper one-third layer of the epidermis is a distinctive histopathological feature of persistent pruritic lesions associated with AOSD. Here, we report 2 cases of AOSD characterized by persistent pruritic lesions resembling those observed in dermatomyositis. Identifying the clinical and histopathological manifestation of the cutaneous lesions is essential for the early diagnosis of AOSD and for differentiating this condition from those presenting with dyskeratotic cells in the epidermis.

Histopathological diagnosis of persistent pruritic eruptions associated with adult-onset Still's disease.

AIMS: Persistent pruritic eruptions (PPEs), presenting with dyskeratotic keratinocytes histologically, are characteristic skin rash in patients with adult-onset Still's disease (AOSD). The lesions may be histologically similar to other entities that present with dyskeratosis. In the present study, we compared the histopathological features between PPEs and other entities presenting with dyskeratosis. METHODS AND RESULTS: To investigate whether histopathological findings can be used to discriminate among PPEs and other entities presenting with dyskeratotic keratinocytes, cutaneous histopathological changes of PPEs associated with AOSD (n = 26) were compared with those of systemic lupus erythematosus (SLE) (n = 16), dermatomyositis (n = 19), and drug eruption (n = 16). Dyskeratosis was observed in the upper one-third of the epidermal layer in all 26 PPEs. The rate of dyskeratosis for PPEs was higher than that for SLE (18.8%) and dermatomyositis (15.8%). In drug eruptions, the dyskeratotic cells were distributed in all levels of the epidermis. Variable densities of neutrophils were found in the dermis in all PPEs. CONCLUSIONS: Although this was a retrospective study conducted at a single centre, presentation of dyskeratotic keratinocytes in the upper one-third of the epidermal layer is a distinctive histopathological reactive pattern of PPEs. This pattern may be a useful histopathological marker for early diagnosis of AOSD.

A systematic review of ustekinumab in the treatment of atopic dermatitis.

AIM: Ustekinumab, a human monoclonal IgG1 antibody targeting the p40-subunit shared by interleukin (IL)12 and IL-23, represents a potential treatment for atopic dermatitis (AD). We evaluated the efficacy and safety of ustekinumab in the treatment of AD. METHODS: We reviewed the published literature by searching from PubMed, EMBASE, Web of Science and ClinicalTrial.gov then retrieved and analyzed several variables from patients records. RESULTS: Ten studies including eight cases and two RCT, comprising 107 patients, were included in the systematic review. Analysis all studies, a total of 58 patients (54.2%) gained an effective treatment with little adverse events. CONCLUSIONS: Ustekinumab is a well-tolerated and safe treatment with no significant difference in effect from placebo in patients with AD. Further, larger randomized controlled trials need to be conducted to identify a suitable regimen for AD and provide more evidence for clinical application.