Artemin causes hypersensitivity to warm sensation, mimicking warmth-provoked pruritus in atopic dermatitis.

BACKGROUND: Itch impairs the quality of life for many patients with dermatoses, especially atopic dermatitis (AD), and is frequently induced by a warm environment. OBJECTIVE: To determine the mechanism underlying itch induction by warmth, we focused on artemin, a member of glial cell line-derived neurotrophic factors (GDNFs). METHODS: A gene array assay revealed that artemin was expressed in substance P-treated dermal fibroblasts. The expression of artemin in healthy and AD-lesional skin was evaluated with immunohistochemistry and in situ hybridization. The impact of fibroblast-derived artemin on the proliferation and morphology of neural cell was investigated in vitro. To confirm the involvement of artemin in skin sensibility, wild-type and GDNF family receptor α3 knockout mice were employed for sensory examination. RESULTS: Artemin-expressing fibroblasts accumulated in skin lesions of patients with AD. Artemin induced cell proliferation of a neuroblastoma cell line in vitro, and intradermal injection of artemin in mice resulted in peripheral nerve sprouting and thermal hyperalgesia. Artemin-treated mice demonstrated scratching behavior in a warm environment, but mice deficient for GDNF family receptor α3, a potent artemin receptor, did not show this behavior. Furthermore, the escaping response to heat stimulus was attenuated in GDNF family receptor α3 knockout mice, suggesting that artemin may contribute to sensitivity to heat. CONCLUSION: These data suggest that dermal fibroblasts secrete artemin in response to substance P, leading to abnormal peripheral innvervation and thermal hyperalgesia. We hypothesize that artemin lowers the threshold of temperature-dependent itch sensation and might therefore be a novel therapeutic target for treating pruritic skin disorders, including AD.

Etanercept is safely used for treating psoriatic arthritis in a patient complicated with type 1 hereditary angioedema.

Hereditary angioedema (HAE) is a life-threatening disorder caused by deficiency or dysfunction of the C1 inhibitor protein. Patients with HAE are restricted in various medical treatments, which can induce an HAE attack. We herein report the first case of psoriatic arthritis (PSA) with type 1 HAE successfully treated with 25 mg of etanercept without HAE attack. Etanercept may represent a useful choice for treating patients with HAE accompanied by intractable PSA and rheumatoid arthritis (RA).

Staphylococcal scalded skin syndrome after intra-articular injection of hyaluronic acid.

One of the severe adverse effects of intra-articular injection in the knee is septic arthritis of the knee joint. Staphylococcus aureus is the most frequent pathogen of septic arthritis. Staphylococcal scalded skin syndrome (SSSS) refers to a spectrum of blistering skin diseases caused by S. aureus exfoliative toxins. Although SSSS is rarely observed in adults, the mortality rate is high in adult cases. We report a case of SSSS due to septic knee arthritis after intra-articular hyaluronic acid injections.

A case of disseminated DLE complicated by atopic dermatitis and Sjögren's syndrome: link between hypohidrosis and skin manifestations.

We report an unusual case of disseminated discoid lupus erythematosus (DLE) complicated by pre-existing atopic dermatitis (AD) and late-onset Sjögren's syndrome (SS). Disseminated DLE lesions were sparse on the expected sites for AD, such as the medial region of the extremities or v-neck area. The patient fulfilled the diagnostic criteria for AD and SS but not for systemic lupus erythematosus. Histopathological analysis of the crusted erythematous lesions revealed typical DLE with few FoxP3(+) cells and a moderate number of IL-17(+) cells. A quantitative sweating test showed impaired sweating of both lesional and non-lesional skin due to underlying hypohidrosis that was related to AD and SS. This finding suggests that dissemination of DLE was triggered by scratching and a Köbner phenomenon-like effect related to hypohidrotic and xerotic skin. To the best of our knowledge, this is the first reported case of disseminated DLE complicated by AD and SS.

Impact of sedative and non-sedative antihistamines on the impaired productivity and quality of life in patients with pruritic skin diseases.

BACKGROUND: The impairment that pruritic skin diseases have on patient productivity at work, in the classroom, and in daily activities is substantial and needs to be characterized. The objective of this study was to determine how pruritic skin diseases impact patient productivity and quality of life (QOL), in order to improve the measurement of these endpoints to allow the influence of treatment options including sedative and non-sedative antihistamines to be analyzed. METHODS: The impact of pruritic skin diseases and the effect of antihistamine therapy on work, classroom, and daily productivity were evaluated using the Work Productivity Assessment Index-Allergy Specific Questionnaire. The intensity of itch and patient QOL were assessed using a visual analogue scale and Skindex-16, respectively. RESULTS: Pruritic skin diseases resulted in significant impairment of work, classroom, and daily productivity. The severity of overall work impairment in atopic dermatitis (AD), urticaria, and prurigo was higher than for other diseases analyzed. However, classroom activity was more adversely affected in patients with urticaria relative to other diseases. All pruritic diseases in this study negatively impacted daily activity to a similar degree. Impaired productivity was significantly improved in patients taking non-sedative antihistamines for 1 month, and the improvements correlated with the alleviation of itch and improved QOL. CONCLUSIONS: These results indicate that pruritic skin diseases reduce patient productivity at work, in the classroom, and during daily activities, and that non-sedative antihistamines may offer an advantage over sedative antihistamines for alleviating certain negative consequences of these skin diseases.

Long-term efficacy and safety of bexarotene for Japanese patients with cutaneous T-cell lymphoma: The results of a phase 2 study (B-1201).

The present study (B-1201 clinical trial) was conducted as a multicenter, open-label, single-arm phase II study to evaluate the long-term safety, tolerability and efficacy of bexarotene. This study enrolled 10 Japanese adults aged more than 20 years with cutaneous T-cell lymphoma (CTCL) who completed the 24-week study period of the B-1101 trial. The objective response rate (ORR) was 53.8% (95% confidence interval, 25.1-80.8). In the early stage (IB), the ORR was 60% (3/5 cases). In the advanced stage (IIB and IIIA), the ORR was 57.1% (4/7 cases). The median time to response was 58 days (range, 27-168). The median treatment duration was 380 days (range, 33-1674). The median duration of response (DOR) could not be reached during the study period. The longest DOR reached 1618 days at the end of the B-1201 trial. Nine patients (56.3%) in the full analysis set (FAS) population experienced dose reduction of bexarotene. Common drug-related adverse events in the FAS population included hypothyroidism (93.8%), hypertriglyceridemia (81.3%), hypercholesterolemia (81.3%), leukopenia (68.8%) and neutropenia (56.3%). Dose-limiting toxicity (DLT) was present in five (38.5%) of the 13 patients in the 300 mg/m2 cohort. Of the five patients, four developed grade 3 neutropenia and one developed grade 4 hypertriglyceridemia. All DLT cases recovered after the discontinuation of bexarotene. None of the five patients discontinued this trial because of DLT. The B-1201 trial shows the long-term safety of oral bexarotene for Japanese patients with CTCL, despite frequent dose reduction.

Intractable wounds caused by calcific uremic arteriolopathy treated with bisphosphonates.

BACKGROUND: Calcific uremic arteriolopathy (calciphylaxis) is a calcification syndrome that predominantly affects relatively small vessels and is a life-threatening entity usually seen in patients with end-stage renal disease. Intractable skin necrosis sometimes causes lethal sepsis because it progresses rapidly as a result of mechanical stress. OBJECTIVE: We sought to investigate the efficacy of etidronate disodium (bisphosphonates) in treating intractable ulcers occurred in a patient on hemodialysis accompanied with calcific uremic arteriolopathy. METHODS AND RESULTS: A 53-year-old patient receiving hemodialysis with chronic renal failure accompanied with calciphylaxis had bilateral leg ulcers caused by minor trauma. The aggressive debridement worsened his skin condition as is usually seen in pyoderma gangrenosum. It eventually healed by lowering calcium-phosphorus levels with the administration of bisphosphonates and with the continuous use of sevelamer hydrochloride. LIMITATIONS: This study reporting a single case limits the interpretation of results. CONCLUSION: Bisphosphonates may be effective in treating calciphylaxis and arteriosclerosis obliterans by reducing the formation of ectopic calcification around blood vessels.

Phase I/II study of the oral retinoid X receptor agonist bexarotene in Japanese patients with cutaneous T-cell lymphomas.

Safety, tolerability, pharmacokinetics and efficacy of bexarotene, a novel retinoid X receptor (RXR)-selective retinoid, were evaluated in Japanese patients with stage IIB-IVB and relapsed/refractory stage IB-IIA cutaneous T-cell lymphomas (CTCL). This study was conducted as a multicenter, open-label, historically controlled, single-arm phase I/II study. Bexarotene was p.o. administrated once daily at a dose of 300 mg/m2 for 24 weeks in 13 patients, following an evaluation of safety and tolerability for 4 weeks at a dose of 150 mg/m2 in three patients. Eight of 13 patients (61.5%) with an initial dose of 300 mg/m2 met the response criteria using the modified severity-weighted assessment tool (mSWAT) at 24 weeks or discontinuation. Dose-limiting toxic effects (DLT) were present in four of 13 patients (31%) at a dose of 300 mg/m2 : two neutropenia, one abnormal hepatic function and one hypertriglyceridemia. No DLT was observed in patients received 150 mg/m2 bexarotene. In the 13 patients at 300 mg/m2 , common drug-related adverse events (AE) included hypothyroidism (92%), hypercholesterolemia (77%), leukopenia or neutropenia (39%), nasopharyngitis or anemia (31%). The treatment-related grade 3 AE included hypertriglyceridemia (4/16 patients, 25%), increased alanine aminotransferase, increased aspartate aminotransferase, dyslipidaemia, leukopenia and neutropenia (1/16 patients, 6%), and one of 16 patients experienced grade 4 hypertriglyceridemia. No patients discontinued bexarotene due to the AE during the study, but dose reduction or suspension was required. Bexarotene was shown to be well tolerated at 300 mg/m2 once daily and effective in Japanese patients with CTCL.

A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid.

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; 400mg/kg/day for 5days) in BP patients who showed no symptomatic improvement with prednisolone (≥0.4mg/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 57days 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.

11ß-hydroxysteroid dehydrogenase 1 specific inhibitor increased dermal collagen content and promotes fibroblast proliferation.

Glucocorticoids (GCs) are one of the most effective anti-inflammatory drugs for treating acute and chronic inflammatory diseases. However, several studies have shown that GCs alter collagen metabolism in the skin and induce skin atrophy. Cortisol is the endogenous GC that is released in response to various stressors. Over the last decade, extraadrenal cortisol production in various tissues has been reported. Skin also synthesizes cortisol through a de novo pathway and through an activating enzyme. 11ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) is the enzyme that catalyzes the conversion of hormonally inactive cortisone to active cortisol in cells. We previously found that 11ß-HSD1 negatively regulates proliferation of keratinocytes. To determine the function of 11ß-HSD1 in dermal fibroblasts and collagen metabolism, the effect of a selective 11ß-HSD1 inhibitor was studied in mouse tissues and dermal fibroblasts. The expression of 11ß-HSD1 increased with age in mouse skin. Subcutaneous injection of a selective 11ß-HSD1 inhibitor increased dermal thickness and collagen content in the mouse skin. In vitro, proliferation of dermal fibroblasts derived from 11ß-HSD1 null mice (Hsd11b1(-/-) mice) was significantly increased compared with fibroblasts from wild-type mice. However, in vivo, dermal thickness of Hsd11b1(-/-) mice was not altered in 3-month-old and 1-year-old mouse skin compared with wild-type mouse skin. These in vivo findings suggest the presence of compensatory mechanisms in Hsd11b1(-/-) mice. Our findings suggest that 11ß-HSD1 inhibition may reverse the decreased collagen content observed in intrinsically and extrinsically aged skin and in skin atrophy that is induced by GC treatment.

Transient wheal attack corresponding to the tumor lesions of primary cutaneous diffuse large B cell lymphoma, leg type after successive rituximab treatment.

An elderly male noticed urticarial patches corresponding to cutaneous B cell lymphoma lesions after rituximab treatment. Along with the resolution of urticaria, the lymphoma lesions completely remitted without recurrence. In this communication, we present an interesting case and the pathophysiological findings of a wheal attack in a case with tumor remission following systemic treatment with rituximab, a monoclonal anti-CD20 antibody.

Immunohistochemical Analysis of Interleukin-17 Producing T Helper Cells and Regulatory T Cells Infiltration in Annular Erythema Associated with Sjögren's Syndrome.

BACKGROUND: Peculiar erythema known as annular erythema associated with Sjögren's syndrome (AESS) can be differentiated from autoimmune annular erythema and subacute cutaneous lupus erythematosus, both clinically and histologically. However, there are no detailed investigations on immune competent cells infiltration. OBJECTIVE: Preferential infiltration of interleukin-17-producing T helper (Th17) cells and regulatory T (Treg) cells into the labial salivary gland is reported to play a role in maintaining mucoepithelitis in patients with Sjögren's syndrome. In this study, we evaluated Th17 and Treg cell infiltration into the lesional skin of AESS. METHODS: We analyzed the numbers and infiltration patterns of Th17 and FoxP3 (+) Treg cells in seven cases of AESS using immunohistochemistry. Seven patients with systemic lupus erythematosus (SLE), atopic dermatitis (AD) and psoriasis vulgaris (PV), which are representatives of Th17 cell-involved skin disorders, were enrolled as disease controls. RESULTS: Periappendageal and epidermal changes, such as follicular plugging and liquefaction, were evident in the annular erythema of SLE, not AESS, tissue samples. In AESS tissue samples, dense perivascular and periappendageal infiltration of lymph cells was observed in the middle-to-deep dermis, as previously described, in contrast to the superficial infiltration pattern observed in both AD and PV samples. While the total number of infiltrated lymphocytes was similar between AESS and SLE tissue samples, Th17 cells were found to be preferentially infiltrated in the middle-to-deep dermis in AESS samples. CONCLUSION: These results suggest that an increased number and distribution of infiltration of Th17 cells is a preferential feature of AESS, rather than a characteristic feature of annular erythema of SLE.

Phase II study of i.v. interferon-gamma in Japanese patients with mycosis fungoides.

A multisite, open-label, non-randomized, single-arm phase II study was conducted to evaluate the efficacy and safety profiles of interferon-γ in Japanese patients diagnosed with stage IA-IIIA mycosis fungoides (MF). Interferon-γ was administrated i.v. to 15 patients at a dose of 2 million Japan reference units once daily over 5 days a week for the first 4 weeks, followed by subsequent intermittent injection. The primary efficacy end-point was the overall skin response during the study as assessed according to the evaluation criteria for chemotherapeutics for malignant skin carcinomas. Of the 15 patients, 11 (73.3%) achieved the objective response. Of the other four patients, three remained on treatment during study with stable disease and one showed disease progression. The median duration of stable disease was not reached but was 170 days or more (range, 29 to ≥253 days). As assessed according to the modified severity weighted assessment tool, nine patients (60.0%) achieved the objective response. The most common drug-related adverse event (AE) was influenza-like illness occurring in all patients enrolled, which did not lead to discontinuation of the study. Two serious AE were reported in two patients: aggravation of MF and aggravation of cataract, neither of which was considered directly related to the study drug. The patient with aggravation of MF died 50 days after the initiation of the study treatment. Another patient was withdrawn from the study due to drug-related cough, which disappeared after discontinuation of the drug. Overall, interferon-γ was effective and well-tolerated in Japanese patients with MF.

Guidelines for the management of cutaneous lymphomas (2011): a consensus statement by the Japanese Skin Cancer Society - Lymphoma Study Group.

In 2010, the first Japanese edition of guidelines for the management of cutaneous lymphoma was published jointly by the Japanese Dermatological Association (JDA) and the Japanese Skin Cancer Society (JSCS) - Lymphoma Study Group. Because the guidelines were revised in 2011 based on the most recent data, we summarized the revised guidelines in English for two reasons: (i) to inform overseas clinicians about our way of managing common types of cutaneous lymphomas such as mycosis fungoides/Sézary syndrome; and (ii) to introduce Japanese guidelines for lymphomas peculiar to Asia, such as adult T-cell leukemia/lymphoma and extranodal natural killer/T-cell lymphoma, nasal type. References that provide scientific evidence for these guidelines have been selected by the JSCS - Lymphoma Study Group. These guidelines, together with the degrees of recommendation, have been made in the context of limited medical treatment resources, and standard medical practice within the framework of the Japanese National Health Insurance system.

A case of giant squamous cell carcinoma of the buttock possibly arose from syringocystadenoma and invaded to the rectum.

We report a rare case of giant squamous cell carcinoma of the buttock infiltrated to the rectum. The tumor may have arisen from syringocystadenoma papilliferum. Since there was no sign of metastasis, radical operation including rectal amputation was performed after successful neoadjuvant therapies. Afterwards, the patient has been alive free from disease for 15 months with no lymph node and distant organ metastasis.

Pilomatrix carcinoma arising from pilomatricoma after 10-year senescent period: Immunohistochemical analysis.

Pilomatrix carcinoma is a rare malignant counterpart of pilomatricoma. To our knowledge, only approximately 90 cases have been published in English literature. Pilomatrix carcinoma is locally aggressive and occasionally shows rapid progression infiltrating to the muscle, bone and vessels. We report a case of pilomatrix carcinoma that developed in a 38-year-old man and started to grow after a long stable period, relapsed for a short time and infiltrated into the muscle underneath. While the initial skin biopsy showed histopathological findings consistent with pilomatricoma, the recurrent tumor contained marked cellular atypia and an aggressive growth pattern. Although it is still controversial whether pilomatrix carcinoma arises de novo or through malignant transformation of a pilomatricoma, the present case might be caused by the latter process considering the patient's clinical course. beta-catenin is a downstream effecter in the canonical pathway of Wnt, acting as a signal for cell differentiation and proliferation. The characteristic nuclear staining pattern of beta-catenin in the basaloid tumor cells, which is usually observed in pilomatrix carcinoma, supported the diagnosis of pilomatrix carcinoma in the present case.