Reduced Toxicity Conditioning and Allogeneic Hematopoietic Progenitor Cell Transplantation for Recessive Dystrophic Epidermolysis Bullosa.

Recessive dystrophic epidermolysis bullosa is a severe, incurable, inherited blistering disease caused by COL7A1 mutations. Emerging evidence suggests hematopoietic progenitor cells (HPCs) can be reprogrammed into skin; HPC-derived cells can restore COL7 expression in COL7-deficient mice. We report two children with recessive dystrophic epidermolysis bullosa treated with reduced-toxicity conditioning and HLA-matched HPC transplantation.

Building a microphysiological skin model from induced pluripotent stem cells.

The discovery of induced pluripotent stem cells (iPSCs) in 2006 was a major breakthrough for regenerative medicine. The establishment of patient-specific iPSCs has created the opportunity to model diseases in culture systems, with the potential to rapidly advance the drug discovery field. Current methods of drug discovery are inefficient, with a high proportion of drug candidates failing during clinical trials due to low efficacy and/or high toxicity. Many drugs fail toxicity testing during clinical trials, since the cells on which they have been tested do not adequately model three-dimensional tissues or their interaction with other organs in the body. There is a need to develop microphysiological systems that reliably represent both an intact tissue and also the interaction of a particular tissue with other systems throughout the body. As the port of entry for many drugs is via topical delivery, the skin is the first line of exposure, and also one of the first organs to demonstrate a reaction after systemic drug delivery. In this review, we discuss our strategy to develop a microphysiological system using iPSCs that recapitulates human skin for analyzing the interactions of drugs with the skin.

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).

Psoriatic arthritis in two patients with an inadequate response to treatment with tocilizumab.

Psoriatic arthritis (PsA) is considered as one of the seronegative spondylarthropathies. Like rheumatoid arthritis (RA), the increased production of interleukin (IL)-6 suggests a pathogenic role of IL-6 in PsA. However, whether humanized anti-IL-6 receptor antibody such as tocilizumab (TCZ) might be effective for PsA as well as RA has yet to be determined. We report herein two cases of PsA treated using TCZ. Although, TCZ treatment resulted in disappearance of serum CRP in both patients, arthritis and skin lesions were not improved despite 6-month administration of TCZ. In contrast, tumor necrosis factor (TNF) inhibitor proved effective against arthritis and skin lesions in these patients. Collectively, these findings not only indicate that IL-6 has distinct pathological roles in RA and PsA, but also suggest that TNF inhibitor therapy (but not TCZ) is effective for arthritis and skin lesions of PsA.

Hereditary angioedema in Japan: genetic analysis of 13 unrelated cases.

INTRODUCTION: The molecular bases and clinical features of hereditary angioedema (HAE) have not been systematically documented in Japan or in other Asian countries. Thus, the authors researched the genetic and clinical characteristics of Japanese patients with HAE. METHODS: The authors analyzed the CIINH gene for mutations in 13 unrelated Japanese patients with HAE by means of the polymerase chain reaction and nucleotide sequencing. In addition, the authors searched the literature from January 1969 to October 2010 on Japanese patients with HAE. RESULTS: Seven of the mutations found were novel, including 4 missense mutations (8728T>G, 8831C>A, 16661T>G and 16885C>A), 2 frameshift mutations (2281_2350del70, 14158delT) and 1 large deletion (at least 1 kb-length deletion including exon 4), whereas 6 mutations had previously been reported in European populations. CONCLUSIONS: The genetic and clinical characteristics in Japanese patients with HAE may be similar to those in Western patients although our sample size is small and the authors identified 7 novel mutations.

A case of bullous pemphigoid exacerbated by irradiation after breast conservative radiotherapy.

We present a case, considered to be a form of the Koebner phenomenon, of bullous pemphigoid that was exacerbated mainly within the irradiated field after breast conservative radiotherapy. In May 2009, a 60-year-old woman was diagnosed with bullous pemphigoid, which was treated with steroid therapy. The following month, she was diagnosed with breast cancer (invasive ductal carcinoma, pT1cN0M0). After breast conservative surgery in December 2009, conservative radiotherapy to the right breast was performed (50 Gy in 25 fractions). Portal skin showed no serious change (up to grade 1 skin erythema) and no bullous neogenesis during conservative radiotherapy. However, 2 months after conservative radiotherapy, new blisters became exacerbated mainly within the irradiated field but also in the area outside the irradiated field. Increasing the dosage of oral steroid and minocycline resulted in relief of bullous pemphigoid, although patchy skin pigmentation remained especially in the irradiated skin.

PDGFRalpha-positive cells in bone marrow are mobilized by high mobility group box 1 (HMGB1) to regenerate injured epithelia.

The role of bone marrow cells in repairing ectodermal tissue, such as skin epidermis, is not clear. To explore this process further, this study examined a particular form of cutaneous repair, skin grafting. Grafting of full thickness wild-type mouse skin onto mice that had received a green fluorescent protein-bone marrow transplant after whole body irradiation led to an abundance of bone marrow-derived epithelial cells in follicular and interfollicular epidermis that persisted for at least 5 mo. The source of the epithelial progenitors was the nonhematopoietic, platelet-derived growth factor receptor α-positive (Lin(-)/PDGFRα(+)) bone marrow cell population. Skin grafts release high mobility group box 1 (HMGB1) in vitro and in vivo, which can mobilize the Lin(-)/PDGFRα(+) cells from bone marrow to target the engrafted skin. These data provide unique insight into how skin grafts facilitate tissue repair and identify strategies germane to regenerative medicine for skin and, perhaps, other ectodermal defects or diseases.

Four cases of atopic dermatitis complicated by Sjögren's syndrome: link between dry skin and autoimmune anhidrosis.

We report four adult cases of atopic dermatitis (AD) complicated by Sjögren's syndrome (SS). The patients fulfilled diagnostic criteria for AD and SS. All cases showed persistent itchy dry skin and eczematous lesions complicated by sicca symptoms including dry eyes and dry mouth with moderate joint pain. One case manifested annular erythema and another manifested widespread discoid erythema. To investigate the underlying cause of dry skin in these cases, sweating function was evaluated using a quantitative sudomotor axon reflex test (QSART) in which the axon reflex is stimulated by acetylcholine iontophoresis. The sweating latency time was significantly prolonged in eczematous skin of AD and AD/SS compared to normal controls. Axon reflex (AXR) sweat volume was also significantly reduced in AD (normal and eczematous skin) and AD/SS (normal and eczema) compared to normal control. In contrast, the direct sweat volume of lesional or non-lesional AD skin induced by direct stimulation with acetylcholine was only slightly reduced compared to that in normal controls, but not in SS and lesional skin of AD/SS patients. These results suggest that the impaired sweat response in AD is attributable to an abnormal sudomotor axon reflex, which is accelerated and modulated when complicated by SS resulting in dry skin in the present cases.

A Male Patient with Humoral Hypercalcemia of Malignancy (HHM) with Leukocytosis Caused by Cutaneous Squamous Cell Carcinoma Resulting from Recessive Dystrophic Epidermolysis Bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin disorder. Although the patients are at risk for cutaneous squamous cell carcinoma (SCC), no case of cutaneous SCC derived from RDEB with humoral hypercalcemia of malignancy (HHM) has been reported. We present the first case report of a male patient with HHM with leukocytosis caused by cutaneous SCC resulting from RDEB. A 20-yr-old Japanese male patient with RDEB; the diagnosis was confirmed by electron microscopic examination, suffered an intractable skin ulcer and hypercalcemia and leukocytosis. PTH-rP, SCC antigen and Granulocyte colony-stimulating factor (G-CSF) levels were elevated. The histological diagnosis of the skin lesion was made well-differentiated SCC. Immunohistochemical staining showed the expression of PTH-rP in atypical tumor cells. For the control of hypercalcemia before an amputation, we used zoledronate safely and could control the serum Ca concentration in the normal range. After the amputation of his right leg including SCC, leukocytosis improved immediately and PTH-rP in blood decreased to the normal range. One month after the amputation, local recurrence of cutaneous SCC and multiple lung metastases were observed. PTH-rP increased gradually associated with hypercalcemia. Although the patient reached an unfortunate turning point about 4 mo after the amputation, we propose that zoledronate is an effective and safe treatment for HHM with cardiorenal complications.

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.

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.

Good's syndrome (hypogammaglobulinemia with thymoma) presenting intractable opportunistic infections and hyperkeratotic lichen planus.

Good's syndrome (GS) is a rare acquired combined T- and B-cell immunodeficiency accompanying thymoma. This report concerns a case of a 57-year-old man with GS manifesting intractable opportunistic infections and hyperkeratotic lichen planus. He had a past history of extended thymectomy for removal of thymoma. He consulted us about scaly and exudative intractable erythematous plaque on his right forearm. The histology was compatible with phlegmon coexisting with lichen planus. Laboratory examination results indicated hypogammaglobulinemia accompanied by complete absence of B cells, which is consistent with GS. Combined treatment with immunoglobulin replacement and administration of antibiotics and antifungal drugs was effective for the phlegmon and overlying fungal infection. The patient also presented with hyperkeratotic lichen planus on both knees and the right elbow, suggesting that intractable opportunistic infection and lichen planus may be associated with GS.

New aspect of anti-inflammatory action of lipo-prostaglandinE1 in the management of collagen diseases-related skin ulcer.

It is considered that the mechanism in intractable cutaneous ulcer is deeply associated with prolongation at the inflammatory phase. Having evaluated the effects of Lipo-prostaglandin E1 (Lipo-PGE1) with indicators such as the reduction ratio of the ulcer area and the values of the inflammatory markers after dividing them into two groups of collagen diseases and non-collagen diseases and giving them Lipo-PGE1, we managed to obtain the result that Lipo-PGE1 administration could influence various inflammatory markers such as C-reactive protein (CRP), IL-6, and VEGF in addition to reduction of the ulcer region. It also suggested that Lipo-PGE1 has the effect of maintaining an appropriate balance of induction of inflammation and angiogenesis. Additionally, it revealed that Lipo-PGE1 controls the production of cytokines, which are associated with the growth of collagen diseases. From these results, it can be expected that Lipo-PGE1 will act favorably on intractable collagen diseases.

Thymoma-associated graft-versus-host disease-like erythroderma.

We report a 40-year-old woman with recurrent thymoma associated with myasthenia gravis, in whom an unusual form of erythroderma developed. A histological examination revealed a graft-versus-host disease (GVHD)-like reaction. After high-dose steroid therapy, the metastatic thymoma lesion in the abdominal cavity was reduced in size from 9.5 x 6 x 7.5 cm to 4 x 3 x 1 cm in diameter. Nevertheless, the GVHD-like erythroderma become aggravated, her condition worsened, and the patient finally suffered from respiratory failure and died of sepsis. A GVHD-like reaction may be a rare presentation of thymoma-associated immunological disorders such as myasthenia gravis or pure red cell aplasia. Herein, we discuss the present case and review pertinent reports of thymoma cases associated with GVHD.

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.

Differential regulation of karyopherin alpha 2 expression by TGF-beta1 and IFN-gamma in normal human epidermal keratinocytes: evident contribution of KPNA2 for nuclear translocation of IRF-1.

Despite a number of studies on signal transduction in epidermal keratinocytes, very little is known about how signals move from the cytosol to the nucleus during the course of keratinocyte proliferation and differentiation. In this study, we first compared the expression patterns of the karyopherin alpha (KPNA) subtypes, and found that KPNA2, KPNA3, and KPNA4 were the major subtypes in both normal human epidermal keratinocytes (NHEKs) and normal human dermal fibroblasts (NHDFs). Stimulation with either transforming growth factor (TGF)-beta1 or IFN-gamma for 24 hours resulted in the downregulation of KPNA2 expression specifically in NHEK at both the mRNA and protein levels. Interestingly, IFN-gamma, but not TGF-beta1, specifically downregulated KPNA2 expression at the promoter level, suggesting differential regulation of KPNA2 expression by IFN-gamma and TGF-beta1. We then demonstrated that KPNA2 physically bound to IFN regulatory factor-1 (IRF-1), a transcription factor induced by IFN-gamma, and induced nuclear translocation of IRF-1 in NHEKs. We finally performed microarray and quantitative real-time PCR analysis for the mRNA expression pattern of NHEK with either overexpression or knockdown of KPNA2, and indicated KPNA2 involvement for various epidermal gene regulations such as involucrin. Our data suggest that KPNA2 may play an important role in the signal-transduction pathways that regulate epidermal proliferation and differentiation.