Kazunari Sugita

Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions through IL-13 in asthmatic patients

&NA; Figure. No caption available. Background: Bronchial epithelial barrier leakiness and type 2 innate lymphoid cells (ILC2s) have been separately linked to asthma pathogenesis; however, the influence of ILC2s on the bronchial epithelial barrier has not been investigated previously. Objective: We investigated the role of ILC2s in the regulation of bronchial epithelial tight junctions (TJs) and barrier function both in bronchial epithelial cells of asthmatic patients and healthy subjects and general innate lymphoid cell– and ILC2‐deficient mice. Methods: Cocultures of human ILC2s and bronchial epithelial cells were used to determine transepithelial electrical resistance, paracellular flux, and TJ mRNA and protein expressions. The effect of ILC2s on TJs was examined by using a murine model of IL‐33–induced airway inflammation in wild‐type, recombination‐activating gene 2 (Rag2)−/−, Rag2−/−Il2rg−/−, and Rorasg/sg mice undergoing bone marrow transplantation to analyze the in vivo relevance of barrier disruption by ILC2s. Results: ILC2s significantly impaired the epithelial barrier, as demonstrated by reduced transepithelial electrical resistance and increased fluorescein isothiocyanate–dextran permeability in air‐liquid interface cultures of human bronchial epithelial cells. This was in parallel to decreased mRNAs and disrupted protein expression of TJ proteins and was restored by neutralization of IL‐13. Intranasal administration of recombinant IL‐33 to wild‐type and Rag2−/− mice lacking T and B cells triggered TJ disruption, whereas Rag2−/−Il2rg−/− and Rorasg/sg mice undergoing bone marrow transplantation that lack ILC2s did not show any barrier leakiness. Direct nasal administration of IL‐13 was sufficient to induce deficiency in the TJ barrier in the bronchial epithelium of mice in vivo. Conclusion: These data highlight an essential mechanism in asthma pathogenesis by demonstrating that ILC2s are responsible for bronchial epithelial TJ barrier leakiness through IL‐13.

Psoriasis vulgaris in a hepatitis B virus carrier successfully treated with secukinumab and entecavir combination therapy.

The use of biologics in patients with psoriasis has recently been increasing because of their effectiveness. Reactivation of hepatitis B virus (HBV) due to the use of biologics in HBV carriers causes severe liver dysfunction [1]. Therefore, the use of biologics and which types of anti-HBV agents are best suited for patients with HBV infection are important issues in dermatology. We report here the first case of psoriasis vulgaris in an HBV carrier who was successfully treated with combination therapy [...]

Fibroblastic connective tissue nevus: the role of histopathological and molecular techniques in differential diagnosis

547 by loss or degeneration of endothelial cells and thickening of the vessel walls. Although lymphocytic infiltration was observed around the degenerated vessels, no active vasculitis was seen (figure 1C, D). The ulcers enlarged despite topical application of a steroid ointment for one week. Thus, oral pazopanib was discontinued, and the ulcers significantly improved and epithelized within two weeks, with slight scarring and pigmentation (figure 1B). We presumed this case to be a cutaneous adverse drug reaction due to pazopanib. No skin ulcer recurrence has been observed in the one-year follow-up period. TKIs are among the most successful drugs for treating metastatic RCC [1]. They are regarded as anti-angiogenic agents, and function primarily by inhibiting tumour angiogenesis and tumour cell survival signalling [1]. Pazopanib targets multiple tyrosine kinases, including VEGFR-1, -2 and -3 [2]. Serious cutaneous adverse effects of TKIs tend to occur during the initial two months of treatment, particularly in males and older patients [3]. Major adverse effects of pazopanib include hypertension, diarrhoea, hair colour changes, nausea, anorexia, and vomiting, whereas cutaneous manifestations are rare [3]. Hand-foot syndrome is frequently seen in patients treated with sorafenib and sunitinib, but less commonly with pazopanib [4]. Regarding the skin ulcers associated with pazopanib, there are only two similar published case reports [5, 6]. Both cases presented with multiple ulcers on the lower legs, as in our patient. To the best of our knowledge, detailed histopathological features of vascular degeneration have never been described in patients treated with pazopanib. In the present case, the vascular degeneration lacked apparent active vasculitis, suggesting that the vascular change was primarily due to the anti-angiogenic effect of pazopanib, rather than to vasculitis. Further cases should be accumulated to elucidate more precisely the mechanisms of pazopanib-associated skin ulcers.

Angiolymphoid hyperplasia with eosinophilia on the abdomen with dendritic cell infiltration

A 79-year-old woman with lymph-node metastatic melanoma developed new metastases in the lungs after radical excision of the primary lesion, lymph-node dissection, and adjuvant chemotherapy with dacarbazine [5]. Since she had no BRAF gene mutations, she started treatment with nivolumab (anti-PD-1 antibody; 2 mg/kg every three weeks). Before the third administration of nivolumab, however, she developed mucosal bleeding and severe (Grade IV) thrombocytopenia (platelet count: 2×109/L). Based on the finding of positive anti-platelet antibodies and the absence of signs of infection and autoimmune disorders, we diagnosed the patient with ITP. Because of no response to the standard therapy for ITP (prednisolone, intravenous immunoglobulin, and platelet transfusion), she was administered the thrombopoietin-receptor agonist, romiplostim. One month later, the platelet count became satisfactory [5]. Prednisolone was tapered over four months without recurrence of thrombocytopenia. Computed tomography (CT) showed a complete response, 1.5 months after the last nivolumab injection, but six months later, follow-up CT revealed new metastases in the lungs (figure 1A). The patient had no symptoms of ITP and no remarkable blood test results, including platelet counts, over a six-month period. Due to the limited treatment options, she was administered ipilimumab (anti-CTLA-4 antibody; 3 mg/kg every three weeks), eight months after the last treatment with nivolumab. During the four courses of ipilimumab, she did not suffer from ITP recurrence or other irAEs. Following the full course, neither anti-platelet antibody nor plateletassociated immunoglobulin G were detected. Fourteen months have passed since she received the last administration of ipilimumab, and no tumour recurrence has been found (figure 1B). Traditional chemotherapy (such as dacarbazine) can be considered for the next treatment. Thrombocytopenia, including ITP, induced by immune checkpoint inhibitors, appears to be a relatively uncommon irAE that is usually mild and resolves spontaneously or with standard treatment regimens [4, 6]. Therefore, there is not much data available on severe ITP as an irAE. A single report showed that a melanoma patient who received anti-CTLA-4 monotherapy, after resolution of severe thrombocytopenia due to anti-PD-1 monotherapy, developed severe ITP with intracranial haemorrhage and was unable to continue treatment for melanoma [6]. Our patient is the first successful case of immune checkpoint inhibitor rechallenge with anti-CTLA-4 monotherapy after severe ITP induced by anti-PD-1 monotherapy. The difference between the former case and ours remains unclear. Further data are needed in order to identify the best treatment option for metastatic melanoma patients who develop severe irAEs.

Reduced IgG anti-desmocollin autoantibody titre and concomitant improvement in a patient with pemphigus vegetans

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Juvenile pemphigus vulgaris manifesting as vegetating skin lesions

N. Tani, K. Sugita, N. Ishii, K. Wakumoto, T. Hashimoto and O. Yamamoto Division of Dermatology, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, Tottori University, Yonago, Japan; Department of Dermatology, Kurume University School of Medicine, Kurume, Japan; Department of Dermatology, Matsue Red Cross Hospital, Matsue, Japan; and Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan

A small nodule on the auricle

A 12-year-old Japanese boy presented with a 3-month history of a painless nodule on his left ear. There was no history of antecedent trauma or infection. Physical examination revealed a small purple nodule, approximately 8 9 7 mm in diameter, located on the left auricle (Fig. 1a). Dermoscopic observation revealed a purple appearance with dotted or globular vessels. In addition, linear, dendritic vessels crossed the spaces within the lesion, forming complete or incomplete polygons (Fig. 1b). Clinically, we suspected lymphangioma, pseudocyst of the auricle or haemangioma as the preoperative diagnosis. To make a final diagnosis, the lesion was resected under local anaesthesia.

CD8+ T cell-mediated interface dermatitis during combination chemotherapy with mogamulizumab in a patient with adult T-cell leukaemia/lymphoma

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Cutaneous squamous cell carcinoma with multiple metastases in a patient with chronic gluteal pyoderma

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Paclitaxel-related scleredema-like skin changes in a patient with breast cancer

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