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Purpose: To predict the potential antitumor effect of antigen-specific T cells in melanoma patients, we investigated T-cell effector function in relation to tumor-escape mechanisms., Experimental Design: CD8(+) T cells isolated from tumor, adjacent normal skin, and peripheral blood of 17 HLA-A2(+) patients with advanced-stage melanoma were analyzed for their antigen specificity and effector function against melanocyte differentiation antigens MART-1, gp100, and tyrosinase by using HLA-A2/peptide tetramers and functional assays. In addition, the presence of tumor-escape mechanisms PD-L1/PD-1 pathway, FoxP3 and loss of HLA or melanocyte differentiation antigens, both required for tumor cell recognition and killing, were studied., Results: Higher percentages of melanocyte antigen-specific CD8(+) T cells were found in the melanoma tissues as compared with adjacent normal skin and peripheral blood. Functional analysis revealed 2 important findings: (i) in 5 of 17 patients, we found cytokine production after specific peptide stimulation by tumor-infiltrating lymphocytes (TIL), not by autologous peripheral blood lymphocytes (PBL); (ii) CD8(+) T cells from 7 of 17 patients did not produce cytokines after specific stimulation, which corresponded with significant loss of tumor HLA-A2 expression. The presence of other tumor-escape mechanisms did not correlate to T-cell function., Conclusions: Our data show that functional T-cell responses could be missed when only PBL and not TIL are evaluated, emphasizing the importance of TIL analysis for immunomonitoring. Furthermore, loss of tumor HLA-A2 may explain the lack of T-cell functionality. These findings have important implications for selecting melanoma patients who may benefit from immunotherapy., (©2011 AACR.)

There is no gold standard for a definite diagnosis of atopic dermatitis. For the time being, several lists of diagnostic criteria have been proposed, some of them in actual use. The Millennium Criteria have been proposed to diagnose atopic dermatitis and to differentiate it from atopiform dermatitis. Our aim was to further refine the Millennium Criteria into a manageable set that can differentiate between atopic and atopiform dermatitis and other entities. The hereby refined Millennium Criteria will be compared with the UK Working Party Criteria and the Hanifin & Rajka Criteria. Data of 210 included patients were used. After multiple logistic regression, a minimum set of five criteria was identified as best discriminators: (i) typical morphology; (ii) early age of onset; (iii) Dennie-Morgan fold; (iv) historical and (v) actual flexural involvement. The refined Millennium Criteria were constituted from these criteria. When comparing the different list for validity in diagnosing atopic dermatitis, the refined Millennium Criteria showed a sensitivity of 81.8% and a specificity of 98.8% compared to a sensitivity of 97.7% and specificity of 72.9% of the UK Criteria and a sensitivity of 100% and specificity of 48.8% of the Hanifin & Rajka Criteria. This refinement and validity study shows that the refined Millennium Criteria are a valid tool to diagnose atopic and atopiform dermatitis in a hospital-based setting and therefore could be incorporated in clinical practice and trials., (© 2011 Japanese Dermatological Association.)

Background: Patients with severe atopic eczema frequently require systemic treatment to control their disease. Methotrexate and azathioprine are proposed as off-label treatment options, but direct comparisons are lacking., Objectives: We sought to compare the efficacy and safety of methotrexate versus azathioprine in adults with severe atopic eczema., Methods: Patients with severe atopic eczema were randomly assigned in a 1:1 ratio to receive either methotrexate (dosage, 10-22.5 mg/wk) or azathioprine (dosage, 1.5-2.5 mg/kg/d) for 12 weeks, followed by a 12-week follow-up period. Primary outcome was the mean change in the severity scoring of atopic dermatitis index after 12 weeks. Efficacy assessors blinded for allocation of treatment were used to perform clinical outcome assessment. Analyses were done on an intention-to-treat basis., Results: Of the 45 patients screened, 42 were included. At week 12, patients in the methotrexate group had a mean relative reduction in the severity scoring of atopic dermatitis index of 42% (SD, 18%) compared with 39% (SD, 25%) in the azathioprine group (P = .52). Proportions of patients achieving at least mild disease and reductions on impact of quality of life, symptoms, and levels of thymus and activation-regulated chemokine were similar in both groups at weeks 12 and 24. No statistically significant differences were found in the number and severity of adverse events. Abnormalities in blood count were more common in the azathioprine group. No serious adverse events occurred., Conclusion: Both treatments achieved clinically relevant improvement and were safe in the short term. Methotrexate and azathioprine are appropriate options for the treatment of severe atopic eczema., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

In this study, we report the previously unknown mechanism of inducing robust anti-melanoma immunity by the vitiligo-inducing compound monobenzone. We show monobenzone to increase melanocyte and melanoma cell immunogenicity by forming quinone-haptens to the tyrosinase protein and by inducing the release of tyrosinase- and melanoma antigen recognized by T cells-1 (MART-1)-containing CD63+ exosomes following melanosome oxidative stress induction. Monobenzone further augments the processing and shedding of melanocyte-differentiation antigens by inducing melanosome autophagy and enhanced tyrosinase ubiquitination, ultimately activating dendritic cells, which induced cytotoxic human melanoma-reactive T cells. These T cells effectively eradicate melanoma in vivo, as we have reported previously. Monobenzone thereby represents a promising and readily applicable compound for immunotherapy in melanoma patients.

Objectives: To provide a comprehensive overview of dermatologic adverse events of etanercept described in the literature (including all study types, case reports, and surveys) and to present information on the occurrence, severity, treatment, and course of these adverse events., Data Sources: MEDLINE and EMBASE., Study Selection: All reports on individual patients who developed a dermatologic adverse event associated with systemic etanercept treatment for any indication in any type of original article were included., Data Extraction: All data were independently extracted by 2 reviewers. Disagreements were resolved by consensus. All articles included (except for case reports/case series) were assessed regarding level of evidence., Data Synthesis: In 126 included study reports, a total of 72 separate specific dermatologic adverse events of etanercept were mentioned. In 101 case reports/case series, 153 individual patients with approximately 65 different specific diagnoses (eg, not rash) were reported., Conclusions: Etanercept is associated with a wide variety of dermatologic adverse events, many of which were described in study reports, but case reports also described numerous exceptional cases. Although the adverse events are usually mild, some reactions are serious and even potentially life threatening. Therefore, all drug-associated cutaneous abnormalities should be carefully evaluated. Diagnostic steps do not deviate from the norm in these patients, but management of the dermatologic adverse events may need special attention.

Background: Although recent studies indicate a crucial role for IL-17A and IL-22 producing T cells in the pathogenesis of psoriasis, limited information is available on their frequency and heterogeneity and their distribution in skin in situ., Methodology/principal Findings: By spectral imaging analysis of double-stained skin sections we demonstrated that IL-17 was mainly expressed by mast cells and neutrophils and IL-22 by macrophages and dendritic cells. Only an occasional IL-17(pos), but no IL-22(pos) T cell could be detected in psoriatic skin, whereas neither of these cytokines was expressed by T cells in normal skin. However, examination of in vitro-activated T cells by flow cytometry revealed that substantial percentages of skin-derived CD4 and CD8 T cells were able to produce IL-17A alone or together with IL-22 (i.e. Th17 and Tc17, respectively) or to produce IL-22 in absence of IL-17A and IFN-γ (i.e. Th22 and Tc22, respectively). Remarkably, a significant proportional rise in Tc17 and Tc22 cells, but not in Th17 and Th22 cells, was found in T cells isolated from psoriatic versus normal skin. Interestingly, we found IL-22 single-producers in many skin-derived IL-17A(pos) CD4 and CD8 T cell clones, suggesting that in vivo IL-22 single-producers may arise from IL-17A(pos) T cells as well., Conclusions/significance: The increased presence of Tc17 and Tc22 cells in lesional psoriatic skin suggests that these types of CD8 T cells play a significant role in the pathogenesis of psoriasis. As part of the skin-derived IL-17A(pos) CD4 and CD8 T clones developed into IL-22 single-producers, this demonstrates plasticity in their cytokine production profile and suggests a developmental relationship between Th17 and Th22 cells and between Tc17 and Tc22 cells.

Background: Recent findings have established the 308-nm xenon chloride excimer laser (EL) as a new option in the area of ultraviolet (UV) B phototherapy. As this laser enables high radiant exposure of narrowband UVB and precise targeting of affected skin, it appears to be a promising treatment for the prurigo form of atopic dermatitis (AD)., Objectives: To investigate the efficacy and safety of the EL compared with clobetasol propionate (CP) in the prurigo form of AD., Methods: In a prospective randomized within-patient controlled study, 13 patients with a prurigo form of AD were randomized to receive EL on one side and topical CP on the other side. Laser treatment was performed twice a week for 10 weeks. Clinical responses were evaluated using Physician Assessment of Individual Signs, Physician Global Assessment, Patient Global Assessment and photographic documentation. Histopathological changes were evaluated and duration of remission was monitored during a 6-month follow-up period., Results: Both treatments resulted in a significant improvement of all outcome measures after 10 weeks of treatment. During follow up, the EL showed more improvement compared with CP. Histopathology demonstrated marked decrease of epidermal thickness and inflammatory infiltrate at the EL-treated sites. No significant side-effects occurred., Conclusions: This study suggests that the EL can safely and effectively be used in the treatment of the prurigo form of AD. For the long term, the EL might be a good alternative to topical corticosteroids and an option in case of therapy-resistant patients., (© 2010 The Authors. Journal Compilation © 2010 British Association of Dermatologists.)

Background: Melasma is a uichronic, often relapsing skin disorder, with poor long-term results from all current therapies., Objective: To assess efficacy and safety of non-ablative 1,550 nm fractional laser therapy (FLT) as compared to the gold standard, triple topical therapy (TTT)., Study Design: Twenty-nine patients with melasma were included in a randomized controlled observer-blinded study with split-face design. Each side of the face was randomly allocated to either 4-5 non-ablative FLT sessions (15 mJ/microbeam, 14-20% coverage) or TTT (hydroquinone 5%, tretinoin 0.05%, triamcinolone acetonide 0.1% cream). TTT was applied once daily for 15 weeks until the last FLT session. After this last treatment, patients were asked to apply TTT twice weekly on both sides of the face during follow-up. Improvement of melasma was assessed by patient's global assessment (PGA), patient's satisfaction, physician's global assessment (PhGA), melanin index, and lightness (L-value) at 3 weeks, and at 3 and 6 months after the last treatment., Results: Mean PGA and satisfaction were significantly lower at the FLT side (P<0.001). PhGA, melanin index, and L-value showed a significant worsening of hyperpigmentation at the FLT side. At the TTT side, no significant change was observed. At 6 months follow-up, most patients preferred TTT. Side effects of FLT were erythema, burning sensation, edema, and pain. Nine patients (31%) developed PIH after two or more laser sessions. Side effects of TTT were erythema, burning sensation, and scaling., Conclusions: Given the high rate of postinflammatory hyperpigmentation, non-ablative 1,550 nm fractional laser at 15 mJ/microbeam is not recommendable in the treatment of melasma. TTT remains the gold standard treatment., (2010 Wiley-Liss, Inc.)

Background: Presently melanoma still lacks adequate treatment options for metastatic disease. While melanoma is exceptionally challenging to standard regimens, it is suited for treatment with immunotherapy based on its immunogenicity. Since treatment-related skin depigmentation is considered a favourable prognostic sign during melanoma intervention, we here aimed at the reverse approach of directly inducing vitiligo as a shortcut to effective anti-melanoma immunity., Methodology and Principal Findings: We developed an effective and simple to use form of immunotherapy by combining the topical skin-bleaching agent monobenzone with immune-stimulatory imiquimod cream and cytosine-guanine oligodeoxynucleotides (CpG) injections (MIC therapy). This powerful new approach promptly induced a melanoma antigen-specific immune response, which abolished subcutaneous B16.F10 melanoma growth in up to 85% of C57BL/6 mice. Importantly, this regimen induced over 100 days of tumor-free survival in up to 60% of the mice, and forcefully suppressed tumor growth upon re-challenge either 65- or 165 days after MIC treatment cessation., Conclusions: MIC therapy is effective in eradicating melanoma, by vigilantly incorporating NK-, B- and T cells in its therapeutic effect. Based on these results, the MIC regimen presents a high-yield, low-cost and simple therapy, readily applicable in the clinic.

Background: Eczema affects approximately 10% of all schoolchildren in the western world and has shown an increase over the past decades in 'developing' countries. Numerous factors have been suggested that might contribute to the increasing prevalence of eczema. A plausible explanation is the role of environmental factors. As part of the 'hygiene hypothesis' it has been thought that eczema is more common in urban than in rural communities, but such a notion has never been assessed systematically., Objective: Our aim was to assess whether there is a rural/urban gradient for the prevalence of eczema and, if so, to what extent., Methods: All data sources were identified through a search in MEDLINE and EMBASE. All primary studies comparing the prevalence rate of eczema between urban and rural populations were assessed for eligibility. Included articles were reviewed for methodological quality and a relative risk was calculated to indicate the risk of eczema in urban over rural areas. Results Twenty-six articles were included for analysis. Nineteen showed a higher risk for eczema in an urbanized area, of which 11 were significant. Six studies showed a lower risk of eczema in an urbanized area, of which one was statistically significant. One study had a relative risk of 1.00., Results: were more homogeneous among studies of good methodological quality. A pooled relative risk could have been calculated but was not because of heterogeneity., Conclusion: There is some evidence of a higher risk for eczema in urban compared with rural areas, suggesting that place of residence may have a role in the pathogenesis of eczema. Future reviews on environmental circumstances should be carried out to reveal the factors associated with a higher prevalence of eczema in urban areas and the association with other allergic diseases.

A large number of clinical measures of psoriasis are used in clinical trials and daily practice. These measures lack uniformity and validation. However, valid outcome and severity measures for psoriasis are a prerequisite for fully informative clinical research and evidence-based medicine. The purpose of this study was to identify all clinical measures of psoriasis severity and outcome in use and to evaluate the quality of these measures using clinimetric criteria; we identified 53 separate clinical measures, which were regrouped into 11 measures for quality analysis. No measure could be scored on all items used in the clinimetric analysis. The Lattice System Physician's Global Assessment and Physician's Global Assessment were most highly noted. We conclude that none of the psoriasis measures is adequately validated. The Psoriasis Area and Severity Index is the most commonly used clinical measure in research, but it has substantial limitations such as low response distribution, no consensus on interpretability, and low responsiveness in mild disease. Nevertheless, because of its widespread use the Psoriasis Area and Severity Index permits some degree of comparison of results among clinical trials. Overall, no best instrument was identified, and different situations may call for different measures.

Age period prevalence of atopic eczema (AE), a very common skin disease, has increased during the past decennia. This expansion seems to be ending in wealthy countries, while an increase is observed in developing nations, for which there is no firm explanation. Recent steps in understanding AE are the detection of skin barrier related filaggrin null mutations in approximately 25% of patients and the recognition of IL-31 as a molecule possibly involved in the itch (pruritus). Also interesting are the recognition of thymus and activation-regulated chemokine (TARC) and proliferating-inducing ligand (APRIL), as being associated with AE severity and activity. Immunocentric and corneocentric views on pathogenesis (the inside-outside paradigm) and the diagnostic entity atopiform dermatitis (AFD) are discussed here. We emphasize that diagnosing AE is not simple but challenging. We accentuate that a diagnosis of AE is only possible when there is allergen-specific IgE. Advice as to the need for elimination of allergens and adjustment of lifestyle are only proficient in patients having atopy and true AE, not in those having AFD.

Objectives: To investigate the extent antibodies to adalimumab are formed in patients with plaque psoriasis and whether these antibodies have clinical consequences. Also, to examine the relationship between antibodies to adalimumab and adalimumab trough titers., Design: Prospective observational cohort study., Setting: Two Dutch dermatology departments in university hospitals., Patients: All consecutive patients starting a regimen of adalimumab for chronic plaque psoriasis. Patients were screened and fulfilled the Dutch reimbursement criteria for adalimumab to treat psoriasis., Intervention: Adalimumab treatment (per label)., Main Outcome Measures: The titer of antibodies to adalimumab, the adalimumab trough concentration, and the Psoriasis Area and Severity Index at weeks 12 and 24., Results: Antibodies to adalimumab were detected in 13 of 29 patients (45%) during 24 weeks of treatment. Differences in response rates among patients with low, high, and no titers of antibodies to adalimumab were significant at weeks 12 and 24 (P = .04 and P < .001, respectively). The median adalimumab trough concentrations varied significantly among patients with low, high, and no titers of antibodies to adalimumab (1.30 [range, 0.01-5.50], 0.0 [range, 0.0-0.0], and 9.6 [range, 0.0-22.6] mg/L, respectively; P < .001). At week 24, the median adalimumab trough concentrations also differed significantly among good responders, moderate responders, and nonresponders (9.7 [range, 0.0-22.6], 8.9 [range, 3.2-12.6], and 0.0 [range, 0.0-13.3] mg/L, respectively; P = .01)., Conclusion: Antibodies to adalimumab are associated with lower serum adalimumab trough concentrations and with nonresponse or loss of response to adalimumab in patients with plaque psoriasis.

Telemedicine is becoming widely used in healthcare. Dermatology, because of its visual character, is especially suitable for telemedicine applications. Most common is teledermatology between general practitioners and dermatologists (secondary teledermatology). Another form of the teledermatology process is communication among dermatologists (tertiary teledermatology). The objective of this systematic review is to give an overview of studies on tertiary teledermatology with emphasis on the categories of use. A systematic literature search on tertiary teledermatology studies used all databases of the Cochrane Library, MEDLINE (1966-November 2007) and EMBASE (1980-November 2007). Categories of use were identified for all included articles and the modalities of tertiary teledermatology were extracted, together with technology, the setting the outcome measures, and their results. The search resulted in 1,377 publications, of which 11 were included. Four categories of use were found: getting an expert opinion from a specialized, often academic dermatologist (6/11); resident training (2/11); continuing medical education (4/11); and second opinion from a nonspecialized dermatologist (2/11). Three modalities were found: a teledermatology consultation application (7/11), a Web site (2/11), and an e-mail list (1/11). The majority (7/11) used store-and-forward, and 3/11 used store-and-forward and real-time. Outcome measures mentioned were learning effect (6), costs (5), diagnostic accuracy (1), validity (2) and reliability (2), patient and physician satisfaction (1), and efficiency improvement (3). Tertiary teledermatology's main category of use is getting an expert opinion from a specialized, often academic dermatologist. Tertiary teledermatology research is still in early development. Future research should focus on identifying the scale of tertiary teledermatology and on what modality of teledermatology is most suited for what purpose in communication among dermatologists.

Tertiary teledermatology (TTD), where a general dermatologist consults a specialized dermatologist on difficult cases, is a relatively new telemedicine service. We evaluated TTD in a Dutch university hospital, where 13 general dermatologists used TTD to consult 11 specialized dermatologists and two residents at the university medical centre. We measured the avoided referrals to the university centre, the usability of the system and the user acceptance of it. During a three-month study, general dermatologists consulted via TTD 28 times. In 17 of the consultations (61%), the general dermatologists would have referred their patients to the university centre if teledermatology had not been available. Referral was not necessary after teledermatology for 12 of these 17 consultations (71%). The mean usability score (0-100) of all the users was 80. All dermatologists were satisfied with TTD (mean satisfaction of 7.6 on a 10-point scale) and acceptance was high. The baseline measurements showed that half of tertiary referrals were suitable for TTD. These results suggest that TTD reduces unnecessary physical referrals and that users are satisfied with it. A large-scale evaluation is now required.

Background: The carriers of loss-of-function mutations in the filaggrin gene (FLG) have reduced levels of natural moisturizing factor (NMF) in the stratum corneum. The concentration of NMF components which are formed by filaggrin protein breakdown in the stratum corneum might therefore be useful as a biomarker of the FLG genotype. OBJECTIVES To investigate the feasibility of different sampling methods for the determination of two NMF components, 2-pyrrolidone-5-carboxylic acid (PCA) and urocanic acid (UCA), in the stratum corneum as biomarkers for the FLG genotype., Methods: PCA and UCA from the stratum corneum were sampled by using a tape stripping technique and an extraction technique using skin patches containing potassium hydroxide (KOH). The concentrations of PCA and UCA were measured by high-performance liquid chromatography. Eleven carriers of an FLG mutation and 10 individuals wild type for the two most common FLG mutations (R501X and R2447X) [corrected] were included in the study., Results: The most significant difference between the FLG genotypes was found for PCA sampled by the tape stripping technique. The mean values of PCA obtained by the tape stripping technique were, respectively, 0.18, 0.50 and 1.64 mmol g(-1) protein in homozygous (or compound heterozygous), heterozygous and wild-type genotypes (P < 0.005 homozygous vs. heterozygous; P < 0.0001 heterozygous vs. wild type). The tape stripping technique showed less intrasubject variation compared with the KOH patches, in particular when the concentrations of UCA and PCA on the tape strips were normalized for protein amount., Conclusions: The concentration of PCA in the stratum corneum collected by tape stripping showed it to be a feasible biomarker of the FLG genotype.

Dermatology is an increasingly growing specialty with several subspecialties that frequently overlap with other disciplines. Dedication to specific areas varies widely between countries, even within the European Union. The lack of uniform criteria that regulate the practice of dermatology and its subspecialties has a negative impact on the distribution of resources. Consequently, this may impair adequate patient care as access to dermatologists, who are the best trained physicians to recognize and treat skin disorders, may be delayed or unavailable. Not uncommonly, especially in the hospital setting, many specialists are consulted for a skin condition before a referral is made to a dermatologist. In this article, through a case series from daily practice, we illustrate the need for dermatologists to be recognized as the most suitable specialists to diagnose and treat skin diseases. A prompt referral is probably more cost-effective than any other measure, reducing patient morbidity and, in some instances, it can also be life-saving. Another issue that merits consideration is the reimbursement of selected, non-medicated pharmaceuticals, that are medically indicated for some patients with serious dermatological disorders.

Background: Vitiligo is commonly regarded as a harmless cosmetic skin problem in Western societies, and the importance of treating patients with vitiligo is often underestimated., Objective: We sought to determine the clinical and sociodemographic variables that adversely affect the quality of life in adult patients with generalized vitiligo so that these variables can be considered in the treatment and care., Methods: A total of 245 adult patients with generalized vitiligo completed two quality-of-life questionnaires (the Medical Outcomes Study 36-Item Short-form General Health Survey and the Skindex-29). Physicians assessed sociodemographic and clinical characteristics of these patients., Results: Dark skin type, vitiligo located on the chest, and treatment in the past appeared to have an adverse impact on the psychosocial domains of quality of life. Moreover, itch was reported by 20% of the patients in this study., Limitations: Psychiatric comorbidity was not evaluated in the analyses., Conclusion: Generalized vitiligo is a serious skin disorder with an adverse impact on the emotional state, comparable with that of other major skin diseases.

In vitiligo, cytotoxic T cells infiltrating the perilesional margin are suspected to be involved in the pathogenesis of the disease. However, it remains to be elucidated whether these T cells are a cause or a consequence of the depigmentation process. T cells we obtained from perilesional skin biopsies, were significantly enriched for melanocyte antigen recognition, compared with healthy skin-infiltrating T cells, and were reactive to melanocyte antigen-specific stimulation. Using a skin explant model, we were able to dissect the in situ activities of perilesional T cells in the effector phase of depigmentation. We show that these T cells could infiltrate autologous normally pigmented skin explants and efficiently kill melanocytes within this microenvironment. Interestingly, melanocyte apoptosis was accompanied by suprabasal keratinocyte apoptosis. Perilesional T cells did, however, not induce apoptosis in lesional skin, which is devoid of melanocytes, indicating the melanocyte-specific cytotoxic activity of these cells. Melanocyte killing correlated to local infiltration of perilesional T cells. Our data show that perilesional cytotoxic T cells eradicate pigment cells, the characteristic hallmark of vitiligo, thereby providing evidence of T cells being able to mediate targeted autoimmune tissue destruction.

To evaluate the anti-inflammatory efficacies of topical drugs, models of contact hypersensitivity (CHS) can be used, but the conventional murine models of CHS need revision in this respect. These models utilize sensitized mice to study suppression of sensitization or elicitation by test compounds. To mimick the events occurring in allergic contact dermatitis (ACD), a modification of the murine model of CHS is needed in a way that a chronic postelicitation phase of CHS is maintained for studies of anti-inflammatory effects of topical drugs, typically relevant for ACD therapy, not for ACD prevention. A method for the quantification of the suppression of ACD by a test compound is presented here. Two experimental drugs for topical use, imidazole-4-carboxylate and imidazole-4-acetate, were tested in parallel with the corticosteroid prednisolone. We found that prednisolone showed strong suppressive effects, while imidazole-4-carboxylate and imidazole-4-acetate showed mild suppressive effects during persistent ACD simulation. Multiple elicitations on the mouse ears led to scratching and the formation of abrasions and scabbings with, presumably, worsening of discomfort. Clear reduction of these side-phenomena was achieved by tailoring the topical amount of contact sensitizer, while the ability of the ACD model to test anti-inflammatory compounds, was not affected. By focussing on a prolonged postelicitation phase of CHS, a simulation of ACD has been established. We demonstrated that this model may provide an improved predictability for the clinical efficacies of (experimental) mild or strong anti-inflammatory drugs.

Atopic dermatitis mainly covers the period of infancy to adulthood, an important period in the development of an individual. The impairment of quality of life and the psychological wellbeing of children with atopic dermatitis have been well documented but so far no data exist about the impact of atopic dermatitis in childhood on fulfilling age-specific developmental tasks and achieving developmental milestones during this period, referred to as the course of life. The aims of this study were to: (i) assess the course of life and define the disease-related consequences in young adult patients with childhood atopic dermatitis and (ii) determine whether the severity of atopic dermatitis is predictive for the course of life, the disease-related consequences and quality of life later in life. Adult patients who grew up with atopic dermatitis were asked to complete a medical history questionnaire, the Skindex-29, the "course of life" questionnaire and a subjective disease-specific questionnaire. Patients with severe atopic dermatitis in childhood showed a significant delayed social development in their course of life. The results of the disease-specific questionnaire demonstrated remarkable high percentages of psycho-social consequences and physical discomfort caused by atopic dermatitis in childhood. Patients showed a severely negative impact of atopic dermatitis on their current quality of life. This is the first study that applied the "course of life" questionnaire in atopic dermatitis. More insight in the course of life, disease-specific consequences and quality of life of atopic dermatitis is of high importance, especially in case of severe atopic dermatitis.

Background: Dendritic cells (DCs) can act both as innate cells in host defense and as antigen-presenting cells for naive T cells in adaptive immunity. These functions, among others, are determined by the level of production of particular cytokines. Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by an initial phase predominated by T(H)2 cytokines that switches into a second, more chronic T(H)1-dominated eczematous phase., Objective: To assess to what extent the AD phenotype is associated with an aberrant phenotype and function of DCs., Methods: Classic CD1c(+)/blood DC antigen (BDCA)-1(+) myeloid (m) DCs and CD304(+)/BDCA4(+) plasmacytoid (p) DCs, the natural IFN-producing cells, were isolated from peripheral blood of patients with AD and healthy controls and analyzed for their phenotype and function., Results: Purified CD1c(+)/BDCA1(+) mDCs from patients with AD showed a selective and dramatic reduction of IL-12p70 and TNF-alpha release. IL-12p70 reduction was attributed to a defective expression of both IL-12p35 and IL-12p40 subunits. Accordingly, mature CD1c(+)/BDCA1(+) mDCs from patients with AD induced considerably less IFN-gamma-producing and more IL-4-producing T(H) cells compared with mDCs from healthy controls. In addition, CD304(+)/BDCA4(+) pDCs from patients with AD produced significantly lower levels of IFN-alpha compared with healthy controls., Conclusion: Myeloid DCs and pDCs from patients with AD show defective IL-12, TNF-alpha, and IFN-alpha production, which may contribute to increased susceptibility to infection and to the maintenance of the T(H)2 cell-mediated allergic state in patients with AD.

Topical therapy in psoriasis is of use in mild cases. It is also applied as an adjunct to phototherapy and systemic treatments in moderate to severe cases. Long-established pharmaceuticals such as cignolin, tar preparations, and glucocorticoids are still in use. Newer topical agents such as vitamin A and D derivatives are gradually replacing them. Combining a vitamin D derivative and a strong glucocorticoid now seems to be the most efficient way to treat psoriasis when topical agents are indicated. There is a growing list of "alternative" treatment options, where evidence is generally absent. Rewarding investments should perhaps be directed at intervening with molecules of innate immunity. Superfluous activation of natural immune system cascades is now in view as the major culprit in psoriasis, replacing the T-cell hypothesis of the disease. Agents directed at tumor necrosis factor alpha, Toll-like receptors, and neutrophils may have great impact in future topical therapy of psoriasis. Finally, innovations in the development of more targeted glucocorticoids and vitamin A and D derivatives, where desired effects are better separated from undesired side effects, may lead to an increased benefit/risk ratio of these nuclear receptor-directed therapies.

Background: The onset of vitiligo occurs before the age of 20 years in 50% of patients. Having a chronic disease in childhood can impede a child's health-related quality of life (HRQL)., Objectives: Firstly, to compare the social and psychosexual development and current HRQL of young adult patients with childhood vitiligo with those of a group of healthy controls. Secondly, to compare these outcomes in patients reporting negative childhood experiences with those of patients not reporting negative childhood experiences., Methods: Eligible patients were mailed questionnaires on (i) sociodemographic and clinical characteristics, (ii) social and psychosexual development, (iii) generic and dermatology-specific HRQL, (iv) presence of negative childhood experiences related to vitiligo, (v) specification of these negative experiences and (vi) patients' recommendations for further care., Results: A total of 232 patients with vitiligo completed the questionnaires. Social and psychosexual development and generic HRQL in young adult patients with childhood vitiligo were not different from those of healthy controls. However, patients reporting negative childhood experiences reported significantly more problems in social development than those not reporting negative experiences. Furthermore, negative childhood experiences were significantly associated with more HRQL impairment in early adulthood., Conclusions: Reporting negative experiences from childhood vitiligo appears to be associated with HRQL impairment in young adults with vitiligo.

Infliximab (Remicade; Schering-Plough, Kenilworth, NJ, U.S.A.) is a chimeric monoclonal antibody that acts as a tumour necrosis factor-alpha inhibitor. Infliximab is registered for the treatment of rheumatoid arthritis, psoriatic arthritis, Crohn disease, ulcerative colitis, ankylosing spondylitis and plaque-type psoriasis. Like other foreign protein-derived agents, infliximab may lead to infusion reactions during and after infusion. Infusion reactions occur in 3-22% of patients with psoriasis treated with infliximab. Most of these reactions are mild or moderate and only few are severe. Nevertheless, they may lead to discontinuation of treatment. As infliximab for psoriasis is prescribed as a last resort and is in most cases very effective, discontinuation of treatment is undesirable. With proper care and prevention of the infusion reactions the need to discontinue treatment with infliximab can be diminished. The objective of this article is to present a guideline for the management of infliximab-related infusion reactions, based on the best available evidence. This guideline can be used in patients with psoriasis as well as in dermatology patients receiving infliximab for off-label indications such as hidradenitis suppurativa or pyoderma gangrenosum.

Background: Atopic dermatitis (AD) has a wide spectrum of dermatological manifestations and despite various validated sets of diagnostic criteria that have been developed over the past decades, there is disagreement about its definition. Nevertheless, clinical studies require valid diagnostic criteria for reliable and reproducible results., Objective: To summarize the evidence concerning the validity of diagnostic criteria for AD., Methods: All data sources were identified through searches on Medline, Embase and Cochrane databases. The Quality Assessment of Diagnostic Accuracy tool (QUADAS) was used. Results are presented in a receiver operating characteristic (ROC) plot., Results: Out of the 20 articles that met the criteria, 27 validation studies were identified. In two studies concerning Hanifin and Rajka diagnostic criteria sensitivity and specificity ranged from 87.9% to 96.0% and from 77.6% to 93.8%, respectively. Nineteen validation studies of the U.K. diagnostic criteria showed sensitivity and specificity ranging from 10% to 100% and 89.3% to 99.1%, respectively. Three validation studies concerning the Schultz-Larsen criteria showed sensitivity from 88% to 94.4% and specificity from 77.6% to 95.9%. In one article concerning the criteria of Diepgen, the sensitivity ranged from 83.0% to 87.7% and the specificity from 83.9% to 87.0%. One article studied the Kang and Tian criteria and reported 95.5% sensitivity and 100% specificity. One article validating the International Study of Asthma and Allergies in Childhood (ISAAC) criteria showed a positive and negative predictive value of 48.8% and 91.1%, respectively., Conclusion: With this systematic review of the existing sets of diagnostic criteria for AD a varying number of validation studies with varying methodological quality was found. The U.K. diagnostic criteria are the most extensively validated. However, improvement of methodological design for validation studies and uniformity in well-validated and applicable diagnostic criteria are needed to improve future intervention studies and to compare study results.

Background: Atopic dermatitis (AD) has been divided into the "extrinsic" and "intrinsic" type, in which "intrinsic AD" is characterized by the absence of allergen-specific IgE. Still, there is no consensus whether this "intrinsic type" of AD, which we denominate as atopiform dermatitis (AFD), is a distinct entity., Objective: A case-control study was performed to compare the clinical and diagnostic features of AD and AFD., Methods: Patients with a clinical diagnosis of AD were selected. Cases did not have demonstrable allergen-specific IgE. Matched control subjects were tested positive for allergen-specific IgE. Patients were evaluated for medical history, quality of life, disease severity, and Hanifin and Rajka, U.K. and Millennium diagnostic criteria., Results: Eight percent (n = 34) of the selected patients had, in fact, AFD. Female predominance, absence of atopic diseases, later onset of disease, and milder disease severity were observed in AFD. A history of atopy, recurrent conjunctivitis, palmar hyperlinearity, keratosis pilaris, pityriasis alba, and hand and/or food eczema were significantly less present in AFD. Dennie-Morgan fold was positively associated with AFD., Limitations: Not all patients with negative allergen-specific IgE participated and a relatively small number of AFD patients were studied., Conclusions: In addition to the absence of allergen-specific IgE, our findings support that AFD is an entity distinct from AD. With a distinction shown between AFD and AD, patient groups will be better defined and more homogeneous. Implications of this distinction will be of importance for preventive and therapeutic advice; diagnostic processes; and for future research.

Background: Hidradenitis suppurativa is a chronic inflammatory skin disease characterized by abscess formation, predominantly in the axillae and groins. The disease is difficult to treat and has a severe impact on quality of life. Recently, several case reports have been published describing successful treatment of hidradenitis suppurativa with infliximab and other tumour necrosis factor alpha inhibitors., Objectives: To evaluate the long-term efficacy of a single course of infliximab., Methods: Ten patients with severe, recalcitrant hidradenitis were treated with infliximab (three infusions of 5 mg kg(-1) at weeks 0, 2 and 6) and followed up for at least 1 year. The disease activity was measured using laboratory parameters and a recently developed acne score. The patients rated the efficacy of infliximab on a 10-point scale at regular intervals. Quality of life was measured before and after treatment using the Dermatology Quality of Life Index (DQLI)., Results: All patients improved within 2-6 weeks. The average acne score diminished from 164+/-50 (mean+/-SD) before treatment to 89+/-49 after 1 year (P=0.002). The mean CRP (C-reactive protein) was reduced from 31.7 mg mL(-1) to 5.5 mg mL(-1) after 1 month (P=0.015). Patients judged the efficacy with a score of 7.9. The mean DQLI was reduced from 18.4+/-7.9 before treatment to 9.3+/-9.1 after 1 year (P=0.007). In three patients long-lasting improvement was observed, with no recurrence of lesions in a 2-year follow-up period. The other patients showed recurrence of lesions after 8.5 months (range 4.3-13.4 months)., Conclusions: Infliximab is an effective treatment in severe hidradenitis suppurativa, leading to reduction of symptoms for a prolonged period.

A 34-year-old woman with terminal renal insufficiency presented with thickening and hardening of the skin of the extremities, resulting in contractures of the joints and severe disability. Serology revealed no signs of autoimmune disease, apart from a positive result for antinuclear antibodies. Histological evaluation of a skin biopsy showed marked fibrosis of the entire dermis, extending into the subcutaneous fat, with CD34-positive fibrocytes. The clinical features resembled a recently reported new disorder: nephrogenic systemic fibrosis (NSF). This disease causes fibrotic changes in the skin and other organs in patients with (pre)terminal renal insufficiency. The cause of the disease is still unknown, although there are strong indications that exposure to gadolinium-containing contrast agents plays a role in the pathogenesis. To prevent more patients from developing NSF, the Dutch Medicines Evaluation Board has changed the clinical indications for the use of gadolinium-containing contrast agents in patients with kidney disease: gadodiamide (Omniscan) and gadopentetate dimeglumine (Magnevist) may not be used in patients with severe renal failure or patients that will undergo or have already undergone liver transplantation. Caution is advised in patients with moderate renal insufficiency; this also applies to the other registered gadolinium-containing contrast agents.

Several reports have indicated that the chemokine receptor CCR5 and its ligands, especially CCL5 (formerly known as RANTES), may play a role in the pathogenesis of psoriasis. The purpose of this investigation was to examine the expression of CCR5 and its ligands in chronic plaque psoriasis and to evaluate the clinical and immunohistochemical effect of a CCR5 receptor inhibitor. Immunohistochemical analysis showed low but significant increased total numbers of CCR5 positive cells in epidermis and dermis of lesional skin in comparison to non-lesional skin. However, relative expression of CCR5 proportional to the cells observed revealed that the difference between lesional and non-lesional skin was only statistically significant in the epidermis for CD3 positive cells and in the dermis for CD68 positive cells. Quantification of mRNA by reverse transcriptase-polymerase chain reaction only showed an increased expression of CCL5 (RANTES) in lesional skin. A randomized placebo-controlled clinical trial in 32 psoriasis patients revealed no significant clinical effect and no changes at the immunohistochemical level comparing patients treated with placebo or a CCR5 inhibitor SCH351125. We conclude that although CCR5 expression is increased in psoriatic lesions, this receptor does not play a crucial role in the pathogenesis of psoriasis.

Objective: The importance of validly identifying and incorporating patients' views for improving health care is generally acknowledged. Common approaches to assess patients' preferences are based on the quality adjusted life year (QALY) framework, but this ignores a number of aspects that may be relevant. As an alternative, we assessed patients' treatment preferences and trade-offs for five common systemic therapies for psoriasis., Study Design and Setting: Twenty-nine patients with moderate-to-severe psoriasis expressed treatment preferences for five oral and phototherapies and indicated the relative importance of various treatment attributes, such as adverse effects, discomforts, and safety measures. In a structured interview, they were presented with clinical scenarios that contained descriptions of process and outcome characteristics and illustrations of the anticipated treatment benefit., Results: Over all paired comparisons, methotrexate (33%), cyclosporin (30%), acitretin (15%), UV-B (14%), and PUVA (8%) were preferred to the other treatment. Patients were willing to trade-off their initial preference for more improvement of psoriasis., Conclusions: Psoriasis patients generally prefer oral to phototherapies and consider most adverse effects and several discomforts important for selecting treatment. Our scenario-based structured interview approach to treatment preferences allowed us to incorporate a broad spectrum of potentially relevant decision components in a clinically meaningful way.

Extrahepatic complement synthesis is believed to play an important role in host defense and inflammation at tissue and organ level. In the epidermis the most abundant cell type, keratinocytes have been shown to produce C3, factor B and factor H. In the present study, we investigated the synthesis of factor I by human keratinocytes. We also studied whether proinflammatory cytokines IL-1alpha, IL-6, TGF-beta1, TNF-alpha and IFN-gamma regulate factor I synthesis in keratinocytes. Human keratinocytes constitutively expressed factor I mRNA and produced factor I protein. Amongst the above-mentioned cytokines, only IFN-gamma regulated the synthesis of factor I, and this effect occurred predominantly at pre-translational level. Factor I produced by keratinocytes was functionally active in cleaving C3b. In conclusion, we demonstrate that keratinocytes are capable of synthesizing factor I, and that this synthesis is regulated by IFN-gamma.

Human keratinocytes are important constituents of the skin immune system. They produce several cytokines, chemokines as well as some complement proteins. As regards soluble complement proteins, so far keratinocytes have been shown to synthesize only C3, factor B, factor H and factor I. Synthesis and regulation of synthesis of other complement proteins has not yet been studied. Here we studied the synthesis of terminal complement components, C5-C9 by human keratinocytes. We also studied the regulation of terminal complement synthesis in keratinocytes by several cytokines, namely, IL-1alpha, IL-2, IL-6, TGF-beta1, TNF-alpha, and IFN-gamma. Human keratinocytes constitutively expressed C5, C7, C8gamma and C9 mRNA but not C6, C8alpha and C8beta mRNA. They released C7 and C9, but not C5, C6 and C8. None of the cytokines tested had any influence on the synthesis of terminal components except TNF-alpha, which strongly upregulated C9 production. In conclusion, we demonstrate that keratinocytes are capable of synthesizing some of the terminal complement components and that the synthesis of C9 is regulated by TNF-alpha.

Recently, emphasis has shifted from T cells to innate (natural) immunity as the possible major culprit in psoriasis. All known elements of innate immune responses are up-regulated in psoriasis lesions, which must have a polygenetic origin. We hypothesize that urbanized populations have been under evolutionary pressure that selects for increased innate immunity responses because those offer relative but immediate protection from epidemic infections. That would have resulted in a changing gene pool, in which alleles of polymorphisms associated with increased innate immunity responses have amplified in these populations. Having too many of these genes together in one individual would result in a relatively low number of infections. On the other hand, it would also result in a higher prevalence of diseases related to increased innate immunity, such as psoriasis, and perhaps also multiple sclerosis and rheumatoid arthritis. Indeed, in indigenous people (Inuit, Aborigines, Ami) who have not been under this selection pressure, morbidity due to infections is high and the prevalence of psoriasis is low or even absent.

It is unknown whether closely related epidermal dendritic cells, Langerhans cells (LCs), and dermal dendritic cells (DDCs) have unique functions. In this study, we show that human DDCs have a broad TLR expression profile, whereas human LCs have a selective impaired expression of cell surface TLR2, TLR4, and TLR5, all involved in bacterial recognition. This distinct TLR expression profile is acquired during the TGF-beta1-driven development of LCs in vitro. Consequently, and in contrast to DDCs, LCs weakly respond to bacterial TLR2, TLR4, and TLR5 ligands in terms of cytokine production and maturation, as well as to whole Gram-positive and Gram-negative bacteria, whereas their responsiveness to viral TLR ligands and viruses is fully active and comparable to DDCs. Unresponsiveness of LCs to bacteria may be a mechanism that contributes to tolerance to bacterial commensals that colonize the skin.

Objectives: To determine blood concentrations of pimecrolimus after long-term intermittent administration of pimecrolimus cream 1% in adult patients with extensive atopic dermatitis (AD)., Methods: This was an open-label, multiple topical dose study in adults with moderate to severe AD and a total body surface area (TBSA) involvement of at least 20%. Pimecrolimus cream 1% was administered twice daily according to treatment need for up to 12 months to all lesions, including the neck and face. Blood samples were collected at regular time points and pimecrolimus concentrations were measured using a radioimmunoassay with a limit of quantitation (LoQ) of 0.5 ng/ml., Results: Forty patients (19 females), aged from 19 to 59 years, with moderate to severe AD entered the study. Twenty patients completed 6 months and 13 completed 1 year in the study. The individual blood concentrations of pimecrolimus were consistently low and there was no sign of drug accumulation. In 900 of the 918 samples examined (98%), pimecrolimus concentrations remained below the LoQ. The maximum concentration observed throughout the entire study was 0.8 ng/ml., Conclusion: Long-term intermittent treatment of adult patients with extensive AD with pimecrolimus cream 1% is associated with minimal systemic exposure and no evidence of drug accumulation.

Involved regions of the skin in atopic dermatitis (AD) patients have an altered barrier function. Whether uninvolved skin also has a diminished barrier is controversial. To assess the barrier function of uninvolved skin in AD patients, the percutaneous penetration of polyethylene glycols (PEGs) of various molecular sizes was determined in vivo in AD patients and control subjects using tape stripping of the stratum corneum (SC). The diffusion and partition coefficients were determined using Fick's second law of diffusion. The SC thickness was similar in both groups; however, the trans-epidermal water loss was higher in atopic skin. The apparent diffusion coefficient of PEGs through atopic skin was twice as high as through normal skin, and decreased with increasing molecular weight (MW) in both groups. The partition coefficient in the skin of AD patients was half of that for normal skin but as for normal skin, there was no MW dependency. Although atopic skin exhibited altered barrier with respect to diffusion and partitioning, the permeability coefficients were nearly the same for atopic and normal skin. The results support the assumption of altered skin barrier of AD patients even in the skin that is visibly unaffected by disease.

Background: There is no effective treatment for progressive macular hypomelanosis. Recent findings indicate that Propionibacterium acnes may play a role in the pathogenesis., Objectives: We sought to compare the effectiveness of antimicrobial therapy with anti-inflammatory therapy in patients with progressive macular hypomelanosis., Methods: A total of 45 patients were randomized to a within-patient left-right comparison study of benzoyl peroxide 5% hydrogel/clindamycin 1% lotion in combination with UVA irradiation versus fluticasone 0.05% cream in combination with UVA irradiation. Repigmentation was determined by photometric measurements of changes in skin color and by patient and dermatologist assessment using before and after photographs., Results: Benzoyl peroxide 5% hydrogel, clindamycin 1% lotion, and UVA led to better repigmentation than fluticasone 0.05% cream in combination with UVA irradiation in all measurements. (Photometric measurements P = .007, patient assessment P < .0001, and dermatologist assessment P < .0001.), Limitations: There was difficult objective color measurement. Therefore, subjective assessment has important additional value. Right-left comparisons have certain inherent limitations., Conclusion: Antimicrobial therapy in conjunction with light was more effective in repigmentation in patients with progressive macular hypomelanosis than a combination of anti-inflammatory therapy and light.