Takuro Kanekura

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.

Changes in Mitochondrial Homeostasis and Redox Status in Astronauts Following Long Stays in Space

The effects of long-term exposure to extreme space conditions on astronauts were investigated by analyzing hair samples from ten astronauts who had spent six months on the International Space Station (ISS). Two samples were collected before, during and after their stays in the ISS; hereafter, referred to as Preflight, Inflight and Postflight, respectively. The ratios of mitochondrial (mt) to nuclear (n) DNA and mtRNA to nRNA were analyzed via quantitative PCR. The combined data of Preflight, Inflight and Postflight show a significant reduction in the mtDNA/nDNA in Inflight, and significant reductions in the mtRNA/nRNA ratios in both the Inflight and Postflight samples. The mtRNA/mtDNA ratios were relatively constant, except in the Postflight samples. Using the same samples, the expression of redox and signal transduction related genes, MnSOD, CuZnSOD, Nrf2, Keap1, GPx4 and Catalase was also examined. The results of the combined data from Preflight, Inflight and Postflight show a significant decrease in the expression of all of the redox-related genes in the samples collected Postflight, with the exception of Catalase, which show no change. This decreased expression may contribute to increased oxidative stress Inflight resulting in the mitochondrial damage that is apparent Postflight.

High-fat diet exacerbates imiquimod-induced psoriasis-like dermatitis in mice

Psoriasis, a chronic inflammatory skin disease, is closely related to systemic metabolism. An elevated body mass index (BMI) is a risk factor for psoriasis; inflammasomes are activated by adipose tissue macrophages in obese subjects. We hypothesized that hyperlipidaemia is involved in the pathogenesis of psoriasis and examined the role of a high‐fat diet (HFD) in the development of psoriasis in imiquimod (IMQ)‐treated mice. The body weight and serum level of cholesterol were significantly higher in mice fed an HFD than in a regular diet (RD). HFD mice had higher psoriasis skin scores, and the number of neutrophils infiltrating into the lesional skin was elevated. IL‐17A mRNA expression was significantly increased in the skin of IMQ‐treated HFD mice; the expression of IL‐22, IL‐23 and TNF‐α mRNA was not enhanced. Caspase‐1 and IL‐1β were activated in the skin of IMQ‐treated HFD mice, and their serum level of IL‐17A, TNF‐α and IL‐1β was significantly upregulated. Our findings strongly suggest that hyperlipidaemia is involved in the development and progression of psoriasis via systemic inflammation and inflammasome activation.

Case of autoimmune autonomic ganglionopathy manifesting anhidrosis

Autoimmune autonomic ganglionopathy (AAG), clinically characterized by gastrointestinal dysmotility, orthostatic hypotension and tonic pupils, is an idiopathic acquired disorder of the autonomic nervous system elicited by antibodies against ganglionic acetylcholine receptor (gAChR). We encountered a 60‐year‐old man who presented with severe anhidrosis, difficulty in thermoregulation, orthostatic hypotension, gastrointestinal dysmotility, tonic pupils and ptosis. Histologically, an anhidrotic skin sample was normal. Routine laboratory examinations of blood, urine and cerebrospinal fluid returned no abnormal findings. Serological examination revealed antibodies against α3 and β4 subunits of gAChR. The diagnosis was AAG. As sudomotor dysfunction reflects ganglionic neuropathy in AAG, we concluded that his anhidrosis was attributable to AAG. Anhidrosis is an important clue for the diagnosis of AAG, a rare neurological disorder.

Spontaneous regression of a primary cutaneous diffuse large B-cell lymphoma, leg type.

1 Harding JJ, Pulitzer M, Chapman PB. Vemurafenib sensitivity skin reaction after ipilimumab. N Engl J Med 2012; 366: 866–868. 2 Imafuku K, Yoshino K, Ishiwata K et al. Severe rash associated with vemurafenib administration following nivolumab therapy. J Eur Acad Dermatol Venereol 2016; 30: e84–e86. 3 Minor DR, Rodvien R, Kashani-Sabet M. Successful desensitization in a case of Stevens-Johnson syndrome due to vemurafenib. Melanoma Res 2012; 22: 410–411. 4 Johnson DB, Wallender EK, Cohen DN et al. Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib administration following anti-PD-1 therapy. Cancer Immunol Res 2013; 1: 373–377.

Hepatocyte growth factor reduces CXCL10 expression in keratinocytes

Keratinocytes secrete vascular endothelial growth factor (VEGF) and angioregulatory chemokines during cutaneous wound healing. Hepatocyte growth factor (HGF) promotes skin re‐epithelialization by increasing VEGF expression in keratinocytes. Here, we investigated the regulatory roles of HGF in the expression of genes encoding angiogenic and angiostatic chemokines in keratinocytes and found that HGF specifically inhibits mRNA expression of the angiostatic chemokine CXCL10 in both mouse primary keratinocytes and in the human keratinocyte cell line HaCaT through the MEK/ERK cascade. Furthermore, HGF inhibited tumor necrosis factor‐α‐induced CXCL10 expression at both mRNA and protein levels in HaCaT cells. Thus, HGF may orchestrate angiogenesis in wounded skin by modulating both VEGF and CXCL10 expression in keratinocytes.

Secondary skin involvement by systemic de novo CD5-positive diffuse large B-cell lymphoma

Dear Editor, An 88-year-old woman presented with a 1-month history of a cutaneous tumor on her right cheek (Fig. 1a) with nasal obstruction. She had no history of lymphoproliferative disorders and did not have B symptoms. Physical examination revealed a 25 mm 9 12 mm, dark red colored plaques at the nasojugal fold without tenderness. Skin biopsy showed diffuse infiltration of large atypical lymphoid cells throughout the dermis and at the bottom marginal edge of the specimen (Fig. 1b, c). Immunohistochemically, the tumor cells expressed CD20, CD79a, BCL2 and BCL6. They were also positive for CD5 (Fig. 1d–h). CD10, CD56, MUM1 and cyclin D1 were negative, as was Epstein–Barr virus-encoded sRNA in situ hybridization. Many small lymphocytes were also seen and these cells were CD3 positive (Fig. 1i), and histiocytes were also observed. Southern blot analysis failed to detect monoclonal rearrangement of the IgH gene. Karyotype analysis of the biopsy specimen revealed the deletion of chromosomes 11 and 14 and two marker chromosomes (46,XX,-11,-14,+2 mar). Peripheral blood analysis did not identify significant anomalies; serum chemistry including lactate dehydrogenase was within normal limits. Serum soluble interleukin-2 receptor was 6792 U/mL (range,

Pyodermatitis vegetans with antibodies to bullous pemphigoid antigen 180

which led to further stabilization of the skin. Importantly, at this time point the skin state had already strongly improved from calcium administration. Generalized pustular psoriasis is a rare, potentially lifethreatening skin disease which is often present in patients with existing or previous psoriasis. Its incidence is less than 1:100 000 and it can be triggered by infections, pregnancy, medication including tumor necrosis factor-a inhibitors and sudden termination of systemic glucocorticoid therapy. Hypocalcaemia in association with pustular psoriasis has been repeatedly reported in the published work. In vitro studies have demonstrated that calcium promotes the proliferation and differentiation of keratinocytes. Amongst one previous report, this is the only other where not secondary but primary hypoparathyroidism was newly diagnosed in a patient with a pustular flare-up, thus strongly supporting the hypothesis that severe hypocalcemia may trigger pustular psoriasis. The pustules vanished within 24 h after the first calcium infusion long before the infection was cured. The patient was also administrated vitamin D, another crucial regulator of epidermal proliferation. Interestingly, the psoriasis plaques improved very quickly and currently the patient does not need any therapy for his psoriasis. He is still being administrated calcium 1000 mg and hydrocortisol 15 mg. In conclusion, this is a report of a newly diagnosed primary hypoparathyroidism in a patient with psoriasis where the severe hypocalcaemia most probably triggered the pustular flare-up, thus showing that calcium in vivo is as crucial for epidermal keratinocytes as it is in vitro. This report also underscores the importance of broad diagnostics in acute skin conditions with a consequent interdisciplinary treatment.

Successful etretinate treatment of recurrent keratoacanthomas on a skin graft: Case report

Dear Editor, Keratoacanthoma (KA) is a benign keratinocytic neoplasm characterized by rapid growth and histopathological features similar to cutaneous squamous cell carcinoma. Recurrent KA is often seen as a part of genetic syndromes such as multiple self-healing KA of Ferguson–Smith, eruptive KA of Grzybowski, and multiple familial KA of Witten and Zak. We report an extremely rare case of relapsing KA at the surgical site of the original KA that was successfully treated with oral etretinate. An 89-year-old woman presented with a tumor on her right lower leg (Fig. 1a). It was removed and full-thickness skin was grafted. The histopathological diagnosis was KA (Fig. 1b,c). Two months later, three nodules appeared at the edge of the skin graft (Fig. 1d). Skin biopsy showed proliferation of squamous epithelium indicating KA (Fig. 1e). The lesions were cleared by 1-month treatment with maxacalcitol ointment. During follow up, a new nodular lesion appeared on her left lower left (Fig. 1f). It was excised and the surgical defect was covered by a skin graft. Again, the histological diagnosis was KA. Subsequently, KA appeared twice at approximately 2-month intervals (Fig. 1g); histologically, all were KA. Because they were resistant to maxacalcitol ointment and their size increased rapidly, they were surgically removed. Two months later, similar lesions appeared at the edge of that graft (Fig. 1h). We posited that surgery triggered their recurrence and chose conservative therapy and oral etretinate (0.5 mg/kg per day). The lesions became smaller and flat in 6 weeks; they cleared completely in 14 weeks (Fig. 1i). No recurrence was seen in the course of 5 months after the discontinuation of etretinate. Keratoacanthoma was first described in 1889 by Hutchinson as a crateriform ulcer of the face. KA is characterized by a rapid onset with potential tissue destruction and rare metasta(a) (b)

Kimura's disease in the oral cavity: A rare manifestation of immunoglobulin G4-related disease

Dear Editor, A 63-year-old woman with a 3-month history of a gradually enlarging oral cavity tumor and a decayed tooth had no history of febrile disorder or pharyngitis. A 35 mm 9 17 mm nodule was found on the left side under her tongue (Fig. 1a). It was palpable in the left submandibular to submental area of the skin and was elastic and soft without tenderness; the overlying skin was not affected. On magnetic resonance imaging it was hypointense on T1(Fig. 1b) and mildly hyperintense on T2-weighted and contrast-enhanced images. Oral mucosa biopsy revealed lymphoid follicle formation with infiltration by eosinophils and mononuclear cells and interstitial fibrosis (Fig. 1c). Eosinophils predominated in follicle centers (Fig. 1d); there was marked infiltration by plasma cells (Fig. 1d). Immunohistochemically, there were more than 10 immunoglobulin (Ig)G4-positive plasma cells per high-power field (Fig. 1e,f); the IgG4 : IgG plasma cell ratio was approximately 52%. Her white blood cell count was 2140/lL with 11% eosinophils. Serum IgE was 2085 IU/mL and serum IgG4 477 mg/dL (normal, <135). Other laboratory examinations returned normal results. A diagnosis of Kimura’s disease (KD) manifesting as a mucocutaneous lesions of an IgG4-related disease was made. Computed tomography showed a submandibular tumor, left cervical lymphadenopathy, but no other lesions. An intralesional injection of 40 mg triamcinolone acetonide was administrated four times monthly, resulting in a moderate reduction of the tumor and lymphadenopathy. The histopathogenesis of KD, a chronic, benign lymphoproliferative disorder of subcutaneous tissue, lymph nodes or salivary glands, and of angiolymphoid hyperplasia with eosinophilia (ALHE) is similar. Most patients are Asian men in their third to fifth decade. Histopathologically, KD is