Riichiro Abe

Linagliptin-associated bullous pemphigoid that was most likely caused by IgG autoantibodies against the midportion of BP180.

Bullous pemphigoid (BP) is a common autoimmune subepidermal blistering disease characterized by autoantibodies against BP180 and/or BP230, both of which are a major structural component of hemidesmosomes. In most cases, autoantibodies against NC16A domain of BP180 (BP180-NC16A) are detected, and as such the pathomechanisms of BP have been becoming clear.1 However, the initial triggers of the disease are still largely unidentified. Nevertheless, it has been shown that certain medications including antibiotics, neuroleptics, and NSAIDs can be associated with the development of BP.2 Recently, dipeptidyl peptidase-4 inhibitors (DPP-4i), also known as gliptins, a newly introduced oral medication for type 2 diabetes mellitus (T2DM), have been paid the most attention as a potent trigger of BP. This article is protected by copyright. All rights reserved.

Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of hereditary skin disorder characterized by an aberrant cornification of the epidermis. ARCI is classified into a total of 11 subtypes (ARCI1-ARCI11) based on their causative genes or loci. Of these, the causative gene for only ARCI7 has not been identified, while it was previously mapped on chromosome 12p11.2-q13.1. In this study, we performed genetic analyses for three Lebanese families with ARCI, and successfully determined the linkage interval to 9.47 Mb region on chromosome 12q13.13-q14.1, which was unexpectedly outside of the ARCI7 locus. Whole-exome sequencing and the subsequent Sanger sequencing led to the identification of missense mutations in short chain dehydrogenase/reductase family 9C, member 7 (SDR9C7) gene on chromosome 12q13.3, i.e. two families shared an identical homozygous mutation c.599T > C (p.Ile200Thr) and one family had another homozygous mutation c.214C > T (p.Arg72Trp). In cultured cells, expression of both the mutant SDR9C7 proteins was markedly reduced as compared to wild-type protein, suggesting that the mutations severely affected a stability of the protein. In normal human skin, the SDR9C7 was abundantly expressed in granular and cornified layers of the epidermis. By contrast, in a patient’s skin, its expression in the cornified layer was significantly decreased. It has previously been reported that SDR9C7 is an enzyme to convert retinal into retinol. Therefore, our study not only adds a new gene responsible for ARCI, but also further suggests a potential role of vitamin A metabolism in terminal differentiation of the epidermis in humans.

SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening, immunologically mediated, and usually drug-induced disease with a high burden to individuals, their families, and society with an annual incidence of 1 to 5 per 1,000,000. To effect significant reduction in short- and long-term morbidity and mortality, and advance clinical care and research, coordination of multiple medical, surgical, behavioral, and basic scientific disciplines is required. On March 2, 2017, an investigator-driven meeting was held immediately before the American Academy of Dermatology Annual meeting for the central purpose of assembling, for the first time in the United States, clinicians and scientists from multiple disciplines involved in SJS/TEN clinical care and basic science research. As a product of this meeting, this article summarizes the current state of knowledge and expert opinion related to SJS/TEN covering a broad spectrum of topics including epidemiology and pharmacogenomic networks; clinical management and complications; special populations such as pediatrics, the elderly, and pregnant women; regulatory issues and the electronic health record; new agents that cause SJS/TEN; pharmacogenomics and immunopathogenesis; and the patient perspective. Goals include the maintenance of a durable and productive multidisciplinary network that will significantly further scientific progress and translation into prevention, early diagnosis, and management of SJS/TEN.

An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity

Drug hypersensitivity may manifest ranging from milder skin reactions (e.g., maculopapular exanthema and urticaria) to severe systemic reactions, such as anaphylaxis, drug reactions with eosinophilia and systemic symptoms (DRESS)/drug-induced hypersensitivity syndrome (DIHS), or Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Current pharmacogenomic studies have made important strides in the prevention of some drug hypersensitivity through the identification of relevant genetic variants, particularly for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). The associations identified by these studies are usually drug, phenotype, and ethnic specific. The drug presentation models that explain how small drug antigens might interact with HLA and T cell receptor (TCR) molecules in drug hypersensitivity include the hapten theory, the p-i concept, the altered peptide repertoire model, and the altered TCR repertoire model. The broad spectrum of clinical manifestations of drug hypersensitivity involving different drugs, as well as the various pathomechanisms involved, makes the diagnosis and management of it more challenging. This review highlights recent advances in our understanding of the predisposing factors, immune mechanisms, pathogenesis, diagnostic tools, and therapeutic approaches for drug hypersensitivity.

Investigating the use of tie-over dressing after skin grafting

Tie‐over bolster dressing after skin grafting can prolong operative time, and cause hematoma and seroma formation because of uneven pressure application. To describe the possibility of discontinuing the use of tie‐over dressing, we carried out a retrospective comparative study of patients who underwent skin grafting at an institution between January 2009 and December 2014. We investigated and compared the take rate, healing period, wound infection rate and hematoma formation rate for the tie‐over dressing group and the non‐tie‐over dressing group. Among 266 patients, 148 and 118 patients were included in the tie‐over dressing group and non‐tie‐over dressing group, respectively. There were no significant differences between the take rate, healing period, wound infection rate and hematoma formation rate for the two groups. Multivariate analysis showed that the complete graft take rate was not significantly influenced by tie‐over dressing, age, sex, graft site, graft procedure and skin graft diameter. Although the use of tie‐over dressing might remain necessary on sites with a free margin, including the eyelids, lips or nostrils, because of the difficulty in using tape fixation, the present study showed that alternative dressing with polyurethane foam is also useful in most cases of skin grafting.

Segmental lichen aureus in infancy.

1 Ecker AM, Donnellan NM, Shepherd JP, Lee TTM. Abdominal wall endometriosis: 12 years of experience at a large academic institution. Am J Obstet Gynecol 2014; 211(363): e1–5. 2 Fernandez Vozmediano JM, Armario Hita JC, Cuevas Santos J. Cutaneous endometriosis. Int J Dermatol 2010; 49: 1410–12. 3 Claas-Quax MJ, Ooft ML, Hoogwater FJH, Veersema S. Primary umbilical endometriosis. Eur J Obstet Gynecol Reprod Biol 2015; 194: 260–1. 4 Douglas C, Rotimi O. Extragenital endometriosis—a clinicopathological review of a Glasgow hospital experience with case illustrations. J Obstet Gynaecol J Inst Obstet Gynaecol 2004; 24: 804–8. 5 Mathai M, Gj H, Ne M. Abdominal surgical incisions for caesarean section. Cochrane Database Syst Rev 2013; 5: CD004453.

Drp1 regulates mitochondrial morphology and cell proliferation in cutaneous squamous cell carcinoma

BACKGROUND Dynamin-related protein 1 (Drp1) mediates mitochondrial fission. Recently, several studies have shown that Drp1 plays an important role in some cancers. However, little is known about Drp1 in cutaneous squamous cell carcinoma (SCC). OBJECTIVE To investigate the role of Drp1 in the tumorigenesis of cutaneous SCCs. METHODS AND RESULTS We investigated cell proliferation, cell cycle, mitochondrial morphology, and MAPK signaling pathway using cutaneous SCC A431 and DJM1 cells that were transfected with shRNA vectors targeting Drp1. The Drp1 gene-knockdown SCC cells showed lower cell proliferation than scramble-control cells, as assessed by direct cell counting and clonogenic assays. DNA content analysis showed Drp1 knockdown to cause G2/M arrest. Morphologically, the depletion of Drp1 resulted in an elongated, hyper-fused mitochondrial network. The MEK inhibitor PD325901 suppressed cell proliferation, as well as inhibiting the phosphorylation of ERK1/2 and Drp1Ser616. Also, PD325901 caused the dysregulation of the mitochondrial network. In tumor xenografts of DJM1 cells, the knockdown of Drp1 suppressed tumor growth in vivo, and clinically, the expression levels of Drp1 were higher in cutaneous SCCs than in normal epidermis, and correlated positively with the advanced clinical stages. CONCLUSION Our results reveal a crucial function for Drp1 in regulating tumor growth, mitochondrial morphology, and cell cycle in cutaneous SCC, suggesting that Drp1 could be a novel target for skin tumor therapies.

Panniculitis as the initial manifestation of dermatomyositis with anti‐MDA5 antibody

nosis. In a previous study, a patient who underwent routine surgical treatment for HS was found to have perinal mucinous adenocarcinoma. The surgery was followed by a combination of adjuvant radiation and chemotherapy, similar to the course of therapy in our patient, but disease recurrence in the perianal region resulted in the patient’s death 1 year post-treatment. This highlights the importance of continual follow-up in patients with a history of cancer. The aetiopathogenetic mechanisms for cancer development in recurring HS are unknown. One partial explanation may be that the chronic degeneration and ulceration creates a favourable microenvironment for cancer growth. The diagnosis of cancer in patients with HS is often delayed because of the formation of fistulas and abscesses. When a diagnosis is established, the tumour may be > 50 mm in diameter and may have already metastasized. A published report demonstrated that a 10-mm lesion of HS can lead to the development of cancer. Although cancer development is a rare association, prompt diagnosis and treatment of HS may improve the overall prognosis of the disease and prevent this fatal outcome.

Case of pemphigus herpetiformis with immunoglobulin G autoantibodies against desmocollin-3

Dear Editor, Pemphigus herpetiformis (PH) is one of the less common forms of pemphigus, which is recognized as a distinct variant of pemphigus characterized by its pruritus, rarity of mucosal involvement and good response to sulfones. Ishii et al. reported that the major antigens of PH were desmoglein (DSG)1 and DSG3, both of which are well-known autoantigens for pemphigus foliaceus and pemphigus vulgaris, respectively. However, it is known that several cases of PH have autoantibodies against desmocollins (DSC), which can be also detected in paraneoplastic pemphigus (PNP) and pemphigus vegetans. We herein report a case of PH with immunoglobulin (Ig)G autoantibodies against DSC3, but without anti-DSGs autoantibodies. A 63-year-old Japanese woman visited our hospital because of itchy edematous erythemas and vesicles on the face, trunk and extremities. She had no particular medical history. On physical examination, there were pruritic annular edematous erythemas on her face, trunk and extremities, some of which were accompanied by vesicles and small tense bullae at the peripheral area (Fig. 1a–c). No mucosal involvement of oral cavity was present. Laboratory tests showed mild eosinophilia, and computed tomography did not suggest internal malignancies. Enzyme-linked immunosorbent assays for IgG antibodies against DSG1, DSG3 and BP180-NC16a were all negative. Biopsy specimen from her left thigh revealed spongiosis with numerous eosinophils in the dermis, but without apparent acantholysis (Fig. 1d,e). Direct immunofluorescence showed deposition of IgG (Fig. 1f) and C3 (data not shown) at the intercellular portion of the epidermis (Fig. 1f). Indirect immunofluorescence using normal skin and the patient’s serum also showed IgG deposition on the cell surface of the epidermis at a titer of 1:64. In order to identify the target molecule(s) of autoantibodies generated in the patient, we performed a series of in vitro experiments (Supporting Information) and found that the patient’s serum specifically reacted with the extracellular domain of DSC3 (Figs S1,1g). Therefore, we diagnosed our

Beneficial effect of hydroxychloroquine on cutaneous vasculitis in a Japanese patient with systemic lupus erythematosus

Dear Editor, Hydroxychloroquine (HCQ) has been used to treat patients with systemic lupus erythematosus (SLE), especially for those with arthralgia, skin rashes, alopecia and oral/genital ulceration. However, there are few reports describing efficacy of HCQ for cutaneous vasculitis of SLE. Herein, we report a case of SLE with cutaneous vasculitis that was successfully treated with HCQ. A 36-year-old Japanese woman was diagnosed with SLE associated with lupus nephritis 20 years prior and had been treated with corticosteroid and several immunosuppressive agents. Since the age of 30 years, cutaneous ulcers had recurrently appeared on her lower legs with repeatedly elevated lupus anticoagulant, even though the activity of SLE including nephritis had not apparently gotten worse. On physical examination, she had purpura and cutaneous ulcers with necrotic tissue on her lower legs and toes (Fig. 1a). A biopsy specimen from an ulcer on the left lower leg showed leukocytoclastic and necrotizing vasculitis in the dermis and the subcutaneous tissue (Fig. 1b,c). Thrombosis of small vessels in the dermis was not observed. Direct immunofluorescence revealed deposition of immunoglobulin M (Fig. 1d), C3 and C1q in vessel walls. On laboratory examination, anti-dsDNA antibody was 8.0 IU/mL (normal, <6) and lupus anticoagulant was 1.41 (normal, <1.3), while anticardiolipin antibody, perinuclear antineutrophil cytoplasmic antibody and cryoglobulin showed negative results. Ultrasonography revealed no thrombosis on her lower legs. Based on these findings, we diagnosed her as having cutaneous vasculitis of SLE. Initial therapy of i.v. methylprednisolone 1000 mg for 3 days, following oral prednisolone 50 mg daily and oral mizoribine 150 mg daily, promoted ulcer healing; however she developed liver dysfunction associated with cytomegalovirus infection. After discontinuation of mizoribine, the cutaneous ulcers suddenly got worse (Fig. 1e). When the dose of oral prednisolone was 20 mg daily, we decided to use HCQ. After confirming an absence of retinopathy, she was treated with HCQ 200 and 400 mg every other day, which dramatically improved the skin lesions (Fig. 1f). At the time of