Shun Ohmori

IL-23 from Langerhans Cells Is Required for the Development of Imiquimod-Induced Psoriasis-Like Dermatitis by Induction of IL-17A-Producing γδ T Cells

Psoriasis is a common chronic inflammatory skin disease that involves dysregulated interplay between immune cells and keratinocytes. Recently, it has been reported that IL-23 induces CCR6+ γδ T cells, which have the pivotal role in psoriasis-like skin inflammation in mice of producing IL-17A and IL-22. Langerhans cells (LCs) are a subset of dendritic cells that reside in the epidermis and regulate immune responses. The role of LCs has been extensively investigated in contact hypersensitivity, but their role in psoriasis remains to be clarified. In this study, we focused on Th17-related factors and assessed the role of LCs and γδ T cells in the development of psoriasis using a mouse psoriasis model triggered by topical application of imiquimod (IMQ). LC depletion by means of diphtheria toxin (DT) in Langerin DT receptor-knocked-in mice suppressed hyperkeratosis, parakeratosis, and ear swelling in the IMQ-treated regions. In addition, LC-depleted mice showed decreased levels of Th17-related cytokines in IMQ-treated skin lesions. Moreover, the IMQ-treated skin of LC-depleted mice showed a decreased number of IL-17A-producing CCR6+ γδ T cells. These results suggest that LCs are required for the development of psoriasis-like lesions induced by IMQ in mice.

Type of skin eruption is an independent prognostic indicator for adult T-cell leukemia/lymphoma

Cutaneous involvement is seen in ~ 50% of adult T-cell leukemia/lymphoma (ATLL) patients. We investigated the association between skin eruption type and prognosis in 119 ATLL patients. ATLL eruptions were categorized into patch (6.7%), plaque (26.9%), multipapular (19.3%), nodulotumoral (38.7%), erythrodermic (4.2%), and purpuric (4.2%) types. When the T stage of the tumor-node-metastasis-blood (TNMB) classification of mycosis fungoides/Sézary syndrome was applied to ATLL staging, 16.0% were T1, 17.7% T2, 38.7% T3, and 4.2% T4, and the remaining 23.5% were of the multipapular and purpuric types. For the patch type, the mean survival time (median survival time could not be estimated) was 188.4 months. The median survival times (in months) for the remaining types were as follows: plaque, 114.9; multipapular, 17.3; nodulotumoral, 17.3; erythrodermic, 3.0; and purpuric, 4.4. Kaplan-Meier curves of overall survival showed that the erythrodermic type had the poorest prognosis, followed by the nodulotumoral and multipapular types. The patch and plaque types were associated with better survival rates. Multivariate analysis demonstrated that the hazard ratios of the erythrodermic and nodulotumoral types were significantly higher than that of the patch type, and that the eruption type is an independent prognostic factor for ATLL. The overall survival was worse as the T stage became more advanced: the multipapular type and T2 were comparable, and the purpuric type had a significantly poorer prognosis than T1.

Nivolumab in the treatment of malignant melanoma: review of the literature

Nivolumab was developed as a monoclonal antibody against programmed death receptor-1, an immune checkpoint inhibitor which negatively regulates T-cell proliferation and activation. Intravenous administration of nivolumab was approved for the treatment of unresectable malignant melanoma in 2014 in Japan. When advanced melanoma patients were treated with nivolumab, median overall survival became longer. Overall survival rate was significantly better in nivolumab-treated melanoma patients than dacarbazine-treated melanoma patients. Nivolumab had an acceptable long-term tolerability profile, with 22% of patients experiencing grade 3 or 4 adverse events related to the drug. Therefore, nivolumab can become an alternative therapy for advanced malignant melanoma.

Increased circulating Th17 cell in a patient with tinea capitis caused by Microsporum canis

Tinea capitis is a relatively common superficial fungal infection. In the infection ofMicrosporum canis (M. canis), the lesion is around a hair shaft and eventually the hairs break off 1e3 mm above the scalp. The patients sometimes experience permanent hair loss, especially after longstanding inflammation. However, the detail mechanism of severe inflammation leading to subcutaneous pustular formation and hair loss caused by tinea capitis remains unclear. Recently, IL-17-producing Th17 cells, which are comprised in established CD4þ T helper cell subsets, exacerbate skin inflammation,

Heparin serves as a natural stimulant of the inflammasome and exacerbates the symptoms of tumor necrosis factor receptor-associated periodic syndrome (TRAPS).

This work was supported by grants from National Natural ience Foundation of China (No. 30671893) and Jiangsu Province tural Science Foundation (No. BK2011128) to M. Li. [8] Lee HM, Shin DM, Choi DK, Lee ZW, Kim KH, Yuk JM, et al. Innate immune responses to Mycobacterium ulcerans via toll-like receptors and dectin-1 in human keratinocytes. Cell Microbiol 2009;11:678–92. [9] Netea MG, Brown GD, Kullberg BJ, Gow NA. An integrated model of the recognition of Candida albicans by the innate immune system. Nat Rev Microbiol 2008;6:67–78. [10] Carlos IZ, Sgarbi DB, Placeres MC. Host organism defense by a peptidepolysaccharide extracted from the fungus Sporothrix schenckii. Mycopathologia 1999;144:9–14.

Combination of skin-directed therapy and oral etoposide for smoldering adult T-cell leukemia/lymphoma with skin involvement

Abstract Approximately 50% of patients with adult T-cell leukemia/lymphoma (ATLL) have skin involvement, and the smoldering, skin lesion-bearing cases are often treated with various skin-directed therapies, such as phototherapy and radiation therapy. Daily oral administration of etoposide plus prednisolone (EP) is also used for smoldering-type ATLL. However, it remains unclear whether these therapies improve patients’ survival. We retrospectively analyzed the prognosis of patients with smoldering, skin lesion-bearing ATLL (n = 62), who were treated, as first therapy, with one skin-directed therapy (n = 29), oral EP alone (n = 14) or a combination of skin-directed therapy and oral EP (n = 19). Multivariate analysis revealed that the hazard ratios (HRs) for the overall survival (OS) and progression-free survival (PFS) with the combination therapy were significantly lower than those with the skin-directed therapy (HR 0.1, p = 0.001; HR 0.2, p = 0.002, respectively). These results suggest that the combination of skin-directed therapy and oral EP improves the clinical outcome of patients with smoldering, skin lesion-bearing ATLL.

Maculopapular type drug eruption caused by silodosin

Silodosin is one of the a1-adrenergic receptor antagonists and is commonly used to treat male lower urinary tract symptoms due to benign prostatic hypertrophy.1 The incidence of silodosin-related adverse events was 69.7%,1 and themost common adverse event after silodosin treatment was abnormal ejaculation.1 However, to our knowledge, there has been no case report on cutaneous drug eruption caused by silodosin in English literature. Herein, we report the first case of silodosin-induced drug eruption. A 58-year-old male, who had suffered from benign prostatic hypertrophy for 5 years, developed his erythematous plaques andwas referred to our department for evaluation of his eruption. Physical examination revealed that papules and erythematous eruption had developed on his trunk (Fig. 1AeC) and extremities without mucosal involvement after the 3rd administration of silodosin for his benign prostatic hypertrophy. Laboratory and biochemical examinations were within normal ranges. At the first visit, a skin biopsy specimen taken from an erythematous lesion on his trunk revealed lymphocyte infiltration around vessels in dermis (Fig. 1D) with less epidermal change. We performed lymphocyte stimulation test (LST) with silodosin as described previously.2,3

Hypopituitarism and hypothyroidism following atrioventricular block during nivolumab treatment

Dear Editor, Nivolumab is a blocking antibody against programmed death receptor-1 (PD-1), which inhibits T-cell proliferation and cytokine production. Nivolumab has exhibited a favorable therapeutic response in patients with malignancies, such as malignant melanoma and lung cancer. Although various sideeffects, such as hematological toxicity and respiratory disease, have been reported, we report an extremely rare case of hypopituitarism and hypothyroidism following atrioventricular block (AV block) possibly due to nivolumab. An 85-year-old Japanese male noticed a black plaque on his head 9 months prior, and the lesion gradually developed. He visited the dermatology clinic, and a skin biopsy from his black plaque was obtained. The histopathological diagnosis was malignant melanoma (Fig. 1a–d). He was referred to our department for evaluation of his skin eruption. A chest computed tomography examination revealed that multiple metastatic tumors were observed in both lungs. Therefore, he was diagnosed with stage IV malignant melanoma, and nivolumab (2 mg/kg) was administrated i.v. for his malignant melanoma every 3 weeks. Three months after the treatment, his heart rate decreased to approximately 50 b.p.m., and an electrocardiogram revealed first-degree AV block (Fig. 1e). Therefore, cardiac pacemaker insertion was performed. Five months after the treatment, lung metastasis lesions decreased in size; however, he suffered from fatigue and loss of appetite. His blood pressure was 96/58 mmHg, indicating hypotension. Laboratory findings revealed lower levels of adrenocorticotropic hormone (ACTH) (2.0 pg/mL; normal range, 7.2– 63.3) and cortisol (0.4 lg/dL; normal range, 2.7–18.0), whereas serum levels of all other anterior pituitary hormones were within normal ranges. Therefore, we suspected that he might be suffering from adrenal insufficiency due to hypopituitarism, and we performed a corticotropin-releasing hormone (CRH) test for the diagnosis. As expected, ACTH and cortisol exhibited no significant responses under CRH stimulation. Furthermore, laboratory examination revealed an increased level of thyroid-stimulating hormone (9.5 mIU/mL; normal range, 0.34–6.50) and a reduced level of free T4 (0.87 ng/dL; normal range, 0.97–1.79). We diagnosed the patient with hypothyroidism and adrenal insufficiency due to hypopituitarism after nivolumab treatment. His symptoms due to hypothyroidism were relatively mild without any treatment. His symptoms dramatically improved after administration of hydrocortisone (15 mg/day). Nivolumab administration was continued without other additional treatments. Although previous studies reported that patients treated with nivolumab occasionally exhibit adverse events, such as

Drug eruption caused by secukinumab

The Th17 cell is a pro-inflammatory T helper cell subset defined by the production of IL-17, which plays an important role in various inflammatory diseases [1]. IL-17 exacerbates inflammatory responses through activation of various immune cells, such as neutrophils and keratinocytes. Therefore, the IL-17 axis is a key therapeutic target for the regulation of inflammatory diseases, such as psoriasis and rheumatoid arthritis [2]. Secukinumab is an IL-17 neutralizing antibody, and widely used for the [...]

Inflammatory response to heparinoid and heparin in a patient with tumor necrosis factor receptor-associated periodic syndrome: the second case with a T61I mutation in the TNFRSF1A gene.

Yuichi KURIHARA, Ryota HAYASHI, Emiko WATANABE, Shun-ichi MIYAKAWA, Kumiko KAJIWARA, Maiko MATSUDA, Kazue YOSHIDA, Yutaka SHIMOMURA, Hironori NIIZEKI Division of Dermatology, Kawasaki Municipal Hospital, Kawasaki, Kanagawa, Laboratory of Genetic Skin Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Division of Pediatrics, Kawasaki Municipal Hospital, Kawasaki, Kanagawa, and Department of Dermatology, National Center for Child Health and Development, Tokyo, Japan