Psoriasis

Effect of cyclosporine on blood pressure.

2010-01-24T07:00:00.000-08:00

Cochrane Database Syst Rev. 2010; CD007893Robert N, Wong GW, Wright JMBACKGROUND: Cyclosporine is an immunosuppressive agent used for different autoimmune diseases. The official Canadian indications for cyclosporine are solid organ transplantation, bone marrow transplantation, psoriasis, rheumatoid arthritis and nephritic syndrome (e-CPS 2008). The expanding range of indications for cyclosporine therapy will lead to more patients receiving chronic therapy with possible side effects, hypertension being one of the most common. Therefore it is essential to know the magnitude of increase of blood pressure (BP) associated with cyclosporine in order to appropriately manage patients receiving the drug. OBJECTIVES: The primary objective of this systematic review is to evaluate the effect of cyclosporine on blood pressure, compared to placebo in randomized trials. SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials (CENTRAL) and bibliographic databases, including MEDLINE (2000-2008) and EMBASE (1980-2008). SELECTION CRITERIA: Selection was made using double-blind, randomized, controlled trials comparing cyclosporine to placebo. All patients treated with cyclosporine were included without restriction by type of disease or by age and sex. DATA COLLECTION AND ANALYSIS: Blood pressure measurements in any setting and by any means were acceptable including the auscultatory or oscillometric method with a preference for the sitting position. Mean blood pressure results were entered as mean change from placebo and standard error of the mean (SEM). If blood pressure data was provided at different times after the initiation of cyclosporine therapy the weighted mean BP change from placebo from all measurements was used. MAIN RESULTS: The search yielded 1340 citations, of which 17 trials met the inclusion criteria. We created dose-ranges according to the usual dose administration recommended by the manufacturer and allocated the 17 included trials to the corresponding dose-range. The results demonstrate a highly statistically significant increase in blood pressure associated with cyclosporine. There appears to be a dose-related effect with lower doses (1-4 mg/kg/d) increasing mean BP by an average of 5 mmHg and higher doses (>10 mg/kg/d) increasing mean BP by 11 mmHg on average. Furthermore in 3 trials the effect appears to be similar after a single dose as with chronic therapy. AUTHORS' CONCLUSIONS: Cyclosporine statistically significantly increases blood pressure compared to placebo in a dose-related fashion. The magnitude of increase in blood pressure is clinically significant and increases the risk of stroke, myocardial infarction, heart failure and other adverse cardiovascular events associated with elevated BP. Consequently prescribers should try to find the lowest effective dose in all patients receiving cyclosporine chronically.

Model-based approaches for time-dependent dose finding with repeated binary data.

2010-01-19T18:22:00.000-08:00

Stat Med. 2010 Jan 15; Benda NThe goal of a clinical Phase II dose finding study is to describe the dose response relationship and to find a target dose (TD) or dose range that ensures a certain efficacy. In many applications, however, it is useful to consider combinations of dose and time under treatment instead of the dose only. The estimation of a minimum effective dose as a function of time allows, e.g. for a decision on an optimal initial treatment duration, if this initial treatment is followed by a maintenance therapy or aftercare which is supposed to start when a certain response rate is achieved. Bretz et al. (Biometrics 2005; 61:738-748) proposed a methodology that combines formal hypothesis testing for dose response with flexible modeling of the dose response relationship and estimating a target dose. In this paper a framework is proposed that allows for an extension of this methodology to a procedure that takes into account both, dose and time under treatment based on repeated binary data. A set of nonlinear mixed effects models is considered. The primary goal of such a study is the estimation of a minimum effective dose defined by the marginal probability, either in absolute terms or relative to placebo, as a function of time.Examples for the TD as a function of time are given under specific model assumptions using a response function which depends on a cumulated dose response over time. The proposed models are illustrated by a case study on the treatment of psoriasis. The precision of the TD estimation as given by its standard error and bias are presented under different dose-response models and scenarios. The precision conditioned on the correct underlying model shape is contrasted with the precision of a procedure that incorporates a model selection step after which the TD is estimated using the selected model, and with the precision obtained under a misspecified model. Copyright (c) 2010 John Wiley & Sons, Ltd.

Comparison of effectiveness and safety of infliximab, etanercept, and adalimumab in psoriatic arthritis patients who experienced an inadequate response to previous disease-modifying antirheumatic drug

2010-01-19T01:44:00.000-08:00

Clin Rheumatol. 2010 Jan 12; Atteno M, Peluso R, Costa L, Padula S, Iervolino S, Caso F, Sanduzzi A, Lubrano E, Del Puente A, Scarpa RThe aim of this study is to compare effectiveness and safety of Infliximab (INF), Etanercept (ETN), and Adalimumab (ADA) in patients with psoriatic arthritis (PsA) with inadequate response to a previous disease-modifying antirheumatic drug (DMARD). One hundred consecutive PsA patients with inadequate response to a previous DMARD entered this study. Clinical and laboratory assessment at baseline (T0) and 12 (T12) months were performed and included physical examination, vital signs, global Psoriasis Area and Severity Index (PASI; extension of psoriasis), tender joints count (TJC), swollen joint count, health assessment questionnaire (HAQ; questionnaire for measuring disability), and monitoring of adverse events (AEs). After enrolment, all patients were randomly given INF 5 mg/Kg every 6-8 weeks, ETN 50 mg weekly, or ADA 40 mg every other week. Baseline therapy with DMARD remained unchanged. Effectiveness was defined as percentage of ACR20 responders and as clinical remission and/or minimal disease activity at 12 months treatment. INF, ETN, and ADA all effectively controlled signs and symptoms of PsA. All variables tested showed at T12 for each treatment a significant variation from the baseline value. In particular, patients on INF and ADA showed the greatest improvement in terms of PASI, while patients on ETN showed the greatest improvement on TJC and HAQ. ACR response rates were 72% of patients on ETN, 70% of those on ADA, and 75% of those patients on INF. Occurrence of AEs was reported in 15% of the cases. Only two AEs in patients on INF were considered drug related, pneumonitis and thrombocytopenia, respectively. All tumor necrosis factor-alpha blockers significantly controlled signs and symptoms of PsA. An increased knowledge of the different profiles of these agents may help in optimizing their use.

Comparison of effectiveness and safety of infliximab, etanercept, and adalimumab in psoriatic arthritis patients who experienced an inadequate response to previous disease-modifying antirheumatic drug

2010-01-18T17:25:00.000-08:00

Comparison of effectiveness and safety of infliximab, etanercept, and adalimumab in psoriatic arthritis patients who experienced an inadequate response to previous disease-modifying antirheumatic drug

2010-01-18T01:26:00.000-08:00

The p38 MAPK regulates IL-24 expression by stabilization of the 3' UTR of IL-24 mRNA.

2010-01-17T22:11:00.000-08:00

PLoS One. 2010; 5(1): e8671Otkjaer K, Holtmann H, Kragstrup TW, Paludan SR, Johansen C, Gaestel M, Kragballe K, Iversen LBACKGROUND: IL-24 (melanoma differentiation-associated gene-7 (mda-7)), a member of the IL-10 cytokine family, possesses the properties of a classical cytokine as well as tumor suppressor effects. The exact role of IL-24 in the immune system has not been defined but studies have indicated a role for IL-24 in inflammatory conditions such as psoriasis. The tumor suppressor effects of IL-24 include inhibition of angiogenesis, sensitization to chemotherapy, and p38 mitogen-activated protein kinase (MAPK)-mediated apoptosis. Current knowledge on the regulation of IL-24 expression is sparse. Previous studies have suggested that mRNA stabilization is of major importance to IL-24 expression. Yet, the mechanisms responsible for the regulation of IL-24 mRNA stability remain unidentified. As p38 MAPK is known to regulate gene expression by interfering with mRNA degradation we examined the role of p38 MAPK in the regulation of IL-24 gene expression in cultured normal human keratinocytes. METHODOLOGY/PRINCIPAL FINDINGS: In the present study we show that anisomycin- and IL-1beta- induced IL-24 expression is strongly dependent on p38 MAPK activation. Studies of IL-24 mRNA stability in anisomycin-treated keratinocytes reveal that the p38 MAPK inhibitor SB 202190 accelerates IL-24 mRNA decay suggesting p38 MAPK to regulate IL-24 expression by mRNA-stabilizing mechanisms. The insertion of the 3' untranslated region (UTR) of IL-24 mRNA in a tet-off reporter construct induces degradation of the reporter mRNA. The observed mRNA degradation is markedly reduced when a constitutively active mutant of MAPK kinase 6 (MKK6), which selectively activates p38 MAPK, is co-expressed. CONCLUSIONS/SIGNIFICANCE: Taken together, we here report p38 MAPK as a regulator of IL-24 expression and determine interference with destabilization mediated by the 3' UTR of IL-24 mRNA as mode of action. As discussed in the present work these findings have important implications for our understanding of IL-24 as a tumor suppressor protein as well as an immune modulating cytokine.

A study of intima media thickness and their cardiovascular risk factors in patients with psoriatic arthritis.

2010-01-16T23:12:00.000-08:00

Acta Medica (Hradec Kralove). 2009; 52(3): 107-16Mazlan SA, bin Mohamed Said MS, Hussein H, binti Shamsuddin K, Shah SA, Basri HINTRODUCTION: Psoriatic Arthritis (PsA) is an inflammatory arthritis associated with Psoriasis. Its recognition as an inflammatory disease distinct from Rheumatoid Arthritis has put forward for consideration several questions regarding its specific CVS mortality and morbidity (9, 11, 16, 26). Carotid intima media thickness is a useful surrogate and sensitive marker to determine atherosclerosis even in its subclinical stages (6, 14, 22, 27, 32). OBJECTIVE: Prevalence of carotid intima media thickness in patients with Psoriatic arthritis is unknown in Asian population. We aim to identify the presence of subclinical atherosclerosis in patients with psoriatic arthritis and disease activity association and its predictors in a series of patients with PsA attended to the rheumatology clinic, tertiary hospitals. METHODS: A total of 63 patients with PsA who fulfilled the CASPAR criteria were recruited from UKM Medical Centre and Hospital Putrajaya. Common carotid intima media thickness (IMT) was measured in both right and left carotid artery by using high resolution B-mode ultrasound. This was a cross sectional study first done in Malaysia for PsA patients. RESULTS: The positive IMT (IMT > 1.00 mm) among PsA was observed in 10 out of 63 patients (15.9 %) regardless of background cardiovascular risk. The mean +/- SD of IMT was 0.725 +/-0.260 mm for this study. Variables significantly associated with positive IMT (p < 0.05) included age at the time of study (p = 0.005), waist circumference (p = 0.001), Hypertension (p = 0.007), Diabetes (p = 0.002) and Metabolic syndrome (p = 0.001) and not associated with gender, ethnicity, duration of PsA disease, pattern of PsA, disease activity and severity. Above all, only age had positive IMT independent predictor (p = 0.032), with OR 1.116; 95 % CI (1.010-1.234). CONCLUSIONS: There was a significant association between CVS risk and positive Intima Media Thickness in Psoriatic Arthritis patients. Otherwise, there was no association in disease activity, disease severity and DMARDS therapy with positive Intima Media Thickness in Psoriatic Arthritis patients. The study was approved by Research and Ethics Committee of the faculty of medicine, Universiti Kebangsaan Malaysia with project code FF-114-2008 and by Community Research Center (CRC) of National Institutes of Health (NIH) for the case study in Hospital Putrajaya with the project code NMRR-08-970-2125.

[Occipitocervical Fixation: Long-Term Follow-up in Fifty-Seven Patients.]

2010-01-15T17:21:00.000-08:00

Acta Chir Orthop Traumatol Cech. 2009 Dec; 76(6): 479-86StulÃk J, KlÃ©zl Z, Sebesta P, Kryl J, Vyskocil TPURPOSE OF THE STUDY Occipitocervical fixation and spondylodesis is indicated in various cases of occipitocervical instability. The aim of this retrospective study was to evaluate the results of occipitocervical fixation at our institutions. MATERIAL Between 1997 and 2007, a total of 57 patients underwent occipitocervical fixation (OC) there were 25 men and 32 women, from four to 77 years of age, with an average of 58.7 years.The patients were allocated to two groups according to the met- hod of OC fixation used: tying wires or cables (group 1) screw-rod or screw-plate systems (group 2). Indications for OC fixa- tion included trauma in 15, rheumatoid arthritis (RA) in 28, destruction due to psoriasis in one, tumour in eight, and con- genital anomalies of the cervico-cranial junction in five patients. In five patients with tumour, OC fixation was completed with a transoral or transmandibular procedure. The C0-T 1 or C0-T 2 segments were fixed in 22 patients, C0-C2 segments in 14, C0-C3 segments in six, C0-C4 segments in two, C0-C5 segments in eight and C0-C6 segments in five patients. METHODS In atlanto-occipital dislocation, comminuted fractures of the ;atlas or similar injuries, C0-C1-C2 segments were fused in congenital anomaly, the C0-to-lower cervical spine was fixed, with C1 being avoided. The RA patients were treated by fixa- tion of the C0 to T1 or T2 segments. The atlas was fixed by the screw method of Goel, the C2 joint by that of Judet, or stab- le fusion of the two vertebrae was carried out by the Magerl transarticular technique. For the middle and lower cervical spi- ne, lateral mass screw fixation by the Magerl method was used, and from C7 caudally the vertebrae were fixed transpedicularly. Occasionally, in small children in particular, a Ransford frame fixed with wires or cables was used. In prin- ciple, an extent of fixation as small as possible was employed. The patients were evaluated at a final follow-up ranging bet- ween 12 and 132 months after the primary surgery (average, 42.7 months). Indications for surgery and the method and extent of instrumentation were recorded. The evaluation included pain and neurological deficit assessment, radiographic evidence of the stability of fixation and bone union and intra-operative and early and late post-operative complications. RESULTS Of the 57 patients, bone fusion was the objective of surgery in 52. Further five patients died of associated injuries or seri- ous medical complications shortly after the operation.Of the remaining 47, bone union was achieved in 44 patients (93.6%). Pseudoarthrosis developed in three patients who, however, because of a higher age and minimal complaints did not requ- ire revision surgery. In terms of bone union, there was no difference between a short (C0-C2) and a long (C0-CX or C-T) fixation. No differences among fixation materials were found. The differences in percent bone union after spondylodesis between the tying-wire and screw-rod fixation systems were not statistically significant (p>0.05). In the patients treated for RA, psoriasis or congenital anomaly, the Nurick scale score significantly improved at 2 years after surgery (p

Comparison of effectiveness and safety of infliximab, etanercept, and adalimumab in psoriatic arthritis patients who experienced an inadequate response to previous disease-modifying antirheumatic drug

2010-01-14T17:09:00.000-08:00

Acquired erythroderma in adults: a clinical and prognostic study.

2010-01-14T01:36:00.000-08:00

J Eur Acad Dermatol Venereol. 2009 Dec 17; Khaled A, Sellami A, Fazaa B, Kharfi M, Zeglaoui F, Kamoun MRAbstract Background Erythroderma is a severe syndrome and prognostic studies are rare in the literature. Objectives Through a retrospective study of erythroderma in adults, we have analysed epidemiological and clinical data and precised the relevant aetiologies and survival in our patients. Methods This study was performed at the Department of Dermatology of Charles Nicolle Hospital of Tunis (1995-2007) including 82 cases of acquired erythroderma (>16 years). We have recorded epidemio-clinical, biological and histological data, treatment and outcome. Clinical-histological correlation was analysed [kappa coefficient (kappa)]. Follow-up time and disease-free survival time were calculated as were Kaplan-Meier estimates of overall survival and relapse-free survival for some aetiologies. Results Erythroderma represented 0.44 per thousand of all dermatoses with an age of 55.13 +/- 18.16 and no sex predilection. Psoriasis was the predominant aetiology (32.9%) with a median duration of 6.75 years and previous one or more episodes of erythroderma. Psoriasis was significantly associated with pruritus (P = 0.0001), pachyonychia (P = 0.00001), palmoplantar keratoderma (P = 0.0001) and hypereosinophilia (P = 0.008). The latter is then not specific for drug induced erythroderma (P = 0.004). Carbamazepine (27.8%) and penicillin (22.2%) were the most implicated drugs. Positive Clinical-histological correlation was found in 77% of cases (kappa = 0.753). Relapse was seen in all aetiologies, but drug reactions and had occurred in the first 3 years in 90% of them. Mortality rate was 11.3 per 1000 patients-years. Conclusions Our study illustrates the severity of erythroderma. It alters heavily the quality of life of patients which is initially altered by the pre-existent dermatosis. It may be life threatening as mortality rate is high.

Comparison of effectiveness and safety of infliximab, etanercept, and adalimumab in psoriatic arthritis patients who experienced an inadequate response to previous disease-modifying antirheumatic drug

2010-01-13T21:18:00.000-08:00

Comparison of effectiveness and safety of infliximab, etanercept, and adalimumab in psoriatic arthritis patients who experienced an inadequate response to previous disease-modifying antirheumatic drug

2010-01-13T06:15:00.000-08:00

Role of AUF1 in splenic size and follicular B cell maintenance.

2010-01-13T04:30:00.000-08:00

BMC Immunol. 2010 Jan 11; 11(1): 1Sadri N, Lu JY, Badura ML, Schneider RJABSTRACT: BACKGROUND: A large number of inflammatory cytokine and immune regulatory mRNAs are encoded by mRNAs that contain AU-rich elements (ARE) in their 3'-untranslated region. The ARE, through the interaction with ARE-binding proteins, regulates the stability and translation of its corresponding mRNA. Heterogeneous nuclear ribonucleoprotein D (HNRNPD), generally known as AUF1, is an ARE-binding protein that is important in the regulation of ARE-mRNA stability. We previously developed an AUF1-deficient mouse and showed that these animals are sensitized to endotoxic shock and development of pruritic inflammatory skin disease similar to human psoriasis as a result of the loss of AUF1 regulation of ARE-mRNAs. These animals also develop profound alterations in immune cell (splenic B lymphocyte) development and function, demonstrating an important new function for AUF1, which we report here. RESULTS: Mice lacking AUF1 exhibit an altered proportion and size of splenic B cell subsets. We show that prominent apoptosis in splenic B cell follicles and reduced expression of Bcl-2, A1, and Bcl-XL in follicular (FO) B cells coincides with a reduced lifespan and significant reduction in the number and proportion of FO B cells in spleens of AUF1-deficient mice. In addition, AUF1-deficient mice exhibit a sharp decrease in splenic size and lymphocyte cellularity. Bone marrow transfer studies demonstrate that AUF1 deficiency induced cell-autonomous defects in mature B cell subsets but not in overall splenic cellularity. While reconstitution of irradiated adult AUF1-deficient mice with wild-type bone marrow restored the proportion of FO and marginal zone (MZ) B cells, it could not rescue the decreased splenic cellularity. CONCLUSIONS: Functionally, AUF1-deficient mice mount an attenuated response to T cell-independent (TI) antigen. These results indicate that AUF1 is important in the maintenance of splenic FO B cells and adequate humoral immune responses.

Sonozaki syndrome: case report and review of literature.

2010-01-12T06:45:00.000-08:00

Rheumatol Int. 2010 Jan 5; BrzeziÅska-WcisÅo L, Bergler-Czop B, Lis-ÅwiÄty ASonozaki syndrome-pustulotic arthro-osteitis (PAO) is a relatively rare, chronic illness. This disease belongs to the group of psoriatic arthritis (psoriasis arthropatica, artropatia psoriatica) which in turn belongs to the group of seronegative arthritis. Sonozaki syndrome includes palmoplantar pustulosis, PPP as well as arthro-osteitis. Clinically, symmetrically localised pustulae are observed on feet and hands. Effected joints are painful, swollen with a visible inflammation. Here, we describe a case of a woman aged 55 with a diagnosis of Sonozaki syndrome and hyperthyroidism. At the moment of admission multiple changes in the form of pustulae were observed on hands and soles, filled with pus and blood of the erythemal basis. Oral and genital mucosa were free from changes. The oedema within clavicle and sternum joints was without features of the severe inflammation and tactical tenderness. In additional tests, increased BSR 36/62 was found. Bone scintigraphy-focuses of increased accumulation of MDP-Tc-99 m were found in the sternal projection of the clavicle ends at both sides, and the left-side change is bigger and more strongly saturated and can probably progress to the sternum's manubrium. As a result of the used treatment during hospitalisation, (cyclosporine 3 mg/kg and steroid external therapy upon the skin changes) the improvement of the local changes was observed as well as no progression in the joints' changes. At the moment, the patient is treated in the dermatological and rheumatological out-clinic. Early and correct diagnostics allows for efficient treatment of Sonozaki syndrome and decreases the risk of potential complications, such as the described systemic amyloidosis.

Increased mast cell expression of PAR-2 in skin inflammatory diseases and release of IL-8 upon PAR-2 activation.

2010-01-11T07:58:00.000-08:00

Exp Dermatol. 2009 Nov 2; Carvalho RF, Nilsson G, Harvima ITPlease cite this paper as: Increased mast cell expression of PAR-2 in skin inflammatory diseases and release of IL-8 upon PAR-2 activation. Experimental Dermatology 2009.Abstract: Mast cells are increasingly present in the lesional skin of chronic skin inflammatory diseases including psoriasis and basal cell carcinoma (BCC). It has previously been shown that proteinase-activated receptor (PAR)-2 is expressed by mast cells, and tryptase is a potent activator of this receptor. In this study, skin biopsies from both healthy-looking and lesional skin of patients with psoriasis and superficial spreading BCC were collected and the expression of PAR-2 immunoreactivity in tryptase-positive mast cells was analysed. PAR-2 expression was confirmed in vitro in different mast cell populations. Cord-blood derived mast cells (CBMC) were stimulated with a PAR-2 activating peptide, 2-furoyl-LIGRLO-NH(2). Consequently, IL-8 and histamine production was analysed in the supernatants. We observed a significant increase in the percentage of mast cells expressing PAR-2 in the lesional skin of psoriasis and BCC patients compared with the healthy-looking skin. HMC-1.2, LAD-2 and CBMC mast cells all expressed PAR-2 both intracellularly and on the cell surface. CBMC activation with the PAR-2 activating peptide resulted in an increased secretion of IL-8, but no histamine release was observed. Furthermore, both PAR-2 and IL-8 were co-localized to the same tryptase-positive mast cells in the lesional BCC skin. These results show that mast cells express increased levels of PAR-2 in chronic skin inflammation. Also, mast cells can be activated by a PAR-2 agonist to secrete IL-8, a chemokine which can contribute to the progress of inflammation.

Induced keratinocyte hyper-proliferation in alpha2beta1 integrin transgenic mice results in systemic immune cell activation.

2010-01-10T03:00:00.000-08:00

Int Immunopharmacol. 2009 Oct 17; Teige I, BÃ¤cklund A, Svensson L, Kvist PH, Petersen TK, Kemp Kalpha2beta1 integrins are normally confined to the proliferating basal layers of the epidermis. However, during wound healing and in psoriasis, these integrins are expressed on keratinocytes in suprabasal layers correlating with a less differentiated phenotype. Transgenic mice expressing alpha2beta1 integrins under the involucrine promoter have previously been demonstrated, to various degrees, spontaneously develop a skin disorder resembling psoriasis. Herein, we show that a mild epidermal wounding induces a uniform acanthosis together with an influx of immune cells. The disease initiates as a normal wound healing process and is completely restored in wildtype mice by day 14. However, in the integrin transgenic mice a chronic inflammation develops, a process that can be compared to the Koebner phenomenon in psoriatic patients. In this study, we have followed the integrin transgenic mice for five weeks, where substantial keratinocyte hyper-proliferation, inflammatory infiltration and high cytokine levels within the skin can still be observed. In addition, draining lymph nodes were dramatically increased in size and contained highly activated T cells, as well as APCs secreting large amounts of pro-inflammatory cytokines. Furthermore, the systemic immune response was affected with increased spleen size, elevated cytokine levels in the serum and altered lymphocyte trafficking patterns, very much resembling what is seen in psoriasis patients. Finally, CD4(+) T cell depletion was not able to affect the onset or progression of skin inflammation. This suggests that altered keratinocyte differentiation and proliferation can drive a skin inflammation and cause chronic immune cell activation both at a local and systemic level.

Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis.

2010-01-08T07:44:00.000-08:00

Br J Pharmacol. 2009 Dec 24; Schafer P, Parton A, Gandhi A, Capone L, Adams M, Wu L, Bartlett J, Loveland M, Gilhar A, Cheung YF, Baillie G, Houslay M, Man HW, Muller G, Stirling DBackground and purpose: Apremilast is an orally administered phosphodiesterase-4 inhibitor, currently in phase 2 clinical studies of psoriasis and other chronic inflammatory diseases. The inhibitory effects of apremilast on pro-inflammatory responses of human primary peripheral blood mononuclear cells (PBMC), polymorphonuclear cells, natural killer (NK) cells and epidermal keratinocytes were explored in vitro, and in a preclinical model of psoriasis. Experimental approach: Apremilast was tested in vitro against endotoxin- and superantigen-stimulated PBMC, bacterial peptide and zymosan-stimulated polymorphonuclear cells, immunonoglobulin and cytokine-stimulated NK cells, and ultraviolet B light-activated keratinocytes. Apremilast was orally administered to beige-severe combined immunodeficient mice, xenotransplanted with normal human skin and triggered with human psoriatic NK cells. Epidermal skin thickness, proliferation index and inflammation markers were analysed. Key results: Apremilast inhibited PBMC production of the chemokines CXCL9 and CXCL10, cytokines interferon-gamma and tumour necrosis factor (TNF)-alpha, and interleukins (IL)-2, IL-12 and IL-23. Production of TNF-alpha by NK cells and keratinocytes was also inhibited. In vivo, apremilast significantly reduced epidermal thickness and proliferation, decreased the general histopathological appearance of psoriasiform features and reduced expression of TNF-alpha, human leukocyte antigen-DR and intercellular adhesion molecule-1 in the lesioned skin. Conclusions and implications: Apremilast displayed a broad pattern of anti-inflammatory activity in a variety of cell types and decreased the incidence and severity of a psoriasiform response in vivo. Inhibition of TNF-alpha, IL-12 and IL-23 production, as well as NK and keratinocyte responses by this phosphodiesterase-4 inhibitor suggests a novel approach to the treatment of psoriasis.

Clinically validated approaches to the treatment of autoimmune diseases.

2010-01-07T13:39:00.000-08:00

Expert Opin Investig Drugs. 2010 Jan 6; Carter PH, Zhao QImportance of the field: Autoimmune diseases are pathological conditions in which "self-tolerance" has been broken, and an immune response has been mounted against the body's own tissues. More than seventy autoimmune diseases have been described, some of which are systemic and others of which are organ-specific. Although many of these diseases are rare, the collective prevalence of autoimmune diseases in the United States alone is between 5 and 8%, and is increasing. Areas covered in this review: Herein, we review the exciting advances made during the past decade (1999 - 2009) in the development of clinically-validated agents for the treatment of autoimmune disease. We focus on five of the most prevalent conditions: rheumatoid arthritis, psoriasis, multiple sclerosis, Crohn's disease, and systemic lupus erythematosus. The discussion is largely restricted to agents - both small molecules and macromolecules - that have advanced through randomized, controlled clinical trials. What the reader will gain: An overview of the pathogenesis of each disease is provided, along with a description of the therapies. Results from pivotal clinical trials are tabulated for four of the disease areas. We also provide summaries of experiences with both failed clinical trials and side effects observed during the course of clinical investigations. We conclude the review with thoughts on current challenges in the field and the prospect for future innovations. Take home message: During the past decade, some of the largest advances in the treatment of autoimmune disease have arisen from highly potent and selective macromolecule-based therapies (e.g. antibodies, recombinant proteins and fusion proteins). Together, these clinical experiences have provided insight into the critical mechanisms in autoimmune pathogenesis, including inflammatory cytokine release, T-cell migration and co-stimulation, and B-cell function.

Development and validation of nail psoriasis quality of life scale (NPQ10).

2010-01-06T08:09:00.000-08:00

J Eur Acad Dermatol Venereol. 2010 Jan; 24(1): 22-7Ortonne JP, Baran R, Corvest M, Schmitt C, Voisard JJ, Taieb CBACKGROUND: The chronic and treatment-resistant nature of nail psoriasis affects patients' lives not only physically but also psychologically. Although there are scoring systems available for disease severity, there is as yet no scale to evaluate the impact of this condition upon the patients' quality of life. OBJECTIVES: This study aims to develop and validate a quality of life scale specifically for nail psoriasis. METHODS: A questionnaire was developed during a study conducted in France between 2004 and 2005. With the cooperation of l'Association Pour la Lutte Contre le Psoriasis, the questionnaire was sent to a random sample of 4000 of its 17,000 members. RESULTS: The response rate was 33%. Of the 1309 questionnaires returned, 795 showed the presence of nail psoriasis and these were eligible. The scale score is obtained by adding together the responses to the 10 questionnaire items and the result is expressed as a percentage. The value of the score obtained is proportional to the functional difficulty experienced. The determination of Cronbach's a coefficient and a Principal Component Factor Analysis show, respectively, very good internal consistency and the unidimensional nature of the scale. Test-retest results on 15 patients showed good reproducibility. Results were validated with reference to the Dermatology Life Quality Index. In this study, the NPQ10 score is significantly influenced by gender (women have a higher score) and by the duration of psoriasis (recent onset implies greater functional difficulty). Finally, the score is much higher when the nail psoriasis affects both the hands and the feet. CONCLUSION: This study confirms a change in the quality of life of patients who have nail psoriasis. The NPQ10 scale, specific to this condition, is simple to use and has the attributes needed in a quality of life scale. The scale must now be tested in longitudinal studies (such as clinical trials) to confirm its ability to measure a change in status.

The skin's barrier.

2010-01-05T04:05:00.000-08:00

G Ital Dermatol Venereol. 2009 Dec; 144(6): 689-700Jensen JM, Proksch EThe skin provides an effective barrier between the organism and the environment, preventing the invasion of pathogens and fending off chemical and physical assaults, as well as the unregulated loss of water and solutes. In this review we provide an overview of several components of the physical barrier, as well as how barrier function is regulated and altered in association with dermatoses. The physical barrier localized primarily in the stratum corneum (SC) and consists of protein-enriched cells (corneocytes with cornified envelope and cytoskeletal elements, as well as corneodesmosomes) and lipid-enriched intercellular domains. The nucleated epidermis, with its tight, gap and adherens junctions, additional desmosomes and cytoskeletal elements, also contributes to the barrier. Lipids are synthesized in the keratinocytes during epidermal differentiation and are then extruded into the extracellular domains, where they form lipid-enriched extracellular layers. The cornified cell envelope, a robust protein/lipid polymer structure, is located below the cytoplasmic membrane on the exterior of the corneocytes. Ceramides A and B, forming the backbone for the subsequent addition of free ceramides, free fatty acids and cholesterol in the SC, are covalently bound to cornified envelope proteins. Filaggrin is cross-linked to the cornified envelope and aggregates keratin filaments into macrofibrils. Cytokines, cAMP and calcium influence the formation and maintenance of barrier function. Changes in lipid composition and epidermal differentiation lead to a disturbed skin barrier, which allows the entry of environmental allergens, immunological reaction and inflammation in atopic dermatitis. A disturbed skin barrier is an important component in the pathogenesis of contact dermatitis, ichthyosis, psoriasis, and atopic dermatitis.

Conditioned Pharmacotherapeutic Effects: A Preliminary Study.

2010-01-04T07:37:00.000-08:00

Psychosom Med. 2009 Dec 22; Ader R, Mercurio MG, Walton J, James D, Davis M, Ojha V, Kimball AB, Fiorentino DObjective: To test the hypothesize that psoriasis patients treated under a partial schedule of pharmacologic (corticosteroid) reinforcement would show less severe symptoms and relapse than those given the same amount of drug under standard conditions. Behavioral conditioning as an inherent component of many pharmacotherapeutic protocols has never been examined. Methods: A double-blind, simple randomization intervention was conducted with 46 patients from California and New York. Initially, lesions were treated with 0.1% acetonide triamcinolone under standard treatment conditions. Thereafter, a Standard Therapy group continued on continuous reinforcement (active drug every treatment) with 100% of the initial dose; Partial Reinforcement patients received a full dose 25% to 50% of the time and placebo medication other times; Dose Control patients received continuous reinforcement with 25% to 50% of the initial dose. Results: Severity of disease scores in California neither supported nor refuted the hypothesis. In New York, where there was no difference between Partial Reinforcement and Dose Control groups at baseline, partial reinforcement effected a greater reduction in lesion severity than Dose Control conditions and did not differ from Standard Therapy patients receiving two to four times more drug. For the entire population, the frequency of relapse under partial reinforcement (26.7%) was lower than in Dose Control patients (61.5%) and did not differ from full-dose treatment (22.2%). Conclusions: A partial schedule of pharmacotherapeutic reinforcement could maintain psoriasis patients with a cumulative amount of corticosteroid that was relatively ineffective when administered under standard treatment conditions. Conceivably, corticosteroid administration only one quarter or half as frequently as currently prescribed is sufficient to treat psoriasis. We posit, however, that these preliminary observations implicate conditioning processes in-and for the design of-regimens of pharmacotherapy.

Genomic Dissection of Population Substructure of Han Chinese and Its Implication in Association Studies.

2010-01-03T07:52:00.000-08:00

Am J Hum Genet. 2009 Nov 25; Xu S, Yin X, Li S, Jin W, Lou H, Yang L, Gong X, Wang H, Shen Y, Pan X, He Y, Yang Y, Wang Y, Fu W, An Y, Wang J, Tan J, Qian J, Chen X, Zhang X, Sun Y, Zhang X, Wu B, Jin LTo date, most genome-wide association studies (GWAS) and studies of fine-scale population structure have been conducted primarily on Europeans. Han Chinese, the largest ethnic group in the world, composing 20% of the entire global human population, is largely underrepresented in such studies. A well-recognized challenge is the fact that population structure can cause spurious associations in GWAS. In this study, we examined population substructures in a diverse set of over 1700 Han Chinese samples collected from 26 regions across China, each genotyped at approximately 160K single-nucleotide polymorphisms (SNPs). Our results showed that the Han Chinese population is intricately substructured, with the main observed clusters corresponding roughly to northern Han, central Han, and southern Han. However, simulated case-control studies showed that genetic differentiation among these clusters, although very small (F(ST) = 0.0002 approximately 0.0009), is sufficient to lead to an inflated rate of false-positive results even when the sample size is moderate. The top two SNPs with the greatest frequency differences between the northern Han and southern Han clusters (F(ST) > 0.06) were found in the FADS2 gene, which associates with the fatty acid composition in phospholipids, and in the HLA complex P5 gene (HCP5), which associates with HIV infection, psoriasis, and psoriatic arthritis. Ingenuity Pathway Analysis (IPA) showed that most differentiated genes among clusters are involved in cardiac arteriopathy (p < 10(-101)). These signals indicating significant differences among Han Chinese subpopulations should be carefully explained in case they are also detected in association studies, especially when sample sources are diverse.

Comparison of skin concentrations following topical versus oral corticosteroid treatment: reconsidering the treatment of common inflammatory dermatoses.

2010-01-01T06:16:00.000-08:00

J Drugs Dermatol. 2009 Dec; 8(12): 1076-9McClain RW, Yentzer BA, Feldman SRBACKGROUND: Topical corticosteroids are often considered to have greater safety and poorer efficacy than oral corticosteroids in treating psoriasis and atopic dermatitis. There are limited data for assessing relative efficacy of topical and systemic corticosteroids, however. The concentration of corticosteroid in skin, adjusted for the relative potency of the active compound, may be a predictor of clinical efficacy and can be estimated for both topical and oral administration. PURPOSE: To analyze the assumption that oral corticosteroid therapy should be more potent than topical therapy by comparing relative corticosteroid concentrations in the skin expected with topical versus systemic administration. METHODS: The estimated skin concentration of prednisone following oral dosing was calculated based on data showing 70-100% bioavailability and an even tissue distribution. Data on the concentration of corticosteroids found in skin after topical application were obtained from the literature. The relative potencies of corticosteroid molecules were then used to compare skin concentrations of corticosteroid following topical versus oral treatment. RESULTS: Data derived from the existing literature demonstrated that hydrocortisone 2.5% ointment, triamcinolone 0.1% ointment, and clobetasol 0.05% foam achieved effective skin concentrations greater than the effective concentration achieved by oral prednisone. Betamethasone 0.1% cream achieved effective concentrations in skin within the range created by oral prednisone. LIMITATIONS: This analysis was limited by the paucity of data regarding cutaneous concentrations of corticosteroids after topical application, and by the differing experimental designs utilized in the available studies. CONCLUSION: Most topical corticosteroids have the potential to achieve greater effective drug levels in the superficial layers of skin than those achieved with standard doses of oral prednisone. The apparently greater efficacy of oral corticosteroid therapy may be attributable, in part, to poor patient compliance with topical therapy. Systemic alterations in immune function following oral, but not topical, corticosteroid use may also play a role.

Novel loci, including those related to Crohn disease, psoriasis, and inflammation, identified in a genome-wide association study of fibrinogen in 17 686 women: the Women's Genome Health Study.

2009-12-30T14:25:00.000-08:00

Circ Cardiovasc Genet. 2009 Apr; 2(2): 134-41Danik JS, ParÃ© G, Chasman DI, Zee RY, Kwiatkowski DJ, Parker A, Miletich JP, Ridker PMBACKGROUND: Fibrinogen is a multifunctional circulating glycoprotein involved in wound healing, thrombosis, platelet aggregation, and inflammation, and elevated levels predict vascular disease. Despite evidence of crucial biological function and moderate heritability, comprehensive analysis of the influence of genetic variation on fibrinogen is not available. METHODS AND RESULTS: To address this issue, we undertook a genome-wide association study evaluating the potential relationships between 337 343 single-nucleotide polymorphisms (SNPs) and plasma fibrinogen levels among 17 686 apparently healthy women participating in the Women's Genome Health Study. As C-reactive protein is also an inflammatory marker known to predict cardiovascular diseases, we compared the determinants of fibrinogen levels with those of C-reactive protein. Four novel loci were identified, in addition to the fibrinogen gene cluster, which were associated with fibrinogen levels at genome-wide levels of significance (range of probability values from 8.82 x 10(-09) to 8.04 x 10(-39)). Two of the loci are related to common chronic inflammatory diseases: the first, at locus 5q31.1 (SLC22A5, SLC22A4, IRF1), lies immediately adjacent to a locus linked to Crohn disease (P value for lead SNP, 1.24 x 10(-12)) and the second, at locus 17q25.1 (CD300LF, SLC9A3R1, NAT9), has been associated with psoriasis (P value for lead SNP, 7.72 x 10(-11)). A third locus at 1q21.3 (IL6R) lies within the interleukin 6 receptor gene, a critical component of the inflammatory cascade (P value for lead SNP, 1.80 x 10(-11)). A novel locus at 2q34 (CPSI) participates in the urea cycle (P=8.82 x 10(-09)). The majority of implicated SNPs showed little evidence of dual association with C-reactive protein levels. CONCLUSIONS: A genome-wide survey of the human genome identifies novel loci related to common chronic inflammatory diseases as genetic determinants of fibrinogen levels, in addition to loci that relate to the inflammatory cascade, the urea cycle, and the fibrinogen gene cluster.

First joint event between Europe and EADV: EADV-AAD Review Course State-of-the-Art in Dermatology Munich, 25-28 June 2009.

2009-12-30T00:27:00.001-08:00

Acta Dermatovenerol Croat. 2009; 17(4): 333-6Ring JThe relations between Europe and the USA, especially the European Academy of Dermato-Venereology (EADV) and the American Academy of Dermatology (AAD), have been increasingly more intense over years. This year in June, a "world premiere" happened with the joint EADV-AAD Review Course in Munich, where EADV and AAD created a program together on the topic of "state-of-the-art in dermatology". The idea of the American regional review courses where a limited number of participants (maximum 200) meet for two days at a nice location was adopted by Johannes Ring, Munich, who developed a program together with Mary Maloney, Worcester, USA. The actual organization was in the hands of the EADV Central Office, with great support from the Department of Dermatology and Allergology Biederstein, Technische UniversitÃ¤t MÃ¼nchen (Martin Mempel). The scientific program covered all aspects of dermatology and venereology without a special "theme". Excellent speakers both from the USA and Europe guaranteed for an outstanding program for 120 participants from 38 countries. Oncology Skin cancer was covered by a lecture by EADV President Andreas Katsambas, and non-melanoma skin cancer by Symposium organizer Mary Maloney. Jean Bologna (North Haven) described and explained "signature nevi", while John Guitart (Chicago) reviewed the difficult subject of cutaneous T cell lymphoma. New opportunities in dermoscopy were presented by EADV past President Alberto Giannetti (Modena). Inflammatory Skin Disease From the vast spectrum of inflammatory skin diseases, the topic of psoriasis was covered by AAD President David Pariser (Norfolk) who remarkably stepped in the last minute for Louis Dubertret whose flight was unable to leave Paris due to technical problems. Gerd Plewig (Munich) covered acne and introduced a new concept for what was formerly called "acne tetrade" as "dissecting terminal folliculitis". Frank Powell, EADV President-Elect (Dublin), showed different subtypes of rosacea, expressing new pathophysiological concepts with a movie howing demodex mites dancing to Beatles music. Allergy Johannes Ring (Munich), organizer of the event, gave an overview on "Skin and allergy", showing clearly that no other discipline has better opportunity to deal with allergy than dermatology! Stephan Weidinger (Munich) covered the recently exploding field of molecular genetics of atopy in atopic eczema with not only filaggrin mutations, but also new findings regarding the IgE receptor and totally new gene associations. The difficult subject of subcutaneous drug eruptions was covered by Lars French (Zurich). Infectious Dermatology and Venereology Martin Mempel (Munich) described the various granulomatous skin diseases, both infectious and non-infectious in origin. The venereological part of our specialty was highlighted by Erwin Tschachler (Vienna) with news on syphilis and HIV infection. Skin Aging The exciting pathophysiological changes occurring during skin aging were highlighted by former EADV President Jean-Hilaire Saurat (Geneva). He introduced the new term "dermatoporosis", stressing the disease character of these findings. Advances in Treatment Latest results in topical treatment of atopic eczema were highlighted by Lawrence Eichenfield (San Diego). David Pariser gave very important tips and tricks for practical management of hyperhidrosis. Michael Landthaler (Regensburg) showed the clear indications for laser or intense pulse light (IPL) treatment in dermatology. In the social program, attendants had an opportunity to see the movie of the musical "Odysee of Allergy", which had been performed at the 10th EADV Congress in Munich in 2001 in the LÃ¶wenbrÃ¤u Beer Hall. Furthermore, in an excursion to the outskirts south of Munich, the participants could enjoy the sights of monastery of Ettal with a beautiful rococo church, King Ludwig's II castle of Linderhof as well as an alpine cottage, Kreutalm. In their summing up, Mary Maloney and Johannes Ring felt that this first common course as a joint event of EADV and AAD was a real success and that the program should be continued, most likely in 2010 in the USA.

Internet-supported gathering of treatment data and patient benefits in psoriasis.

2009-12-04T00:05:00.001-08:00

J Eur Acad Dermatol Venereol. 2009 Oct 21; Langenbruch A, SchÃ¤fer I, Franzke N, Augustin MAbstract Background Studies about health care of psoriasis patients in Germany are predominantly carried out in dermatological centres, which results in a certain selection bias. To collect data from other sources of patients, the German Centre of Health Services Research in Dermatology conducted a series of web-based studies. The extent of how data on health care on psoriasis gathered online vary from paper and pencil data is yet to be explored. Objective 1 To collect reliable treatment and benefit online data from psoriasis patients in Germany. 2 To compare these with data gathered at dermatological centres. Methods On the 'psoriasis-hilfe.de' web portal, psoriasis patients were asked to complete the online version of a questionnaire, which has already been used as a paper and pencil version in the national psoriasis study 'PsoHealth'. Subsequently, difference analyses were conducted between the two data sets. Results The PsoWeb sample (n = 1071) varies to a high extent from the PsoHealth sample (n = 2009) regarding the achievement of treatment goals and treatment satisfaction. Irrespective of age, sex and duration of disease, the online sample showed lower treatment satisfaction and fewer patient-defined benefits. Conclusion The findings suggest that patients in the online sample are less satisfied with their health care, which also could have been their motive for participating online. It is important to gather data online because it increases the data pool and permits inclusion of people who are not incorporated in clinical settings. However, online data cannot directly replace data collected in clinics because they are also subject to selections.

An Italian shared dermatological and rheumatological proposal for the use of biological agents in psoriatic disease.

2009-11-30T22:58:00.001-08:00

J Eur Acad Dermatol Venereol. 2009 Oct 23; Marchesoni A, Altomare G, Matucci-Cerinic M, Balato N, Olivieri I, Salvarani C, Lotti T, Scarpa R, Vena G, Valesini G, Giannetti AAbstract Background As psoriatic disease (PD) is a condition characterized by the combination of inflammatory skin (psoriasis) and osteo-articular manifestations (psoriatic arthritis), its treatment should cover both its clinical components. Objective The objective of this study was to propose a flexible framework for the use of biological agents in PD. Methods The proposal was drawn up by a group of dermatologists and rheumatologist expert in PD and was based on existing evidence and personal opinion. Results The three TNF-alpha inhibitors (adalimumab, etanercept, infliximab) are effective in all of the psoriatic manifestations and should be used in the case of moderate/severe disease refractory to systemic treatment with non-biological drugs. We propose the following definitions of moderate/severe disease: PASI > 10 or BSA > 10 or DLQI > 10 for plaque-psoriasis; BSA >/= 10 or DLQI >/= 10 for the other psoriatic skin lesions; DLQI >/= 10 or meaningful values of the NAPSI or mNAPSI for psoriatic nail involvement; >/= 1 inflamed joint + patient global VAS(3)4 + physician's judgement or arthritic joint deformities or radiographic joint damage plus >/= 5 inflamed small joints or >/= 1 large joints for peripheral joint involvement; >/= 1 digit with dactylitis and >/= 1 enthesitic sites + patient global VAS(3)4 + physician's judgement for dactylitis and enthesitis. BASDAI >/= 4 + physician's judgement for spondylitis; recurrent flares or risk of developing irreversible damage for uveitis. Other assessment instruments can be used if the physician is more familiar with them and if they have been validated. Conclusion We provide a shared dermatological and rheumatological proposal for the use of biological agents in PD.

Simple and rapid screening for HLA-Cw*06 in Polish patients with psoriasis.

2009-11-29T22:59:00.001-08:00

Clin Exp Dermatol. 2009 Oct 23; RÄbaÅa K, Szczerkowska-Dobosz A, Niespodziana K, Wysocka JSummary Background. The human leucocyte antigen (HLA) C allele Cw*06 is currently recognized as a major disease allele at the PSORS1 locus. It has been suggested that characterization of this gene could be used as a convenient criterion for classification of psoriasis phenotypes. Aim. To design and optimize a DNA typing procedure, suitable for identification of HLA-Cw*06 and its zygosity status verification in large-scale analyses, and to test for its robustness in a case-control study. Methods. PCR assays with sequence-specific primers (PCR-SSP) were used for specific detection of HLA-Cw*06. PCR with analysis of restriction fragment length polymorphism was used to distinguish between patients homozygous and heterozygous for HLA-Cw*06. Additionally, those homozygous for HLA-Cw*06 were screened for nonspecific digestion by degenerated PCR-SSP. This three-step procedure was used in the examination of 383 patients with psoriasis that developed at the age of >/= 30 years of age and of 143 healthy subjects from northern Poland. Results. A simple and rapid procedure for screening of HLA-Cw*06 was produced. A significant difference in HLA-Cw*06 frequency between patients with psoriasis and controls was seen (P = 0.02). Detailed examination of the age of disease onset among patients with psoriasis revealed that involvement of HLA-Cw*06 in the genetic background of psoriasis developing as late as the age of 45 years cannot be neglected. Conclusions. The low cost, high-throughput capacity and requirement for small sample amounts make this procedure a useful one for HLA-Cw*06 typing in clinical practice and large population studies. We recommend that patients with psoriasis diagnosed before 45 years of age should be considered for diagnostic HLA-Cw*06 typing.

Recovery from tanning induced by narrow-band UVB phototherapy in brown-skinned individuals with psoriasis: Twelve-month follow-up.

2009-11-28T05:42:00.001-08:00

J Dermatol Sci. 2009 Nov 12; Kwon IH, Woo SM, Choi JW, Kwon HH, Youn JIBACKGROUND: Pigmentation induced by narrow-band UVB (NBUVB) phototherapy can cause complaints by psoriasis patients, especially those with brown skin. Nevertheless, the recovery process from tanning after the completion of NBUVB treatment is not known. OBJECTIVE: The purpose of this study was to evaluate the extent of tanning recovery after the end of NBUVB treatment and determine the time required to recover from the fully tanned state. METHOD: Sixteen psoriasis patients with brown skin were observed. The skin color changes on the lower back were measured before beginning phototherapy, upon completion of NBUVB treatment, and subsequently every month for the first one-half year, then bimonthly for the second one-half year, using two different reflectance spectrophotometers. The results are presented as the erythema index (EI) and melanin index (MI), L*a*b* values as recommended by the Commission Internationale de l'Eclairge, and the individual typology angle (ITA degrees ). RESULTS: The mean L* value reached 64.4 by the 10th month after the end of NBUVB treatment, with no significant difference from the value before beginning phototherapy. The mean ITA degrees approximated the initial angle at the 8th month after completing NBUVB treatment with no significant difference, thus representing recovery to the original intermediate skin color. The MI recovered to the initial values earlier than the L* value and ITA degrees . The EI appeared the earliest recovery value. CONCLUSION: Understanding the recovery process from tanning induced by NBUVB treatment will improve the patient's compliance for treatment and bring higher efficacy and safety to the retrial of phototherapy in brown-skinned individuals with psoriasis.

The status of biologic therapies in the treatment of moderate to severe psoriasis.

2009-11-27T20:18:00.001-08:00

Cutis. 2009 Oct; 84(4 Suppl): 14-24Menter APsoriasis is a chronic inflammatory, immune-mediated, genetic disease predominantly affecting the skin and associated with significant patient morbidity. Conventional topical and systemic treatment options are numerous and generally effective, with varying degrees of success and rapidity of action. However, recurrence of disease is inevitable. Biologic agents that target pathogenic T cells have been shown to be effective in patients with moderate to severe psoriasis, with the remittive effects of alefacept encouraging in a small proportion of patients. Efalizumab recently was withdrawn from the US market after 5 years of use because of 3 cases of progressive multifocal leukoencephalopathy (PML), a serious life-threatening infection. The tumor necrosis factor alpha (TNF-alpha) inhibitors etanercept, infliximab, and adalimumab have demonstrated notable initial and maintenance efficacy in the treatment of moderate to severe psoriasis but require monitoring because of safety concerns, including risk for infections. A new class of biologic agents, anti-IL-12 and IL-23 antibodies (ustekinumab and ABT-874), shows significant promise for the treatment of moderate to severe psoriasis. However, as new agents in medicine, more evidence is required regarding long-term safety. Despite the efficacy of these biologic agents, which have revolutionized the therapy for moderate to severe psoriasis, complete clearances are not always obtained and relapses occur in a proportion of patients. To maintain better control of the disease, many physicians and patients are choosing combination or adjunctive therapies to augment the results seen with biologic agents. However, to date, there are no well-controlled studies demonstrating safety and/or efficacy of biologic agents in combination with other therapies. Prospective trials of this sort are therefore needed to better understand the potential risks and benefits of such approaches.

Identifying the biologic closest to the ideal to treat chronic plaque psoriasis in different clinical scenarios: using a pilot multi-attribute decision model as a decision-support aid.

2009-11-24T20:18:00.001-08:00

Curr Med Res Opin. 2009 Dec; 25(12): 2835-43Guibal F, Iversen L, Puig L, Strohal R, Williams POBJECTIVE: Multi-attribute decision-making (MADM) models evaluate competing solutions for complex problems to identify the closest fit to the ideal solution. MADM models may assist dermatologists when selecting between biologics for plaque psoriasis. Here, is described the development of a pilot model to identify the preferred biologic from the dermatologist's perspective. RESEARCH DESIGN AND METHODS: A group of European dermatologists were surveyed to identify treatment attributes they consider when prescribing a biologic. The relative importance of each was determined by allocation of 100 importance points in the context of seven case vignettes, reflecting the breadth of disease encountered in dermatological practice. Biologic performance was rated anonymously on a scale of 1-10, scores entered into a MADM matrix, and TOPSIS (Technique for Ordered Preference by Similarity to the Ideal Solution) analysis applied to identify the biologic closest to the hypothetical ideal. RESULTS: Long-term efficacy and safety were the most important attributes considered by dermatologists when selecting a biologic. For one case vignette (chronic stable psoriasis), TOPSIS scores showed that etanercept was closest to the ideal for 63% of respondents, with adalimumab closest to the ideal for 32% of respondents. Differences among the biologics were highly significant (p < 0.0001). For severe unstable psoriasis, infliximab and adalimumab were preferred. LIMITATION: This study was conducted with a group of dermatologists attending a Wyeth-sponsored advisory board meeting. CONCLUSIONS: Based on responses from this expert group, etanercept was the preferred choice for stable chronic plaque psoriasis for the majority, with infliximab preferred for more severe disease. However, there are several limitations to this pilot model, most notably the non-random selection of the expert group. Further development of the model encompassing a random survey of dermatologists and inclusion of other treatment alternatives and the latest clinical data, will add to the clinical utility of the tool.

Clobetasol propionate spray 0.05% add-on therapy to a stable regimen of biologic treatment in patients with moderate to very severe plaque psoriasis.

2009-11-23T20:26:00.001-08:00

Cutis. 2009 Oct; 84(4 Suppl): 25-32Feldman SR, Koo JY, Johnson LA, Preston NJModerate to severe psoriasis often requires systemic treatment, but even biologic medications do not always induce complete clearing in patients. In many instances, physicians supplement biologic treatment with topical agents as adjunctive therapy to obtain additional clearing of plaques. To evaluate the effectiveness of the addition of a superpotent corticosteroid--clobetasol propionate spray 0.05%--to various psoriasis treatments, a phase 4, multicenter, open-label, community-based trial was conducted. In this study, clobetasol propionate spray 0.05% applied twice daily was added on to a variety of existing stable treatments including systemic biologic agents in participants with moderate, severe, or very severe plaque psoriasis. The decision to add clobetasol propionate spray 0.05% to stable psoriasis therapy was determined by each investigator based on his/her evaluation of a participant's needs. A total of 159 participants from the trial adhered to stable (> or = 3 months' duration) therapeutic regimens that included a biologic treatment. In this population, at the end of the study period, 81.0% of participants with moderate disease at baseline, 79.5% of participants with severe disease at baseline, and 58.8% of participants with very severe disease at baseline were rated as clear or almost clear (target plaque severity [TPS]). Worst skin tolerability response was assessed postbaseline and included erythema (20.3% mild, 8.9% moderate, 1.9% severe), peeling (26.6% mild, 7.0% moderate, 1.3% severe), dryness (34.8% mild, 8.9% moderate, 1.3% severe), and stinging (25.3% mild, 3.8% moderate, 0.6% severe). Telangiectasia and skin atrophy were reported in 1.3% of participants each at some point during the study (postbaseline). Pruritus was reported in 7.6% of participants and folliculitis was reported in 1.9% of participants. Eight participants experienced adverse events (AEs) that were regarded as probably related to the study medication (clobetasol propionate spray 0.05%). Because those participants who entered the study already were receiving one medication (the biologic agent), it is believed that most of the reported AEs were due to the addition of clobetasol propionate spray 0.05%, and those AEs associated with the biologic agent and/or the combination of the two may be underreported. Although the results of this study are intriguing, further research is needed to evaluate if the addition of topical therapies, such as superpotent corticosteroids, are effective and safe options for treating psoriasis plaques when control with biologic therapy is not fully effective on its own.

Sunitinib for the treatment of gastrointestinal stromal tumours: a critique of the submission from Pfizer.

2009-11-19T00:32:00.001-08:00

Health Technol Assess. 2009 Sep; 13 Suppl 2: 69-74Bond M, Hoyle M, Moxham T, Napier M, Anderson RThis paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of infliximab for the treatment of moderate to severe plaque psoriasis, in accordance with the licensed indication, based on the evidence submission from Schering-Plough to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The outcomes stated in the manufacturer's definition of the decision problem were severity [Psoriasis Area and Severity Index (PASI) score], remission rates, relapse rates and health-related quality of life. The main evidence in the submission comes from four randomised controlled trials (RCT) comparing infliximab with placebo and eight RCTs comparing either etanercept or efalizumab with placebo. At week 10, patients on infliximab had a significantly higher likelihood of attaining a reduction in PASI score than placebo patients. There were also statistically significant differences between infliximab and placebo in the secondary outcomes. In the comparator trials both the efalizumab and etanercept arms included a significantly higher proportion of patients who achieved a reduction in PASI score at week 12 than the placebo arms. No head-to-head studies were identified directly comparing infliximab with etanercept or efalizumab. The manufacturer carried out an indirect comparison, but the ERG had reservations about the comparison because of the lack of information presented and areas of uncertainty in relation to the included data. The economic model presented by the manufacturer was appropriate for the disease area and given the available data. The cost-effectiveness analysis estimates the mean length of time that an individual would respond to infliximab compared with continuous etanercept and the utility gains associated with this response. The base-case incremental cost-effectiveness ratio (ICER) for infliximab compared with continuous etanercept for patients with severe psoriasis was 26,095 pounds per quality-adjusted life-year. A one-way sensitivity analysis, a scenario analysis and a probabilistic sensitivity analysis were undertaken by the ERG. The ICER is highly sensitive to assumptions about the costs and frequency of inpatient stays for non-responders of infliximab. The guidance issued by NICE in August 2007 as a result of the STA states that infliximab within its licensed indication is recommended for the treatment of adults with very severe plaque psoriasis, or with psoriasis that has failed to respond to standard systematic therapies. Infliximab treatment should be continued beyond 10 weeks in people whose psoriasis has shown an adequate response to treatment within 10 weeks. In addition, when using the Dermatology Life Quality Index (DLQI), care should be taken to take into account the patient's disabilities, to ensure DLQI continues to be an accurate measure.

Adalimumab for the treatment of psoriasis.

2009-11-18T01:20:00.001-08:00

Health Technol Assess. 2009 Sep; 13 Suppl 2: 49-54Turner D, Picot J, Cooper K, Loveman EThis paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of adalimumab for the treatment of moderate to severe plaque psoriasis based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submission's clinical evidence came from three randomised controlled trials comparing adalimumab with placebo, two extension studies and one ongoing open-label extension study. The studies were of reasonable quality and measured a range of clinically relevant outcomes. A higher proportion of patients on 40 mg adalimumab every other week achieved an improvement on the Psoriasis Area and Severity Index (PASI) of at least 75% (PASI 75) compared with placebo groups after 12 or 16 weeks of treatment, and there was a statistically significant difference in favour of adalimumab for the proportion of patients achieving a PASI 50 and a PASI 90. In a mixed treatment comparison, for each PASI outcome the probability of a response was greater for infliximab than for adalimumab, but the probability of response with adalimumab was greater than that with etanercept, efalizumab and non-biological systemic therapies. Adverse event rates were similar in the treatment and placebo arms and discontinuations because of adverse events were low and comparable between groups. The submission's economic model presents treatment effectiveness for adalimumab versus other biological therapies based upon utility values obtained from two clinical trials. The model is generally internally consistent and appropriate to psoriasis in terms of structural assumptions and the methods used are appropriate. The base-case incremental cost-effectiveness ratio for adalimumab compared with supportive care for patients with severe psoriasis was 30,538 pounds per quality-adjusted life-year. Scenario analysis shows that the model was most sensitive to the utility values used. Weaknesses of the clinical evidence included not undertaking a systematic review of the comparator trials, providing very little in the way of a narrative synthesis of outcome data from the key trials and not performing a meta-analysis so that the overall treatment effect of adalimumab achieved across the trials is unknown. Weaknesses of the economic model included that the assumptions made to estimate the cost-effectiveness of intermittent etanercept used inconsistent methodology for costs and benefits and there were no clear data on the amount of inpatient care required under supportive care. The NICE guidance issued as a result of the STA states that adalimumab is recommended as a treatment option for adults with plaque psoriasis in whom anti-tumour necrosis factor treatment is being considered and when the disease is severe and when the psoriasis has not responded to standard systemic therapies or the person is intolerant to or has a contraindication to these treatments.

Infliximab for the treatment of psoriasis in Greece. Four years of clinical experience at a single center.

2009-11-16T20:40:00.001-08:00

Br J Dermatol. 2009 Nov 10; Antoniou C, Stefanaki I, Stratigos A, Moustou E, Vergou T, Stavropoulos P, Avgerinou G, Rigopoulos D, Katsambas ADAbstract Background. Infliximab, a chimeric monoclonal antibody, has been shown to be effective for moderate to severe psoriasis. Clinical experience with long-term Infliximab therapy for psoriasis is accumulating, and it is therefore important to share our experience with its use in real-life clinical practice. Objective. To report our experience with Infliximab (Remicade((R)) - Schering Plough) for the treatment of moderate to severe plaque psoriasis (and/or arthritis) from a single clinic in Greece. Patients. From August 2004 to March 2008, 62 patients presenting to our Clinic with moderate to severe psoriasis were treated with infliximab. Disease phenotype, clinical course, disease severity and adverse events were assessed throughout the treatment period. Results. Infliximab resulted in a reduction of median Psoriasis Area and Severity Index (PASI) of 70% at week 6 and 84.4% at week 14. Nineteen patients who have completed 1 year on infliximab treatment experienced sustained efficacy with a median PASI improvement of 92.16% and a Physician's Global Assessment (PGA) of "clear" or "almost clear", while 9 patients have reached approximately 20 months of continuous therapy. All patients with psoriatic arthritis showed marked improvement in their clinical symptoms following the 1st infusion. Eight patients (12.9%) experienced adverse events that required discontinuation of treatment. There were no statistically significant differences in PASI and Dermatology Life Quality Index (DLQI) scores between patients with arthritis and those with only skin lesions, or between those who received methotrexate, either from the beginning or during infliximab therapy, and those who did not receive methotrexate at all. Selected cases of interest are discussed. Conclusions. The above data confirm previous reports that treatment with infliximab is an efficacious and safe option for patients with moderate to severe plaque psoriasis (and/or arthritis). Long-term follow-up, continued pharmacovigilance, and controlled comparative studies will be required to fully evaluate its use in psoriasis.

Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes.

2009-11-13T14:29:00.001-08:00

J Allergy Clin Immunol. 2009 Nov; 124(5): 1022-10.e1-395Zaba LC, SuÃ¡rez-FariÃ±as M, Fuentes-Duculan J, Nograles KE, Guttman-Yassky E, Cardinale I, Lowes MA, Krueger JGBACKGROUND: TNF inhibitors have revolutionized the treatment of psoriasis vulgaris as well as psoriatic and rheumatoid arthritis and Crohn disease. Despite our understanding that these agents block TNF, their complex mechanism of action in disease resolution is still unclear. OBJECTIVE: To analyze globally the genomic effects of TNF inhibition in patients with psoriasis, and to compare genomic profiles of patients who responded or did not respond to treatment. METHODS: In a clinical trial using etanercept TNF inhibitor to treat psoriasis vulgaris (n = 15), Affymetrix gene arrays were used to analyze gene profiles in lesional skin at multiple time points during drug treatment (baseline and weeks 1, 2, 4, and 12) compared with nonlesional skin. Patients were stratified as responders (n = 11) or nonresponders (n = 4) on the basis of histologic disease resolution. Cluster analysis was used to define gene sets that were modulated with similar magnitude and velocity over time. RESULTS: In responders, 4 clusters of downregulated genes and 3 clusters of upregulated genes were identified. Genes downmodulated most rapidly reflected direct inhibition of myeloid lineage immune genes. Upregulated genes included the stable dendritic cell population genes CD1c and CD207 (langerin). Comparison of responders and nonresponders revealed rapid downmodulation of innate IL-1beta and IL-8 sepsis cascade cytokines in both groups, but only responders downregulated IL-17 pathway genes to baseline levels. CONCLUSION: Although both responders and nonresponders to etanercept inactivated sepsis cascade cytokines, response to etanercept is dependent on inactivation of myeloid dendritic cell genes and inactivation of the T(H)17 immune response.

Optical coherence tomography imaging of psoriasis vulgaris: correlation with histology and disease severity.

2009-11-12T20:00:00.001-08:00

Arch Dermatol Res. 2009 Nov 6; Morsy H, Kamp S, Thrane L, Behrendt N, Saunder B, Zayan H, Elmagid EA, Jemec GBEpidermal thickness (ET) has been suggested as a surrogate measure of psoriasis severity. Optical coherence tomography (OCT) is a recent imaging technology that provides real-time skin images to a depth of 1.8 mm with a micrometre resolution. OCT may provide an accurate in vivo measure of ET. It is, therefore, speculated that OCT may be used in the assessment of psoriasis vulgaris. A total of 23 patients with psoriasis vulgaris were systematically evaluated by OCT imaging and skin biopsy during treatment. Biopsies were graded for disease severity, and additional evaluation was done by the physician via psoriasis area and severity index (PASI) score, and by the patient through measures such as self-administered PASI, psoriasis life stress inventory index and dermatology life quality index. ET was calculated from OCT images. In comparison to normal skin, psoriasis appeared with a more irregular surface with a stronger entrance signal, a serrated dermo-epidermal junction was found and a less signal intensity in the dermis as shown in OCT images. ET measured in untreated plaques was thicker reflecting epidermal hyperproliferation and inflammation. The changes were significantly correlated with the biopsy grading (r (2) = 0.41, p = 0.001) and ET significantly decreased with treatment (p = 0.0001). ET correlated significantly with self-reported measures of disease severity, but not with physician-assessed global PASI. The data suggest that OCT may be used to measure ET in psoriasis and the measurements correlate with several other parameters of disease severity. This implies that OCT assessment of psoriatic plaques may provide a useful method for non-invasive in vivo method to follow the evolution of psoriasis lesions.

Ustekinumab: new drug. Suspicion of carcinogenicity: too great a risk for psoriasis patients.

2009-11-08T23:20:00.001-08:00

Prescrire Int. 2009 Oct; 18(103): 202-4(1) For adults with plaque psoriasis, after failure of topical symptomatic treatments and PUVA therapy, several systemic immunosuppressive agents are acceptable for severe disease: methotrexate, then ciclosporin, and possible a TNF alpha antagonist (etanercept, etc.); (2) Ustekinumab is an inhibitor of interleukins 12 and 23, which are believed to be implicated in the onset of psoriasis. It is authorized in the European Union for patients who fail to respond to conventional systemic treatments; (3) In one trial with a low level of evidence (single-blind), 2 subcutaneous injections of ustekinumab at an interval of 4 weeks appeared to be statistically more effective than twice-weekly subcutaneous injections of etanercept for 12 weeks. More patients achieved a 75% reduction in the score most widely used to evaluate the extent and intensity of plaque psoriasis lesions (PASI score): about 71% versus 57%. The results beyond this period have not been reported; (4) Two randomised, double-blind, placebo-controlled trials in a total of 1996 patients showed that at least two-thirds of patients treated with ustekinumab achieved at least a 75% reduction in their PASI score versus fewer than 4% with placebo; (5) In animal studies, interleukin 12 and 23 inhibitors cause cancer. There is therefore a high risk of cancer developing during prolonged treatment with ustekinumab; (6) The main adverse effects identified in clinical trials include infections, injection-site reactions, psychological disorders and development of anti-ustekinumab antibodies; (7) There is insufficient follow-up to evaluate the cardiac risks associated with ustekinumab; (8) As maintenance therapy, ustekinumab is administered as one subcutaneous injection every 12 weeks. This practical advantage compared to TNF alpha antagonists must be weighed against the risks inherent in prolonged immunosuppression; (9) In summary, for symptomatic relief of patients whose psoriasis poses major problems despite treatment with methotrexate or ciclosporin, in the absence of a better alternative, it is better to use a TNF alpha antagonist and to avoid exposing patients to the risks associated with ustekinumab, particularly its carcinogenic risk.

Polymorphisms in the FOXP3 gene in Han Chinese psoriasis patients.

2009-11-07T16:45:00.001-08:00

J Dermatol Sci. 2009 Oct 30; Gao L, Li K, Li F, Li H, Liu L, Wang L, Zhang Z, Gao T, Liu YBACKGROUND: Psoriasis is a common dermatological disorder, in which autoimmunity plays an important role. CD4(+)CD25(+) regulatory T cells (T-regs) have been suggested to be involved in the pathogenesis of some autoimmune diseases. T-regs express the fork head/winged helix transcription factor, FOXP3, which appears to be of key importance in the development and function of T-regs. Studies have found that single-nucleotide polymorphisms (SNPs) in the FOXP3 gene contribute to susceptibility to some autoimmune disorders. However, information about FOXP3 gene in psoriasis is limited. OBJECTIVE: This study evaluated the association between FOXP3 gene SNPs and susceptibility to psoriasis in a Han Chinese population. METHODS: In a hospital-based case-control study, 524 patients with psoriasis and 549 psoriasis-free controls were recruited according to age and gender. We investigated four SNPs in the FOXP3 gene (-6054, deletion/ATT; -3279, A/C; -924, A/G; IVS9+459, A/G) in psoriatic patients, and assessed allele and genotype frequencies in psoriatic patients (237 females, 287 males) and normal controls (272 females, 277 males). The polymorphisms were genotyped using the PCR sequence-specific primer (PCR-SSP) technique and PCR-restriction fragment length polymorphism (RFLP) analysis. RESULTS: We found that increased risk of psoriasis was associated with the FOXP3 -3279 AC genotype (adjusted OR, 1.32; 95% CI, 1.01-1.74) and the combined AC+AA genotype (adjusted OR, 1.38; 95% CI, 1.07-1.78), compared with the -3279 CC genotype. We also found that an increased risk of psoriasis was associated with the FOXP3 IVS9+459 GG genotype (adjusted OR, 2.24; 95% CI, 1.41-3.58). However, the combined GA+GG genotype showed no such tendency (adjusted OR=1.28; 95% CI, 1.00-1.64), compared with the IVS9+459 AA genotype. There was no evidence of an increased risk associated with the FOXP3-6054 deletion/ATT or FOXP3-924 A/G genotype. In combined genotype analyses, the FOXP3-3279 AC+AA genotype was more obviously associated in males (adjusted OR=1.60, 95% CI=1.11-2.31) and severe psoriasis patients (PASI score >20; adjusted OR=1.97, 95% CI=1.41-2.75). Meanwhile, the FOXP3 IVS9+459 GA+GG genotype was also associated with severe psoriasis patients (adjusted OR=1.69, 95% CI=1.21-2.36). CONCLUSIONS: FOXP3 polymorphisms appear to contribute to the risk of psoriasis in a Han Chinese population. Larger studies are needed to confirm these findings.

Association of ERAP1, but not IL23R, with ankylosing spondylitis in a Han Chinese population.

2009-11-04T01:33:00.001-08:00

Arthritis Rheum. 2009 Oct 29; 60(11): 3263-3268Davidson SI, Wu X, Liu Y, Wei M, Danoy PA, Thomas G, Cai Q, Sun L, Duncan E, Wang N, Yu Q, Xu A, Fu Y, Brown MA, Xu HOBJECTIVE: The results of a recent genome-wide association study have shown that ERAP1 and IL23R are associated with ankylosing spondylitis (AS) in Caucasian populations from North America and the UK. Based on these findings, we undertook the current study to investigate whether single-nucleotide polymorphisms (SNPs) covering the genes ERAP1 and IL23R are associated with AS in a Han Chinese population. METHODS: A case-control study was performed in Han Chinese patients with AS (n = 527) and controls (n = 945) from Shanghai and Nanjing. All patients met the modified New York criteria for AS. The Sequenom iPlex platform was used to genotype cases and controls for 21 tag SNPs covering IL23R and 38 tag SNPs covering ERAP1. Statistical analysis was performed using the Cochran-Armitage test for trend. RESULTS: Multiple SNPs in ERAP1 were significantly associated with AS (for rs27980, P = 0.0048; for rs7711564, P = 0.0081). However, no association was observed between IL23R and AS (for all SNPs, P > 0.1). The nonsynonymous SNP in IL23R, rs11209026, widely thought to be the primary AS-associated SNP in IL23R in Europeans, was found not to be polymorphic in Chinese. CONCLUSION: Our results demonstrate that genetic polymorphisms in ERAP1 are associated with AS in Han Chinese, suggesting a common pathogenic mechanism for the disease in Chinese and Caucasian populations, and that IL23R is not associated with AS in Chinese, indicating a difference in the mechanism of disease pathogenesis between Chinese and Caucasian populations. This may result from the fact that rs11209026, the nonsynonymous SNP in IL23R, is not polymorphic in Chinese patients, providing further evidence that rs11209026 is the key polymorphism associated with AS (and likely inflammatory bowel disease and psoriasis) in this gene.

The risk of psoriatic arthritis remains constant following initial diagnosis of psoriasis among patients seen in European dermatology clinics.

2009-10-31T00:45:00.001-07:00

J Eur Acad Dermatol Venereol. 2009 Oct 23; Christophers E, Barker J, Griffiths C, DaudÃ©n E, Milligan G, Molta C, Sato R, Boggs RAbstract Background Estimates of psoriatic arthritis (PsA) prevalence among psoriasis patients vary widely (5-40%). The time to development of PsA in patients with plaque psoriasis also remains unclear. Objectives To examine whether length of time since diagnosis of psoriasis affects risk of developing PsA, and to assess differences in quality of life (QoL), work-related issues, comorbidities and healthcare resource utilization (HCRU) for patients with PsA vs. psoriasis. Methods This large cross-sectional observational study was conducted in the UK, Italy, France, Spain and Germany in 2006. Dermatologists who actively treated patients with psoriasis recruited 10 consecutive patients with psoriasis. Presence of PsA, body surface area (BSA) affected with psoriasis and HCRU were recorded; patients completed EUROQoL (EQ5D) and employment disadvantages questionnaires. Results Patients with psoriasis (n = 1560) included 126 with PsA. Ninety per cent of these patients with PsA were seen by dermatologists who involved a rheumatologist in the care of their patients with PsA. Survival analysis indicated that the incidence of PsA among psoriasis patients remained constant (74 per 1000 person-years), while the prevalence increased with time since diagnosis of psoriasis, reaching 20.5% after 30 years. In addition, those with high BSA currently affected by psoriasis were more likely to have developed PsA (P < 0.028). PsA patients reported reduced QoL compared with psoriasis patients (EQ5D score: 0.56 vs. 0.82: P < 0.0005), as well as more work problems. PsA patients were more likely to be hospitalized (0.27 +/- 0.84 vs. 0.14 +/- 0.71 per year; P < 0.0005) and have additional comorbidities than those without PsA. Conclusions The incidence of PsA was constant after initial diagnosis of psoriasis, leading to a higher prevalence of concomitant PsA over time. PsA is associated with decreased QoL and increased work-related problems, HCRU and comorbidities. Dermatologists should screen for PsA in their patients, especially long-standing patients who did not initially present with PsA.

Influence of narrowband UVB phototherapy on vitamin D and folate status.

2009-10-28T23:31:00.001-07:00

Exp Dermatol. 2009 Oct 22; Cicarma E, MÃ¸rk C, Porojnicu AC, Juzeniene A, Tam TT, Dahlback A, Moan JPlease cite this paper as: Influence of narrowband UVB phototherapy on vitamin D and folate status. Experimental Dermatology 2009.Abstract Background: A variety of studies have shown beneficial effects of different types of phototherapy in skin disorders. Such therapy leads to enhanced cutaneous vitamin D synthesis, which may be one of the mechanisms of action. Furthermore, another nutrient, folate, can probably also be influenced by UV radiation. Objective: The aim of our study was to investigate the influence of low-dose narrowband UVB (nUVB) phototherapy of patients with psoriasis, atopic eczema and other skin disorders on serum levels of 25(OH) vitamin D (the serum marker for vitamin D status) and on serum and erythrocyte-folate. Methods: 25(OH) vitamin D (25(OH)D), serum and erythrocyte-folate levels were measured before and after low-dose nUVB (TL-01 tubes) phototherapy of these patients. The spectrum of the TL-01 tube was compared with the solar spectrum, and the efficiency spectra of vitamin D photosynthesis were calculated. Results: For patients with a high initial 25(OH)D serum level (> 80 nmol/l), no significant (P = 0.36) increase in 25(OH)D levels was seen, in contrast to patients with a low initial level (< 80 nmol/l) where a significant increase (P < 0.001) was observed. The increase was 30-60%, depending on the UVB dose (2.35-13.4 J/cm(2)). No significant nUVB-effect was found on the erythrocyte and serum-folate level. Conclusion: Low-dose nUVB treatment gives a significant increase (P < 0.001) of the vitamin D status in persons with low initial levels of 25(OH)D, but no effect on the folate level.

[Clinical and experimental study on effect of qinbal ointment in treating psoriasis in the active stage of blood-heat syndrome type]

2009-10-28T21:27:00.001-07:00

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2009 Jul; 29(7): 614-8Xu J, Zhang C, Qu XOBJECTIVE: To investigate and compare the efficacy and safety of two kinds of Qinbai ointment prepared conventionally and finely (C-QBO and F-QBO) in treating psoriasis in the active stage of blood-heat syndrome type, and to observe their influences on vaginal epithelial cell mitosis, also on keratinization of caudal flakes in mice. METHODS: Clinical observation: Adopting randomized, single-blinded, controlled design, 93 patients administered orally with Liangxue Huoxue Decoction were randomized into three groups treated externally with C-QBO, F-QBO and white vaseline respectively, applied twice a day for 8 weeks. The safety was checked and the changes of modified psoriasis area severity index (PASI), as well as the conditions of skin lesions (size, erythema, infiltration, squama, and itching) and symptom improving time were compared. Experimental study 1: Mice were randomized into the model group, the C-QBO group, the F-QBO group and the blank group, 7 in each group. Their vaginal epithelial cell mitosis indices were compared after 3 days of treatment with corresponding remedies. Experimental study 2: Mice were randomized into the C-QBO group, the F-QBO group and the blank group, 7 in each group. After the mice had been treated with corresponding remedies for 28 days, the granular layer formation in their caudal scales was compared. RESULTS: Clinical observation: The markedly effective rate was 63.3% (25/30) in the C-QBO group, 66.7% (20/30) in the F-QBO group, and 36.7% (11/30) in the control group. No statistical difference was showen between the two QBO treated groups (P > 0.05), but that in both of them was significantly different from that in the control group (P < 0.05). PASI scores lowered after treatment in all the three groups (P < 0.01), but the improvement in the two QBO groups was better than that in the control group (P < 0.05); the conditions of skin lesion were improved in all groups, but the improvements were more significant in the two QBO groups in terms of squama, infiltration and itching (P < 0.05), in aspects of improving time on erythema, infiltration and itching, especially the itching, F-QBO was superior to the C-QBO. Experimental study 1: The mitosis index in both QBO groups was lower than that in the blank group and the model group (P < 0.01). Experimental study 2: Number of scales with granular layer formation was higher in the two QBO groups than in the blank group (P < 0.01). CONCLUSION: C-QBO and F-QBO can effectively relieve the skin lesion of psoriasis patients in the active stage of blood-heat type, and they could also promote the formation of epithelial granular layer in the caudal scales of mice.

Therapeutic effect of hyperbaric oxygen in psoriasis vulgaris: two case reports and a review of the literature.

2009-10-25T22:04:00.001-07:00

J Med Case Reports. 2009; 3: 7023Butler G, Michaels JC, Al-Waili N, Finkelstein M, Allen M, Petrillo R, Carrey Z, Kolanuvada B, Lee BY, Riera AG, Michaels CC, Urteaga GINTRODUCTION: Psoriasis is an inflammatory and immunological cutaneous disease. The high morbidity in patients with psoriasis results from severe clinical manifestations and/or adverse effects of treatment. The Undersea and Hyperbaric Medical Society and Federal Medicare and Medicaid Services have approved the use of hyperbaric oxygen (HBO(2)) for more than 15 indications, including wound healing, infections and late effects of radiation, which are largely unresponsive to conventional treatments. Accumulated data show that HBO(2) has anti-inflammatory effects and other positive influences on the immune system, making it a rational treatment in the management of psoriasis plaques and arthritis. CASE PRESENTATION: We present the cases of two patients with long histories of psoriasis vulgarus who exhibited marked improvement with use of HBO(2.) The first patient was 40 years old and had pustular psoriasis and psoriatic arthritis. He was treated with six sessions of HBO(2) (at 2.8 atmospheres of pressure for 60 minutes), which successfully controlled his symptoms. At the 18-month post-treatment follow up, the patient exhibited complete remission of psoriasis and marked improvement in psoriatic arthritis without medication. The second patient was 55 years old with extensive psoriatic lesions, and exhibited marked improvement within 15 sessions of HBO(2). No adverse effects of HBO(2) were identified. CONCLUSIONS: HBO(2) may possess potential therapeutic efficacy in the management of psoriasis. We outline the pathogenesis of psoriasis and the selective anti-inflammatory and immunosuppressive effects of HBO(2). We hope that this will provide a basis for elucidating the mechanisms of action and consequently pave the way for further controlled studies.

Serum cytokines and growth factor levels in Japanese patients with psoriasis.

2009-10-24T01:20:00.001-07:00

Clin Exp Dermatol. 2009 Oct 19; Takahashi H, Tsuji H, Hashimoto Y, Ishida-Yamamoto A, Iizuka HSummary Background. Although the precise pathomechanism of psoriasis is still unknown, various cytokines and growth factors derived from T cells, dendritic cells or keratinocytes, are critically involved in this disease. There have been several studies determining the serum levels of cytokines in patients with psoriasis, but with conflicting results. The levels of various cytokines and growth factors were measured in the sera of patients with psoriasis and compared with those of healthy controls. The correlation with disease severity was also determined. Methods. Sera were collected from 122 patients with psoriasis and 78 healthy controls for ELISA analysis to evaluate the levels of cytokines and growth factors. The severity of psoriasis was determined by the Psoriasis Area and Severity Index (PASI). Results. Serum levels of tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-2, IL-6, IL-7, IL-8, IL-12, IL-17, IL-18 and vascular endothelial growth factor (VEGF) were significantly increased in patients with psoriasis compared with those of healthy controls. The serum levels of IL-2, soluble intercellular adhesion molecule-1, epidermal growth factor, hepatocyte growth factor and amphiregulin were not significantly different from those of healthy controls. Increased serum levels of TNF-alpha, IFN-gamma, IL-12, IL-17, IL-18 and VEGF correlated with PASI. Furthermore, these cytokine levels were decreased after psoriasis treatment. In contrast, serum levels of IL-10 were decreased in psoriasis and negatively correlated with PASI. Discussion. Serum levels of TNF-alpha, IFN-gamma, IL2, IL-6, IL-7, IL-8, IL-12, IL-17, IL-18 and VEGF were positively correlated and that of IL-10 was negatively correlated with PASI in Japanese patients with psoriasis. These parameters might be useful for determining the disease activity of psoriasis.

Topical clobetasol propionate in the treatment of psoriasis: a review of newer formulations.

2009-10-21T21:46:00.001-07:00

Am J Clin Dermatol. 2009; 10(6): 397-406Feldman SR, Yentzer BAUltrapotent topical corticosteroids are the mainstay of psoriasis treatment, used either alone or in combination with a topical vitamin D analog. Traditionally used in an ointment vehicle for psoriasis, clobetasol propionate 0.05% is also available in spray, foam, lotion, and shampoo formulations, which may provide for improved convenience and acceptance in many patients with similar efficacy, safety, and tolerability as the traditional ointment and cream formulations. To compare newer formulations with traditional ointment and cream formulations, we performed a systematic review of the literature. Search terms included 'clobetasol propionate,' in combination with 'psoriasis,' 'vasoconstriction,' 'vasoconstrictor,' or 'absorption' for each of the four vehicles ('spray,' 'foam,' 'lotion,' and 'shampoo'). While there are very few direct comparison studies between clobetasol propionate in different vehicles, the efficacy rates (with success defined as clear or almost clear of psoriasis) for more recent formulations are high, with most patients achieving success after 2-4 weeks of treatment in well controlled clinical trials, with response rates that are similar to those with the traditional clobetasol propionate ointment. Small differences in vasoconstrictor potency or cutaneous absorption have been noted among the formulations, but the clinical significance of these observations is difficult to discern. Recent research has emphasized the importance of treatment adherence in the management of psoriasis. Adherence to treatment is likely to be a far more important determinant of success than are small differences in drug delivery, especially in actual clinical use as opposed to the well controlled environment of clinical trials. For patients who prefer a less messy vehicle, adherence and outcomes are likely to be better with the more recent formulations compared with the traditionally recommended ointment.

Effectiveness of adalimumab in treating patients with active psoriatic arthritis (PsA) and predictors of good clinical responses for arthritis, skin, and nail lesions.

2009-10-12T18:38:00.001-07:00

Ann Rheum Dis. 2009 Oct 7; van den Bosch F, Manger B, Goupille P, McHugh N, RÃ¸devand E, Holck P, van Vollenhoven RF, Leirisalo-Repo M, Fitzgerald O, Kron M, Frank M, Kary S, Kupper HOBJECTIVE: We evaluated the effectiveness of adalimumab in patients with psoriatic arthritis (PsA) and identified predictors of good clinical responses for joint and skin lesions. METHODS: Patients received adalimumab 40 mg every other week in addition to standard therapy in this prospective, 12-week, open-label, uncontrolled study. We used four definitions of good clinical response: >/=50% improvement in American College of Rheumatology (ACR50) response criteria, good European League Against Rheumatism (EULAR) response, >/=3-grade improvement in Physician's Global Assessment of psoriasis (PGA), and >/=50% improvement in the Nail Psoriasis Severity Index (NAPSI). Response predictors were determined by logistic regression with backward elimination (selection level, 5%). RESULTS: Of 442 patients, 94% completed 12 weeks of treatment. At Week 12, 74%, 51%, and 32% of the patients achieved ACR20, 50, and 70, respectively; 87% and 61% experienced a moderate and good EULAR response, respectively. The percentage of patients with PGA "Clear/Almost Clear" increased from 34% (baseline) to 68%. The mean NAPSI was reduced by 44%. No new safety signals were detected. A lower Health Assessment Questionnaire Disability Index score, greater pain assessment, male sex, and absence of systemic glucocorticoid therapy were strongly associated with achievement of ACR50 and good EULAR response. In addition, greater C-reactive protein concentration and polyarthritis predicted ACR50, and noninvolvement of large joints predicted good EULAR response. CONCLUSION: Adalimumab was effective in patients with PsA. Lower impairment of physical function, greater pain, male sex, and no systemic treatment with glucocorticoids were factors that increased the chance of achieving good clinical response.

[Investigation of tinea pedis and toenail onychomycosis prevalence in patients with psoriasis]

2009-10-09T02:28:00.001-07:00

Mikrobiyol Bul. 2009 Jul; 43(3): 439-47Altunay ZT, Ilkit M, Denli YThe data about the prevalence of onychomycosis in patients with psoriasis is contradictory. In this study, we investigated the prevalence of onychomycosis and tinea pedis in patients with psoriasis compared to control group. A total of 60 patients with psoriasis (27 male, 33 female; mean age: 40.8 +/- 17.6 years) and 60 subjects without psoriasis (27 male, 33 female; mean age: 42.8 +/- 17.3 years) who were admitted to dermatology outpatient clinics of our hospital were included to the study. Scrapings from both normal and abnormal toenails as well as toewebs were examined using microscopy and fungal culture. Foot dermatomycosis was diagnosed in 6 (5 onychomycosis and 1 tinea pedis) patients with psoriasis (10%) and in 8 (5 onychomycosis and 3 tinea pedis) control subjects (13.3%) (p > 0.05). The only dermatophyte fungi isolated in both patients with psoriasis and control group were Trichophyton rubrum (75%) and Trichophyton interdigitale (25%). Onychomycosis was more predominant in male psoriatic patients (p = 0.01). Both distero-lateral subungual onychomycosis (DLSO) and total dystrophic onychomycosis were detected in patients with psoriasis, however, DLSO, was the only clinical type in the control group. Pitting is the most typical lesions in nails in patients with psoriasis (p = 0.04). The use of common showers play a role in transmission of foot dermatomycosis (p = 0.04). In this study, psoriasis was not found as a risk factor for onychomycosis. However, onychomycosis is a major problem in psoriatic nails, and mycological methods would be useful in differential diagnosis. Since dermatomycosis is still an important public health problem, it may be controlled by education of the patient about proper foot hygiene and avoiding walking barefooted in shower areas.

Expression of chemokines and chemokine receptors in lesional and nonlesional upper skin of patients with atopic dermatitis.

2009-10-08T18:11:00.001-07:00

J Allergy Clin Immunol. 2009 Sep 18; Gros E, Bussmann C, Bieber T, FÃ¶rster I, Novak NBACKGROUND: Trafficking of dendritic cell (DC) subtypes to and from the skin plays a pivotal role in atopic dermatitis (AD). OBJECTIVES: We sought to determine the CCR pattern of epidermal DC subtypes and CCL expression in relation to the state of AD. METHODS: Shave biopsy specimens were taken from patients with AD before and after 24 and 72 hours of atopy patch testing and from the skin of patients with chronic AD, skin of patients with psoriasis, and healthy skin. CCR expression of epidermal DCs was studied by using flow cytometry, and chemokine mRNA levels in the skin were quantified by means of real-time PCR. RESULTS: The total number of CD1a(+) epidermal DCs increased and the proportion of Langerin-positive CD1a(+) DCs decreased whereas the percentage of Langerin-negative CD1a(+) DCs increased after allergen application. Expression of CCR5 and CCR6 of Langerin-negative CD1a(+) DCs was characteristic for acute AD. Expression of CCL1, CCL3, CCL4, and CCL11 mRNA was greater in patients with acute AD versus that seen in patients with chronic AD. Only a strong increase of CCLs, in particular CCL1, CCL17, and CCL18, went along with eczema development, and increased CCL1, CCL13, CCL17 and CCL18 expression was specific for patients with chronic AD compared with those with psoriasis. CONCLUSION: Modified recruitment and differentiation of DCs from their dermal and blood precursors occurs in the acute phase of AD. A boost in the amplitude of CCLs after allergen application goes along with eczema development.

Treatment of nail psoriasis with adalimumab: an open label unblinded study.

2009-10-08T02:23:00.001-07:00

J Eur Acad Dermatol Venereol. 2009 Oct 6; Rigopoulos D, Gregoriou S, Lazaridou E, Belyayeva E, Apalla Z, Makris M, Katsambas A, Ioannides DSummary Background Despite numerous advances in the therapeutic management of cutaneous psoriasis, there is a lack of standardized therapeutic regimens for psoriatic nail disease. Objective An open, non-randomized, unblinded study was designed to evaluate the efficacy and safety of adalimumab in the treatment of nail psoriasis. Patients/methods Seven patients suffering from severe plaque-type psoriasis and 14 with psoriatic arthritis and cutaneous psoriasis with concomitant nail involvement were enrolled into the study. The applied dose regimen of adalimumab was the same as the one recommended for cutaneous psoriasis. Outcome measures were assessed at baseline and at weeks 12 and 24 using the Nail Psoriasis Severity Index (NAPSI). Patients also filled in a Greek translation of the international onychomycosis-specific questionnaire to assess the impact of the nail improvement on their quality of life. Results All 21 patients completed the study and were eligible for statistical analysis. Significant improvement was recorded after the eighth injection. Mean NAPSI (NAPSIm) at baseline was 10.57 +/- 1.21 for the fingernails and 14.57 +/- 2.50 for the toenails in patients with just cutaneous psoriasis and 23.86 +/- 2.00 for the fingernails and 29.29 +/- 2.87 for the toenails in patients with psoriatic arthritis. NAPSIm at week 12 was 5.57 +/- 0.78 for the fingernails and 9.57 +/- 2.17 for the toenails in patients with just cutaneous psoriasis and 12.86 +/- 1.05 for the fingernails and 19.21 +/- 2.07 for the toenails in patients with psoriatic arthritis. NAPSIm after 24 weeks of treatment was 1.57 +/- 0.20 for the fingernails and 4.14 +/- 1.58 for the toenails in patients with cutaneous psoriasis and 3.23 +/- 0.32 for the figernails and 10.00 +/- 1.40 for the toenails in patients with psoriatic arthritis. Treatment was well tolerated with minimal and temporary side-effects limited to the site of injection. All patients were satisfied, while marked improvement in their quality of life was recorded based on the reduction of the scores obtained from the international quality of life questionnaire. Conclusions Despite the lack of a control group, our results demonstrate a beneficial effect of adalimumab on psoriatic nail disease.

Psoriasis patients generate increased serum levels of autoantibodies to tumor necrosis factor-alpha and interferon-alpha.

2009-10-07T02:17:00.001-07:00

J Dermatol Sci. 2009 Oct 1; Bergman R, Ramon M, Wildbaum G, Avitan-Hersh E, Mayer E, Shemer A, Karin NBACKGROUND: It has been shown in experimental animal models that were extended to humans that during autoimmune conditions, the immune system generates beneficial autoantibody (auto Ab) response to a limited number of inflammatory mediators that drive the pathogenesis of the disease. OBJECTIVE: To investigate the presence of auto Abs to cytokines and chemokines in psoriasis. METHODS: Sera were obtained from patients with psoriasis (n=37), atopic dermatitis (AD) (n=18) and healthy volunteers (n=56). The titers of auto (Abs) to TNF-alpha, interferon-alpha (IFN-alpha), interleukin-17 (IL-17), and chemokines CCL2, CCL3 and CCL5 were determined using enzyme-linked immunosorbant assay. Neutralizing activities of high-titer auto Abs to TNF-alpha and IFN-alpha were determined using functional in vitro assays. RESULTS: Highly significant increased titers of auto Abs to TNF-alpha and IFN-alpha were detected in patients with psoriasis compared with healthy subjects and patients with AD (mean titers more than fourfold). These auto Abs demonstrated some neutralizing activity in vitro, but their serum levels did not correlate with the intensity and duration of the disease and with phototherapy induced remissions. Significantly increased titers albeit to a lesser extent, of auto Abs to CCL3 were detected in AD. CONCLUSIONS: Psoriasis patients produce markedly increased levels of auto Abs to TNF-alpha and IFN-alpha which are two of the key cytokines in this disorder. The presence of these auto Abs which possess some neutralizing activity in vitro, may be an epiphenomenon or might play a role in attempting to suppress the ongoing inflammatory process.

Elevated platelet-monocyte complexes in patients with psoriatic arthritis.

2009-10-06T22:40:00.001-07:00

Platelets. 2009 Sep 14; 1-5Pamuk GE, NurÄ± Pamuk O, Orum H, Arican O, Turgut B, DemÄ±r MWe evaluated platelet and endothelial activation parameters in psoriatic arthritis (PsA), a disease reported to be associated with the development of endothelial dysfunction and increased atherosclerotic complications. Twenty patients with PsA, eight psoriasis and 20 healthy controls were included into the study. The patients' clinical features and acute phase parameters were assessed. In all patients and controls, platelet-monocyte complexes (PMC), platelet-neutrophil complexes (PNC), and basal and ADP-stimulated P-selectin expression were determined with flow cytometry; soluble E-selectin (sE-selectin) and soluble CD40L (sCD40L) were determined with ELISA. Patterns of joint involvement and degrees of skin involvement in PsA patients were assessed. PMC in PsA patients were significantly higher than in the control group (p = 0.02). PNC were not significantly different among the three groups (p values > 0.05). sE-selectin levels in both PsA and psoriasis groups were significantly higher than in healthy controls (p values, respectively, 0.05). Polyarticular PsA patients had significantly higher sCD40L than oligoarticular plus spondylitic PsA groups (p = 0.04). sCD40L level was higher in active PsA group than in inactive PsA group (p = 0.03). Groups with limited and extensive skin involvement did not differ significantly in the evaluated parameters. C-reactive protein (CRP) level in PsA patients correlated with sCD40L (r = 0.69, p = 0.012), basal CD62P expression (r = 0.89, p < 0.001) and ADP-stimulated CD62P expression (r = 0.73, p = 0.001). Endothelial activation might be have a role in the pathogenesis of both psoriasis and PsA. Among parameters of platelet activation, only PMC might play a role in the pathogenesis of PsA.

Lipid profile in patients with psoriasis presenting at Liaquat University Hospital Hyderabad.

2009-10-05T17:48:00.001-07:00

J Pak Med Assoc. 2009 Aug; 59(8): 512-5Bajaj DR, Mahesar SM, Devrajani BR, Iqbal MPOBJECTIVE: To determine the lipid abnormalities in patients with psoriasis and compare it with healthy controls. METHODS: Across-sectional controlled study was conducted at the Department of Dermatology Liaquat University Hospital Hyderabad from January 2007 to November 2007. The study included 158 consecutive patients; among which 88 were males (44 patients and 44 controls) and 70 females (35 patients and 35 controls). The patients with psoriasis having less than 30% body involvement were included in the study. Patients with severe psoriasis, high BMI (.30 kg/m2), hypertension, diabetes, smoking, alcohol consumption and personal or family history of hyperlipedemia were excluded. The patients were examined clinically and findings recorded on a pre-designed proforma. Fasting lipids were measured using SELECTRA XL chemistry analyzer using Spin react kits (made in Spain) by direct method. RESULTS: All patients had psoriasis involving less than 30% of body surface. Their ages ranged from 18 years to 68 years (mean 37 +/- 7.96 years). Family history of disease was positive in 10 (6.32%) patients. 134 (84.8%) had plaque type psoriasis, 10 (6%) had in addition scalp and nail involvement, 05 (3.16%) guttate lesions, 05 (3.16%) had palmoplantar lesions while remaining 04 (2.43%) comprised of hyperkeratotic and flexural psoriasis. The duration of disease ranged between 18 months to 10 years with a mean of 4.5 +/- 1.89 years. Serum cholesterol, triglycerides and low density lipoprotein (LDL) cholesterol were significantly higher than in the normal control group (P < 0.01). There was no significant statistical difference in serum levels of very low density lipoprotein cholesterol (VLDL) and high density lipoprotein cholesterol (HDL-C) between the two groups. CONCLUSION: Psoriasis is an independent risk factor for hyperlipidaemia and its possible subsequent sequelae such as obstructive vascular disease.

Targeting NF-{kappa}B with a Natural Triterpenoid Alleviates Skin Inflammation in a Mouse Model of Psoriasis.

2009-10-05T02:08:00.001-07:00

J Immunol. 2009 Sep 14; Wang H, Syrovets T, Kess D, BÃ¼chele B, Hainzl H, Lunov O, Weiss JM, Scharffetter-Kochanek K, Simmet TPsoriasis vulgaris is a common chronic inflammatory skin disease involving cytokines and an activated cellular immune system. At variance to skin from patients with atopic dermatitis or from healthy subjects, human psoriatic skin lesions exhibit strong activation of transcription factor NF-kappaB that is mainly confined to dermal macrophages, whereas only a few dendritic cells but no CD3(+) lymphocytes show activated NF-kappaB. Since NF-kappaB signaling is required for the induction and/or function of many cytokines and aberrant cytokine expression has been proposed as an underlying cause of psoriasis, we investigated whether NF-kappaB targeting would affect the course of the disease in the CD18 hypomorphic (CD18(hypo)) mouse model of psoriasis. When mice with severe psoriasiform lesions were treated systemically or locally with the IkappaB kinase inhibitor acetyl-11-keto-beta-boswellic acid (AKbetaBA), NF-kappaB signaling and the subsequent NF-kappaB-dependent cytokine production as shown by the TNF-alpha production of macrophages were profoundly suppressed. Additionally, application of the compound counteracted the intradermal MCP-1, IL-12, and IL-23 expression in previously lesional skin areas, led to resolution of the abundant immune cell infiltrates, and significantly reduced the increased proliferation of the keratinocytes. Overall, the AKbetaBA treatment was accompanied by a profound improvement of the psoriasis disease activity score in the CD18(hypo) mice with reconstitution of a nearly normal phenotype within the chosen observation period. Our data demonstrate that NF-kappaB signaling is pivotal for the pathogenesis in the CD18(hypo) mouse model of psoriasis. Therefore, targeting NF-kappaB might provide an effective strategy for the treatment of psoriasis.

Dermatology outpatient case-mix survey for all Welsh Trusts, 2007.

2009-10-04T23:22:00.001-07:00

Br J Dermatol. 2009 Aug 3; Hill GM, Sowden JM, Lister RK, Logan RA, Finlay AYSummary Background In 2006 a U.K. government White Paper recommended making NHS care in England more accessible by shifting services from secondary care into community settings. There is a shortage of contemporary activity data for U.K. dermatology units to allow benchmarking for service development. This study will not only provide useful comparative data for the future in Wales, but will also serve to highlight the impact of changes made in England. Objective To provide an overview of 1 week's dermatology outpatient activity for the whole of Wales. Methods All dermatology units in Wales collected data for 1 week in early 2007. The case mix, appropriateness of referral, requirement for surgery or second-line therapies and follow-up requirements were all determined. Results A total of 2142 patients were seen. Of new patients, 21% had skin cancer. Seventeen per cent of skin cancers had no diagnosis suggested by the general practitioner (GP) and 10% of basal cell carcinomas, 33% of squamous cell carcinomas and 17% of malignant melanomas were inappropriately diagnosed. In all, 26% of new patients had benign lesions, and this group caused the greatest diagnostic difficulty for GPs. Seventy-one per cent of these patients were diagnosed, reassured and discharged at their first visit without the need for biopsy or surgery. Thirty-seven per cent of new patients required surgery, of which 21% required complex intervention. Twenty-six per cent of follow-up patients were receiving second-line therapies. The new to follow-up ratio varied considerably according to diagnosis, the mean ratio being 1 : 0.21 for benign lesions through to 1 : 5.53 for psoriasis. This highlights the inappropriate nature of a 'one fits all' ratio. The majority of follow-up patients in secondary care required this level of input for monitoring of cancer, complex second-line therapies or surgery. Conclusions This study provides evidence to support logical planning of dermatological services and to assess the impact of proposed changes on different healthcare systems in the U.K.

Randomized, double-blind, placebo-controlled evaluation of the efficacy of oral psoralen plus ultraviolet A for the treatment of plaque-type psoriasis using the Psoriasis Area Severity Index score (im

2009-10-02T22:02:00.001-07:00

J Am Acad Dermatol. 2009 Sep 17; Sivanesan SP, Gattu S, Hong J, Chavez-Frazier A, Bandow GD, Malick F, Kricorian G, Koo JBACKGROUND: Psoralen plus ultraviolet A (PUVA) for the treatment of psoriasis has never been evaluated using the Psoriasis Area Severity Index (PASI) in a randomized, double-blind, placebo-controlled trial. The lack of such data limits our capacity to estimate PUVA's efficacy relative to other treatment options that are available today. OBJECTIVES: The purpose of this study was to evaluate the efficacy of PUVA therapy for patients with plaque-type psoriasis. METHODS: This study involved 40 patients with psoriasis; 30 received PUVA and 10 received UVA with placebo. PASI scores were assessed at baseline and every 4 weeks thereafter for 12 weeks. RESULTS: By nonresponder imputation, 60% (18 of 30) in the PUVA group achieved 75% or more improvement in PASI score after 12 weeks of treatment compared with 0% (0 of 10) in the UVA plus placebo group (P < .0001). Using intent to treat with last observation carried forward analysis, 63% (19 of 30) in the PUVA group achieved 75% or more improvement in PASI score compared with 0% (0 of 10) in the UVA plus placebo group (P < .0001). By per protocol analysis, 86% (18 of 21) in the PUVA group as compared with 0% (0 of 7) in the UVA plus placebo group reached 75% or more improvement in PASI score after 12 weeks (P < .0001). LIMITATIONS: The study was relatively small with only 40 patients enrolled and 28 patients who completed the protocol. Further studies that involve head-to-head comparison of PUVA with other treatment modalities are needed. Nonresponder imputation, last observation carried forward with intent to treat, and per protocol analyses each have separate advantages and limitations when determining clinical significance. CONCLUSIONS: This study supports the observation that PUVA is a highly efficacious treatment for chronic plaque psoriasis.

Randomized, double-blind, placebo-controlled evaluation of the efficacy of oral psoralen plus ultraviolet A for the treatment of plaque-type psoriasis using the Psoriasis Area Severity Index score (im

2009-09-30T18:15:00.001-07:00

The Burden of Psoriasis in Canada: Insights from the pSoriasis Knowledge IN Canada (SKIN) Survey.

2009-09-30T02:29:00.001-07:00

J Cutan Med Surg. 2009 Sep-Oct; 13(5): 235-52Lynde CW, Poulin Y, Guenther L, Jackson CBACKGROUND:Although some data addressing the burden of illness associated with psoriasis and psoriatic arthritis (PsA) have been reported for American and European patient populations, similar data have been lacking for Canadians with these diseases.OBJECTIVE:We sought to characterize the natural history of disease in a sample of Canadians with a history of moderate to severe psoriasis, with or without diagnosed PsA or other recognized comorbid conditions, and to identify factors that influenced their perception of psoriasis as a problem in their daily lives.METHODS:A nationwide telephone survey, pSoriasis Knowledge IN Canada (SKIN), was conducted between April 30 and June 2, 2007, on 500 people who indicated that they had been diagnosed with psoriasis and that their skin lesions had at some time affected an area at least as large as three palms of their hand (3% of body surface area [BSA]).RESULTS:The mean age at diagnosis for psoriasis among SKIN survey respondents was 28 years, with 31% (155 of 500) indicating that they developed the disease prior to age 18 years. At the time of the survey, 54% (269 of 500) of respondents were experiencing lesions affecting a BSA equivalent to at least three palms (3%). In response to questions on the burden of illness, 35% (176 of 500) of respondents indicated that they considered psoriasis to be a substantial problem in their daily life. Both affected BSA at the time of the survey and self-reported extent of skin involvement at the height of the condition (BSAmax) correlated with the perception of psoriasis as a substantial problem. Other subpopulations in which psoriasis was commonly identified as a substantial problem included women and individuals with diagnosed PsA. Whereas 18% (88 of 500) of respondents were diagnosed with PsA, the number who reported joint pain or stiffness was substantially higher (51%; 256 of 500), suggesting that some respondents may have had incipient or undiagnosed PsA.CONCLUSIONS:This survey reveals that psoriasis, PsA, and their associated comorbidities impose a severe burden on the daily lives of Canadians with a history of moderate to severe psoriasis.

Paediatric psoriasis - narrowband UVB treatment.

2009-09-29T18:40:00.001-07:00

J Eur Acad Dermatol Venereol. 2009 Sep 14; Zamberk P, VelÃ¡zquez D, Campos M, Hernanz J, LÃ¡zaro PAbstract Narrowband UV-B is a safe and efficacious option for the treatment of adult psoriasis. However, the use of this therapy has been limited in children due to its long-term carcinogenic potential. It has proven to be an adequate alternative in patients whose condition is refractory to topical treatment. Aims To evaluate the efficacy and short-term safety of narrowband UV-B in the treatment of paediatric psoriasis, and to compare our results with those obtained in other studies on paediatric psoriasis. Materials and methods Over a period of 2 years and 4 months, we administered narrowband UV-B to 20 children diagnosed with psoriasis that was refractory to topical therapy. The therapeutic response was measured using the Psoriasis Area and Severity Index (PASI). Results Between August 2005 and December 2007, 20 children received narrowband UV-B. Their median age was 13 years (range, 5-17 years), and the median initial PASI score was 8.25 (2.7-22.2). A median of 28 (10-59) sessions was required to achieve clearance, reaching almost complete or total remission (median final PASI) in all but two patients. Six patients required a new therapeutic course because of relapse, and the mean duration of remission was 8 months (4-18). No patients experienced severe adverse events during therapy, and only one discontinued treatment, for unrelated reasons. Discussion and conclusion Narrowband UV-B for the treatment of paediatric psoriasis has received little attention in the literature. This treatment has been limited in children because of its potential long-term carcinogenic effects, and most information has been extrapolated from adults. Nevertheless, narrowband UV-B phototherapy is an effective and well-tolerated therapeutic alternative in paediatric patients with severe psoriasis.

Genetic evidence for involvement of the IL23 pathway in Thai psoriatics.

2009-09-21T17:23:00.001-07:00

Arch Dermatol Res. 2009 Aug 25; Nair RP, Stuart PE, Kullavanijaya P, Kullavanijaya P, Tejasvi T, Voorhees JJ, Elder JTA recent genome-wide association analysis of psoriasis identified IL12B and IL23R as significantly associated with psoriasis. Here we report association test results of a Thai cohort consisting of 206 psoriasis cases and 114 controls. The IL23R SNPs rs7530511 and rs11209026, and IL12B SNPs rs3212227 and rs6887695 were genotyped using Taqman assays. Data were analyzed using a logistic regression model for linear trend of association. One of the IL23R markers, rs7530511, was marginally significant (P = 0.017). The other IL23R marker, rs11209026, was not polymorphic. One of the IL12B markers, rs3212227, showed significant association with psoriasis (OR = 1.64, P = 0.0058) while the other, rs6887695, did not (OR = 1.29, P = 0.12). Haplotype analysis of the two IL12B SNPs yielded highly significant association (P = 0.00081, OR = 1.73). These results showed that IL12B is an important genetic factor in psoriasis pathogenesis in the Thai population, with an association strong enough to yield significant confirmatory evidence using a modest sample size. Together with previously reported evidence for IL12B association in Caucasian, Japanese, and Chinese psoriatics, our results support the hypothesis that genes encoding components of the IL23-mediated inflammatory pathway are important determinants of psoriasis pathogenesis across multiple racial groups.

Valrubicin in a Topical Formulation Treats Psoriasis in a Xenograft Transplantation Model.

2009-09-14T06:25:00.001-07:00

J Invest Dermatol. 2009 Sep 10; Rosada C, Stenderup K, de DarkÃ³ E, Dagnaes-Hansen F, Kamp S, Dam TNValrubicin is a cytostatic drug currently approved by the American Federal Drug Administration as a trademarked Valstar sterile solution for the treatment of bladder cancer. Valrubicin has shown an excellent therapeutic potential with minimal toxicity. This study investigated the effect in vivo of treating psoriasis with a daily topical application of valrubicin cream in a psoriasis xenograft transplantation model. Psoriasis is characterized by an accelerated keratinocyte proliferation, resulting in increased epidermal thickness. We thus studied the cytostatic potential of valrubicin on epidermal keratinocytes. In vivo, valrubicin treatment resulted in a normalization of epidermal morphology and a reduction in epidermal thickness after 12 days. In addition, the dermal vessel pattern was reduced and the stratum granulosum was regained. Staining for a regenerative proliferation marker showed a decrease in keratinocyte proliferation, and scattered epidermal cells showed apoptosis. In vitro, valrubicin was shown to localize solely to the cell cytoplasm in cultured keratinocytes and to reduce keratinocyte proliferation as well as increase apoptosis by activation of caspases 3, 7, and 9. Our results indicated that valrubicin successfully treats psoriasis in a xenograft transplantation model, suggesting that topical valrubicin may become an upcoming treatment for psoriasis.Journal of Investigative Dermatology advance online publication, 10 September 2009; doi:10.1038/jid.2009.277.

The relationship between symptoms and patient characteristics among psoriasis patients.

2009-09-13T17:36:00.001-07:00

Indian J Dermatol Venereol Leprol. 2009 Sep-Oct; 75(5): 551Bilac C, Ermertcan AT, Bilac DB, Deveci A, Horasan GDBACKGROUND: Pruritus is a common symptom of many dermatological and systemic diseases. It is a common complaint among patients with psoriasis of the chronic plaque type. Patients with pruritus suffer from more severe psoriasis although some authors did not find a significant relationship between pruritus intensity and psoriasis severity. AIMS: In this study, we aimed to investigate the relationship between clinical features and symptoms among psoriasis patients. And also we aimed to evaluate whether the severity of disease, depression and quality of life scores could effect these symptoms or not. METHODS: Eighty seven patients with psoriasis were enrolled in this study. Epidemiological data of patients were noted. Clinical symptoms, such as pruritus, pain, burning, exudation, bleeding, weakness, etc. were interrogated. The answers to these questions were classified as 'never', 'rare', 'sometimes', 'often' and 'all the time'. Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), Hamilton Anxiety-Depression Scale (HAD) were calculated for each patient. PASI and DLQI scores were classified as > or = and < 10. RESULTS: We found that the most frequent symptom was pruritus (96.6%). Other frequent symptoms were burning (56.3%), exudation (56.3%) and bleeding (49.4%). Hurting, sensitiveness and bothering were more frequent in women. Percentages of hurting, pain, exudation and weakness symptoms had been increasing with age. Frequency of weakness was significantly high in PASI > or = 10 patients. CONCLUSION: Pruritus is a very common symptom in psoriasis. Burning, exudation and bleeding are also common symptoms seen in psoriasis. New scoring systems including symptoms of psoriasis patients may be developed for evaluating the severity of the disease.

European S3-Guidelines on the systemic treatment of psoriasis vulgaris.

2009-09-12T15:57:00.001-07:00

J Eur Acad Dermatol Venereol. 2009 Oct; 23 Suppl 2: 1-70Pathirana D, Ormerod AD, Saiag P, Smith C, Spuls PI, Nast A, Barker J, Bos JD, Burmester GR, Chimenti S, Dubertret L, Eberlein B, Erdmann R, Ferguson J, Girolomoni G, Gisondi P, Giunta A, Griffiths C, HÃ¶nigsmann H, Hussain M, Jobling R, Karvonen SL, Kemeny L, Kopp I, Leonardi C, Maccarone M, Menter A, Mrowietz U, Naldi L, Nijsten T, Ortonne JP, Orzechowski HD, Rantanen T, Reich K, Reytan N, Richards H, Thio HB, van de Kerkhof P, Rzany BOf the 131 studies on monotherapy or combination therapy assessed, 56 studies on the different forms of phototherapy fulfilled the criteria for inclusion in the guidelines. Approximately three-quarters of all patients treated with phototherapy attained at least a PASI 75 response after 4 to 6 weeks, and clearance was frequently achieved (levels of evidence 2 and 3). Phototherapy represents a safe and very effective treatment option for moderate to severe forms of psoriasis vulgaris. The onset of clinical effects occurs within 2 weeks. Of the unwanted side effects, UV erythema from overexposure is by far the most common and is observed frequently. With repeated or long-term use, the consequences of high, cumulative UV doses (such as premature aging of the skin) must be taken into consideration. In addition, carcinogenic risk is associated with oral PUVA and is probable for local PUVA and UVB. The practicability of the therapy is limited by spatial, financial, human, and time constraints on the part of the physician, as well as by the amount of time required by the patient. From the perspective of the cost-bearing institution, phototherapy has a good cost-benefit ratio. However, the potentially significant costs for, and time required of, the patient must be considered.

Fumaric Acid and its esters: an emerging treatment for multiple sclerosis.

2009-09-11T17:52:00.001-07:00

Curr Neuropharmacol. 2009 Mar; 7(1): 60-4Moharregh-Khiabani D, Linker RA, Gold R, Stangel MFumaric acid is an intermediate product of the citric acid cycle that is a source of intracellular energy in the form of adenosine triphosphate (ATP). It is generated by oxidation of adenylsuccinate by the enzyme succinate dehydrogenase and is then converted to maleate by the enzyme fumarase. At present, fumaric acid esters (FAE) are licensed for the treatment of psoriasis. Several lines of evidence have demonstrated immunomodulatory effects for FAE. Clinical studies in psoriasis showed a reduction of peripheral CD4(+)- and CD8(+)-T-lymphocytes due to the ability of FAE to induce apoptosis. In vitro studies with the ester dimethyl fumarate (DMF) described an inhibitory effect on nuclear factor kappa B (NF-kappaB)-dependent transcription of tumor necrosis factor-alpha (TNF-alpha) induced genes in human endothelial cells. Animal studies using a model of central nervous system demyelination, MOG-induced experimental autoimmune encephalomyelitis (EAE), revealed a reduction of microglia and macrophages in inflamed lesions. A phase II clinical study in relapsing-remitting multiple sclerosis (RRMS) patients with a modified fumaric acid ester, BG-12, showed as "proof of principle" a significant reduction in the number of gadolinium enhancing lesions after 24 weeks of treatment as compared to placebo. Further phase III studies have now started to explore the long-term efficacy of FAE.

The role of topical vitamin D modulators in psoriasis therapy.

2009-09-10T23:35:00.001-07:00

J Drugs Dermatol. 2009 Aug; 8(8 Suppl): s4-8Tanghetti EAPsoriasis affects more than 5 million adults in the United States (U.S.), causing significant impairments in quality of life and incurring substantial costs in treatment. The disease is characterized by hyperproliferation and abnormal differentiation of epidermal keratinocytes resulting from a disordered immune response. Topical therapies, such as corticosteroids, are the most common treatment for psoriasis. However, long-term use of more potent topical corticosteroids is associated with potential risk for side effects. Topical vitamin D agents have been developed as a newer therapeutic option for use in place of, or in addition to, topical corticosteroids. These agents act to inhibit keratinocyte proliferation, normalize differentiation and modulate the activity of immune cells with minimal effect on serum calcium hemostasis. Calcipotriene is the most widely used member of this class, and is one of the most frequently prescribed topical agents for psoriasis. Although evidence suggests that it is approximately as effective as low-to-medium potency corticosteroids, it is associated with cutaneous irritation, especially when used in sensitive areas. Calcitriol ointment is a new option for topical therapy and is the only vitamin D3 ointment available for use in the U.S. and contains the naturally occurring active form of vitamin D3 that is associated with a relatively low rate of side effects.

Adenosine deaminase activity, trypsin inhibitory capacity and total antioxidant capacity in psoriasis.

2009-09-10T17:44:00.000-07:00

J Eur Acad Dermatol Venereol. 2009 Sep 1; Hashemi M, Mehrabifar H, Daliri M, Ghavami SAbstract Background Psoriasis is a chronic inflammatory skin disease characterized by pathological skin lesions because of various exogenous and endogenous factors and associated with a number of biochemical and immunological disturbances. Objective The aim of the present study was to determine the level of adenosine deaminase activity, serum trypsin inhibitory capacity and total antioxidant capacity of plasma in psoriatic patients. Subjects and methods The study was performed in controls (n = 46) and in psoriatic patients (n = 40). The patients were scored with PASI (psoriasis area and severity index). The serum ADA activity was determined using Aguisti and Galanti method and serum trypsin inhibitory capacity (sTIC) were measured by enzymatic assay. Besides, serum total antioxidant capacity was measured using ferric reducing ability of plasma. Results The serum ADA activity of the psoriatic patients was found to be significantly higher (P < 0.001) than that of the healthy control. We also found that the trypsin inhibitory capacity was significantly higher in patients than in control group (P < 0.001). Total antioxidant capacity of plasma was significantly lower in psoriatic patients than in healthy controls (P = 0.025). There were no significant correlations among ADA, TAC and TIC. Conclusion Serum ADA activity and sTIC were increased in psoriatic patients. In parallel, serum total anti-oxidant activity was decreased in these patients.

Therapy of spondyloarthritides.

2009-09-09T23:26:00.001-07:00

Adv Exp Med Biol. 2009; 649: 133-47Braun JAnkylosing spondylitis (AS) is the major subtype and a major outcome of an interrelated group of rheumatic diseases now named as spondyloarthritides (SpA). The most important clinical features of this group are inflammatory back pain (IBP), asymmetric peripheral oligoarthritis, predominantly of the lower limbs, enthesitis and specific organ involvement such as anterior uveitis, psoriasis and chronic inflammatory bowel disease. Aortic root involvement and conduction abnormalities are rare complications ofAS. For clinical purposes, five subgroups are differentiated: AS, psoriatic SpA (PsSpA), reactive SpA (ReSpA), SpA associated with inflammatory bowel disease (SpAIBD) and undifferentiated SpA (uSpA). The SpA are genetically linked, the strongest known contributing factor is the MHC class I molecule HLA B27, ARTS-7, and IL-23R, others still remain to be identified. Most frequently and characteristically, AS starts in the sacroiliac joints at a mean age of26 years affecting men only slightly more frequent than women. In about 80% of the patients the disease spreads to the spine where all three segments are affected, most frequently the thoracic spine. Osteodestructive structural changes such as erosions occur less frequently than osteoproliferative changes which are pathognomonic for AS being clinically impressive by their appearance as syndesmophytes and ankylosis. Established classification criteria for AS and SpA perform less well in early disease stages. This partly contributes to the delay of diagnosis which is in the range of 5-10 years-mainly due the high frequency of back pain in the population. Major factors to improve the rate of AS patients diagnosed early are HLA B27 and imaging of the sacroiliac joints. International recommendations for the management ofAS have been published. The conventional treatment is mainly based on NSAIDs, patients with peripheral arthritis may be treated with sulfasalazine and patients with persistently active disease benefit from therapy with anti-TNF agents. Physiotherapy is of major importance in the general approach to patients with AS.

Are vitamin D receptor activators useful for the treatment of thrombosis?

2009-09-09T02:37:00.001-07:00

Curr Opin Investig Drugs. 2009 Sep; 10(9): 919-27Wu-Wong JRVitamin D3 is produced in the skin and modified in the liver and kidneys to form the active metabolite 1,25-dihydroxyvitamin D3 (calcitriol). Calcitriol binds to the vitamin D receptor (VDR), a nuclear receptor. The binding of calcitriol to the VDR activates the recruitment of cofactors that form a transcriptional complex that binds vitamin D response elements in the promoter region of target genes. During the past three decades, VDR research has focused mainly on the role of the receptor in the regulation of parathyroid hormone, intestinal calcium and phosphate absorption, and bone metabolism, and several VDR activators have been developed for the treatment of osteoporosis, psoriasis and hyperparathyroidism secondary to chronic kidney diseases. Emerging evidence suggests that VDR activators may be useful for treating cardiovascular, immunological, inflammatory and renal diseases. In addition, the VDR may have a role in modulating thrombogenicity. For example, VDR-/- mice display a phenotype of increased thrombogenic activity. VDR activators modulate the expression of various factors involved in thrombogenicity. Calcitriol was demonstrated to reduce the rate of oncology-related thrombosis in a clinical trial. This review discusses evidence from preclinical and clinical studies to investigate the potential role of VDR in thrombogenicity, and assesses whether VDR activators can be useful in the treatment of thrombosis.

IL-17 and IL-22 mediate IL-20 subfamily cytokine production in cultured keratinocytes via increased IL-22 receptor expression.

2009-09-08T17:28:00.001-07:00

Eur J Immunol. 2009 Sep 3; Tohyama M, Hanakawa Y, Shirakata Y, Dai X, Yang L, Hirakawa S, Tokumaru S, Okazaki H, Sayama K, Hashimoto KIL-20 cytokine subfamily members, including IL-19, IL-20, and IL-24, are highly expressed in psoriatic skin lesions. Here, we demonstrate that psoriasis mediators IL-17 and IL-22 synergistically induce the production of IL-20 subfamily proteins in cultured human keratinocytes. Interestingly, expression of the IL-22 receptor (IL-22R) also increased in epidermal lesions versus normal skin. IL-22R over-expression using an adenoviral vector to mimic psoriatic conditions in cultured keratinocytes significantly enhanced IL-17- and IL-22-induced production of IL-20 subfamily cytokines. Furthermore, IL-17 and IL-22 coordinately enhanced MIP-3alpha, IL-8, and heparin-binding EGF-like growth factor (HB-EGF) production, depending on the amount of IL-22R expression. Additionally, because IL-20 and IL-24 share the IL-22R with IL-22, the function of IL-20 and IL-24 was also increased. IL-20 and IL-24 have effects similar to that of IL-22; IL-24 showed more potent expression than IL-20. A combination of IL-24 and IL-17 increased the production of MIP-3alpha, IL-8, and HB-EGF, as did a combination of IL-22 and IL-17. These data indicate that increased IL-22R expression in epidermal keratinocytes contributes to the pathogenesis of psoriasis through enhancing the coordinated effects of IL-22 and IL-17, inducing the production of the IL-20 subfamily, chemokines, and growth factors.

Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8.

2009-09-08T02:34:00.001-07:00

J Exp Med. 2009 Aug 24; Ganguly D, Chamilos G, Lande R, Gregorio J, Meller S, Facchinetti V, Homey B, Barrat FJ, Zal T, Gilliet MDendritic cell (DC) responses to extracellular self-DNA and self-RNA are prevented by the endosomal seclusion of nucleic acid-recognizing Toll-like receptors (TLRs). In psoriasis, however, plasmacytoid DCs (pDCs) sense self-DNA that is transported to endosomal TLR9 upon forming a complex with the antimicrobial peptide LL37. Whether LL37 also interacts with extracellular self-RNA and how this may contribute to DC activation in psoriasis is not known. Here, we report that LL37 can bind self-RNA released by dying cells, protect it from extracellular degradation, and transport it into endosomal compartments of DCs. In pDC, self-RNA-LL37 complexes activate TLR7 and, like self-DNA-LL37 complexes, trigger the secretion of IFN-alpha without inducing maturation or the production of IL-6 and TNF-alpha. In contrast to self-DNA-LL37 complexes, self-RNA-LL37 complexes also trigger the activation of classical myeloid DCs (mDCs). This occurs through TLR8 and leads to the production of TNF-alpha and IL-6, and the differentiation of mDCs into mature DCs. We also found that self-RNA-LL37 complexes are present in psoriatic skin lesions and are associated with mature mDCs in vivo. Our results demonstrate that the cationic antimicrobial peptide LL37 converts self-RNA into a trigger of TLR7 and TLR8 in human DCs, and provide new insights into the mechanism that drives the auto-inflammatory responses in psoriasis.

Biological drugs targeting the immune response in the therapy of psoriasis.

2009-09-07T17:48:00.001-07:00

Biologics. 2008 Dec; 2(4): 687-97Pastore S, Gubinelli E, Leoni L, Raskovic D, Korkina LChronic plaque psoriasis affects more than 2% of world population, has a chronic recurrent behavior, gives a heavy burden to the patients' quality of life, and hence remains a huge medical and social problem. The clinical results of conventional therapies of psoriasis are not satisfactory. According to the current knowledge of the molecular and cellular basis of psoriasis, it is defined as an immune-mediated chronic inflammatory and hyperproliferative skin disease. A new generation of biological drugs, targeting molecules and cells involved into perturbed pro-inflammatory immune response in the psoriatic skin and joints, has been recently designed and applied clinically. These biological agents are bioengineered proteins such as chimeric and humanized antibodies and fusion proteins. In particular, they comprise the antitumor necrosis factor-alpha agents etanercept, infliximab, and adalimumab, with clinical efficacy in both moderate-severe psoriasis and psoriatic arthritis, and the anti-CD11a efalizumab with selective therapeutic action exclusively in the skin. Here, we overview recent findings on the molecular pathways relevant to the inflammatory response in psoriasis and present our clinical experience with the drugs currently employed in the dermatologic manifestations, namely etanercept, infliximab, and efalizumab. The growing body of clinical data on the efficacy and safety of antipsoriasis biological drugs is reviewed as well. Particular focus is given to long-term safety concerns and feasibility of combined therapeutic protocols to ameliorate clinical results.

Patterns of psoriatic arthritis.

2009-09-06T18:13:00.001-07:00

J Coll Physicians Surg Pak. 2009 Sep; 19(9): 553-6Ejaz A, Iftikhar A, Iftikhar NObjective: To describe the clinical patterns of arthritis in psoriasis. Study Design: Cross-sectional, observational study. Place and Duration of Study: Combined Military Hospital, Kharian Cantonment, Pakistan, from January to December 2007. Methodology: One hundred consecutive patients with psoriasis reporting to dermatology outpatient department were included. Pregnant ladies (due to X-ray hazard) and rheumatoid factor positive patients were excluded. The demographic profile of patients was recorded. Psoriatic arthritis was diagnosed on the basis of Moll and Wright criteria. Standardized examination of axial and peripheral joints was made. The severity of psoriasis was assessed by PASI score. The presence of a clinical type of psoriatic arthritis, enthesitis, dactylitis, and nail changes were noted. X-ray films of involved joints were taken. A statistical analysis using chi-square test and student's t-test were done where applicable. Results: The mean age of patients was 39.8+15.8 years. Seventy one percent were males and 29% were females. Forty six percent of the patients gave a history of joint involvement and fulfilled the Moll and Wright criteria. The mean PASI score in non-arthritic patients was 26.8+34.8 and in psoriatic arthritis patients it was 28.4+41.2, p=0.08. Thirteen patients (28.2%) had predominantly axial disease, while the rest had predominantly peripheral disease. Single joint involvement (monoarthritis) was the commonest clinical presentation. Nail involvement was seen in 29% of the patients without arthritis while in patients having arthritis, nail involvement was 74% (p=0.001). Conclusion: Joint involvement is common in psoriatic patients. However, the criteria of diagnosis lack consensus.

Recombinant Murine Interleukin 4 Protein Therapy for Psoriasis in a Transgenic VEGF Mouse Model.

2009-09-06T05:30:00.001-07:00

Dermatology. 2009 Aug 29; Ren X, Li J, Zhou X, Luo X, Huang N, Wang Y, Chen X, Wei YBackground: Psoriasis is a typical autoimmune disease caused by a deregulation of the Th1/Th2 balance, and immunotherapy for psoriasis has been shown to be clinically efficacious. Vascular endothelial growth factor (VEGF) is a potent mediator of angiogenesis. Evidence suggests that the chronic delivery of VEGF to the skin can result in a profound inflammatory condition with many of the cellular and molecular hallmarks of human psoriasis. In this study, we investigated whether the transgenic VEGF mouse is a suitable model for antipsoriatic studies. Aim: To determine the effect of a recombinant murine interleukin 4 (rmIL-4) in the transgenic VEGF mouse model. Methods: Fifteen homozygous K14-VEGF transgenic mice were injected subcutaneously with rmIL-4 protein for 30 consecutive days with a prospective dose escalation of 0.5, 2 or 5 mug/kg. Hematoxylin-eosin staining, immunohistochemistry and real-time polymerase chain reaction analyses were performed with ear samples. Results: The rmIL-4 protein therapy was well tolerated. Tissue sections from treated skin showed improvements upon morphological and histological examinations: diminution of erythematous appearance and regression of epidermal thickness were observed, and T lymphocyte infiltration decreased significantly. The expressions of adhesion molecules, such as vascular cell adhesion molecule 1 and intracellular adhesion molecule 1, were found reduced. The level of IL-4 mRNA also increased while the level of gamma-interferon mRNA decreased, resulting in a 10-fold increase in the ratio of Th1/Th2. Conclusions: Our results reveal that rmIL-4 has clinical efficacy for the treatment of K14-VEGF transgenic mice. Angiogenesis and inflammation were ameliorated by therapy with rmIL-4.

Xanthogranulomatous pyelonephritis: Review of 10 cases.

2009-09-05T16:28:00.001-07:00

Arch Esp Urol. 2009 May; 62(4): 259-271Leoni AF, Kinleiner P, Revol M, Zaya A, Odicio ABACKGROUND: OBJECTIVE: To report our experience with clinical presentation, appearance, diagnosis and treatment of Xanthogranulomaous pyelonephritis (XP). METHODS: Multicenter, observational, descriptive and retrosprospective study carried out during six years. RESULTS: We studied 10 patients, 8 women and 2 males, with an average age of 50 years. All cases presented with lumbar and abdominal pain, loss of weight, conjuntival pallor, renal lithiasis and chronic evolution Fever and palpable abdominal mass, were present in 80% of cases and 60% presented history of urinary tract infection. Initial diagnosis, in most cases, was pyonephrosis. Two cases (20 %). were associated with cancer and other 2 (20 %)with Psoriasis. Mortality was of (10 %).Laboratory hallmark were anemia, high SGV rate and leukocytosis. Urinary sediment showed pyuria. Urine culture was positive in the 50 % of the patients. On the other hand urine cultures obtained from nephrostomy tube were always positive. The onset was unilateral and diffuse in all cases without predominance in the location. Direct abdominal x-ray showed lithiasis, ultrasound showed increased renal size, with a pattern of hydronephrosis and/or intraparenchymatous abscesses. CT scan was useful to demonstrate disease extension. CONCLUSIONS: Xanthogranulomatous pyelonephritis (XP) is a chronic and unusual inflammatory-infectious disease with acute episodes involving renal parenchyma. Most cases appear in medium aged women. Histopathologic study offers the accurate diagnosis. Antibiotic therapy avoids septic complications. Total or partial nephrectomy is the definitive treatment. We propose nephrostomy because it facilitates the microbiological diagnosis and surgery (nephrectomy).

Insulin-Like Growth Factor-Binding Protein 7 Regulates Keratinocyte Proliferation, Differentiation and Apoptosis.

2009-09-04T18:29:00.001-07:00

J Invest Dermatol. 2009 Aug 27; Nousbeck J, Sarig O, Avidan N, Indelman M, Bergman R, Ramon M, Enk CD, Sprecher EInsulin-like growth factor (IGF)-binding protein 7 (IGFBP7) belongs to the IGFBP superfamily, which is involved in the regulation of IGF and insulin signaling. Recently, a global gene expression study revealed that IGFBP7 is downregulated in the psoriatic epidermis, with UVB phototherapy restoring its expression to normal. In the present study, we confirmed that IGFBP7 expression is decreased in psoriatic lesions. Given the previous data suggesting a role for IGFBP7 in the control of cancer cell growth, we investigated its involvement in the regulation of keratinocyte (KC) proliferation and differentiation, which are abnormal in psoriasis. To model IGFBP7 downregulation in vitro, we used IGFBP7-specific small interfering RNA or small hairpin RNA-expressing lentiviral vectors in HaCaT cells or primary human KCs. Downregulation of IGFBP7 was found to markedly enhance KC proliferation in both systems, was associated with a significant decrease in KC susceptibility to tumor necrosis factor-alpha-induced apoptosis, but did not affect senescence. Downregulation of IGFBP7 was also shown to block expression of genes associated with calcium-induced differentiation of human KCs. Finally, recombinant IGFBP7 was found to inhibit KC proliferation and enhanced their apoptosis. These data position IGFBP7 as a regulator of KC proliferation and differentiation, suggesting a potential role for this protein in the pathophysiology and treatment of hyperproliferative dermatoses such as psoriasis.Journal of Investigative Dermatology advance online publication, 27 August 2009; doi:10.1038/jid.2009.265.

Effects of virtual reality immersion and audiovisual distraction techniques for patients with pruritus.

2009-09-03T18:43:00.001-07:00

Pain Res Manag. 2009 Jul-Aug; 14(4): 283-6Leibovici V, Magora F, Cohen S, Ingber ABACKGROUND: Virtual reality immersion (VRI), an advanced computergenerated technique, decreased subjective reports of pain in experimental and procedural medical therapies. Furthermore, VRI significantly reduced pain-related brain activity as measured by functional magnetic resonance imaging. Resemblance between anatomical and neuroendocrine pathways of pain and pruritus may prove VRI to be a suitable adjunct for basic and clinical studies of the complex aspects of pruritus. OBJECTIVES: To compare effects of VRI with audiovisual distraction (AVD) techniques for attenuation of pruritus in patients with atopic dermatitis and psoriasis vulgaris. METHODS: Twenty-four patients suffering from chronic pruritus -- 16 due to atopic dermatitis and eight due to psoriasis vulgaris -- were randomly assigned to play an interactive computer game using a special visor or a computer screen. Pruritus intensity was self-rated before, during and 10 min after exposure using a visual analogue scale ranging from 0 to 10. The interviewer rated observed scratching on a three-point scale during each distraction program. RESULTS: Student's t tests were significant for reduction of pruritus intensity before and during VRI and AVD (P=0.0002 and P=0.01, respectively) and were significant only between ratings before and after VRI (P=0.017). Scratching was mostly absent or mild during both programs. CONCLUSIONS: VRI and AVD techniques demonstrated the ability to diminish itching sensations temporarily. Further studies on the immediate and late effects of interactive computer distraction techniques to interrupt itching episodes will open potential paths for future pruritus research.

Long-term experience with etanercept in psoriatic arthritis patients: A 3-year observational study.

2009-09-02T18:32:00.001-07:00

J Dermatolog Treat. 2009 Jan 1; 1-6Mazzotta A, Esposito M, Schipani C, Chimenti SObjective: To evaluate the clinical efficacy and tolerability of etanercept in the treatment of active and progressive psoriatic arthritis (PsA) in patients who have previously demonstrated an inadequate response to standard treatments, such as disease-modifying anti-rheumatic drugs (DMARDs) and non-steroidal anti-inflammatory drugs (NSAIDs). Methods: An open-label, non-controlled, prospective study was conducted including 32 patients affected by PsA with variable skin involvement who had responded inadequately to at least two DMARDs. Patients received etanercept subcutaneously administered as monotherapy at the dosage of 50 mg twice weekly for 12 weeks followed by 25 mg twice weekly. Clinical response was evaluated using the EULAR (European League Against Rheumatism) disease activity score (DAS) in 28 joints (DAS-28) and the Psoriasis Area and Severity Index (PASI). The percentage improvement in DAS-28 and the proportion of patients achieving a PASI improvement from baseline of between 50% and 75% (PASI 50), > 75% (PASI 75) and > 90% (PASI 90) were analysed as primary endpoints. Results: Twenty-seven (27/32) patients (84.3%) completed 3 years (144 weeks) of continuous treatment, while 5/32 (15.6%) patients were withdrawn from the study. At week 144, a significant improvement in DAS-28 was registered with a reduction in mean DAS-28 from 5.3 at baseline to 1.8, while 25/27 patients (92.5%) achieved PASI 75 with a mean PASI score of 0.7; the mean pain visual analogue scale (pain-VAS) score decreased from 64.2 at baseline to 2 at week 144, corresponding to an improvement of 94.7%. Conclusions: Etanercept is a safe and effective agent in the long-term management of PsA patients. After 3 years of continuous treatment, symptoms were under control in the majority of patients and there was a low level of disease activity.

Calcitriol ointment: optimizing psoriasis therapy.

2009-09-02T08:09:00.001-07:00

J Drugs Dermatol. 2009 Aug; 8(8 Suppl): s23-7Gold LFThe topical vitamin D3 modulator calcitriol, the naturally occurring active form of vitamin D3, has long been used for topical psoriasis therapy in Europe and other countries and was recently approved in the United States (U.S.) for the treatment of plaque psoriasis. In vehicle-controlled clinical trials, calcitriol 3 microg/g ointment has been shown to significantly improve the symptoms of psoriasis with a low incidence of adverse effects and without affecting calcium homeostasis, even when applied continuously for up to one year. A number of studies have examined the efficacy and safety of calcitriol ointment in combination therapy regimens that also included topical corticosteroid therapy or ultraviolet B (UVB) phototherapy. Calcitriol 3 microg/g ointment is a new option that provides flexibility for use in a variety of psoriasis treatment regimens. According to guidelines developed by the American Academy of Dermatology (AAD), the goals of psoriasis treatment are to produce durable remission of psoriasis symptoms, to achieve "substantial" clearing with the possibility of complete clearing, to maintain the initial benefits of therapy, and to minimize the risk of adverse events. Topical medications are the most commonly used treatments for psoriasis in the U.S. and are important in meeting the goals of psoriasis therapy. These agents offer high response rates with generally favorable safety and tolerability profiles and are useful for both acute treatment and long-term maintenance. Topical medications are used by approximately 85% of patients with psoriasis.

Psoriatic arthritis in Asia.

2009-09-01T08:14:00.001-07:00

Rheumatology (Oxford). 2009 Aug 27; Tam LS, Leung YY, Li EKGeographic or ethnic differences in the occurrence of disease often provide insights into causes of disease and possible opportunities for disease prevention. A wide variation on the incidence and prevalence of PsA was reported in different countries. The prevalence in China was similar to the rest of the world, whereas the incidence and prevalence of PsA was much lower in Japan. Among patients with psoriasis, 6-42% of the Caucasians were reported to have PsA, but figures were lower from Asian countries (1-9%). Divergent distribution of HLA in different ethnic groups and other genetic determinants may account for these differences in prevalence. PsA affects men and women almost equally in Chinese, Japanese and Iranians, which is similar to their Caucasian counterparts. Polyarthritis developing in the fourth decade was the commonest pattern of arthritis among Chinese, Indians, Iranians, Kuwaiti Arabs and Malays. Arthritis mutilans and eye lesions have rarely been reported in Asian countries. Chinese patients with nail disease and DIP joints involvement have a significantly higher risk of developing deformed joints. More data are required on the safety, efficacy and cost effectiveness of TNF blockers for the treatment of PsA in Asia. Premature atherosclerosis has been recognized as an important co-morbidity in Asian patients with PsA. Increased prevalence of traditional cardiovascular risk factors associated with PsA suggested that the two conditions may share the same inflammatory pathway. Carotid intima-media thickness can identify PsA patients with subclinical atherosclerosis who may benefit from early intervention.

Practice of Phototherapy in the Treatment of Moderate-to-Severe Psoriasis.

2009-08-31T18:43:00.001-07:00

Curr Probl Dermatol. 2009; 38: 59-78Nguyen T, Gattu S, Pugashetti R, Koo JThis chapter will discuss the entire spectrum of phototherapy, including narrowband UVB photo-therapy, broadband UVB phototherapy, PUVA, targeted excimer laser phototherapy, and combination treatments. Phototherapy can range from simple treatments in a UVB phototherapy box, with or without concurrent use of various tar preparations, to more elaborate modalities in which the intensity of UVB radiation applied varies according to different anatomical regions. Combining PUVA or UVB phototherapy with topical and systemic agents can also enhance phototherapy. Certain forms of phototherapy, such as the traditional Goeckerman regimen of using black tar daily with UVB light, induce a prolonged remission. Outpatient phototherapy is usually reserved for patients whose disease is not adequately controlled with topical medications, including steroids, vitamin D analogues, tazarotene, tar, or anthralin. It is also indicated for patients with such extensive psoriasis that topical therapy is nearly impossible. Additionally, phototherapy may be an excellent option for patients with specific medical problems for whom systemic medications such as methotrexate, cyclosporine, or biological agents may not be suitable. For patients with generalized psoriasis, phototherapy is a reasonable first choice among the available options because of its superior systemic safety profile in comparison to systemic or biological agents. As with all other forms of psoriasis therapy, it is essential to consider the impact of the treatment on the patient's lifestyle when selecting the treatment plan. Important points to consider when initially discussing phototherapy are the patient's employment schedule, commitment, flexibility, location of the phototherapy unit, and transportation. Copyright (c) 038 S. Karger AG, Basel.

International multicenter psoriasis and psoriatic arthritis reliability trial for the assessment of skin, joints, nails, and dactylitis.

2009-08-30T15:51:00.001-07:00

Arthritis Rheum. 2009 Aug 27; 61(9): 1235-1242Chandran V, Gottlieb A, Cook RJ, Duffin KC, Garg A, Helliwell P, Kavanaugh A, Krueger GG, Langley RG, Lynde C, McHugh N, Mease P, Olivieri I, Rahman P, Rosen CF, Salvarani C, Thaci D, Toloza SM, Wong MY, Zhou QM, Gladman DDOBJECTIVE: Clinical trials in psoriasis and psoriatic arthritis (PsA) involve assessment of the skin and joints. This study aimed to determine whether assessment of the skin and joints in patients with PsA by rheumatologists and dermatologists is reproducible. METHODS: Ten rheumatologists and 9 dermatologists from 7 countries met for a combined physical examination exercise to assess 20 PsA patients (11 men, mean age 51 years, mean PsA duration 11 years). Each physician assessed 10 patients according to a modified Latin square design that enabled the assessment of patient, assessor, and order effect. Tender joint count (TJC), swollen joint count (SJC), dactylitis, physician's global assessment (PGA) of PsA disease activity (PGA-PsA), psoriasis body surface area (BSA), Psoriasis Area and Severity Index (PASI), Lattice System Physician's Global Assessment of psoriasis (LS-PGA), National Psoriasis Foundation Psoriasis Score (NPF-PS), modified Nail Psoriasis Severity Index (mNAPSI), number of fingernails with nail changes (NN), and PGA of psoriasis activity (PGA-Ps) were assessed. Variance components analyses were carried out to estimate the intraclass correlation coefficient (ICC), adjusted for the order of measurements. RESULTS: There is excellent agreement (ICC >/=0.80) on the mNAPSI, substantial agreement (0.6 >/= ICC < 0.80) on the TJC, PASI, and NN, moderate agreement (0.4 >/= ICC < 0.60) on the PGA-Ps, LS-PGA, NPF-PS, and BSA, and fair agreement (0.2 >/= ICC < 0.40) on the SJC, dactylitis, and PGA-PsA. The only measure that showed a significant difference between dermatologists and rheumatologists was dactylitis (P = 0.0005). CONCLUSION: There is substantial to excellent agreement on the TJC, PASI, NN, and mNAPSI among rheumatologists and dermatologists.

Familial Association of Inflammatory Bowel Diseases With Other Autoimmune and Related Diseases.

2009-08-30T08:13:00.001-07:00

Am J Gastroenterol. 2009 Aug 25; Hemminki K, Li X, Sundquist K, Sundquist JOBJECTIVES:Familial risk estimates are useful for genetic counseling, etiological understanding, and design of gene identification studies. We wanted to estimate the associations of ulcerative colitis (UC) and Crohn's disease (CD) with 32 autoimmune and related diseases among parents and offspring, singleton siblings, twins, and spouses.METHODS:The Multigeneration Register in Sweden provides reliable access to information on families among 11.5 million individuals throughout the last century. The diseases in individual family members were obtained through linkage to the Hospital Discharge Register. Standardized incidence ratios (SIRs) and 95% confidence intervals were calculated as relative risks for UC/CD in family members of patients diagnosed with any of the 34 diseases compared with those lacking affected family members through years 1964-2004.RESULTS:Among a total of 441,642 patients diagnosed with autoimmune and related conditions, 25,846 were diagnosed with UC and 18,885 with CD. Familial cases amounted to 5.4% of all UC patients and 6.5% of CD patients. SIR for UC was 3.9 (95% confidence interval 3.5-4.3) in offspring of affected parents, 4.6 (3.0-7.4) in siblings, 10.4 (6.5-15.8) in families of affected parents and siblings, and 6.3 (1.9-17.7) for monozygotic twins. The respective SIRs for CD were 6.0 (5.4-6.7), 6.3 (4.1-9.8), 34.0 (24.9-45.3), and 23.4 (10.1-51.1). All discordant associations, i.e., those between CD and other diseases, were also found for UC, including ankylosing spondylitis, asthma, polymyalgia rheumatica, psoriasis, and sarcoidosis. For UC, six additional associations were observed. No correlations between specific diseases were found among spouses, but between UC or CD and any disease it was 1.1 (1.0-1.1).CONCLUSIONS:The concordant familial risks for UC and CD were lower than those commonly cited. Both diseases are associated with several autoimmune and related diseases, suggesting genetic sharing.Am J Gastroenterol advance online publication, 25 August 2009; doi:10.1038/ajg.2009.496.

Retinoids, methotrexate and cyclosporine.

2009-08-30T03:50:00.001-07:00

Curr Probl Dermatol. 2009; 38: 79-94Dubertret LAcitretin alone is efficient (PASI 90: 40%). In responders, it is the best long-term maintenance treatment (up to 29 years of continuous treatment). The main side effect is its teratogenicity in females. It is necessary to begin retinoid treatment at low doses (10 mg/day), increasing the dose step by step, looking for the maximum well-tolerated dose (usually defined as a mild cheilitis). Doses higher than the highest well-tolerated dose are frequently responsible for the Kobner phenomenon. In children, retinoids are very efficient and nearly always well tolerated, but it seems important to never give more than 0.5 mg/kg/day. Methotrexate is the best treatment for severe psoriasis. Given at low doses once a week, it is a safe, cheap, convenient and efficient treatment, if carefully monitored. The main problem is the possible long-term liver toxicity of methotrexate. The risk is very low in patients not at risk (no liver disease). In these cases, liver biopsies are dangerous and useless. In the other cases, the need for liver biopsy is very rare, decided only by the hepatologist, and should be replaced by FibroTest and FibroScan. The old American guidelines should not be followed, and new guidelines are needed. Cyclosporine at low doses is an outstanding emergency treatment. It was first used as the last possible systemic treatment, but long-term continuous treatments are seldom possible due to alterations in kidney functions. A careful follow-up of kidney functions, with measurement of the glomerular fil-tration rate after each year of cumulative treatment, is necessary. The cyclosporine dose must be calculated according to the theoretical body weight in obese patients to avoid overdosage. Cyclosporine is mainly used now as a short-term treatment that is very efficient for young people, who find this illness particularly difficult. Cyclosporine is not contraindicated during pregnancy. Copyright (c) 038 S. Karger AG, Basel.

Japanese version of cutaneous body image scale: translation and validation.

2009-08-29T15:42:00.001-07:00

J Dermatol. 2009 Sep; 36(9): 477-84Higaki Y, Watanabe I, Masaki T, Kamo T, Kawashima M, Satoh T, Saitoh S, Nohara M, Gupta MACutaneous body image, defined as the individual's mental perception of the appearance of their skin, hair and nails, is an important psychodermatological element in skin diseases. To measure individuals' cutaneous body image, a practical and accurate instrument is necessary. In this study, we translated the Cutaneous Body Image Scale (CBIS), a 7-item instrument originally created by Gupta et al. in 2004, into Japanese using a forward- and back-translation method and evaluated the reliability and validity of the instrument by psychometric tests. A total of 298 healthy adults (64 men and 234 women, aged 28.9 +/- 9.9 years) and 165 dermatology patients (56.7% eczema/dermatitis, 9.8% acne, 7.5% alopecia, 6.9% psoriasis, 19.1% skin tumor/fleck/other) (30 men and 135 women, aged 37.9 +/- 15.2 years) responded to the Japanese version of the CBIS. The internal-consistency reliability of the instrument was high (Cronbach's alpha, healthy adults 0.88, patients 0.84). The CBIS measure demonstrates good test-retest reliability (healthy adults gamma = 0.92, P < 0.0001; patients gamma = 0.79, P < 0.001). Compared to the healthy adults (4.11 +/- 1.80), the CBIS scores among dermatology patients (3.18 +/- 1.69, P = 0.000) were significantly low. The CBIS scores showed moderate correlation with the "emotions" and "global" scores of Skindex-16 in healthy adults (gamma = -0.397 and -0.373, respectively) and in patients (gamma = -0.431 and -0.38, respectively). A stepwise multiple regression analysis revealed that an emotional aspect of skin-condition related quality of life was the best predictor of cutaneous body image in both healthy adults and patients (beta = -0.31 and -0.41, respectively) followed by "body dissatisfaction" (beta = -0.17, and -0.23, respectively). Adjusted R(2) was 0.246 in healthy adults and 0.264 in patients. These were consistent with the results from the original the CBIS. These results suggest that the Japanese version of the CBIS is a reliable and valid instrument to measure the cutaneous body image of Japanese adults and also dermatology patients.

Psoriasis and systemic inflammation: underdiagnosed enthesopathy.

2009-08-28T22:17:00.001-07:00

J Eur Acad Dermatol Venereol. 2009 Sep; 23 Suppl 1: 3-8Girolomoni G, Gisondi POur understanding of the pathogenesis of psoriasis is changing rapidly and the traditional view that it is a disease limited to the skin continues to be challenged. Indeed, there is convincing evidence that psoriasis patients have a higher prevalence of comorbid disease, particularly cardio-metabolic disorders and psoriatic arthritis (PsA). The results of recent investigations into psoriasis and cardiovascular or metabolic comorbidities provide increasing evidence for a possible shared pathogenic mechanism for these disorders, linked by an underlying chronic systemic inflammatory state. This highlights the importance of investigating associated comorbidities beyond skin manifestations. Psoriatic arthritis is a chronic inflammatory arthropathy that can occur in association with psoriasis and most commonly affects the distal joints in the hands and feet. Skin lesions precede arthritic symptoms in approximately 75% of cases; typically, the cutaneous manifestations of the disease develop 10 years prior to the onset of joint symptoms. This disease course, therefore, provides a potential window of opportunity to initiate effective and aggressive therapies to prevent long-term damage, if symptoms of PsA can be detected early. One of the major features of PsA is enthesitis, yet clinically asymptomatic cases of entheseal abnormalities are likely to go undiagnosed. This concept was evaluated in a prospective study in which entheseal changes in clinically asymptomatic psoriasis patients were compared with findings from a control group. Ultrasonography detected a significantly higher incidence of entheseal abnormalities in patients with psoriasis, despite the absence of clinical symptoms of arthropathy. Ongoing monitoring of these patients has also revealed that a higher baseline score for enthesitis may be associated with a more severe psoriasis outcome. These findings demonstrate that detecting early signs of PsA in asymptomatic patients with psoriasis may have the potential to positively influence disease prognosis and ultimately clinical outcome. Dermatologists can, therefore, play a key role in the early detection and management of PsA.

Therapies for childhood psoriasis.

2009-08-28T16:13:00.001-07:00

Curr Probl Dermatol. 2009; 38: 137-59Trueb RMWith a prevalence of 2% of the general population of Europe and North America, psoriasis repre-sents one of the most common and significant dermatologic disorders. While it has been claimed that psoriasis is uncommon in children, in fact 27% of cases manifest before the age of 16 years; moreover, psoriasis represents 4.1% of all dermatoses seen in children under the age of 16 years. Both recognition and treatment of psoriasis in children represent unique challenges. Early diagnosis and appropriate management are particularly important in children to lessen long-term disease-related psychosocial problems and comorbidities. Psoriasis in childhood is a disease of many forms, which may change over time. It may be difficult to recognize, since the frequencies of some types of patterns of psoriasis differ between adults and children, and some clinical features are distinctive to the pediatric age group. Management involves education of the child and parents concerning the nature of the disease and the effects of treatment. Environmental triggers should be sought and eliminated, particularly infection, trauma, and stress. The treatment options available are basically the same as for adults, but special care should be taken in order not to endanger the development or the future health of the child. In children, treatment modalities are limited because of safety concerns and/or poor compliance associated with messy and time-consuming therapies. Randomized controlled clinical trials involving children under the age of 12 years suffering from psoriasis have been reported only for 2 topical treatments, namely, calcipotriol and corticosteroids. Phototherapy and systemic therapy with methotrexate, acitretin and cyclosporin have limited use because of lower tolerability in children and cumulative toxicities. For this reason, treatments of psoriasis with the newer biologic agents, particularly the soluble tumor necrosis factor receptor fusion protein etanercept, are emerging. Finally, it is important to acknowledge that topical and systemic treatments are only part of a 'total care' package combining treatment, disease-specific education, and psychologi-cal support to cope with a possible lifelong skin condition. Copyright (c) 038 S. Karger AG, Basel.

Calcitriol 3 microg/g ointment: an effective and safe addition to the armamentarium in topical psoriasis therapy.

2009-08-28T04:41:00.001-07:00

J Drugs Dermatol. 2009 Aug; 8(8 Suppl): s17-22Abramovits WHigh-potency topical corticosteroids are very effective for the treatment of psoriasis, but are associated with a number of cutaneous adverse effects. Vitamin D modulators have emerged as an important alternative to corticosteroids for the long-term topical treatment of psoriasis. Calcitriol 3 microg/g ointment has long been used to treat psoriasis in Europe and is now the only vitamin D3 ointment available for use in the United States (U.S.). Several randomized clinical trials have compared the safety, efficacy, and cosmetic acceptability of calcitriol ointment with other topical psoriasis therapies. In a three-week investigator-blinded study of 25 healthy subjects, calcitriol 3microg/g ointment was associated with markedly less cumulative skin irritation than was calcipotriene ointment. A multicenter, investigator-blinded study of patients with psoriasis found that investigator-rated global improvement of psoriasis symptoms with calcitriol ointment was statistically noninferior to calcipotriene ointment and that calcitriol use produced significantly fewer patients with cutaneous reactions or discomfort. A multicenter clinical trial of patients with psoriasis who had lesions affecting sensitive skin areas found that calcitriol use produced less skin irritation than did calcipotriene and was generally preferred to calcipotriene ointment by patients. Calcitriol was also significantly more effective for the treatment of psoriasis lesions affecting flexural areas. In another study, patients who received calcitriol ointment exhibited improvement in psoriasis symptoms that was similar to the corticosteroid betamethasone propionate, but were much less likely to have relapsed eight weeks after treatment discontinuation. Two clinical studies also suggested that calcitriol is similar in efficacy to short-contact dithranol, but with a lower incidence of skin irritation and staining. Together, the results of these studies demonstrate that calcitriol 3 microg/g ointment is a significant new option for topical therapy of psoriasis. Calcitriol ointment produces improvement in psoriasis symptoms that is generally similar to the improvement attained with other (except for high potency steroid) topical psoriasis therapies, with a low incidence of adverse events.

Approach to managing patients with nail psoriasis.

2009-08-27T16:00:00.001-07:00

J Eur Acad Dermatol Venereol. 2009 Sep; 23 Suppl 1: 15-21Reich KPsoriasis is a chronic inflammatory skin condition that affects approximately 2% of the population. Up to 50% of patients with psoriasis have concurrent nail psoriasis, with a lifetime incidence of 80% to 90%. Up to 30% of patients with skin psoriasis also have psoriatic arthritis (PsA) and of these, approximately 80% have nail disease. However, nail involvement is often overlooked by physicians, despite the significant burden it places on patients as a result of functional impairment of manual dexterity, pain and psychological stress. Affected nail plates often thicken and crumble, and because they are very visible, patients are usually concerned about the appearance of their nails, often causing them to avoid normal day-to-day activities (including work). In the longer-term, nail involvement may be a signal of a more severe form of psoriasis or a precursor of PsA. Conventional treatment of nail psoriasis is generally considered inconvenient by patients, and it is limited by adverse effects and often a reduction in efficacy over time. There is also a lack of controlled clinical trials' data and no consistent treatment approach has been advocated. Recently, the effects of biologic agents targeted against tumour necrosis factor alpha (TNFalpha) on nail psoriasis have been investigated. The multicentre, double-blind EXPRESS [European Infliximab for Psoriasis (Remicade) Efficacy and Safety Study] trial revealed that infliximab 5 mg/kg at weeks 0, 2, 6, and then every 8 weeks significantly improved nail psoriasis, evaluated using the Nail Psoriasis Severity Index (NAPSI) in 378 patients with moderate to severe psoriasis. Significant improvement was reported as early as week 10, and at week 50 full nail clearance was evident in 45% of patients receiving infliximab. There is also evidence from small studies that infliximab significantly improves nail lesions and quality of life in patients with nail psoriasis. There is a need for improving the awareness of nail psoriasis and its impact on patients' quality of life. Moreover, the potential role for nail involvement as a link between psoriasis and PsA underlines its importance and the need for effective management. Infliximab has been shown to improve psoriatic nail lesions and quality of life, and it should be considered as one of the most appropriate available treatment options for the many patients with this distressing condition.

The burden of autoimmune disease: a comparison of prevalence ratios in patients with psoriatic arthritis and psoriasis.

2009-08-27T02:35:00.001-07:00

J Am Acad Dermatol. 2009 Sep; 61(3): 405-10Makredes M, Robinson D, Bala M, Kimball ABBACKGROUND: Current research has confirmed that many inflammatory autoimmune (AI) diseases are due to derangements in multiple cytokine pathways. Some of these cytokines appear to play comparable key roles across diseases, suggesting that a similar underlying systemic inflammatory cascade could be responsible for various disease states. A recent study supports the hypothesis of a common cytokine-based pathology by showing that having one AI disease significantly increased the risk of having another AI disease. Psoriasis is an AI, manifesting as a chronic inflammatory skin condition and is clearly associated with other conditions, most obviously psoriatic arthritis (PsA). OBJECTIVE: We sought to examine whether patients with PsA enrolled in managed health care plans carry a higher AI disease burden than patients with cutaneous psoriasis only (PsO). METHODS: Patients 18 years or older enrolled in a health claims database were classified by two clinical subtypes: PsA and PsO. Control subjects were matched 3:1 to patients with psoriasis on age, sex, census region, and length of previous medical insurance coverage. AI disease diagnoses were identified through International Classification of Diseases, Ninth Revision codes. The association of other AI diseases with each psoriasis cohort was assessed using a prevalence ratio. RESULTS: PsO was associated with a higher prevalence ratio for the 3 gastrointestinal diseases: Crohn disease (1.6 [confidence interval {CI} 1.4-2.0]), ulcerative colitis (1.3 [CI 1.1-1.6]), and inflammatory bowel disease (1.4 [CI 1.2-1.6]). PsA was also associated with a higher prevalence ratio for the gastrointestinal diseases: Crohn disease (2.1 [CI 1.3-3.3]), ulcerative colitis (2.0 [CI 1.3-3.1]), and inflammatory bowel disease (1.8 [CI 1.3-2.5]). Patients with PsA had an increased prevalence ratio associated with giant cell arteritis (4.8 [CI 1.5-15.7]) and pulmonary fibrosis (1.9 [CI 1.2-3.0]). LIMITATIONS: Detection and misclassification biases may have affected these findings. CONCLUSIONS: These findings support the hypothesis that PsA and PsO are associated with development of other AI diseases. The data suggest that evaluating patients with psoriasis for other associated disorders in a prospective manner may be important, because they may be more likely to experience the onset of another AI disease. Treatment planning for these patients could, therefore, require the medical management of more than one AI disease. Further, our data suggest that PsA and PsO may be divergent in ways previously not described that could inform future research.

Enthesitis: an autoinflammatory lesion linking nail and joint involvement in psoriatic disease.

2009-08-26T16:11:00.001-07:00

J Eur Acad Dermatol Venereol. 2009 Sep; 23 Suppl 1: 9-13McGonagle DThe traditional model for psoriasis and psoriatic arthritis (PsA) is that autoimmunity directed against a common skin and joint autoantigen leads to chronic autoreactive T cell driven inflammation. However, recent imaging, histological and genetic studies have challenged this view, especially with respect to joint and nail disease, and provide a broader insight into the pathogenesis of PsA and associated nail involvement. Clinically unrecognized enthesitis (inflammation at tendon and ligament attachments) is commonly seen in early PsA at all sites of the disease. Specifically, enthesitis is associated with adjacent osteitis or bone and synovial inflammation. Even in normal joints, normal insertions are associated with microdamage and inflammatory change, strongly suggesting that local tissue specific, or what has been described as autoinflammatory factors, may dictate disease expression. Distal interphalangeal (DIP) joint disease in PsA is associated with diffuse inflammation that envelops the nail root and adjacent bone. In fact, the nail is intimately linked to entheses, with the extension tendon of the DIP joint sending fibres from bone that envelop the nail root in an interdigitating fashion. Furthermore, the joint collateral ligament enthesis has fibres that merge with the lateral borders of the nail. Other anchorage mechanisms include fibres that directly tether the nail plate to the underlying periosteum, which itself is closely anchored to the extension tendon. The frequent microdamage and tissue repair at normal enthesis attachment sites in healthy joints has resulted in a proposed new model of PsA pathogenesis embracing the concept of autoinflammation, whereby tissue specific factors, including microtrauma, lead to regional innate immune activation and persistent inflammation, as an alternative to primary immunopathology driven by T and B cell abnormalities. Unlike the classical autoimmune diseases, which may attack a completely normal organ, autoimmunity in psoriatic disease is likely to involve tissues where there is intrinsic dysregulation of the target tissues. These tissue specific factors related to the enthesis appear to be key to the phenotypic expression of diseases hitherto regarded as autoimmune. The pathogenesis of PsA, nail disease and to a lesser extent psoriasis therefore appear to have an autoinflammatory (innate immune driven) rather than autoimmune basis. Taken together, these findings are important for better understanding PsA, nail disease and psoriasis, and for conceptualizing the immunopathogenic basis of these diseases and further exploring the role of enthesitis in their pathophysiology.

Downregulation of SMAD2, 4 and 6 mRNA and TGFbeta Receptor I mRNA in Lesional and non-lesional psoriatic skin.

2009-08-24T23:02:00.001-07:00

Acta Derm Venereol. 2009; 89(4): 351-6Yu H, Mrowietz U, Seifert OTransforming growth factor beta (TGFbeta) has been suggested to be an effective inhibitor of the increased keratinocyte proliferation in psoriasis. Three TGFbeta isoforms are described (TGFbeta1, 2 and 3), signalling via a heteromeric receptor complex of TGFbetaRI and TGFbetaRII. Receptor binding activates SMAD2, 3 and 4, which translocate into the nucleus and regulate TGFbeta-responsive genes. SMAD6 and 7 proteins represent a negative feedback loop inhibiting the TGFbeta-SMAD signalling path-way. As TGFbeta1 overexpression inhibits keratinocyte proliferation, the aim of this study was to investigate with real-time RT-PCR the expression of TGFbeta1, 2 and 3, TGFbetaRI and TGFbetaRII and SMAD2, 3, 4, 6 and 7 in lesional and non-lesional psoriatic skin from 13 patients with chronic plaque-type psoriasis as compared to skin from 10 healthy subjects . The study data demonstrate significantly downregulated TGFbetaRI and SMAD2, 4 and 6 mRNA expression in lesional and non-lesional psoriatic skin. SMAD7 mRNA expression was significantly decreased in lesional psoriatic skin compared with both non-lesional psoriatic skin and healthy skin. A significant TGFbeta3 and TGFbetaRII mRNA upregulation exclusively in non-lesional psoriatic skin but no significant difference in the expression of TGFbeta1 and 2 was found. The results of this study suggest that the expression of TGFbeta isoforms, receptors and SMADs may be involved in the increased proliferation of keratinocytes in psoriatic skin.

Psoriasis vs allergic contact dermatitis in palms and soles: a quantitative histologic and immunohistochemical study.

2009-08-24T16:14:00.001-07:00

APMIS. 2009 Aug; 117(8): 629-34Cesinaro AM, Nannini N, Migaldi M, Pepe P, Maiorana AA systematic histologic and immunohistochemical study of cases of psoriasis (PSO) and allergic contact dermatitis (ACD) in palmo-plantar skin was performed to find differences between these two diseases that usually show overlapping features in these specific sites. Skin biopsies from 42 (22 female, 20 male) patients were evaluated for several histopathologic parameters and immunohistochemistry was applied to quantify keratinocytic proliferation, the number of dendritic cells (DCs) and the phenotype of the mononuclear cell infiltrate. Regular epidermal hyperplasia and marked parakeratosis were found to be more frequent in PSO than in ACD cases, but only the first parameter reached the level of significance (p = 0.03). The number of S100 protein-positive DCs was significantly higher in ACD (p = 0.006), whereas keratinocytic proliferation, studied with Mib-1, was found to be higher in PSO than in ACD, but the difference was not statistically significant. No significant difference was detected in the number of CD4+, CD8+ and bcl2+ lymphocytes in PSO and ACD cases. In the palms and soles, the finding of irregular epidermal hyperplasia and the detection of a higher number of S100 protein-positive DCs favor the diagnosis of ACD over PSO. The differential diagnosis between PSO and ACD can be practically approached using a histopathologic parameter and a commercially available antibody.

Prevalence, characteristics and severity of non-alcoholic fatty liver disease in patients with chronic plaque psoriasis.

2009-08-24T08:21:00.001-07:00

J Hepatol. 2009 Jun 26; Miele L, Vallone S, Cefalo C, Torre GL, Stasi CD, Vecchio FM, D'Agostino M, Gabrieli ML, Vero V, Biolato M, Pompili M, Gasbarrini G, Rapaccini G, Amerio P, Simone CD, Grieco ABACKGROUND / AIMS: The association between NAFLD and psoriasis has never been explored in prospective epidemiological studies. The aim of this 2-phase study was to study the clinical features of NAFLD in patients with psoriasis. METHODS: Phase 1: Investigation of prevalence and characteristics of NAFLD in an unselected cohort of 142 adult Italian outpatients with psoriasis vulgaris. Phase 2: Comparison of the psoriasis cohort subgroup with NAFLD and an age- and body mass index-matched retrospective cohort of 125 non-psoriasis patients with biopsy proven NAFLD. RESULTS: Based on histories, laboratory tests, and ultrasound studies, 84 (59.2%) received clinical diagnosis of NAFLD; 30 had factors potentially associated with liver disease other than NAFLD (e.g., viral hepatitis, significant ethanol, methotrexate use); and 28 (19.7%) had normal livers. Comparison of the normal-liver and NAFLD subgroups revealed that NAFLD in psoriasis patients (Ps-NAFLD) was significantly correlated with metabolic syndrome (p1. CONCLUSIONS: NAFLD is highly prevalent among psoriasis patients, where it is closely associated with obesity (overall and abdominal), metabolic syndrome, and PsA, and more likely to cause severe liver fibrosis (compared with nonPs-NAFLD). Routine work-up for NAFLD may be warranted in patients with psoriasis, especially when potentially hepatotoxic drug therapy is being considered.

The universal detection of antigens from one skin biopsy specimen.

2009-08-23T23:31:00.001-07:00

J Cutan Pathol. 2009 Sep; 36(9): 972-9van der Velden HM, van de Kerkhof PC, Pasch MC, de Boer-van Huizen RT, van Lingen RG, van Erp PEBACKGROUND: Immunohistochemistry is an important tool in dermatology but is limited. Certain antigens can only be preserved in formalin-fixed paraffin-embedded sections, while others can only be detected on frozen sections, resulting in situations where two biopsies are needed. We aimed to develop a technique for universal detection of different antigens out of just one biopsy specimen. METHODS: Single biopsies were obtained from lesional skin of patients with psoriasis. Standard sample procedures for frozen and paraffin-embedded sections were used. To convert frozen tissue into paraffin-embedded sections, the biopsy specimen was disposed of the embedding medium and subsequently fixed in 10% neutral buffered formalin. We applied various antigen retrieval techniques with alkaline solutions. The differential expression of keratin 10, keratin 15, CD3, CD26 and human beta defensin-2 (HBD-2) was examined using immunohistochemical staining. RESULTS: We showed that keratin 10 and 15 can be stained on both frozen and paraffin-embedded sections. Staining of paraffin-embedded sections required unmasking with trypsin and Tris-buffered saline Tween solution, respectively. CD3 and CD26 can only be detected on frozen sections, while HBD-2 can only be detected on paraffin-embedded sections. CONCLUSION: We have described a straightforward technique that gives us the opportunity to use just one biopsy specimen to obtain frozen sections as well as paraffin-embedded sections.

Synthesis of all possible A-ring diastereomers at the 1- and 3-positions of 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71) using C2-symmetrical epoxide as a common starting material.

2009-08-23T07:24:00.001-07:00

Anticancer Res. 2009 Sep; 29(9): 3571-8Kubodera N, Hatakeyama SThe active vitamin D3, 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3), is now well recognized as a potent regulator of cell proliferation and differentiation in addition to possessing a regulatory effect on calcium and phosphorus metabolism. From research on the synthesis of 1,25(OH)2D3 analogs with the goal of separating these biological activities, we have already reported two characteristic analogs of active vitamin D3, namely 1alpha,25-dihydroxy-22-oxavitamin D3 (OCT) and 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy) vitamin D3 (ED-71). OCT, a 22-oxa analog obtained from modification of the side chain of 1,25(OH)2D3, has been used clinically as an injection for the treatment of secondary hyperparathyroidism underlying renal insufficiency and as an ointment for the skin disease, psoriasis. OCT has also been reported to exhibit antiangiogenic activity, exerting antitumor effects without producing serious side effects such as hypercalcemia. On the other hand, ED-71, which possesses a hydroxypropoxy substituent at the 2beta-position of the A-ring of 1,25(OH)2D3, has more potent biological effects on bone compared to 1 and phase III clinical studies for bone-fracture prevention have been completed. To explore structure activity relationship between ED-71 and related analogs, significant attention was now focused on the diastereomer of 3 at both the 1- and 3-positions of the A-ring, namely 3-epi-ED-71, 1-epi-ED-71 and 1,3-diepi-ED-71. All possible A-ring diastereomers at the 1- and 3-positions of ED-71 were synthesized using C2-symmetrical epoxide as a common starting material by convergent Trost methodology.

TNF-alpha as a therapeutic target in inflammatory diseases, ischemia-reperfusion injury and trauma.

2009-08-23T00:18:00.001-07:00

Curr Med Chem. 2009; 16(24): 3152-67Esposito E, Cuzzocrea STumor necrosis factor-alpha (TNF-alpha) is a central regulator of inflammation, and TNF-alpha antagonists may be effective in treating inflammatory disorders in which TNF-alpha plays an important pathogenetic role. Recombinant or modified proteins are an emerging class of therapeutic agents. To date, several recombinant or modified proteins which acts as TNF antagonists have been disclosed. In particular, antibodies that bind to and neutralise TNF have been sought as a means to inhibit TNF activity. Inhibition of TNF has proven to be an effective therapy for patients with rheumatoid arthritis and other forms of inflammatory disease including psoriasis, psoriatic arthritis, and ankylosing spondylitis, inflammatory bowel disease. Additionally, the efficacy of preventing septic shock and AIDS has been questioned as a result of recent research. The currently available therapies include a soluble p75 TNF receptor:Fc construct, etanercept, a chimeric monoclonal antibody, infliximab, and a fully human monoclonal antibody, adalimumab. Certolizumab pegol is a novel TNF inhibitor which is an antigen-binding domain of a humanized TNF antibody coupled to polyethylene glycol (PEG) to increase half-life, and thus is Fc-domain-free. In this review, we discuss briefly the present understanding of TNF-alpha-mediated biology and the current therapies in clinical use, and focus on some of the new therapeutic approaches with small-molecule inhibitors. Moreover, we examine recent reports providing important insights into the understanding of efficacy of thalidomide and its analogs, as TNF-alpha activity inhibitories, especially in therapies of several inflammatory diseases within the nervous system.

[Enlightenment from genome-wide association study to genetics of psoriasis.]

2009-08-22T21:30:00.001-07:00

Zhejiang Da Xue Xue Bao Yi Xue Ban. 2009 Jul; 38(4): 333-7Zhang XJOBJECTIVE: Psoriasis is a common autoimmune and hyper proliferative skin disease, characterized by thick, silvery scale patches. Numerous family studies have provided compelling evidence of a genetic predisposition to psoriasis, although the inheritance pattern is unclear. However, few of these studies have achieved consistent results, except for the MHC locus, a problem frequently encountered in the investigation of complex disease. Using high-throughput techniques to genotype hundreds of thousands of single nucleotide polymorphisms explore their relationship with phenotypes, genome-wide association studies (GWAS) are now proven to be a powerful approach for screening the susceptibility genes (loci) of complex disease. Recently, three GWAS on psoriasis published in Nature Genetics have provided us with many novel clues concerning disease pathogenesis, in both immune and non-immune pathways. The MHC locus (HLA-Cw6 and other MHC variance), the major locus involved in the immune reactions of human immune disease, has consistently been shown to be associated with psoriasis, both in previous linkage and present GWAS. IL-12B and IL23R, which are the two non-MHC genes with highly associated evidence with psoriasis in multiple studies performed so far and potent cytokines with complex biological activities, should be of great importance in the pathogenesis of psoriasis. Recent clinical trials, in which anti-IL-12p40 antibodies were used for the treatment of psoriasis, have provided further evidence of the role of IL-12/23 in the pathophysiology of psoriasis,and highlighted a new road of treatment for psoriasis. In 2008,we performed the first large GWAS in the Chinese population and identified a novel susceptibility locus within the late cornified envelope (LCE) gene cluster: LCE3A and LCE3D on chromosome 1q21, with conclusive evidence (rs4085613, p(combined)=6.69*10(-30); odds ratio=0.76). Meanwhile, another group also identified a deletion comprising and LCE gene cluster of LCE3B and LCE3C, which is significantly associated with a risk of psoriasis in Spain, Netherland, Italy and USA. Both of these independent studies provided substantial association evidence for the LCE genes involved in the pathogenesis of psoriasis. The LCE genes encode the stratum-corneum proteins of the cornified envelope, which plays an important role in epidermal terminal differentiation. As we know, psoriasis is a disease of interfollicular epidermis and rapid keratinocyte proliferation may cause the production of parakeratotic keratinocytes in psoriatic skin and, thus, the formation of poorly adherent stratum corneum, which in turn results in the characteristic scale or flakes of psoriasis lesions. Although some of the highlighted genes are already targeted by effective psoriasis therapies, others could become future targets for treatments,especially for the LCE genes, which will be very useful for unlocking new drug targets and tailored treatments for this painful, disfiguring skin disease. Meanwhile larger samples and improved strategy for identification of other susceptibility variants to psoriasis and downstream functional study to elucidate the underlying mechanisms of diseases are also needed. Taken together, unremitting efforts of the basic research on psoriasis will lead us to achieve a better treatment and diagnosis for psoriasis in the near future.

Cytokine imbalance with increased production of interferon-alpha in psoriasiform eruptions associated with antitumour necrosis factor-alpha treatments.

2009-08-22T17:49:00.001-07:00

Br J Dermatol. 2009 Jun 5; Seneschal J, Milpied B, Vergier B, Lepreux S, Schaeverbeke T, TaÃ¯eb ASummary Background Psoriasiform eruptions occur in association with antitumour necrosis factor (TNF)-alpha treatments in autoinflammatory diseases. The major reported clinical presentation is palmoplantar pustulosis, sometimes accompanied with plaque-like psoriasis. In some reports, histological findings suggest psoriasis whereas others favour a lichenoid drug reaction. We present a case series with a comprehensive clinical, histopathological and immunohistochemical study. Objectives To investigate the mechanism involved in psoriasiform eruptions in patients receiving anti-TNF-alpha inhibitors. Methods Between July 2004 and May 2008, 13 patients with psoriasiform eruptions arising under anti-TNF-alpha treatment were enrolled in the study. Punch biopsy specimens of lesions were processed for standard and immunohistochemical analyses using antibodies against CD3, CD4, CD8, CD20, CD1a, KP1, CXCR3, CXCL9, Tia1 and MxA, which is specifically induced by type I interferons (IFNs). Additionally, we analysed biopsies from lesional skin of patients with cutaneous discoid lupus erythematosus, lichen planus and psoriasis. Control biopsies were taken from unaffected skin. Results All patients developed psoriasiform plaques on the body accompanied with palmoplantar keratoderma or pustulosis in three patients. Histological and immunohistochemical findings showed a psoriasiform pattern with focal lichenoid and spongiotic features. We detected strong production of the MxA protein in inflammatory cells, indicating involvement of type I IFNs, and the expression was higher than in control psoriasis samples. Expression of MxA was closely associated with the recruitment of CXCR3+ lymphocytes in the skin bearing markers of cytotoxic capacity. Conclusions Results support the hypothesis that psoriasiform eruptions are a new model of drug reaction characterized by an increased expression of type I IFNs induced by anti-TNF-alpha.

Expression of Tolerance Associated Gene-1, a Mitochondrial Protein Inhibiting T Cell Activation, Can Be Used to Predict Response to Immune Modulating Therapies.

2009-08-21T18:53:00.001-07:00

J Immunol. 2009 Aug 14; Keeren K, Friedrich M, Gebuhr I, Philipp S, Sabat R, Sterry W, Brandt C, Meisel C, GrÃ¼tz G, Volk HD, Sawitzki BImmune modulating therapies gain increasing importance in treatment of patients with autoimmune diseases such as psoriasis. None of the currently applied biologics achieves significant clinical improvement in all treated patients. Because the therapy with biologics is cost intensive and sometimes associated with side effects, noninvasive diagnostic tools for early prediction of responders are of major interest. We studied the effects of Alefacept (LFA3Ig), an approved drug for treatment of psoriasis, on leukocytes in vitro and in vivo to identify gene markers predictive for treatment response and to further investigate its molecular mechanisms of action. In an open-label study, 20 psoriasis patients were treated weekly with 15 mg Alefacept over 12 wk. We demonstrate that transcription of the tolerance-associated gene (TOAG-1) is significantly up-regulated whereas receptor for hyaluronic acid mediated migration (RHAMM) transcription is down-regulated in PBMCs of responding patients before clinical improvement. TOAG-1 is exclusively localized within mitochondria. Overexpression of TOAG-1 in murine T cells leads to increased susceptibility to apoptosis. Addition of Alefacept to stimulated human T cells in vitro resulted in reduced frequencies of activated CD137(+) cells, increased TOAG-1 but reduced RHAMM expression. This was accompanied by reduced proliferation and enhanced apoptosis. Inhibition of proliferation was dependent on enhanced PDL1 expression of APCs. Thus, peripheral changes of TOAG-1 and RHAMM expression can be used to predict clinical response to Alefacept treatment in psoriasis patients. In the presence of APCs Alefacept can inhibit T cell activation and survival by increasing expression of TOAG-1 on T cells and PDL1 on APCs.

E6201, a Novel Kinase Inhibitor of MEK1 and MEKK1: In vitro characterization of its anti-inflammatory and anti-hyperproliferative activities.

2009-08-20T20:55:00.000-07:00

J Pharmacol Exp Ther. 2009 Aug 14; Goto M, Chow J, Muramoto K, Chiba KI, Yamamoto S, Fujita M, Obaishi H, Tai K, Mizui Y, Tanaka I, Young D, Yang H, Wang YJ, Shirota H, Gusovsky FThe goal of this study is to identify a novel inhibitor with anti-inflammatory and anti-proliferative properties for the treatment of psoriasis. Compound f152A1 was identified as the main active metabolite with strong inhibitory activity against TNFalpha transcription in a fraction originated from the fermentation broth of the fungus Curvularia verruculosa. Although active in cell based assays, f152A1 was unstable in plasma and liver microsome preparations, thus limiting its pharmaceutical utilization. To improve the metabolic properties of f152A1, a medicinal chemistry program was undertaken, resulting in the generation of over 400 analogues of f152A1. Eventually, E6201 [(3S, 4R, 5Z, 8S, 9S, 11E)-14-(ethylamino)-8, 9, 16-trihydroxy-3, 4-dimethyl-3, 4, 9, 19-tetrahydro-1H-2-benzoxacyclotetradecine-1, 7(8H)-dione] was identified as a promising analog in this series. In the present study, we characterized the in vitro activities of E6201 and discovered that the compound inhibits LPS-activated TNFalpha reporter activity in THP-1-33 cells with an IC50 value of 50 nM and selectively inhibits MEKK1 and MEK1 in cell-free biochemical assays. In addition, E6201 showed inhibitory activity in several other cell-based systems: 1) phosphorylation of JNK and p38 MAPKs; 2) NF-kappaB and AP-1 activation in various cell types; 3) IL-2 production from human lymphocytes; 4) hyperproliferation of human keratinocytes; 5) IL-8 production from human keratinocytes and 6) pro-inflammatory cytokine production from human PBMCs. Based on the data presented here, E6201 may be beneficial for treatment of inflammatory and hyper-proliferative diseases such as psoriasis through its anti-inflammatory activities on immune cells and anti-hyperproliferative activities on keratinocytes.