Guselkumab is superior to fumaric acid esters in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment: results from a randomized, active-comparator-controlled phase IIIb trial (POLARIS).

BACKGROUND: Guselkumab, a fully human interleukin-23 antibody, is approved for systemic treatment of patients with moderate-to-severe plaque psoriasis. OBJECTIVES: To compare the efficacy and safety of guselkumab with those of fumaric acid esters (FAE) in patients with moderate-to-severe plaque psoriasis who are naive to systemic treatment. METHODS: Eligible patients were randomized to this multicentre, randomized, open-label, assessor-blinded, active-comparator-controlled phase IIIb study to receive guselkumab 100 mg by subcutaneous injection or oral FAE according to local label guidelines. RESULTS: Through week 24, 56 of 60 patients completed guselkumab treatment and 36 of 59 completed FAE treatment. The primary endpoint (proportion of patients with ≥ 90% improvement from their baseline Psoriasis Area and Severity Index; PASI 90 response) was achieved by significantly more patients receiving guselkumab than FAE at week 24 (82% vs. 14%, P < 0·001). Analysis of the major secondary endpoints confirmed a statistically significant difference between the treatments with regards to PASI 75 response (90% vs. 27%, P < 0·001) and Dermatology Life Quality Index score of 0 or 1 (no effect at all on the patient's quality of life; 62% vs. 17%, P < 0·001). More patients in the guselkumab group achieved completely clear skin (PASI 100 response) than in the FAE group (32% vs. 3%, P < 0·001). The incidence of adverse events was lower with guselkumab than with FAE (73% vs. 98%). Overall, 28% of patients on FAE discontinued due to an adverse event, compared with none receiving guselkumab. No new safety findings were observed for guselkumab. CONCLUSIONS: Guselkumab demonstrated superiority over FAE in systemic-treatment-naive patients with moderate-to-severe plaque psoriasis through 24 weeks.

Patient-reported health outcomes in patients with non-melanoma skin cancer and actinic keratosis: results from a large-scale observational study analysing effects of diagnoses and disease progression.

BACKGROUND: Non-melanoma skin cancer (NMSC) and actinic keratosis (AK) are very common among fair-skinned individuals. A disease continuum from AK to squamous cell carcinoma (SCC) has been frequently postulated. AK and NMSC may influence quality of life (QL) of patients, and it can be suspected that disease progression entails a QL reduction. The purpose of this study was to document QL in patients with NMSC and AK using the health-outcome questionnaire EQ-5D-5L. METHODS: The study was designed as a non-interventional, prospective, cross-sectional study. Patients with AK, SCC, basal cell carcinoma (BCC) or multiple diagnoses were enrolled in this study in 29 dermatological centres across Germany. Patients were asked to complete the EQ-5D-5L (compromising EQ Index and EQ VAS), and the dermatologists provided diagnosis, disease history and treatment data. RESULTS: A total of 1184 patients were enrolled and diagnosed as follows: 73% AK, 49% BCC and 17% SCC. 66% had a single diagnosis, 28% two different diagnoses and 6% three different diagnoses. QL was strongly associated with patients' diagnosis. Patients with a single AK diagnosis had significantly higher mean EQ VAS (78) than patients with BCC (74), SCC (72), and BCC plus SCC (69), P < 0.050. When the effects of disease progression were calculated, patients with AK plus SCC reported significantly less mean EQ VAS (71) than patients with a single AK diagnosis (78), P < 0.011. CONCLUSIONS: While rarely being imminently life-threatening, NMSC and AK have an impact on QL as quantified by the EQ-5D-5L. This impact is associated with diagnosis (AK vs. NMSC) and clinical progression (AK vs. AK plus SCC). Both lead to a clear decline in QL. This shows that disease progression is perceived and judged as detrimental by patients and that AK and NMSC should be diligently treated to preserve and restore QL.

Developing transboundary river basin monitoring programmes using the DPSIR indicator framework.

Policymakers are often dissatisfied by the lack of what they consider useful information to support water management. Analysis of this 'water information gap' shows that this is caused by a lack of proper communication between information users and information producers. To improve this communication the process of specification of information needs has been structured. Earlier experiences showed that this not only entailed developing a structure to manage the process, but also developing a structure to guide the breakdown of policy objectives into information needs. Such a structure to organise the problem supports policy makers and monitoring specialists in their communication. This paper describes three pilot projects where the DPSIR indicator framework was used to organise the problem. It is concluded that the DPSIR framework is useful for improving the communication between information users and information producers and is helpful in breaking down policy objectives into information needs in a structured way. The structured approach in this way assists in narrowing the water information gap. Use of the DPSIR framework however leads to a bias towards water management problems and does not provide for all the relevant information needs.

A methodology to bridge the water information gap.

The metaphor of the water information gap is used to describe the discontent between information users and information producers about the use of and need for specific information. This paper describes the rugby-ball methodology for specification of information needs that was developed on the basis of an analysis of the water information gap and insights from the literature on policy- and decision-analysis, problem-structuring, and information management. The methodology consists of a process-architecture to manage the process of assessing information needs and a structure to organise the information needs related to water policy objectives. The methodology was developed and enhanced through a Reflection-in-Action process in which interaction between ideas and practice leads to improved results. The paper describes the methodology and its development, and concludes both on the development process and on the abilities of the methodology to narrow the water information gap.

Specifying information needs for Dutch National Policy evaluation.

There is mutual dissatisfaction among policy makers and monitoring specialists about producing what is considered useful information for policy development, implementation and evaluation. Insufficient or inappropriate communication between information users and producers is considered to be a main cause for this water information gap. This paper tests the rugby-ball methodology that has been designed to bridge the gap. The rugby-ball methodology consist of a five step plan that helps policy makers and monitoring specialists to communicate in a proper way and to come to a joint process of defining information needs. The methodology is first tested in a study to assess the information needs for the 4th National Policy Document on Water Management in the Netherlands. From the study it is concluded that the rugby-ball methodology is an important step in bridging the water information gap by better defining what useful information is. The methodology is also improved on the basis of this study by including a structure to support the breakdown of policy objectives into information needs.

Management of actinic cheilitis using diclofenac 3% gel: a report of six cases.

BACKGROUND: Actinic cheilitis is a frequent manifestation of actinic dysplasia and requires early therapy to prevent its progression into invasive squamous cell carcinoma (SCC). Several therapies are used, ranging from unspecific lesion-adapted destructive techniques (i.e. laser) to ambitious surgical field-management (vermillionectomy). There is increasing awareness of the effectiveness of field adapted, non destructive therapies, such as photodynamic therapy or 5% imiquimod. Diclofenac 3% gel is used in the treatment of actinic keratosis (AK), but it has not been evaluated for the treatment of actinic cheilitis. OBJECTIVES: This non-blinded, uncontrolled case series study evaluated the effects of diclofenac 3% gel in the treatment of actinic cheilitis. PATIENTS/METHODS: Six patients with histologically verified actinic cheilitis were treated with diclofenac 3% gel, twice daily for 6 weeks. Clinical assessment was performed 2-4 weeks after the end of treatment. RESULTS: Four out of six patients showed clinical clearing of actinic cheilitis 2-4 weeks after the end of treatment. Biopsies were taken from the treated areas at the final visit to verify clinical clearance. Side effects in most of the patients included mild erythema and mild to moderate swelling of the lips. CONCLUSIONS: Topical therapy with diclofenac 3% gel may be an efficient, cosmetically more appealing alternative treatment for actinic cheilitis than currently used destructive therapies. However, future studies and long-term follow-up of patients will be needed to compare its efficacy with established forms of therapy.

[Erythema annulare centrifugum Darier. Successful therapy with topical calcitriol and 311 nm-ultraviolet B narrow band phototherapy]. / Erythema anulare centrifugum Darier. Erfolgreiche Therapie mit topischem Calcitriol und UVB-Schmalspektrumbestrahlung.

Erythema annulare centrifugum is an acute dermatosis of unclear etiology, which presents with annular erythematous lesions with marginal scale. Therapeutically, systemic and topical glucocorticosteroids are used primarily. We treated a patient with large lesions in the area of the thighs resistant to a therapy with topical glucocorticosteroids, with topical calcitriol in combination with 311 nm ultraviolet B narrow band phototherapy. After four weeks of treatment the skin lesions had cleared nearly completely without any side effects. The combination topical vitamin D3-analogue calcitriol and 311 nm ultraviolet B narrow band phototherapy was effective and can be regarded as a useful alternative to glucocorticosteroids for erythema annulare centrifugum.

The role of CD44 during CD40 ligand-induced dendritic cell clustering and maturation.

The interaction between CD40 on dendritic cells (DC) and its ligand CD154 has been recognized to be an important feature in the maturation of DC. Here, we were interested in the role of CD44 a surface receptor shown to mediate cell-cell adhesion and binding to Hyaluronic acid (HA). Western blot analysis of human DC stimulated for 3-12 h with CD154 revealed the rapid induction of the 85 kDa standard form of CD44 and an increased HA-binding affinity. Time-lapse video-imaging microscopy of human DC co-cultured on CD154-transfected murine fibroblasts showed that the CD44 up-regulation coincided with the rapid induction of homotypic DC clustering, which did not occur on empty vector-transfected fibroblasts. In this system, addition of anti-CD44s mAbs abrogated DC-cluster formation, thereby inhibiting further maturation, as shown by a reduced TNF-alpha production and inhibition of CD154-induced MHC class II up-regulation. However, co-incubation with HA-degrading enzymes induced no changes in the CD154-mediated DC clustering and maturation.

Hypericin photo-induced apoptosis involves the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and activation of caspase-8.

Hypericin (HYP) is a photosensitizing pigment from Hypericum perforatum that displays cytotoxic effects in neoplastic cell lines. Therefore, HYP is presently under consideration as a new anticancer drug in photodynamic therapy. Here, we investigated the mechanism of action of HYP photo-induced apoptosis of Jurkat cells compared to the cytostatic drug paclitaxel (PXL). Both photoactivated HYP and PXL similarly increased the activity of caspase-8 and caspase-3, and drug-induced apoptosis of Jurkat cells was completely blocked by inhibitors of caspase-8 (Z-IETD-FMK) and caspase-3 (Z-DEVD-FMK). The involvement of death receptors was analyzed using neutralizing monoclonal antibodies against Fas (SM1/23), FasL (NOK-2) and TNF-R1 (MAB225), and a polyclonal rabbit anti-human TNF-related apoptosis-inducing ligand (TRAIL) antiserum. TRAIL antibody blocked TRAIL-induced and HYP photo-induced, but not PXL-induced apoptosis of Jurkat cells. In contrast, PXL-induced, but not HYP-induced apoptosis was blocked by the SM1/23 and NOK-2 antibodies. Anti-TNF-R1 antibody had no effect. These findings suggest that HYP photo-induced apoptosis of Jurkat cells is mediated in part by the TRAIL/TRAIL-receptor system and subsequent activation of upstream caspases.

CD44 is the principal mediator of hyaluronic-acid-induced melanoma cell proliferation.

Interactions of the extracellular matrix component hyaluronic acid and its cellular receptors CD44 and RHAMM/IHABP have been linked to tumor progression and metastasis formation. We investigated the expression and hyaluronic-acid-dependent functions of CD44 and RHAMM/IHABP in human melanoma. Immunohistochemistry of tumor specimens at different stages of melanoma progression revealed an increased expression of CD44 and RHAMM/IHABP. High mRNA expression of CD44 was found in three highly tumorigenic melanoma cell lines compared with less tumorigenic melanoma cells or nontransformed melanocytes. RHAMM/IHABP expression was upregulated in all cell lines analyzed but not in melanocytes. In contrast to the cell surface localization of CD44, RHAMM/IHABP was detected exclusively within the cytoplasm of melanoma cells. Binding and adhesion of melanoma cells to hyaluronic acid is mainly CD44 dependent as it was inhibited to 60%--80% by an anti-CD44 monoclonal antibody whereas anti-RHAMM/IHABP sera had no effect. Culture of melanoma cells in the presence of hyaluronic acid resulted in a dose-dependent, CD44-mediated increase of melanoma cell proliferation and enhanced release of basic fibroblast growth factor and transforming growth factor beta 1. We conclude that (i) the expression of CD44 and RHAMM/IHABP is increased during melanoma progression, (ii) CD44 is the principal hyaluronic acid surface receptor on melanoma cells, and (iii) the hyaluronic-acid-induced increase of the proliferative capacity of melanoma cells is mainly dependent on CD44--hyaluronic acid interactions.

Human dendritic cells are a physiological source of the chemotactic arachidonic acid metabolite 5-oxo-eicosatetraenoic acid.

OBJECTIVE: The arachidonic acid metabolite, 5-oxo-eicosatetraenoic acid (5-oxo-ETE), is a potent chemotaxin for neutrophils and eosinophils. The aim of this study was to identify physiological conditions and stimulators of 5-oxo-ETE synthesis, because no such conditions have yet been identified. METHODS: Human neutrophils and monocyte-derived dendritic cells were prepared and 5-oxo-ETE synthesis analyzed using precolumn/reversed-phase HPLC under different conditions and with several physiological and unphysiological stimuli. RESULTS: Incubation of neutrophils with 5-hydroxyeicosatetraenoic acid (5-HETE) resulted in the synthesis of about 3.4 nM 5-oxo-ETE per 10(6) cells in 1 ml under optimal conditions. The synthesis was enhanced about 8-fold with the unphysiological stimuli calcium ionophore A23187 and phorbol 12-myristate 13-acetate (PMA). No significant effect was observed with different physiological activators. Under optimal conditions, human dendritic cells produced about 50 nM 5-oxo-ETE per 10(6) cells in 1 ml. The synthesis could be increased with PMA and A23187 by about 50%. Again, no effect could be observed with physiological agents for dendritic cells such as complement fragment C5a, platelet activating factor, N-formyl peptides and interleukin-5. CONCLUSIONS: These data identified dendritic cells as the only yet known physiological source of relevant amounts of 5-oxo-ETE. This suggests a regulatory function of dendritic cells in the induction of inflammatory neutrophil and eosinophil infiltration caused by 5-oxo-eicosatetraenoic acid.

Downregulation of platelet-activating factor responsiveness during maturation of human dendritic cells.

Dendritic cells (DCs) are specialized antigen-presenting cells characterized by their ability to migrate into target sites, process antigens, and activate naive T-cells. Biological activities of platelet-activating factor (PAF) and the cytokine macrophage inflammatory protein-3beta (MIP-3beta) as well as the mRNA expression of their receptors were characterized in human DCs during lipopolysaccharide (LPS)-promoted maturation. Platelet-activating factor induced calcium transients, migration-associated actin polymerization response, and chemotaxis in immature human dendritic cells differentiated in vitro from monocytes with interleukin-4 and granulocyte macrophage colony stimulating factor. In addition, RT-PCR experiments indicated mRNA expression of the PAF receptor in these immature DCs. Cell studies and mRNA analyses further revealed that immature DCs neither respond to MIP-3beta nor express its specific receptor, CCR7. Induction of cell differentiation by LPS led to the loss of the mRNA expression of the PAF receptor, accompanied by decreasing intracellular calcium release, actin polymerization, and migration after stimulation with PAF. In contrast, LPS treatment induced increasing responsiveness toward MIP-3beta and mRNA expression of CCR7. Comparable data regarding mRNA expression of PAF receptor and PAF responsiveness were also obtained with another maturation protocol using TNFalpha instead of LPS. The direct comparison between the two different protocols showed a slower decrease of PAF responsiveness induced by TNFalpha than by LPS. These results show the loss of PAF responsiveness associated with downregulation of PAF receptor mRNA expression during LPS- and TNFalpha-induced maturation in human DCs. Therefore, these findings point to a functional relevance of PAF in recruiting immature DCs, whereas MIP-3beta might regulate the migration of DCs at a later stage of maturation.

Oligosaccharides of hyaluronan are potent activators of dendritic cells.

The extracellular matrix component hyaluronan (HA) exists physiologically as a high m.w. polymer but is cleaved at sites of inflammation, where it will be contacted by dendritic cells (DC). To determine the effects of HA on DC, HA fragments of different size were established. Only small HA fragments of tetra- and hexasaccharide size (sHA), but not of intermediate size (m.w. 80, 000-200,000) or high m.w. HA (m.w. 1,000,000-600,000) induced immunophenotypic maturation of human monocyte-derived DC (up-regulation of HLA-DR, B7-1/2, CD83, down-regulation of CD115). Likewise, only sHA increased DC production of the cytokines IL-1beta, TNF-alpha, and IL-12 as well as their allostimulatory capacity. These effects were highly specific for sHA, because they were not induced by other glycosaminoglycans such as chondroitin sulfate or heparan sulfate or their fragmentation products. Interestingly, sHA-induced DC maturation does not involve the HA receptors CD44 or the receptor for hyaluronan-mediated motility, because DC from CD44-deficient mice and wild-type mice both responded similarly to sHA stimulation, whereas the receptor for hyaluronan-mediated motility is not detectable in DC. However, TNF-alpha is an essential mediator of sHA-induced DC maturation as shown by blocking studies with a soluble TNFR1. These findings suggest that during inflammation, interaction of DC with small HA fragments induce DC maturation.

Newcastle disease virus infection induces B7-1/B7-2-independent T-cell costimulatory activity in human melanoma cells.

Viral oncolysates of Newcastle disease virus (NDV) have been widely used for the treatment of malignant melanoma. Apparently, this nononcogenic and apathogenic paramyxovirus can alter the immunogenicity of tumor cells. To determine the influence of NDV infection on a tumor-specific T-cell response on a functional level, we used autologous primary melanoma cells infected with the NDV-strain Ulster. Therefore, melanoma cells and tumor-infiltrating lymphocytes were prepared from a freshly resected tumor, and tumor-infiltrating lymphocytes were subjected to limited dilution cloning. Proliferation assays of the T-helper cell clone sTS3 (CD4+) showed that the T-cell clone was rendered nonreactive against its autologous major histocompatibility complex II+, B7-1/B7-2- melanoma SMS, even remaining unresponsive to subsequent stimulation by interleukin-2. NDV infection of the SMS melanoma cell line not only completely restored the proliferative response of sTS3 to SMS, comparable with stimulation by cross-linking of anti-CD3/anti-CD28 monoclonal antibodies, but also inhibited the induction of anergy. Electrophoretic mobility shift assays of sTS3 cell lysates revealed the induction of the CD28-responsive complex by coincubation with NDV-infected melanoma cells. Because the induction of this complex of nuclear proteins shows specificity for the activation of the CD28 pathway but functional B7-1/B7-2 expression was not detectable on SMS melanoma cells at any timepoint, we propose the induction of a costimulatory factor different from B7 by NDV viral proteins.

Colocalization of basic fibroblast growth factor and CD44 isoforms containing the variably spliced exon v3 (CD44v3) in normal skin and in epidermal skin cancers.

Previous in vitro studies have shown CD44 isoforms containing the alternatively spliced exon v3 (CD44v3) to be modified with heparan sulphate (HS) and to bind HS-binding basic fibroblast growth factor (bFGF). Here, we demonstrate that exogenously added bFGF is also bound in vivo by CD44v3-positive keratinocytes in normal skin and by tumour cells in basal cell carcinoma and squamous cell carcinoma (SCC), two skin cancers of keratinocyte origin. bFGF binding and CD44v3 expression were colocalized in cultured human normal keratinocytes (HNK) and on the SCC cell line A431. By contrast, benign or malignant tumours of melanocyte origin failed to express CD44v3 and bound no bFGF. The bFGF binding to normal or transformed keratinocytes in vivo and in vitro was dependent on HS modification, as it was completely eliminated by pretreatment with heparitinase or by blocking with free heparin, whereas chondroitinase had no effect. In addition, specific removal of CD44v3 by antibody-induced shedding also diminished bFGF binding to keratinocytes. Furthermore, bFGF stimulated the proliferation of CD44v3-positive HNK and A431 in a dose-dependent fashion. This bFGF effect was again completely abolished by heparitinase or free heparin, but not by chondroitinase. In aggregate, our results suggest that a function of HS-modified CD44 isoforms such as CD44v3 in skin is to present the HS-binding growth factor bFGF, thereby stimulating the proliferation of normal or transformed keratinocytes.

[Linear IgA dermatosis in an adult with clinical signs of Stevens-Johnson syndrome]. / IgA-lineare Dermatose im Erwachsenenalter mit klinischen Zeichen eines Stevens-Johnson-Syndroms.

Immunohistologically linear IgA disease presents with unambiguous features, whereas clinical manifestations are variable. It sometimes shows similarity to other bullous dermatoses such as bullous pemphigoid and dermatitis herpetiformis. A 73 year old female patient was referred with the diagnosis of bullous pemphigoid. One day after admission clinical examination revealed the classical features of Stevens-Johnson syndrome (SJS): widespread confluent atypical target lesions, partly raised, partly flat with central blisters, and erythematous spots, but few typical targets, as well as blisters and large areas of skin detachment on her back and buttocks, accompanied by erosions of the oral and genital mucosa. Direct immunofluorescence performed on peri-lesional skin showed linear deposition of IgA along the basement membrane zone, leading to the diagnosis of linear IgA disease of adults. Our case report shows that linear IgA disease may present with the clinical pattern of SJS.

In vivo UVA-1 and UVB irradiation differentially perturbs the antigen-presenting function of human epidermal Langerhans cells.

Ultraviolet B (UVB, 290-320 nm) radiation is known to suppress the immune function of epidermal Langerhans cells. We have recently described that in vitro UVB irradiation perturbs the antigen-presenting cell function of Langerhans cells by inhibiting their expression of functional B7 costimulatory molecules (B7-1, B7-2). The aim of this study was to determine wavelength-specific UV effects on Langerhans cells function in vivo, specifically UVB and UVA-1. To address this issue, volunteers were irradiated on the sun protected volar aspects of their forearms with 3 x minimal erythema dose of UVB (Philips TL-12) and UVA-1 (UVASUN 5000 Mutzhaas). Langerhans cells were isolated from suction blister roofs immediately following irradiation. Langerhans cells isolated from UVB- but not from UVA-1-irradiated skin failed to activate naïve resting allogeneic T cells (mixed epidermal cell leukocyte reaction) or primed tetanus toxoid reactive autologous T cells. Langerhans cells isolated from sham-irradiated or UVA-1-irradiated skin strongly upregulated B7-2 molecules during short-term tissue culture. By contrast, Langerhans cells from UVB-irradiated skin did not upregulate B7-2 molecules. Furthermore, exogenous stimulation of the B7 pathway by anti-CD28 stimulatory monoclonal antibodies restored the capacity of UVB-irradiated Langerhans cells to activate both alloreactive and tetanus toxoid-reactive T cells, implying suppressed antigen-presenting cell activities and perturbed B7 expression of Langerhans cells isolated from UVB-irradiated skin are related. Those studies demonstrate that in vivo UVB, but not UVA-1, interferes with the activation-dependent upregulation of B7 molecules on Langerhans cells, which in turn is of functional relevance for the perturbed antigen-presenting cell function of Langerhans cells within UVB- but not UVA-1-irradiated skin.