小宮根 真弓

Adalimumab is a biologic that is very effective for treatment of psoriasis. However, recalcitrant or recurrent lesions sometimes occur during treatment. Maxacalcitol is an active vitamin D3 ointment that is effective in treatment of psoriasis. Topical therapy may be beneficial in treatment of recalcitrant or recurrent lesions during treatment with systemic therapy, but there is little evidence on this topic. We investigated the effect of maxacalcitol on skin lesions during treatment with adalimumab in patients with psoriasis. Twelve patients with psoriasis were randomly assigned to two groups after informed consent - treatment with adalimumab only (n = 6), and treatment with adalimumab and maxacalcitol (n = 6) - and they were evaluated every 4 weeks for 44 weeks. Exacerbation was defined as an increase of the Psoriasis Area and Severity Index (PASI) score. The interval between adalimumab treatments was elongated to 3-4 weeks from 2 weeks according to the individual patient's condition. The PASI score was evaluated every 4 weeks, and the frequency of exacerbations was counted. The overall improvement in PASI score was not statistically different between the two groups, but the frequency of exacerbations was significantly less in the maxacalcitol combination group compared with the adalimumab monotherapy group (Mann-Whitney U-test, P < 0.05). The better control of skin lesions in patients who elongated the interval of adalimumab administration was achieved in the maxacalcitol combination group compared with the adalimumab monotherapy group. Topical maxacalcitol treatment is effective and useful in controlling skin lesions in patients with psoriasis when used in combination with adalimumab.

Generalized pustular psoriasis (GPP) is a severe inflammatory skin disease characterized by the presence of sterile pustules covering almost the entire body and systemic symptoms such as fever. Secukinumab, a fully human-recombinant anti-interleukin-17A monoclonal antibody was indicated for psoriasis vulgaris and psoriatic arthritis in Japan but is not yet investigated for GPP. In this phase III, open-label multicenter single arm study, the efficacy and safety of secukinumab as monotherapy or with co-medication was evaluated in 12 Japanese patients with GPP. All the patients received secukinumab 150 mg s.c. at baseline, week 1, 2, 3 and 4, and then every 4 weeks. Two non-responders were up-titrated to 300 mg. Change in GPP severity from baseline was evaluated by clinical global impression (CGI) categorized as "worsened", "no change", "minimally improved", "much improved" or "very much improved". Treatment success was achieved by 83.3% (n = 10) of patients at week 16 (primary end-point) with CGI evaluated as "very much improved" (n = 9) and " much improved" (n = 1). Moreover, the area of erythema with pustules improved as early as week 1 and resolved by week 16 in most of the patients. The improvements were sustained throughout 52 weeks. Over the 52-week treatment period, secukinumab was well tolerated with no unexpected safety signals. Nasopharyngitis, urticaria, diabetes mellitus and arthralgia were the frequent adverse events reported. The data from this study shows that secukinumab can become one of the potent treatment options for GPP.

Matrix metalloproteinases (MMPs) are zinc-containing endopeptidases with an extensive range of substrate specificities. Collectively, these enzymes are able to degrade various components of extracellular matrix (ECM) proteins. Based on their structure and substrate specificity, they can be categorized into five main subgroups, namely (1) collagenases (MMP-1, MMP-8 and MMP-13); (2) gelatinases (MMP-2 and MMP-9); (3) stromelysins (MMP-3, MMP-10 and MMP-11); (4) matrilysins (MMP-7 and MMP-26); and (5) membrane-type (MT) MMPs (MMP-14, MMP-15, and MMP-16). The alterations made to the ECM by MMPs might contribute in skin wrinkling, a characteristic of premature skin aging. In photocarcinogenesis, degradation of ECM is the initial step towards tumor cell invasion, to invade both the basement membrane and the surrounding stroma that mainly comprises fibrillar collagens. Additionally, MMPs are involved in angiogenesis, which promotes cancer cell growth and migration. In this review, we focus on the present knowledge about premature skin aging and skin cancers such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma, with our main focus on members of the MMP family and their functions.

We report a case involving a 62-year-old woman with invivo-bound immunoglobulin (Ig)G and IgA antibodies in both the intercellular space (ICS) and basement membrane zone (BMZ). Her clinical and histopathological features were identical with those of pemphigus vulgaris, while the immunopathological findings suggested IgG/IgA pemphigus. Direct immunofluorescence (IF) showed invivo-bound IgG and IgA antibodies in the ICS and BMZ, whereas indirect IF showed circulating IgG but not IgA antibodies in the ICS and BMZ. The anti-ICS IgG bound to desmoglein-3, while the anti-BMZ antibodies bound to the epidermal side of 1mol/L NaCl-split skin. To the best of our knowledge, only two similar cases have been reported so far. Furthermore, we also examined IgG subclass distribution of the invivo-bound and circulating anti-ICS and BMZ antibodies, and found that IgG1, IgG2 and IgG4 bound to ICS of the lesional skins, while IgG1 and IgG3 bound to the BMZ. The circulating anti-ICS antibodies belonged to IgG1 and IgG4, while the circulating anti-BMZ antibodies to IgG1, IgG2 and IgG4. We report a case involving a 62-year-old woman with invivo-bound immunoglobulin (Ig)G and IgA antibodies in both the intercellular space (ICS) and basement membrane zone (BMZ). Her clinical and histopathological features were identical with those of pemphigus vulgaris, while the immunopathological findings suggested IgG/IgA pemphigus. Direct immunofluorescence (IF) showed invivo-bound IgG and IgA antibodies in the ICS and BMZ, whereas indirect IF showed circulating IgG but not IgA antibodies in the ICS and BMZ. The anti-ICS IgG bound to desmoglein-3, while the anti-BMZ antibodies bound to the epidermal side of 1mol/L NaCl-split skin. To the best of our knowledge, only two similar cases have been reported so far. Furthermore, we also examined IgG subclass distribution of the invivo-bound and circulating anti-ICS and BMZ antibodies, and found that IgG1, IgG2 and IgG4 bound to ICS of the lesional skins, while IgG1 and IgG3 bound to the BMZ. The circulating anti-ICS antibodies belonged to IgG1 and IgG4, while the circulating anti-BMZ antibodies to IgG1, IgG2 and IgG4.

We describe a case of H syndrome with massive skin involvement, retroperitoneal fibrosis and Raynaud's phenomenon. A 48-year-old man with parents of a consanguineous marriage, first appeared with decreased urine output, skin sclerosis on his inner thighs and short stature (142 cm, 47 kg). The patient had suffered from hearing loss since the age of 1 year, and his secondary sexual characteristics had not developed. Computed tomography showed periaortic fibrosis, bilateral ureteral stenosis, hydronephrosis and sclerosis of the germinal cords. A biopsy from the retroperitoneal mass revealed remarkable fibrosis with chronic inflammatory cells. Biopsies from the skin lesion showed thick collagen bundles through the dermis and lymphohistiocytic infiltration with numerous plasma cells. Serum inflammatory markers, such as C-reactive protein, vascular endothelial factor, transforming growth factor-beta and soluble interleukin-2 receptor, were elevated. Prednisolone was effective in treating skin lesions and in lowering serum inflammatory markers. After a long period of follow up, genomic DNA of the patient was obtained, and we identified a homozygous mutation in exon 5, c.625G>A, which caused transition of glycine to arginine, p.Gly208Arg, in the patient, but not in DNA samples from another 50 healthy individuals. This is the first case of H syndrome with Raynaud's phenomenon and retroperitoneal fibrosis, and the first Japanese case of H syndrome reported in the English published work with a novel mutation in the SLC29A3 gene.

We report a case of sarcomatoid carcinoma of the skin in a 63-year-old man who was treated with the carbon dioxide snow freezing method for a huge congenital pigmented nevus that extended from the right upper extremity to the right trunk during childhood. He had an exophytic red tumor on the nevus in the right upper extremity that grew slowly for 4years and rapidly recently. Histological and immunohistochemical studies revealed both epithelial and mesenchymal malignancy in the same tumor. The epithelial component was composed of basaloid cells forming multiple nests with peripheral palisading, positive for keratins and BerEP4, implying basal cell carcinoma. The mesenchymal component was composed of spindle-shaped cells negative for keratins and positive for vimentin, suggesting sarcoma. This is, to our knowledge, the first report of sarcomatoid carcinoma arising in the primary pigmented nevus that had been treated by the carbon dioxide snow freezing method.

Toyonaga E, Nishie W, Komine M, Murata S, Shinkuma S, Natsuga K, Nakamura H, Ohtsuki M, Shimizu H, The British journal of dermatology, 2014

CC chemokine ligand 17 (CCL17) and CCL22 are the functional ligands for CCR4. We previously reported that inhibitors of nuclear factor-kappa B and p38 mitogen-activated protein kinase (p38 MAPK), but not of extracellular signal-related kinase (ERK), inhibited tumor necrosis factor (TNF)- alpha - and interferon (IFN)- gamma -induced production of CCL17 by the human keratinocyte cell line, HaCaT. Further, an inhibitor of epidermal growth factor receptor (EGFR) enhanced the CCL17 production by these keratinocytes. Objective: To identify the mechanism underlying CCL22 production by HaCaT cells. Methods: We investigated the signal transduction pathways by which TNF- alpha and IFN- gamma stimulate HaCaT cells to produce CCL22 by adding various inhibitors. Results: TNF- alpha - and IN-gamma - induced CCL22 production was inhibited by PD98059, PD153035, Bay 11-7085, SB202190, c-Jun N-terminal kinase (INK) inhibitor II, and Janus kinase OAK) inhibitor 1. Conclusion: Our results indicate that CCL22 production in HaCaT cells is dependent on ERK, EGFR, p38 MAPK, JNK, and JAK and is mediated by different signal pathways from those regulating CCL17 production. Altogether, our previous and present results suggest that EGFR activation represses CCL17 but enhances CCL22 production by these cells.

Intravascular large B-cell lymphoma (IVLBCL) is classified as a rare type of non-Hodgkin's B-cell lymphoma by the World Health Organization. It is characterized by the presence of lymphoma cells in the lumens of the small vessels of several organs, most notably the skin. Diagnosis of IVLBCL is difficult because of the lack of lymphadenopathy and because lesions need to be histologically confirmed via a biopsy of the affected organs. Random skin biopsy (RSB) of normal-appearing skin is a useful and apparently safe means of evaluating IVLBCL. However, patients with IVLBCL often exhibit thrombocytopenia, and we describe a case in which a patient with thrombocytopenia experienced hemorrhagic shock and died shortly after RSB. For this reason, we reviewed cases of RSB performed at our hospital and found that the middle adipose tissue contained a higher percentage of atypical lymphoid cells than other layers of the skin. On the basis of our findings, we propose a strategy for the safer performance of RSB in IVLBCL patients with thrombocytopenia and coagulation abnormalities.

The interleukin-33 (IL-33)-ST2L signaling pathway has been shown to play important roles in the field of immunology, especially as a trigger for allergic reactions such as bronchial asthma. However, coming back to the original finding that the ST2 gene is induced during initiation of the cell cycle of fibroblastic cell lines, the possible functions of the ST2 gene products and their specific ligand, IL-33, in the field of cell growth regulation are still interesting problems to be solved. In this study, we used NIH-3T3 mouse cell line and added IL-33 before and after cell proliferation assay, which revealed the dual function of IL-33. When IL-33 was added to the confluent cells before the start of cell proliferation, it suppressed the cell growth concentration-dependently. On the other hand, if IL-33 was added after the start of cell proliferation, it enhanced the cell growth. The negative effect of IL-33 on cell proliferation is a novel finding and would provide an important clue to the roles of IL-33 and ST2/ST2L in growth regulation. (C) 2014 Elsevier Ltd. All rights reserved.

The cutaneous T cell-attracting chemokine (CTACK)/CCL27 is indispensable in skin inflammation. CTACK/CCL27 is exclusively produced by epidermal keratinocytes to attract CCR10-expressing T lymphocytes to the skin. We investigated the mechanism of CTACK/CCL27 production from normal human epidermal keratinocytes (NHEKs) by the proinflammatory cytokines TNF and IFN. CTACK/CCL27 production was induced by TNF via ERK, JNK, p38, and NFB. The induction of CTACK/CCL27 by TNF was suppressed by IFN via a pathway dependent on JAK, STAT1, and STAT3. Our results also demonstrated that IFN and TNF induced the phosphorylation of EGFR and the following phosphorylation of ERK, which is partly responsible for the suppressive effect of IFN on TNF-induced production of CTACK/CCL27. Peri-lesional skin of psoriasis demonstrates early inflammatory changes as we have previously reported. CTACK/CCL27 expression was diffuse in the peri-lesional epidermis, while it was restricted to basal layer in lesional epidermis, suggesting that CTACK/CCL27 expression was induced in the early stage of psoriatic plaque formation, and IFN could participate in the suppression of CTACK/CCL27 expression in the lesional epidermis, reflecting the later stage of psoriatic plaque formation. Our study suggests that CTACK/CCL27 may have a pivotal role in the early stage of psoriasis plaque formation, but should be downregulated in the later stage to induce inflammation characteristic for chronic psoriasis plaques. J. Cell. Physiol. 229: 1935-1945, 2014. (c) 2014 Wiley Periodicals, Inc.

The tyrosine kinase inhibitor (TKI) imatinib has been shown to promote psoriasis in some patients with chronic myelogenous leukaemia (CML), but it remained unclear whether second-generation TKIs such as nilotinib and dasatinib had a similar potential. Here, we present a patient in whom psoriatic erythema appeared at 26months after initiation of nilotinib treatment. Topical ointments of activated vitamin D-3 derivative and corticosteroid were applied; whereupon, the erythema gradually improved. During the clinical course, nilotinib administration continued without reduction in its dose. This is the first report of psoriasis that developed during nilotinib treatment. We also discuss the mechanisms of nilotinib-mediated progression of psoriasis.

The clinical use of adalimumab and infliximab, human anti-tumor necrosis factor (TNF)-α monoclonal antibodies, for psoriasis began in January 2010. In January 2011, ustekinumab, a human anti-interleukin-12/23p40 (IL-12/23p40) monoclonal antibody, was newly approved as the third biologic with an indication for psoriasis. While all of these biologics are expected to exhibit excellent therapeutic effect for psoriasis and to contribute to the improvement of quality of life in patients, these drugs require careful safety measures to prevent adverse drug reactions, such as serious infections. The new guidance, an English version prepared by revising the Japanese Guidance/Safety Manual for Use of Biologics for Psoriasis 2011 (in Japanese), is intended to provide up-to-date, evidence-based recommendations and safety measures on the use of biologics, and describes the optimal use of the three biologics, medical requirements for facilities for using biologics, details of safety measures against reactivation of tuberculosis and hepatitis B virus infection, and recommendable combination therapies with biologics. © 2013 Japanese Dermatological Association.

Background: Interleukin (IL)-33 is a dual functional, IL-1 family member cytokine, whose exact roles in inflammatory skin diseases are still unknown. IL-17A is a key cytokine in the pathogenesis of psoriasis. Objectives: We investigated if IL-17A could induce IL-33 in epidermal keratinocytes, and the signaling mechanisms involved. Methods: IL-33 levels were evaluated by RT-PCR and western blot in human keratinocytes following IL-17A simulation. IL-33 immunohistochemical staining of psoriatic skin samples was also performed and compared with that of control tissues. The role of signaling pathways downstream of IL-17A was investigated using small molecule inhibitors of EGFR, ERK, p38, and JAK. Adenovirus vector expressing dominant negative STAT1 was also utilized. Results: IL-33 and its receptor, ST2L, were expressed in the psoriatic epidermis, and the associated infiltrating cells. IL-17A induced IL-33 expression at mRNA and protein levels in a time- and concentration-dependent manner. IL-17A caused phosphorylation of EGFR, ERK, p38, and STAT1. IL-17A-induced IL-33 expression was blocked by the addition of EGFR, ERK, p38, and JAK inhibitors, and dominant negative STAT1-expressing adenovirus vector. Conclusion: IL-17A induced IL-33 in NHEKs through EGFR, ERK, p38, and JAK/STAT1 pathways, which were necessary for the induction of IL-33. IL-33, induced by IL-17A in epidermal keratinocytes, may be involved in the pathophysiology of inflammatory skin diseases, including psoriasis. (C) 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

Background: Degos disease or malignant atrophic papulosis is a rare occlusive vasculopathic disease characterized by pathognomonic cutaneous lesions and frequently fatal systemic involvement. The etiology of malignant atrophic papulosis remains unclear, and there is currently no effective treatment for malignant atrophic papulosis. Several chemokines can potentiate and expand the platelet response to increase thrombus formation. Among these chemokines, this study examined the expression of stromal cell-derived factor (SDF)-1/CXCL12, which is secreted by bone-marrow stromal and endothelial cells, activates megakaryocyte precursors, and costimulates platelet activation. Objective: We sought to investigate and compare the expression of SDF-1/CXCL12 in tissue sections taken from 2 patients with Degos disease, 2 patients with other vaso-occlusive diseases, and 2 healthy control subjects. Methods: Immunohistochemical staining involving antibodies to SDF-1/CXCL12 was performed on 3 skin biopsy specimens taken from 2 patients with Degos disease, 1 from a patient with antiphospholipid syndrome, 1 from a patient with cryoglobulinemia, and 2 from healthy control subjects. Results: Strong SDF-1/CXCL12 staining was observed in the infiltrating inflammatory cells in the perivascular, intravascular, and perineural areas in tissue samples from patients with Degos disease. No staining was observed in samples from patients with antiphospholipid syndrome or cryoglobulinemia or from healthy control subjects. Limitations: The number of cases available for evaluation was small. The findings were based primarily on the immunohistochemical results and were not confirmed using other techniques. Conclusions: The intense staining of SDF-1/CXCL12 in lesions attributed to Degos disease, demonstrated for the first time to our knowledge in this study, suggests SDF-1/CXCL12 involvement in the pathogenesis of the disease. (J Am Acad Dermatol 2013;68:138-43.)

Background. Vitamin D3 is a potent regulator of cell growth, differentiation and death, tumour invasion, and angiogenesis. Production of matrix metalloproteinase (MMP)-9 and MMP-13 by tumour cells may promote tumour growth, invasion and metastasis. Aim. To investigate whether calcipotriol could suppress the expression of MMP-9 and MMP-13 in a human squamous cell carcinoma (SCC) cell line (DJM cells), and to examine the mechanism of modulation of MMP-9 and MMP-13 by calcipotriol in DJM cells treated with tumour necrosis factor (TNF)-α. Methods. Protein and mRNA levels of MMP-9 and MMP-13 were examined by ELISA and real-time PCR, respectively. Activation of signalling cascades was assessed using several inhibitors of signalling molecules and western blot analysis. Results. Production of MMP-9 and MMP-13 markedly increased when the cells were treated with TNF-α. Calcipotriol suppressed the production of MMP-9 and MMP-13 mRNA and proteins significantly, in a dose-dependent manner. Induction of MMP-9 by TNF-α was suppressed by an extracellular signal-regulated kinase (ERK) inhibitor but not by a p38 inhibitor, whereas induction of MMP-13 was inhibited by a p38 inhibitor but not by an ERK inhibitor. Calcipotriol inhibited the phosphorylation of both ERK and p38, as shown by western blotting. Conclusion. Calcipotriol reduces MMP-9 and MMP-13 production through inhibiting the phosphorylation of ERK and p38, respectively. © 2012 British Association of Dermatologists.

Soluble ST2 (sST2) is a soluble form of the transmembrane receptor for interleukin (IL)-33, ST2L, and is a member of the IL-1 receptor family. sST2 antagonizes IL-33-ST2L signaling by competing with ST2L as a decoy receptor for IL-33. We investigated the sST2 and IL-33 levels in the sera and bullous fluid of bullous pemphigoid patients and compared these with the corresponding levels in normal healthy controls. As controls, we used the bullous fluid of burn patients and that from suction blisters induced in normal healthy volunteers. The serum sST2 concentrations of bullous pemphigoid patients were higher than those of healthy controls. Serum sST2 levels correlated with the area of skin involvement and serum lactate dehydrogenase levels, suggesting that serum sST2 levels reflect disease severity. The sST2 concentrations in bullous fluid from bullous pemphigoid patients were higher than those from controls. The concentration of IL-33 ligand was below the detectable limits in all enzyme-linked immunosorbent assay samples. Thus, our study suggested that the serum sST2 level may be a useful marker of disease severity and that sST2 functions as a negative regulator in the pathophysiology of bullous pemphigoid.

The remission period of psoriasis vulgaris following narrowband ultraviolet B (NB-UVB) light therapy with topical vitamin D(3) application was evaluated retrospectively to investigate the therapeutic efficacy. Fifty-two patients (60 cases) were treated with a 5-day/week protocol of NB-UVB light irradiation plus topical vitamin D ointment application for 1 month and followed up for at least 12 months. We considered re-exacerbation as the time when the patients needed treatment other than topical therapy. The remission period was defined as the duration from the end of treatment until re-exacerbation. Twenty-seven cases (56%) of psoriasis showed a remission period longer than 12 months. The patients with a past history of systemic therapy or phototherapy had a significantly shorter remission period than those without such a history. No statistically significant differences were observed in sex, age, period before treatment, Psoriasis Area and Severity Index score and total irradiation dose. A previous history of systemic therapy or phototherapy may mean that the disease is severe and sufficiently active to form multiple new lesions requiring these treatments. Our results suggest that the 5-day/week NB-UVB light protocol for 4 weeks is an effective and safe treatment for psoriasis vulgaris and can induce long-term remission.

Background: Serum levels of S100A8/A9 may correlate with disease activity in psoriasis. Objective: We sought to elucidate the association of serum levels of S100A8/A9 heterodimers with the clinical subtypes of psoriasis and the major cell source. Methods: Serum samples were collected from patients with psoriasis vulgaris (n = 30), psoriatic arthritis (PA) (n = 16),. pustular psoriasis (n = 24), and atopic dermatitis (n = 14) and from healthy control subjects (n = 21). Serum concentrations of S100A8/A9 were measured, and the expression levels were examined in psoriatic lesions. The messenger RNA levels were quantified in circulating monocytes and neutrophils. Results: Serum levels of S100A8/A9 were significantly increased in all subtypes of psoriasis as compared with healthy controls and atopic dermatitis. Among the psoriatic subtypes, PA and pustular psoriasis showed remarkably high concentrations of S100A8/A9 heterodimers. The higher serum levels were associated with the presence of articular symptoms, but not significantly correlated with body surface areas of psoriatic lesions. S100A8 was expressed by both keratinocytes and infiltrating mononuclear cells, whereas S100A9 was predominantly expressed by neutrophils. The expression levels of S100A8 and S100A9 messenger RNA in monocytes were increased by approximately 2.25- and 1.91-fold in PA, respectively, whereas no significant increase was observed in psoriasis vulgaris and pustular psoriasis. Limitations: Difficulty in acquisition of clinical and laboratory samples in untreated patients, and of a sufficient number of subjects, were limitations. Conclusions: Although serum levels of S100A8/A9 were increased in all types of psoriasis examined, patients with PA had higher levels of S100A8/A9, probably because of an activated monocyte/macrophage system. (J Am Acad Dermatol 2011;64:879-87.)

Histamine is a biological amine that plays an important role in allergic responses. However, the involvement of histamine signaling in late allergic responses in the skin is poorly understood. Therefore, we attempted to investigate the involvement of histamine signaling in late allergic responses, especially in keratinocytes (KCs). HaCaT KCs and normal human KCs (NHKs) predominantly expressed histamine H1 receptor (Hi R) and H2 receptor (H2R). Histamine suppressed tumor necrosis factor alpha (TNF-alpha)- and interferon-gamma (IFN-gamma)-induced production of CC chemokine ligand 17(CCL17), a type 2 T-helper (Th2) chemokine, by HaCaT KCs. It suppressed the phosphorylation of p38 mitogen-activated protein (MAP) kinase, but not that of extracellular signal-regulated kinases (ERKs), and TNF-alpha- and IFN-gamma-induced nuclear factor kappa B (NF kappa B) activity. In contrast, histamine enhanced the production of CXC chemokine ligand 10 (CXCL10), a Th1 chemokine, by TNF-alpha- and IFN-gamma-stimulated HaCaT KCs and NHKs. TNF-alpha- and IFN-gamma-induced CXCL10 production was upregulated by suppression of p38 MAP kinase or NF-kappa B activity, which could explain histamine involvement. We concluded that histamine suppresses CCL17 production by KCs by suppressing p38 MAP kinase and NF-kappa B activity through H1R and may act as a negative-feedback signal for existing Th2-dominant inflammation by suppressing CCL17 and enhancing CXCL10 production. (C) 2011 Elsevier Ltd. All rights reserved.