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Impaired keratinocyte functions are major factors that are responsible for delayed diabetic wound healing. In addition to its antimicrobial activity, the antimicrobial peptide derived from insulin-like growth factor-binding protein 5 (AMP-IBP5) activates mast cells and promotes keratinocyte and fibroblast proliferation and migration. However, its effects on diabetic wound healing remain unclear. Human keratinocytes were cultured in normal or high glucose milieus. The production of angiogenic growth factor and cell proliferation and migration were evaluated. Wounds in normal and streptozotocin-induced diabetic mice were monitored and histologically examined. We found that AMP-IBP5 rescued the high glucose-induced attenuation of proliferation and migration as well as the production of angiogenin and vascular endothelial growth factors in keratinocytes. The AMP-IBP5-induced activity was mediated by the epidermal growth factor receptor, signal transducer and activator of transcription 1 and 3, and mitogen-activated protein kinase pathways, as indicated by the inhibitory effects of pathway-specific inhibitors. In vivo, AMP-IBP5 markedly accelerated wound healing, increased the expression of angiogenic factors and promoted vessel formation in both normal and diabetic mice. Overall, the finding that AMP-IBP5 accelerated diabetic wound healing by protecting against glucotoxicity and promoting angiogenesis suggests that AMP-IBP5 might be a potential therapeutic target for treating chronic diabetic wounds.

Human cathelicidin LL-37 is a multifunctional antimicrobial peptide that exhibits antimicrobial and immunomodulatory activities. LL-37 regulates skin barrier function and was recently reported to activate autophagy in macrophages. Because autophagy deficiency is associated with skin diseases characterized by a dysfunctional epidermal barrier, we hypothesized that LL-37 might regulate the skin barrier through autophagy modulation. We showed that LL-37 activated autophagy in human keratinocytes and three-dimensional skin equivalent models as indicated by increases in LC3 puncta formation, decreases in p62, and autophagosome and autolysosome formation. LL-37‒induced autophagy was suppressed by P2X

Background: Although psoriasis is a Th1-dominant disease, certain investigations have also revealed the involvement of Th2 cells in the disease. Soluble CD30 (sCD30) is predominantly associated with various Th2 diseases. Therefore, the role of sCD30 in psoriasis requires further evaluation. Objectives: To evaluate the association between sCD30 and psoriasis. Methods: In this cross-sectional analytical study, the association between serum sCD30 levels and psoriasis was evaluated using enzyme-linked immunosorbent assay in sera obtained from patients with psoriasis. Results: The results indicated elevated sCD30 levels in 79 patients with psoriasis, and the levels were significantly higher in those with a prolonged duration of disease (duration > 10 years). Furthermore, there was a significant positive correlation between the duration of disease (years) and sCD30 (pg/mL) levels. These findings suggest that sCD30 is a useful marker for chronicity of psoriasis. Conclusion: Elevated sCD30 levels in psoriasis are associated with disease duration, and they may reflect the chronicity of psoriasis. Further research is required to determine the role of sCD30 in psoriasis.

The pemphigoid group is a category of autoimmune subepidermal blistering diseases in which autoantibodies deposit linearly at the epidermal basement membrane zone (BMZ). The main subtypes of pemphigoid mediated by immunoglobulin G autoantibodies are bullous pemphigoid (BP), mucous membrane pemphigoid (MMP) and epidermolysis bullosa acquisita (EBA). To establish the first guidelines approved by the Japanese Dermatological Association for the management of pemphigoid diseases, the Committee for Guidelines for the Management of Pemphigoid Diseases (Including EBA) was founded as part of the Study Group for Rare Intractable Skin Diseases under the Ministry of Health, Labor and Welfare Research Project on Overcoming Intractable Diseases. These guidelines aim to provide current information for the management of BP, MMP and EBA in Japan. Based on evidence, the guidelines summarize the clinical and immunological manifestations, pathophysiologies, diagnostic criteria, disease severity determination criteria, treatment algorithms and treatment recommendations. Because of the rarity of these diseases, there are few clinical studies with a high degree of evidence, so several parts of these guidelines were established based on the opinions of the Committee. To further optimize these guidelines, periodic revision in line with the new evidence is necessary.

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Background: Mesenchymal stem cells (MSCs) have been reported to promote wound healing in both animal models and human studies. Among MSCs, adipose-derived stem cells (ADSCs) can be easily harvested in large quantities. Objective: We investigated whether skin wound healing in mice can be facilitated by keratinocyte-like cells differentiated from ADSCs (KC-ADSCs). Methods: For the wound contraction and epithelialization model, a 20 mm×20 mm fullthickness skin wound was made on the dorsum. For the wound epithelialization model, a 6 mm×6 mm full-thickness skin wound was made on the dorsum. A nitrile rubber stent with an inner diameter of 8 mm was sutured around the wounds to minimize wound contraction. Undifferentiated ADSCs (uADSCs) or KC-ADSCs was injected around the wound base in both models. To evaluate whether the injected ADSCs could enhance wound contraction in a skin wound, the contractile activity of ADSCs was assessed by an in vitro type I collagen gel contraction assay. Alpha-smooth muscle actin (αSMA) expressions in uADSCs and KC-ADSCs were also evaluated by flow cytometry and real-time polymerase chain reaction. Results: In a wound contraction and epithelialization model, KC-ADSCs further facilitated wound healing compared with uADSCs. In a wound epithelialization model, KC-ADSCs also further facilitated wound epithelialization compared with uADSCs. The contractile activity of KC-ADSCs was lower than that of uADSCs. The uADSCs expressed high levels of αSMA, which decreased after the differentiation into keratinocyte-like cells. Conclusion: Our results suggest that the wound healing effect of KC-ADSCs depends primarily on re-epithelialization rather than wound contraction. (Ann Dermatol 33(4) 324∼332, 2021)

Background: Congenital ichthyoses (CIs) adversely affect quality of life (QOL) in patients. However, the effects of CIs on patient QOL have not been studied sufficiently. Objective: To investigate the association between disease severity and QOL in patients with harlequin ichthyosis (HI) and ichthyosis: syndromic forms (ISFs) Methods: Clinical information of patients with HI and ISFs from 2010 to 2015 were obtained from 100 dermatology departments/divisions of principal institutes/hospitals throughout Japan. We examined the relationship between disease severity and QOL in patients with HI and ISFs. Patients who were aged 8 years or older and participated in a multicenter retrospective questionnaire survey in Japan were assessed by dermatology life quality index (DLQI, range of 0–30) and clinical ichthyosis score (range of 0–100). Results: Netherton syndrome patients had a significantly higher risk of allergy to food or environmental allergens than patients with other phenotypes. Keratitis-ichthyosis-deafness (KID) syndrome patients showed a significantly higher risk of skin infections than patients with other phenotypes. Complete data on DLQI were obtained from 13 patients, whose median age was 21 (8–71) years. Nine patients were male, and 4 were female. Systemic retinoids were administrated to 2 of the 3 HI patients. The Spearman’s correlation coefficient between the clinical ichthyosis score and DLQI was 0.611 (P, ファイル公開：2019-11-01

Generalized pustular psoriasis (GPP) is a rare disease characterized by recurrent fever and systemic flushing accompanied by extensive sterile pustules. The committee of the guidelines was founded as a collaborative project between the Japanese Dermatological Association and the Study Group for Rare Intractable Skin Diseases under the Ministry of Health, Labour, and Welfare Research Project on Overcoming Intractable Diseases. The aim of the guidelines was to provide current information to aid in the treatment of patients with GPP in Japan. Its contents include the diagnostic and severity classification criteria for GPP, its pathogenesis, and recommendations for the treatment of GPP. Since there are few clinical trial data with high levels of evidence for this rare disease, recommendations by the committee are described in the present guidelines.

Psoriatic arthritis (PsA), a chronic inflammatory arthropathy associated with psoriasis, is an intractable immune disorder and refractory to pharmacological intervention. We assessed efficacy of selective depletion of myeloid lineage leukocytes in patients with PsA in a multicenter setting. A total of 20 patients with moderate to severe PsA refractory to conventional and biological disease-modifying antirheumatic drugs were included. Eligible patients had 3 points or more in the classification criteria for PsA. Each patient received five sessions, once a week, of adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn® . The primary efficacy outcome was 20% or more decrease in the American College of Rheumatology score 20 (ACR20). Partial responders could receive an additional five GMA sessions. Of 20 patients, two did not complete the study, nine responded to five GMA sessions and nine received 10 sessions. At the first evaluation 2 weeks after the last GMA session, 13 of the 20 (65.0%) patients achieved ACR20. ACR20 was maintained in seven of 10 (70%) and five of 10 (50%) patients at the follow-up evaluation points 8 and 20 weeks after the last GMA session, respectively. GMA was well tolerated without any safety concern. This study demonstrates that GMA with the Adacolumn was effective with good safety profile in patients with PsA refractory to pharmacologicals. The results indicate a major role for myeloid leukocytes in the immunopathogenesis of PsA. A large controlled study is warranted to fully evaluate the efficacy of Adacolumn GMA in patients with PsA.

A 26-year-old female homemaker presented with an approximately 2-month history of an erythematous lesion with agminated seropapules in the right popliteal fossa associated with scales and crusts. The lesion was initially treated as contact dermatitis, but there was no improvement. KOH examination revealed filamentous fungi. The fungal culture was positive, and the morphological characteristics were identical to those of Trichophyton mentagrophytes complex. The fungus was identified as T. erinacei based on genetic analysis. This is the second case report of human tinea corporis due to this fungus in Japan.

Background Antimicrobial peptide derived from insulin-like growth factor binding protein-5 (AMP-IBP5) is a potent antimicrobial agent that possesses various immunomodulatory activities. The parent protein of AMP-IBP5, IGFBP-5, has been shown to exert its effects via an insulin-like growth factor-1 receptor-independent mechanism, including binding to multifunctional low-density lipoprotein receptor-related protein 1 (LRP1), which contributes to several biological processes involved in skin wound healing. Objectives To investigate whether LRP1 is involved in AMP-IBP5-induced migration and proliferation of human epidermal keratinocytes and dermal fibroblasts. Methods The mRNA expression of LRP1 and IGFBP-5 was assessed by quantitative real-time PCR, whereas Western blotting was used to evaluate the protein expression. Production of cytokines was determined by ELISA. Cell migration was measured by the scratch wound assay, whereas cell proliferation was analyzed using the BrdU labeling assay. MAPK activation was determined by Western blotting. Results We found that AMP-IBP5 markedly induced the migration and proliferation of keratinocytes and fibroblasts, and this effect was reversed by specific siRNA and neutralizing antibody targeting the LRP1 receptor. In addition, LRP1 was upregulated by lipopolysaccharide, flagellin and AMP-IBP5 in keratinocytes and fibroblasts. LRP1 knockdown also inhibited MAPK pathway activation, which was required for AMP-IBP5-mediated cell migration and proliferation, as evidenced by the specific inhibitors for extracellular signal-regulated kinase, c-Jun N-terminal kinase and p38. Conclusions Our results suggest that LRP1 expressed in human epidermal keratinocytes and dermal fibroblasts contributes to AMP-IBP5-mediated cell migration and proliferation, supporting its crucial role in cutaneous wound healing process.

Background In addition to their antimicrobial activities, antimicrobial peptides, also known as host defense peptides (HDPs) activate keratinocytes; promote wound healing; and improve the skin barrier. AG-30/5C is a novel angiogenic HDP that activates various functions of fibroblasts and endothelial cells, including cytokine/chemokine production and wound healing. Objectives To investigate whether AG-30/5C activates human keratinocytes and to examine the underlying mechanisms. Methods Production of cytokines/chemokines was assessed by ELISA. Expression of Mas-related G-protein coupled receptors X (MrgXs) in keratinocytes was determined by real-time PCR and Western blot. MAPK and NF-κB activation was analysed by Western blot. Cell migration was assessed by chemotaxis microchamber and in vitro wound closure assay, whereas cell proliferation was analysed using an XTT assay. Results We found that AG-30/5C was more efficient than its parent peptide AG-30 in increasing the production of various cytokines/chemokines and promoting keratinocyte migration and proliferation. Furthermore, MrgX3 and MrgX4 receptors were constitutively expressed in keratinocytes at higher levels than MrgX1 and MrgX2, and were up-regulated upon stimulation with TLR ligands. Because MrgX3 and MrgX4 siRNAs suppressed AG-30/5C-mediated cytokine/chemokine production, keratinocyte migration and proliferation, we propose that AG-30/5C utilizes these MrgXs to stimulate keratinocytes. In addition, AG-30/5C-induced activation of keratinocytes was controlled by MAPK and NF-κB pathways, as evidenced by the inhibitory effects of ERK-, JNK-, p38- and NF-κB-specific inhibitors. Indeed, we confirmed that AG-30/5C enhanced phosphorylation of MAPKs and IκB. Conclusions Our findings provide novel evidence that AG-30/5C may be a useful therapeutic agent for wound healing by activating human keratinocytes.

Allergen sources such as mites, insects, fungi, and pollen contain proteases. Airway exposure to proteases induces allergic airway inflammation and IgE/IgG1 responses via IL-33-dependent mechanisms in mice. We examined the epicutaneous sensitization of mice to a model protease allergen, papain; the effects of tape stripping, which induces epidermal barrier dysfunction; and the atopic march upon a subsequent airway challenge. Papain painting on ear skin and tape stripping cooperatively promoted dermatitis, the skin gene expression of proinflammatory cytokines and growth factors, up-regulation of serum total IgE, and papain-specific IgE/IgG1 induction. Epicutaneous sensitization induced T helper (Th) 2 cells and Th17 differentiation in draining lymph nodes. Ovalbumin and protease inhibitor-treated papain induced no or weak responses, whereas the co-administration of ovalbumin and papain promoted ovalbumin-specific IgE/IgG1 induction. Wild-type and IL-33-deficient mice showed similar responses in the epicutaneous sensitization phase. The subsequent airway papain challenge induced airway eosinophilia and maintained high papain-specific IgE levels in an IL-33-dependent manner. These results suggest that allergen source-derived protease activity and mechanical barrier damage such as that caused by scratching cooperatively promote epicutaneous sensitization and skin inflammation and that IL-33 is dispensable for epicutaneous sensitization but is crucial in the atopic march upon a subsequent airway low-dose encounter with protease allergens.

Darier disease (DD) is a type of inherited keratinizing disorder that exhibits autosomal dominant inheritance. DD is caused by the mutations of ATP2A2, which encodes an endoplasmic reticulum calcium pump, sarco/endoplasmic reticulum ATPase type 2 (SERCA2). DD often develops in childhood, persists through adolescence, and causes small papules predominantly in seborrheic areas such as the face, chest and back. Further, scales and scabs may gradually develop. DD may be accompanied by non-dermal symptoms, including psychiatric symptoms. Histologically, DD is characterized by corps ronds and grains in addition to suprabasal cleavage. There are no currently validated curative treatments available for DD, with the majority of cases treated symptomatically. Despite demonstrating efficacy in the treatment of DD, the use of oral retinoids has been limited due to the association with various adverse effects.

Background Interleukin (IL)-37, a new member of the IL-1 family, is characterized as a fundamental inhibitor of innate immunity: it dampens the production of proinflammatory cytokines, protects against inflammatory and autoimmune diseases, and plays a potent immunosuppressive role in the pathogenesis of psoriasis. IL-37 is highly expressed in psoriatic skin, in which human β-defensins (hBDs) have been detected. Although hBDs enhance the production of cytokines, including IL-1 cytokines, whether they stimulate the production of IL-37 remains unclear. Objectives To assess the ability of hBDs to stimulate IL-37 expression/production by human keratinocytes and to determine the mechanism involved. Methods Real-time PCR and Western blotting were used to evaluate IL-37 expression. Caspase activities were assessed using colorimetric assay kits. A CCR6 antibody, siRNA, and caspase, Smad3, MAPK and NF-κB inhibitors were used to investigate the signaling mechanism of hBDs. Results Among the four hBDs used, only hBD-3 up-regulated the mRNA and protein expression of IL-37. The combination of TNF-α, EGF and poly (I:C) with hBD-3 synergistically enhanced the mRNA but not the protein expression of IL-37. Furthermore, hBD-3 increased the release of IL-37 into the culture supernatants. Evaluation of the signaling mechanism of hBD-3 suggested that caspases 1 and 4, Smad3, CCR6, MAPKs and NF-κB were required for hBD-3-mediated IL-37 expression. Conclusions The finding that hBD-3 stimulates IL-37 expression, a novel target for the pathogenesis and therapy of cutaneous inflammatory diseases, provides evidence that hBDs contribute to the suppression of inflammatory and innate immune responses through the regulation of IL-37 expression.

Background Autosomal recessive congenital ichthyosis (ARCI) and ichthyosis syndrome (IS) are rare genetic skin disorders. Objective To estimate the number of patients with ARCI and IS in Japan and clarify the clinicoepidemiologic features of these diseases. Methods We performed a nationwide survey of patients treated for ARCI or IS during January 2005-December 2009. We developed diagnostic criteria and conducted a primary survey in a stratified random sample of Japanese hospitals to quantify the number of outpatients and inpatients with ARCI or IS. We performed a secondary survey of clinicoepidemiologic features in positive cases. Results The estimated number of patients receiving treatment for ARCI and IS during 2005-2009 was 220 (95% confidence interval [CI] 180-260). The estimated disease distribution was as follows: 95 (95% CI 80-110) patients with nonbullous congenital ichthyosiform erythroderma, 30 (95% CI 20-40) with lamellar ichthyosis, 15 (95% CI 10-20) with harlequin ichthyosis, and 85 (95% CI 50-120) with IS. Limitations Patients with a mild case of the disease might not have visited a dermatology department, potentially causing underestimation of affected patients. Conclusion We report the estimated number of patients with ARCI and IS in Japan and sex differences in the age distribution.

Type VII collagen (Col7) is a major component of the anchoring fibrils at the dermoepidermal junction. Adipose-derived stem cells (ADSCs) are a cell population highly useful in regenerative medicine because of their ease of isolation and their potential for multilineage differentiation. Based on the observations that K14 was expressed in undifferentiated ADSCs and the expression was downregulated after differentiation into adipocytes, we speculated that ADSCs are keratinocyte stem/progenitor cells. ADSCs were co-cultured with fibroblasts on type IV collagen in a medium containing all-trans retinoic acid and bone morphogenetic protein 4. At day 14 of culture in keratinocyte serum-free medium, the cells were harvested and subjected to immunofluorescence, flow cytometry, real-time PCR, and western blotting. Approximately, 45% of ADSCs were immunostained positively for anti-human cytokeratin 10, and approximately 80% were stained positively for Col7. Flow cytometry, real-time PCR, and western blotting also confirmed that differentiated ADSCs expressed higher levels of Col7. These findings support the therapeutic potential of ADSCs, not only for wound healing, but also for the correction of Col7 deficiencies.

As a major intracellular degradation system, autophagy contributes to the maintenance of skin keratinocyte homeostasis. However, the precise role of autophagy in skin differentiation has not been fully investigated. To clarify whether autophagy plays a role in skin differentiation and maturation, autophagy-related gene 7 (Atg7)-deficient mice were generated. Atg7-deficient mice cannot survive for more than 24 h after birth. Therefore, the skins of Atg7-deficient mice and wild-type mice (as a control) were grafted onto severe combined immunodeficient mice. The resulting morphological and pathological changes were monitored for 28 days. Histopathological examination revealed acanthosis, hyperkeratosis, and abnormal hair growth in the skin grafts from the Atg7-deficient mice. Immune-density analysis of the skin grafts revealed reduced immunostaining of keratinization-related proteins, including loricrin, filaggrin, and involucrin, in the skin grafts from the Atg7-deficient mice. Furthermore, quantitative RT-PCR and Western blot analyses revealed the reduced expression of these three keratinization-related proteins in the skin grafts from the Atg7-deficient mice. Morphometric analysis using electron microscopy further revealed a reduction in the number and diameter of the keratohyalin and trichohyalin granules in these skin grafts. The differences were maintained for at least 1 month after transplantation. These results show that autophagy has a significant role in epidermal keratinization and hair growth until a certain stage of maturation.

The Committee for Guidelines for the Management of Pemphigus was organized as one element of the Japanese Dermatological Association (JDA) and the Ministry of Health, Labour, and Welfare (MHLW) Research Project on Measures for Research Committee for Intractable Skin Disease. Pemphigus has been defined as a group of intractable autoimmune blistering diseases caused by anti-desmoglein 1 and/or anti-desmoglein 3 IgG autoantibodies by the MHLW. The diagnosis of this condition and the criteria for assessing its severity are based on suggestions from the MHLW Research Group. The clinical practice guidelines presented here are those that are currently recommended in Japan. However, symptoms and complications can vary widely among individual pemphigus patients, so not all therapies will be required to be in complete agreement with these guidelines.

The expression of autophagy-related markers has occasionally been reported to correlate with the clinical stage of disease in patients with solid cancer, indicating autophagy activation. However, there have been no such reports for cutaneous squamous cell carcinoma. In this study, we investigated the expression levels of two autophagy-related markers, microtubule-associated protein IA/IB light chain 3 (LC3) and p62/sequestosome-1 (p62), in cutaneous squamous cell carcinoma specimens and assessed their correlation to clinicopathological factors in patients with this type of cancer. As a marker of the autophagosome, LC3 expression increases with autophagosome formation/accumulation, whereas p62 expression decreases due to selective degradation via autophagy. We performed immunostaining for LC3 and p62 in 50 cutaneous squamous cell carcinoma specimens obtained from patients treated by surgical resection, counted the number of cells that showed positive staining, and calculated the percentage of positive cells per low-power microscopic field. We next investigated the correlations between the expression levels of these markers and various clinicopathological factors. The results indicated that LC3 expression increased significantly with advanced clinical stage (P

We conducted a retrospective cohort study on clinical and mycological features of tinea pedis and tinea unguium in psychiatric inpatients in Japan. Of the 317 inpatients (152 with schizophrenia and 165 with depression), 46.1% had tinea pedis and 23.7% had tinea unguium. Of those with tinea pedis, 48.6% also had tinea unguium. The most common clinical type of tinea pedis was the combination of interdigital type and hyperkeratotic type. The mean clinical score of tinea pedis was 5.9, and that of tinea unguium based on the Scoring Clinical Index for Onychomycosis (SCIO) was 15.8. The main causative species of tinea pedis were Trichophyton rubrum (68.4%) and T. mentagrophytes (26.3%). No statistically significant differences were observed in incidence rates of tinea pedis or tinea unguium between men and women or between patients with schizophrenia and those with depression. As for incidence rates by age, patients with depression showed a single peak for tinea pedis and / or tinea unguium in their 50's, while patients with schizophrenia exhibited twin peaks for tinea pedis and / or tinea unguium in their 50's and 70's. Both tinea pedis and tinea unguium tended to become more severe in patients with chronic schizophrenia. Our study suggests that schizophrenia and depression, like diabetes mellitus and HIV infections, should be regarded as risk factors for tinea pedis and tinea unguium.

Background Generalized pustular psoriasis (GPP) is a chronic autoimmune disease characterized by fever, erythema, and neutrophilic pustules over large areas of the skin. GPP does not respond well to pharmacologic intervention. Objective We sought to assess efficacy of selectively depleting the myeloid lineage leukocytes in patients with GPP. Methods Fifteen patients with persistent moderate to severe GPP despite conventional therapy were included. Eligible patients had more than 10% of their skin area covered by pustules. Treatment with oral etretinate, cyclosporine, methotrexate, prednisolone, and topical prednisolone/vitamin D3 was continued if had been initiated well in advance of study entry. Five sessions of adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn (JIMRO Co Ltd, Takasaki, Japan) were administered (1 session/wk over 5 weeks) to selectively deplete Fcγ receptor and complement receptor bearing leukocytes. Efficacy was assessed by measuring the skin areas covered by pustules at baseline and 2 weeks after the last GMA session. Results One patient did not complete the first GMA session. Based on the GPP severity scores relative to entry, the overall scores improved (n = 14, P = .0027), and the area of erythroderma ( P = .0042), pustules ( P = .0031), and edema ( P = .0014) decreased. Likewise, Dermatology Life Quality Index improved ( P = .0016), reflecting better daily function and quality of life. Twelve patients were judged as responders (85.7%), and 10 patients maintained the clinical response for 10 weeks after the last GMA session without any change in medication. Limitations This study was unblinded and without a placebo arm. Conclusion GMA in this clinical setting was safe and effective, suggested a major role for granulocytes/monocytes in the immunopathogenesis of GPP.

Background Detailed nationwide surveys of the epidemiologic and clinical characteristics of bullous congenital ichthyosiform erythroderma (BCIE) (novel synonym: keratinolytic ichthyosis) in a large population have not been performed previously to our knowledge. Objective We sought to estimate the number of patients with BCIE who visited dermatology departments in Japan in 2002 and to clarify the clinical and epidemiologic features of the disease. Methods A nationwide mail survey was sent to dermatology departments and consisted of an initial survey to estimate the number of individuals with BCIE and a second survey to obtain data on the clinical characteristics of these patients. Results The total number of patients with BCIE in Japan was estimated to be 55 (95% confidence interval, 35-75). Clinical data were able to be collected from 28 cases. Clinical manifestations included rash in 27 cases (96.4%), erythroderma in 19 cases (67.9%), and generalized blistering in 15 cases (57.7%). Approximately 75% of patients younger than 20 years showed generalized blistering. Hystrixlike scales were present in 8 female patients (57.1%), whereas large scales were present in 8 male patients (57.1%). Among the 19 patients for whom histopathological information was available, 17 (89.5%) showed granular degeneration. Limitations Patients with BCIE who have few subjective symptoms may not have visited a dermatology department, potentially resulting in an underestimation of the number of patients with BCIE. Conclusion Important epidemiologic and clinical information on characteristics of BCIE in Japan was obtained, including an estimate of the total number of patients with BCIE in Japan.

Background In addition to their microbicidal properties, host defense peptides (HDPs) display various immunomodulatory functions, including keratinocyte production of cytokines/chemokines, proliferation, migration and wound healing. Recently, a novel HDP named AMP-IBP5 (antimicrobial peptide derived from insulin-like growth factor-binding protein 5) was shown to exhibit antimicrobial activity against numerous pathogens, even at concentrations comparable to those of human β-defensins and LL-37. However, the immunomodulatory role of AMP-IBP5 in cutaneous tissue remains unknown. Objectives To investigate whether AMP-IBP5 triggers keratinocyte activation and to clarify its mechanism. Methods Production of cytokines/chemokines and growth factors was determined by appropriate ELISA kits. Cell migration was assessed by in vitro wound closure assay, whereas cell proliferation was analyzed using BrdU incorporation assay complimented with XTT assay. MAPK and NF-κB activation was determined by Western blotting. Intracellular cAMP levels were assessed using cAMP enzyme immunoassay kit. Results Among various cytokines/chemokines and growth factors tested, AMP-IBP5 selectively increased the production of IL-8 and VEGF. Moreover, AMP-IBP5 markedly enhanced keratinocyte migration and proliferation. AMP-IBP5-induced keratinocyte activation was mediated by Mrg X1-X4 receptors with MAPK and NF-κB pathways working downstream, as evidenced by the inhibitory effects of MrgX1-X4 siRNAs and ERK-, JNK-, p38- and NF-κB-specific inhibitors. We confirmed that AMP-IBP5 indeed induced MAPK and NF-κB activation. Furthermore, AMP-IBP5-induced VEGF but not IL-8 production correlated with an increase in intracellular cAMP. Conclusions Our findings suggest that in addition to its antimicrobial function, AMP-IBP5 might contribute to wound healing process through activation of keratinocytes.

Background Patients with steroid-resistant bullous pemphigoid (BP) require an appropriate treatment option. Objective A multicenter, randomized, placebo-controlled, double-blind trial was conducted to investigate the therapeutic effect of high-dose intravenous immunoglobulin (IVIG; 400 mg/kg/day for 5 days) in BP patients who showed no symptomatic improvement with prednisolone (≥0.4 mg/kg/day) administered. Methods We evaluated the efficacy using the disease activity score on day15 (DAS15) as a primary endpoint, and changes in the DAS over time, the anti-BP180 antibody titer, and safety for a period of 57 days as secondary endpoints. Results We enrolled 56 patients in this study. The DAS15 was 12.5 points lower in the IVIG group than in the placebo group (p = 0.089). The mean DAS of the IVIG group was constantly lower than that of the placebo group throughout the course of observation, and a post hoc analysis of covariance revealed a significant difference (p = 0.041). Furthermore, when analyzed only in severe cases (DAS ≥ 40), the DAS15 differed significantly (p = 0.046). The anti-BP180 antibody titers showed no difference between the two groups. Conclusion IVIG provides a beneficial therapeutic outcome for patients with BP who are resistant to steroid therapy.

Generalized pustular psoriasis (GPP) is a rare form of psoriasis characterized by the presence of variable numbers of sterile pustules appearing in erythematous and scaly lesions, which are associated with moderate to severe constitutional symptoms. It can be life-threatening especially in the elderly; therefore, medical care must be performed in rapid succession of treatment especially in refractory cases. We have performed granulocyte and monocyte adsorption apheresis (GCAP) on three GPP cases associated with several systemic and laboratory findings. As a result, the edema, erythema and numbers of sterile pustules on the skin lesions were reduced dramatically in all three patients after the first sessions of GCAP therapy. The sizes of the psoriatic lesions were reduced in all three patients following a weekly GCAP treatment for 5 consecutive weeks. Psoriasis area and severity index on discharge had improved in all three patients. No serious adverse effects were observed for up to at least 8 months after treatment. We therefore considered GCAP as one effective alternative to currently existing therapies, especially for recalcitrant cases of GPP.