Histopathological Findings and Increased D-Dimer Are Predictive Factors of Systemic Thromboses in Eosinophilic Granulomatosis With Polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA; ie, Churg-Strauss syndrome) is one of the antineutrophil cytoplasmic antibody-associated vasculitis syndromes. Although extravascular granulomatoses are a well-known histopathological feature, the diverse histopathologic spectrum of cutaneous lesions has not been described in detail. Thus, this study sought to investigate the possible correlation between the clinical features and histopathology of cutaneous lesions in EGPA cases, focusing on systemic thrombogenic conditions, such as visceral infarction and deep vein thrombosis. Fourteen cases of EGPA diagnosed at the Department of Dermatology in Asahikawa Medical University from 1977 to 2017 were clinically and histopathologically reviewed. In 6 (43%) cases, skin lesions were the initial manifestation of EGPA. Among the cutaneous lesions, purpura and erythema were the most common. Persistent proteinuria and macrohematuria were observed in only 2 myeloperoxidase-antineutrophil cytoplasmic antibody-positive cases. Systemic thrombotic symptoms, such as cerebral infarction and deep vein thrombosis, were detected in 5 (36%) cases, and, in 3 of those cases, thromboses in dermal or subcutaneous vessels were observed histopathologically. Elevation of plasma D-dimer level (>2.5 µg/mL) was significantly correlated with concomitant systemic thrombotic symptoms (P = 0.0152, Fischer exact test). The histopathological finding of thrombotic features and increased plasma D-dimer were predictive factors of EGPA accompanied with systemic thromboses, such as deep vein thromboses and cerebral infarction.

Clinical and molecular delineation of classical-like Ehlers-Danlos syndrome through a comprehensive next-generation sequencing-based screening system.

Classical-like Ehlers-Danlos syndrome (clEDS) is an autosomal recessive disorder caused by complete absence of tenascin-X resulting from biallelic variation in TNXB. Thus far, 50 patients from 43 families with biallelic TNXB variants have been identified. Accurate detection of TNXB variants is challenging because of the presence of the pseudogene TNXA, which can undergo non-allelic homologous recombination. Therefore, we designed a genetic screening system that is performed using similar operations to other next-generation sequencing (NGS) panel analyses and can be applied to accurately detect TNXB variants and the recombination of TNXA-derived sequences into TNXB. Using this system, we identified biallelic TNXB variants in nine unrelated clEDS patients. TNXA-derived variations were found in >75% of the current cohort, comparable to previous reports. The current cohort generally exhibited similar clinical features to patients in previous reports, but had a higher frequency of gastrointestinal complications (e.g., perforation, diverticulitis, gastrointestinal bleeding, intestinal obstruction, rectal/anal prolapse, and gallstones). This report is the first to apply an NGS-based screening for TNXB variants and represents the third largest cohort of clEDS, highlighting the importance of increasing awareness of the risk of gastrointestinal complications.

Acute exacerbation of idiopathic hypereosinophilic syndrome following asymptomatic coronavirus disease 2019: a case report.

BACKGROUND: Previous research has suggested that some autoimmune diseases develop after the occurrence of coronavirus disease 2019. Hypereosinophilic syndrome is a rare disease presenting with idiopathic eosinophilia and multiple organ involvement, including the skin, lungs, gastrointestinal tract, heart, and nervous system. The diagnosis of idiopathic hypereosinophilic syndrome poses a dilemma because clinical manifestation and serum biomarkers are similar to those of eosinophilic granulomatosis with polyangiitis. Only a few cases have been reported where coronavirus disease 2019 may have caused the new onset or exacerbation of eosinophilic granulomatosis with polyangiitis or idiopathic hypereosinophilic syndrome. CASE PRESENTATION: We present the case of a 48-year-old Japanese woman with history of asthma who developed deteriorating symptoms of insidiously developed idiopathic hypereosinophilic syndrome following asymptomatic coronavirus disease 2019. She developed acute-onset back pain, tachycardia, abdominal discomfort, loss of appetite, weight loss, skin rash on the back, and numbness of the extremities 3 days after the quarantine period. Extreme hypereosinophilia with multiple abnormal findings including pulmonary ground-glass opacity lesions and mononeuritis multiplex was consistent with hypereosinophilic syndrome. Normal cellularity with eosinophilic proliferation in the bone marrow and negative FIP1L1-PDGFRA raised the diagnosis of idiopathic hypereosinophilic syndrome. Although the patient tested negative for anti-neutrophilic cytoplasmic antibodies and skin biopsy was negative for vasculitis, eosinophilic granulomatosis with polyangiitis could not be excluded. Since glucocorticoids are a standard therapy for both idiopathic hypereosinophilic syndrome and eosinophilic granulomatosis with polyangiitis, we initiated glucocorticoids following a multidisciplinary discussion. CONCLUSION: Although the relationship between asymptomatic coronavirus disease 2019 and acute idiopathic hypereosinophilic syndrome exacerbation was uncertain, the chronological order of the symptomatic development suggested a possible link. More clinical cases and population-based studies are needed to determine the potential effect of coronavirus disease 2019 on autoimmune diseases.

Kawasaki disease in adolescence and adulthood: Report of four cases.

Kawasaki disease (KD) in adolescence and adulthood is often underrecognized, because KD predominantly affects infants and young children below the age of 5 years. We report four cases of KD in patients 16-32 years of age. The first department that the patients visited was the Department of Otolaryngology, Obstetrics, or General Internal Medicine. Since KD almost always develops as cutaneous and mucosal manifestations, dermatologists have a particularly significant role in diagnosing KD in adolescents and adults. KD should be kept in mind for febrile patients of any age group presenting with exanthem.

Salivary chromogranin A levels correlate with disease severity but do not reflect anxiety or personality of adult patients with atopic dermatitis.

Stress-induced scratching is an issue in patients with adult atopic dermatitis (AD). Although itching and stress are believed to be intimately related, no objective index is available; therefore, most evaluations are subjective. Using saliva, which is easily collected, we investigated the degree to which AD severity and patient stress levels are reflected in stress proteins in the saliva. Here, we evaluated the severity (Scoring Atopic Dermatitis [SCORAD] score), stress (State-Trait Anxiety Index [STAI] score), personality (Tokyo University Egogram [TEG] II score) and quality of life (Dermatology Life Quality Index [DLQI] score) of 51 patients with AD who were examined in the Department of Dermatology of Shimane University between April and December 2015. We collected saliva and measured salivary chromogranin A (CgA), amylase and cortisol. The amount of salivary CgA per protein in patients with AD was correlated with their SCORAD score (r = 0.458, P < 0.001). There was no correlation between cortisol or amylase levels and SCORAD score. SCORAD score was correlated with DLQI (r = 0.390, P = 0.006). CgA per protein was correlated with DLQI (r = 0.393, P = 0.004). There was no correlation between scores for the anxiety component of the STAI, TEG II or DLQI. Our results suggested that patients with more severe AD may have high stress levels. The personalities of these patients with AD tended to involve elevated anxiety levels.

Prevalence of coronary artery calcification in Japanese patients with psoriasis: A close correlation with bilateral diagonal earlobe creases.

Psoriasis is a multifactorial inflammatory disorder, in which the inflammation affects not only the skin but also the other internal organs, and can induce cardiovascular and cerebrovascular involvements. However, few predictive factors of cardiovascular diseases have been clarified in patients with psoriasis. This study was performed to verify whether diagonal earlobe creases (ELC) can reflect the hidden comorbidities in Japanese psoriatic patients. Prevalence and subtypes of ELC were analyzed in patients with psoriatic and with non-psoriatic skin diseases, and the correlation with coronary artery calcification (CAC) or fatty liver (FL) detected by computed tomography. Prevalence of CAC was approximately twice higher than data of a Japanese resident-based study previously reported. Generally, prevalence of ELC in a psoriatic group and mean age of psoriatic groups accompanied by ELC were higher and younger than those of a non-psoriatic skin disease group, respectively. Statistically significant differences were detected in the mean age of total or male subjects accompanied by bilateral ELC with complete and incomplete length. Bilateralism of ELC was closely correlated with prevalence of CAC and CAC on multiple branches in psoriatic patients (P = 6.6e-6 and odds ratio [OR] = 14.1, P = 0.00884 and OR = 10.7, respectively), but not with that of FL. On the contrary, body mass index of more than 25 was closely correlated with prevalence of FL, but not that of CAC. Comorbidities of psoriatic patients are frequently unnoticed. ELC, an apparatus-related feature, can be a useful predictive factor for hidden coronary artery involvements in psoriatic patients.

Serum carcinoembryonic antigen specifically increases among various serum markers of adenocarcinoma in hypohidrosis or conditions related to hypohidrosis.

Anhidrosis/hypohidrosis are conditions presenting various level of sweating dysfunction. Among them, acquired idiopathic generalized anhidrosis (AIGA) presents inadequate decrease or loss of sweating without apparent neurological and dermatological symptoms except cholinergic urticaria. Recently, serum level of carcinoembryonic antigen (CEA), one of the most well-known tumor markers, has been proposed as a clinical marker reflecting activity of AIGA. This study was performed to verify the specificity and independence of serum CEA level from the other serum tumor markers especially related to adenocarcinoma. The expression of various tumor markers in the serum collected from three healthy control subjects, four AIGA cases, and a cholinergic urticaria (CU) case with elevation of serum CEA level and history of hyperthermia was analyzed using a membrane-based antibody array. In all AIGA and CU cases, the intensity of CEA was significantly increased (7.60-15.9 times compared with that of control), relatively well-reflecting the serum CEA level, and the mean intensity of CEA was 11.8 times higher than the control subjects (P = 0.0011). On the other hand, the ratio of carbohydrate antigen (CA)125 and CA19-9 was 1.93 and 0.23 times compared with the mean intensity of the control subjects, respectively, and there was no statistical significance. Immunohistochemistry on 10 AIGA cases showed increased expression of CEA but not CA19-9 and CA125 in the eccrine sweat glands. In conclusion, the elevation of serum CEA level was independent from the other tumor markers in hypohidrotic condition represented by AIGA.

Incomplete KLK7 Secretion and Upregulated LEKTI Expression Underlie Hyperkeratotic Stratum Corneum in Atopic Dermatitis.

Atopic dermatitis (AD) is a common inflammatory skin disorder. Chronic AD lesions present hyperkeratosis, indicating a disturbed desquamation process. KLK7 is a serine protease involved in the proteolysis of extracellular corneodesmosome components, including desmocollin 1 and corneodesmosin, which leads to desquamation. KLK7 is secreted by lamellar granules and upregulated in AD lesional skin. However, despite increased KLK7 protein levels, immunostaining and electron microscopy indicated numerous corneodesmosomes remaining in the uppermost layer of the stratum corneum from AD lesions. We aimed to clarify the discrepancy between KLK7 overexpression and retention of corneodesmosomes on AD corneocytes. Western blot analysis indicated abnormal corneodesmosin degradation patterns in stratum corneum from AD lesions. The KLK activity of tape-stripped corneocytes from AD lesions was not significantly elevated in in situ zymography, which was our new attempt to detect the protease activity more precisely than conventional assays. This ineffective KLK activation was associated with impaired KLK7 secretion from lamellar granules and increased expression of LEKTI in AD. Such imbalances in protease-protease inhibitor interactions could lead to abnormal proteolysis of corneodesmosomes and compact hyperkeratosis. Upregulated expression of LEKTI might be a compensatory mechanism to prevent further barrier dysfunction in AD.

A Marked Response to Immunosuppressive Intervention for Abruptly Occurring Cardiac Complications in a Case of Juvenile Systemic Sclerosis Overlapped with Dermatomyositis.

Juvenile-onset systemic sclerosis (jSSc) is a rare condition, having unique characteristic features compared to adult-onset SSc. Although cardiac involvement (CI) is known as a leading cause of mortality overall in SSc, the importance of CI in jSSc has not been emphasized. Here we present a 13-year-old female with jSSc overlapped with dermatomyositis (DM) complicated CI. She developed skin thickness and induration, Raynaud's phenomenon, digital pitting scars in fingertips, and skeletal myositis. Oral prednisolone and pulse methotrexate treatment led to the improvement of skin findings; however two weeks after the initiation she suddenly presented with muscle pain and dyspnea within a few days. Cardiac investigations then showed pericardiac effusion and diastolic dysfunction due to significant biventricular hypertrophy causing heart failure. As pericardiac effusion and exacerbation of skeletal myositis were evident, steroid pulse therapy was initiated. Unexpectedly, not only the myositis but also the CI including diastolic dysfunction was improved. She thereafter followed a favorable clinical course without reactivation of the CI or cardiac fibrosis. As a conclusion, close attention to CI must be paid in jSSc patients, especially when skeletal muscle involvement is evident and immunosuppressive therapy may be effective for CI in jSSc in cases where it occurs abruptly.

Correlation of disease activity and serum level of carcinoembryonic antigen in acquired idiopathic generalized anhidrosis: A case report.

Hypohidrosis and anhidrosis are congenital or acquired conditions which are characterized by inadequate sweating. Acquired idiopathic generalized hypohidrosis/anhidrosis (AIGA) includes idiopathic pure sudomotor failure (IPSF), which has the following distinct features: sudden onset in youth, increased serum immunoglobulin E and responds favorably to systemic corticosteroid. No clinical markers reflecting the disease severity or activity have been established. Here, we report a case of AIGA in a Japanese patient successfully treated with repeated methylprednisolone pulse therapy. In this case, serum carcinoembryonic antigen (CEA) levels increased up to 19.8 ng/mL along with aberrant CEA immunoreactivity of eccrine sweat glands. Interestingly, the serum CEA level normalized as sweating improved with repeated methylprednisolone pulse therapy. Therefore, serum CEA level may serve as a useful clinical marker of hypohidrosis or anhidrosis.

Defective barrier function accompanied by structural changes of psoriatic stratum corneum.

Although barrier function of psoriatic skin is shown to be decreased by measuring transepidermal water loss (TEWL), few reports exist examining other physical skin properties and components including stratum corneum hydration, natural moisturizing factor (NMF), free fatty acids (FFA), ß-sheet and α-helix ratio of structural protein(s), and sebum content. We compared the skin properties and components of normal, involved and uninvolved skin of psoriasis. Using a corneometer and attenuated total reflection-infrared spectrometer, we measured TEWL, stratum corneum hydration, NMF, FFA, ß/α ratio and sebum in psoriasis vulgaris patients and healthy controls. TEWL and ß/α ratio of involved psoriatic skin were significantly increased compared with uninvolved skin and normal control skin. In contrast, stratum corneum hydration, NMF and FFA, but not sebum, are significantly decreased in the involved skin compared with uninvolved skin and normal skin. TEWL and stratum corneum hydration returned to the normal levels following clinical improvement of the lesion. Barrier function and hydration of psoriatic skin are defective and secondary structure in stratum corneum protein is altered in the involved psoriatic skin.

Cutaneous lesions of Kikuchi's disease: evolution of histopathological findings.

We report a 38-year-old male patient who presented with cutaneous lesions mimicking widespread discoid lupus erythematosus with high-grade fever, arthralgia and lymphadenopathy. Additional lymph node and skin biopsies, however, revealed karyorrhectic debris without neutrophils and numerous CD68-positive cells, a characteristic finding of Kikuchi's disease (KD). Comparing skin biopsies on different occasions, we could see different forms of histopathology. The histopathology of skin lesions of KD may vary during the clinical course, which may reflect the stage of the disease.

Developmental alterations of physical properties and components of neonatal-infantile stratum corneum of upper thighs and diaper-covered buttocks during the 1st year of life.

BACKGROUND: Although physical properties of neonatal-infantile stratum corneum (SC) change drastically after birth, precise developmental alterations of specific sites have not been fully elucidated. OBJECTIVE: To determine the longitudinal alterations of neonatal-infantile SC functions and components of upper thighs and diaper-covered buttocks during the first year of life. The data were compared with those of adults. METHODS: Nineteen full-term neonates and their mothers were subjected to the measurements. Skin hydration, water sorption/retention capacity, TEWL were measured. Superficial SC analyses for NMF, ester binding sebum, and free fatty acids were performed by ATR-FTIR spectrometer. Total amount of ceramides (CERs) and CER subclasses were analyzed by NPLC-ESI-MS. RESULTS: SC hydration of neonatal thighs was lower than that of their mothers, which rapidly increased during the 1st month. Skin hydration of neonatal buttocks was similar to that of their mothers. This also rapidly increased during the 1st month. The neonatal TEWL was less than those of their mothers indicating more efficient barrier function at both sites, which significantly increased during the 1st year development. This was mostly correlated decreased in the ω-hydroxy fatty acid-esterified CERs. Superficial ester-binding sebum content of neonates was similar to that of their mothers, which significantly decreased during the measurement; the decrease was more marked on buttocks. Neither NMF nor FFA of the superficial SC showed significant alteration during the 1-year development. CONCLUSION: Our results indicate that physical functions and components of neonatal-infantile SC show considerable alterations between diaper-covered buttocks and upper thighs during the 1st year development.

Podoplanin expression in wound and hyperproliferative psoriatic epidermis: regulation by TGF-ß and STAT-3 activating cytokines, IFN-γ, IL-6, and IL-22.

BACKGROUND: Podoplanin (PDPN)/T1α/aggrus/PA2.26 antigen, a transmembranous glycoprotein, is a well-known lymphatic endothelial marker. Recent evidence indicates that PDPN is also expressed in keratinocytes especially of sebaceous glands. OBJECTIVE: To verify expression-pattern and the regulatory mechanism of PDPN in human epidermal keratinocytes. METHODS: PDPN-expression pattern was analyzed in normal and psoriatic epidermis by immunostaining. The regulatory mechanism of PDPN-expression of keratinocytes by cytokines was analyzed using specific inhibitors, siRNA, and adenoviral shRNA of signaling pathways. RESULTS: In normal skin, PDPN was expressed on the basal cell layer of sebaceous glands and on the outer root sheath of hair follicles. While no expression was detected in the normal interfollicular epidermis, PDPN was detected in the basal cell layer of wound and hyperproliferative psoriatic epidermis, where the granular layer is lacking. TGF-ß1 and IFN-γ independently upregulated PDPN-expression of keratinocytes via TGF-ß receptor-Smad pathway and JAK-STAT pathway, respectively. IL-6 and IL-22 also stimulated PDPN-expression of keratinocytes accompanied by STAT-3 phosphorylation. siRNA of STAT-1, inhibitors of STAT-3 signaling, AG490, STAT-3 inhibitor VI, and si/shRNA of STAT-3 inhibited the PDPN-expression of keratinocytes induced by IFN-γ, IL-6 and IL-22 but not by TGF-ß1. CONCLUSION: These results indicate that TGF-ß1, IFN-γ, IL-6, and IL-22 induce PDPN-expression of keratinocytes, which might be significantly involved in the wound healing process as well as in the pathomechanism of hyperproliferative psoriatic epidermis.