Higher Expression of Lympho-epithelial Kazal-type-Related Inhibitor-1 Fragments and Decreased Desquamation in the Lesional Skin of Nummular Eczema.

Nummular eczema, a chronic dermatitis characterized by coin-shaped lesions, was first documented in 1857. However, its pathophysiological characteristics are still not well known. To investigate differences in the regulation of the desquamation process in the stratum corneum of lesional and nonlesional skin of patients with nummular eczema and healthy control subjects, tape-stripped stratum corneum samples from patients with nummular eczema and healthy volunteers were analysed using immunofluorescence staining and western blot analysis. In the nummular eczema lesional skin, expression of desmoglein-1, desmocollin-1, and corneodesmosin exhibited a disorganized, dense or partially diffuse non-peripheral pattern with increased intensity, compared with the peripheral patterns observed in healthy or nonlesional skin, suggesting the impaired desquamation process in nummular eczema. Furthermore, although the expression of the desquamation-related serine proteases, kallikrein-related peptidase 7 and 5, was increased in nummular eczema lesional skin, the immunofluorescence staining of lympho-epithelial Kazal-type-related inhibitor-1, an endogenous inhibitor of various kallikrein-related peptidases, and its fragments were significantly increased in the nummular eczema lesional skin, suggesting its contribution to the inhibition of corneodesmosomal degradation. Therefore, the increased detection of corneodesmosomal proteins in nummular eczema lesions may be due to the increased amount of the fragments of lympho-epithelial Kazal-type-related inhibitor-1, which could contribute to delayed desquamation.

'Eczematous' dermatitis of the nipple: clinical and histopathological differential diagnosis of Paget disease.

The nipple can be affected by many malignant and benign entities. A wide variety of diseases including Paget disease, atopic dermatitis and nipple candidiasis can cause eczema-like changes in the nipple. In cases of diagnostic uncertainty, tissue sampling may be indicated. A true eczematous lesion, such as atopic dermatitis, typically shows a spongiotic dermatitis pattern. Paget disease, on the other hand, presents with infiltration of the nipple epidermis by neoplastic cells. The presence of atypical cells scattered in the epidermis in a pagetoid pattern opens up a histopathological differential diagnosis encompassing squamous cell carcinoma in situ and malignant melanoma, among others. Immunohistochemistry is commonly used to render a diagnosis. The objective of this article is to discuss Paget disease and highlight relevant clinical and histopathological differential diagnoses.

Successful treatment with baricitinib of linear morphea following the lines of Blaschko mimicking lichen striatus.

Linear morphea, also known as linear scleroderma, is a localized form of scleroderma characterized by the presence of lesions that follow a linear distribution pattern. Apart from the typical inflammation and fibrosis of the skin, the linear subtype of morphea often affects underlying structures such as muscles and bones, which can lead to functional limitations. Lichen striatus, a linear inflammatory skin condition, primarily affects children aged 5 to 15 years. Interestingly, both diseases can exhibit lesions that follow the lines of Blaschko. Here we report a case with linear morphea following the lines of Blaschko mimicking lichen striatus in a 4-year-old child. This unique case represents the first documented instance of linear morphea exhibiting a precise Blaschko pattern and being successfully treated with baricitinib. The patient received oral baricitinib at a daily dosage of 2 mg for a duration of 1 year, resulting in remarkable improvement. The majority of the lesions softened, and there was no significant disease progression or occurrence of adverse events throughout the treatment period. Recognizing linear morphea at an early stage is of utmost importance in ensuring effective treatment and preventing disfiguring sequelae. Patients suspected of lichen striatus should also be closely followed and linear morphea should be excluded during the follow-up. The recent breakthrough in the application and the safety of baricitinib in scleroderma is also reviewed.

Potential inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced inflammation, hyperproliferation, and hyperplasiogenic responses by celecoxib in mouse skin.

PURPOSE: Skin exposure to noxious agents leads to cutaneous lesion marked by an increase in inflammation, cellular proliferation, and hyperplasiogenic reactions. Studies have demonstrated that these damages breach the skin integrity resulting in the aetiology of various cutaneous disorders like atopic dermatitis, eczema, psoriasis, and development of non-melanoma skin cancer. Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, is an effective treatment for a variety of inflammatory diseases. Its importance in the therapy of skin problems, however, remains under appreciated. METHODS: We tested efficacy of topically applied celecoxib in mitigating skin inflammation, cellular proliferation, and hyperplasia induced by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in Swiss albino mice. RESULTS: Celecoxib (5 and 10 µmol) markedly reduced TPA (10 nmol) induced prostaglandin E2 (PGE2) production, oedema formation, myeloperoxidase (MPO) activity, and levels of pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), and interleukin-6 (IL-6). It also resulted in a considerable decrease in ornithine decarboxylase (ODC) activity and the incorporation of [3H]-thymidine into DNA. In addition, there was a significant reduction in histoarchitectural abnormalities such as epidermal thickness, number of epidermal cell layers, neutrophil infiltration, intercellular oedema, and vasodilation. CONCLUSION: Our results demonstrate that topical celecoxib can reduce the inflammation, hyperproliferation, and hyperplasiogenic events of skin insults suggesting that it may prove to be a valuable management option for cutaneous lesion and associated illnesses such as atopic dermatitis, eczema, and psoriasis, as well as the emergence of non-melanoma cancer.

Soluble adenylyl cyclase contributes to imiquimod-mediated inflammation and is a potential therapeutic target in psoriasis.

Cyclic AMP (cAMP) has a key role in psoriasis pathogenesis, as indicated by the therapeutic efficacy of phosphodiesterase inhibitors that prevent the degradation of cAMP. However, whether soluble adenylate cyclase (sAC) (encoded by the ADCY10 gene), which is an important source for cAMP, is involved in Th17 cell-mediated inflammation or could be an alternative therapeutic target in psoriasis is unknown. We have utilized the imiquimod model of murine psoriasiform dermatitis to address this question. Adcy10-/- mice had reduced erythema, scaling and swelling in the skin and reduced CD4+ IL17+ cell numbers in the draining lymph nodes, compared with wild-type mice after induction of psoriasiform dermatitis with imiquimod. Keratinocyte-specific knock out of Adcy10 had no effect on imiquimod-induced ear swelling suggesting keratinocyte sAC has no role in imiquimod-induced inflammation. During Th17 polarization in vitro, naive T cells from Adcy10-/- mice exhibited reduced IL17 secretion and IL-17+ T-cell proliferation suggesting that differentiation into Th17 cells is suppressed without sAC activity. Interestingly, loss of sAC did not impact the expression of Th17 lineage-defining transcription factors (such as Rorc and cMaf) but rather was required for CREB-dependent gene expression, which is known to support Th17 cell gene expression. Finally, topical application of small molecule sAC inhibitors (sACi) reduced imiquimod-induced psoriasiform dermatitis and Il17 gene expression in the skin. Collectively, these findings demonstrate that sAC is important for psoriasiform dermatitis in mouse skin. sACi may provide an alternative class of topical therapeutics for Th17-mediated skin diseases.

The neglected twin: Nummular eczema is a variant of atopic dermatitis with codominant TH2/TH17 immune response.

BACKGROUND: Nummular eczema (NE) is a common chronic inflammatory skin disease characterized by multiple, pruritic, discoid-shaped lesions. Since the underlying immune mechanisms are not fully understood, it is unclear whether NE should be regarded as variant of atopic dermatitis (AD) or a distinct disease. OBJECTIVE: We compared the clinical, histopathologic, and molecular signatures of NE with that of type 2 and type 3 skin diseases. METHODS: We performed bulk RNA sequencing as well as histologic and clinical studies in lesional and nonlesional skin biopsy specimens from NE (n = 50), AD (n = 47), and psoriasis (n = 90) patients. RESULTS: NE displayed typical hallmarks of AD, such as an impaired epidermal barrier, microbial colonization, spongiosis, and eosinophil infiltration, but also aspects of psoriasis, including increased epidermal thickness, number of Ki-67+ cells, and neutrophilic infiltration. At the gene expression level, neutrophil-attracting cytokines (IL19, CXCL8, CXCL5) were upregulated, whereas TH2-related cytokines (IL13, CCL17, CCL18, CCL26, CCL27) were similarly expressed in NE compared to AD. Principal component analysis of transcriptome data from lesional skin showed that AD and NE cluster together distinct of psoriasis. In line with this, an established molecular classifier identified NE as AD rather than psoriasis. Finally, we demonstrated clinical and molecular efficacy of dupilumab treatment in NE. CONCLUSION: NE shows overlapping type 2 and type 3 immune signatures, while type 2 immunity predominates and should be the primary target of specific therapeutic interventions. This supports the view of NE as a variant of AD.

[Paget's disease of the nipple]. / Pagets sykdom i brystvorten.

BACKGROUND: Paget's disease of the nipple comprises approximately 1 % of all breast cancers, and presents with unilateral eczematoid changes to the nipple, areola or surrounding skin. Symptoms can be pain, itching or stinging in the area. CASE PRESENTATION: A female patient in her sixties presented to the skin clinic 18 months after initial detection of a rash surrounding her left nipple. Earlier ultrasound and mammography had not indicated pathology. Clinical suspicion and punch biopsies revealed a ductal carcinoma in situ. Surgical excision had to be repeated three times before the underlying malignancy was totally removed. INTERPRETATION: Eczematoid changes in the nipple area are associated with underlying ductal carcinoma or a carcinoma in situ, and biopsies should be taken.

Nipple eczema: A systematic review and practical recommendations.

The nipple is the focal point of the human breast and serves important physiological, sexual, and aesthetic purposes. It can be affected by atopic, irritant, and allergic contact eczema, which often reduce the patient's quality of life. The objective of this article is to discuss the different types of nipple eczema and highlight relevant differential diagnoses and treatment options. A systematic search of PubMed was conducted to identify and critically appraise the existing literature on the topic. All articles on nipple eczema were considered eligible, regardless of publication date, language or study design. A final of 33 manuscripts on nipple eczema remained. The scarce literature and the limited number of high-quality manuscripts impedes provision of structured data on nipple eczema. To securely reach the educative value of this manuscript, the systematic review was combined with a manual databank search and selected manual search of textbooks. The differential diagnosis of nipple eczema encompasses among others nipple psoriasis, nipple candidiasis and Paget's disease. In case of diagnostic uncertainty, swabs or biopsies are indicated. Treatment of nipple eczema needs to rapidly control the signs and symptoms of the disease, since it can have a negative effect on quality of life and can lead to premature arrest of breastfeeding. The key treatment step is starting with topical corticosteroids or calcineurin inhibitors, both of which are considered safe during lactation. Avoidance of provoking factors, such as repetitive friction, chemical agents, or allergens, can help. The use of nipple protection devices can be proposed for nursing women and sometimes adjusting of latch/suck positioning during breastfeeding is needed. Furthermore, patients should be advised to moisturize the nipple intensively and to switch to emollient wash products. Warm water compresses, black tea compresses or commercially available tannin containing topicals can provide comfort.

Objective hand eczema severity assessment with automated lesion anatomical stratification.

Hand eczema (HE) is one of the most frequent dermatoses, known to be both relapsing and remitting. Regular and precise evaluation of the disease severity is key for treatment management. Current scoring systems such as the hand eczema severity index (HECSI) suffer from intra- and inter-observer variance. We propose an automated system based on deep learning models (DLM) to quantify HE lesions' surface and determine their anatomical stratification. In this retrospective study, a team of 11 experienced dermatologists annotated eczema lesions in 312 HE pictures, and a medical student created anatomical maps of 215 hands pictures based on 37 anatomical subregions. Each data set was split into training and test pictures and used to train and evaluate two DLMs, one for anatomical mapping, the other for HE lesions segmentation. On the respective test sets, the anatomy DLM achieved average precision and sensitivity of 83% (95% confidence interval [CI] 80-85) and 85% (CI 82-88), while the HE DLM achieved precision and sensitivity of 75% (CI 64-82) and 69% (CI 55-81). The intraclass correlation of the predicted HE surface with dermatologists' estimated surface was 0.94 (CI 0.90-0.96). The proposed method automatically predicts the anatomical stratification of HE lesions' surface and can serve as support to evaluate hand eczema severity, improving reliability, precision and efficiency over manual assessment. Furthermore, the anatomical DLM is not limited to HE and can be applied to any other skin disease occurring on the hands such as lentigo or psoriasis.

The mixed spongiotic and interface reaction pattern: A study of clinical and histopathologic findings.

BACKGROUND: Categorization of biopsy specimens into inflammatory reaction patterns is central to dermatopathologic assessment. Mixed inflammatory patterns are poorly characterized and may represent clinicopathologic challenges. The purpose of this study was to identify clinical and histopathologic findings associated with the mixed spongiotic-interface dermatitis (SID) histopathologic pattern. METHODS: Fifty-one institutional biopsy specimens of SID were identified over a 2-year period by retrospective natural language search. Histopathologic and clinical features were identified. RESULTS: The most common histopathologic features associated with SID were mild spongiosis (51%), focal vacuolar interface change (72%), lymphocytic exocytosis (92%), and superficial-dermal lymphocytic infiltrate (94%) with variable eosinophils (61%). Clinically, 80% of subjects presented with a symmetric morbilliform eruption. Polypharmacy (94%), immunosuppression (47%), and history of malignancy (47%) were common. The most common diagnoses were drug reaction (37%), possible drug reaction (12%), and viral exanthem (12%). Drug reaction with eosinophilia and systemic symptoms represented 25% of all confirmed cutaneous adverse drug reactions (CADR). Average time from drug initiation to symptom initiation was 20 days (SD: 22.3, range: 0-90); median disease duration was 25.5 days. Spongiotic vesicles and Langerhans cells were less common in patients with a strong clinicopathologic diagnosis of drug reaction compared to non-drug eruptions (p = 0.04). CONCLUSIONS: The mixed SID pattern is commonly encountered in CADR but may represent a more subacute course, implying consideration for inciting medication(s) started before the typical 7- to 14-day window.

Delayed eczematous skin reaction as an adverse drug reaction to immunoglobulin infusions: A case series.

BACKGROUND: Pompholyx and eczematous reactions are known adverse reactions to intravenous immunoglobulins (IVIg) infusion, but little is known about their clinical characteristics, associated outcomes and management. OBJECTIVE: To describe IVIg-induced eczematous skin reactions. METHODS: We conducted a retrospective study on cases of delayed skin reactions post-IVIg infusion notified to the French Regional Pharmacovigilance Centre from 1985 to 2020. RESULTS: A total of 27 patients were identified, of whom 85% were male. IVIg infusions were given in a neurological indication in 82% of cases. Eczematous skin reactions occurred in two-thirds of cases after the first infusion, with a median time to onset of 11 days. Palmoplantar pompholyx was the most common presentation, being seen in 63% of patients. Other eruptions were erythemato-squamous or maculopapular. Eight patients were classified as severely affected and developed extensive lesions (>50% BSA). One third of the 27 patients required hospitalization. All of the severe eczematous reactions involved males receiving high doses of IVIg for neurological diseases. Biopsies of severe cases revealed a common non-specific eczematous pattern. Relapses were frequent and more severe than the initial reaction. Reintroduction of the same IVIg product consistently resulted in relapse, whereas switching IVIg type produced relapse in only 53% of patients. CONCLUSION: We present the largest retrospective study of delayed skin reactions after IVIg infusions. This side-effect may be severe and have a polymorphic presentation. Relapse occurs frequently but less consistently after IVIg switch.

Anti-Inflammatory Effects of Cycloheterophyllin on Dinitrochlorobenzene-Induced Atopic Dermatitis in HaCaT Cells and BALB/c Mice.

Atopic dermatitis (eczema) is a condition that makes skin red and itchy. Though common in children, the condition can occur at any age. Atopic dermatitis is persistent (chronic) and tends to recur periodically. It may be accompanied by asthma or hay fever. No cure has been found for eczema. Therefore, it is very important to develop ingredients that aid the prevention and treatment of atopic dermatitis. Cycloheterophyllin is derived from Artocarpus heterophyllus and has antioxidant and anti-inflammatory activities. However, it still is not understood whether cycloheterophyllin is an anti-atopic dermatitis agent. Keratinocytes (HaCaT cells) and BALB/c mice for inducing AD-like cutaneous lesions were used to evaluate the potential of cycloheterophyllin as an anti-atopic dermatitis agent. The release of pro-inflammatory cytokines induced by treatment of TNF-α/IFN-γ was reduced after pretreatment with cycloheterophyllin. The inhibitory effects could be a contribution from the effect of the MAP kinases pathway. Moreover, the symptoms of atopic dermatitis (such as red skin and itching) were attenuated by pretreatment with cycloheterophyllin. Epidermal hyperplasia and mast cell infiltration were decreased in the histological section. Finally, damage to the skin barrier was also found to recover through assessment of transepidermal water loss. Taken together, prenylflavone-cycloheterophyllin from Artocarpus heterophyllus is a potential anti-atopic dermatitis ingredient that can be used in preventing or treating the condition.

Artemisia annua water extract attenuates DNCB-induced atopic dermatitis by restraining Th2 cell mediated inflammatory responses in BALB/c mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia annua L. (A. annua) is a traditional Chinese medicine that has been used since ancient times to treat malaria, eczema, dermatomycosis, jaundice, and boils. Modern pharmacological studies show that it has immunosuppressive and anti-inflammatory effects. However, the mechanism of A. annua in the treatment of atopic dermatitis (AD) remains unclear. AIM OF THE STUDY: This study was aimed to investigate the effect of A. annua water extract (AWE) on 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse model and tried to explore its possible underlying mechanisms. MATERIALS AND METHODS: AD was induced in BALB/c mice by the topical repeated application of DNCB. Oral drug intervention of AWE and dexamethasone (DEX, positive control) began from the 7th day and continued for 13 consecutive days. The clinical skin score, ear thickness and the weight of ear and spleen were assessed. The ear tissue were stained with toluidine blue and hematoxylin and eosin (H&E) to detect inflammatory cell infiltration. IgE, terleukin (IL)-4 and IL-13 levels in the serum and IgE level in splenocytes were quantified by enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of IL-4, IL-6, IL-13, IL-17, tumor necrosis factor (TNF)-α and thymic stromal lymphopoietin (TSLP) were measured by quantitative real time polymerase chain reaction. The phosphorylation levels of mitogen-activated protein kinases (MAPKs)-p38 and nuclear factor (NF)-κB in ear tissue were detected by Western blot. RESULTS: Results demonstrated that AWE treatment significantly attenuated the AD-like symptoms in DNCB-induced BALB/c mice, including the skin dermatitis severity and ear edema. Further study disclosed that AWE treatment suppressed the expressions of IgE, IL-4, IL-6, IL-13, IL-17, TNF-α and TSLP at mRNA and protein levels. Moreover, AWE showed inhibitory effect on the phosphorylation of p38 MAPK and NFκB in ear tissues of AD mice. CONCLUSIONS: Collectively, our results suggested that AWE suppressed DNCB-induced AD in mice probably by restraining Th2 type inflammatory response. These findings might pave the road for the potential clinical application of AWE for AD treatment.

Topical Melatonin Exerts Immunomodulatory Effect and Improves Dermatitis Severity in a Mouse Model of Atopic Dermatitis.

Oral melatonin supplement has been shown to improve dermatitis severity in children with AD, but the mechanism of the effect is unclear, and it is uncertain whether melatonin has a direct immunomodulatory effect on the dermatitis. Topical melatonin treatment was applied to DNCB-stimulated Balb/c mice, and gross and pathological skin findings, serum IgE, and cytokine levels in superficial lymph nodes were analyzed. Secretion of chemokines and cell proliferative response after melatonin treatment in human keratinocyte HaCaT cells were also studied. We found that in DNCB-stimulated Balb/c mice, topical melatonin treatment improved gross dermatitis severity, reduced epidermal hyperplasia and lymphocyte infiltration in the skin, and decreased IP-10, CCL27, IL-4, and IL-17 levels in superficial skin-draining lymph nodes. Melatonin also reduced cytokine-induced secretion of AD-related chemokines IP-10 and MCP-1 and decreased IL-4-induced cell proliferation in HaCaT cells. Melatonin seems to have an immunomodulatory effect on AD, with IP-10 as a possible target, and topical melatonin treatment is a potentially useful treatment for patients with AD.

An Interleukin-4 and Interleukin-13 Induced Atopic Dermatitis Human Skin Equivalent Model by a Skin-On-A-Chip.

Currently, the mechanism of progression of atopic dermatitis (AD) is not well understood because there is no physiologically appropriate disease model in terms of disease complexity and multifactoriality. Type 2 inflammation, mediated by interleukin (IL)-4 and IL-13, plays an important role in AD. In this study, full-thickness human skin equivalents consisting of human-derived cells were fabricated from pumpless microfluidic chips and stimulated with IL-4 and IL-13. The morphological properties, gene expression, cytokine secretion and protein expression of the stimulated human skin equivalent (HSE) epidermis were investigated. The results showed epidermal and spongy formations similar to those observed in lesions in AD, and decreased expression of barrier-related filaggrin, loricrin and involucrin genes and proteins induced by IL-4Rα signaling. In addition, we induced the expression of carbonic anhydrase II (CAII), a gene specifically expressed in the epidermis of patients with AD. Thus, AD human skin equivalents can be used to mimic the key pathological features of atopic dermatitis, overcoming the limitations of existing studies that rely solely on mouse models and have been unable to translate their effects to humans. Our results will be useful for future research on the development of therapeutic agents for atopic dermatitis.

IL-36α and IL-36γ expressions in the differential diagnosis of palmoplantar psoriasis and palmoplantar eczema: A retrospective histopathologic and immunohistochemical study.

BACKGROUND: Diagnosing hyperkeratotic lesions on the palms and soles is often challenging for both clinicians and pathologists. Interleukin (IL)-36 cytokines play an important role in the pathogenesis of psoriasis. METHODS: We retrospectively re-evaluated hematoxylin-eosin-stained biopsy specimens of 30 patients with clinically diagnosed palmoplantar psoriasis (PP) and 30 patients with palmoplantar eczema (PE), and then performed IL-36α and IL-36γ immunohistochemistry. RESULTS: Among the histopathologic features, thinning of the rete ridges and vertical alternation of parakeratosis and orthokeratosis had the highest positive predictive value (PPV) in diagnosing PP (72.7% and 69.3%, respectively). Immunohistochemically, patients with PP predominantly showed diffuse or focal strong expression with IL-36α and IL-36γ staining in the upper layers of the epidermis (86.7% and 83.3%, respectively). The comparison of the mean IL-36α and IL-36γ expression scores significantly differed between PP and PE (P < .001). Among all histopathologic and immunohistochemical features, diffuse strong expression of IL-36α and IL-36γ staining had the highest PPVs in favor of a diagnosis of PP (75% and 76.7%, respectively). CONCLUSIONS: Our data suggest that IL-36α and IL-36γ immunohistochemistry can be used in the differential diagnosis of PP and PE.

A 52 weeks dupilumab treatment for moderate to severe atopic dermatitis in Korea: long-term efficacy and safety in real world.

Previously, we have reported short term effectiveness and safety of dupilumab in Korea. In this study, we are trying to report the long-term effectiveness and safety of dupilumab in Korea. Ninety-nine patients with moderate to severe AD were analyzed. They were evaluated using Eczema Area and Severity Index (EASI), Numerical Rating Scale (NRS), Patient Oriented Eczema Measure (POEM), and Dermatology Quality of Life Index (DLQI) at baseline, week 16, 32 and 52. Efficacy outcomes showed higher improvement at 52 weeks compared with 16 weeks; high percentual reductions in EASI (88.1%), peak pruritus NRS (65.6%), POEM (67.2%), and DLQI (69.0%) compared to baseline. Proportion of patients achieving EASI 75 and 90 were 90.2% and 53.7%. POEM and DLQI had high correlation with clinical measured outcomes. In the analysis for the factors affecting achievement of EASI 90, female gender (OR 2.5), eosinophilia (OR 0.2) and elevated LDH (OR 0.07) were significantly associated. Most frequent adverse events included facial erythema (19.2%) and conjunctivitis (17.2%), which were mild/moderate and resolved during treatment. In conclusion, dupilumab treatment for 52 weeks in Korean patients with moderate-to-severe AD confirmed long term effectiveness and safety.