British Journal of Dermatology

doi: 10.1111/j.1365-2133.2006.07720.xpmid: N/A

Callen, J.; Chamlin, S.; Eichenfield, L.F.; Ellis, C.; Girardi, M.; Goldfarb, M.; Hanifin, J.; Lee, P.; Margolis, D.; Paller, A.S.; Piacquadio, D.; Peterson, W.; Kaulback, K.; Fennerty, M.; Wintroub, B.U.

doi: 10.1111/j.1365-2133.2006.07538.xpmid: 17223859

SummaryBackground The safety of topical therapies for atopic dermatitis (AD), a common and morbid disease, has recently been the focus of increased scrutiny, adding confusion as how best to manage these patients.Objectives The objective of these systematic reviews was to determine the safety of topical therapies for AD.Methods Databases searched included: OVID Medline, Medline In‐Process and Other Non‐Indexed Citations, Embase, and the Cochrane Central Register of Controlled Trials. In addition to the articles identified by this search, investigators were also referred to a list of links (most recently updated 25 September 2005) to recent Food and Drug Administration (FDA) studies, reports and meetings regarding the topical calcineurin inhibitors for further potential references. Only fully published papers available in English and data obtained from FDA sites were included. Furthermore, the criteria for inclusion and exclusion for each systematic review were further evaluated at a meeting of all of the content and evidence‐based medicine experts participating in this process and alteration of the inclusion criteria was done at that time when it was felt necessary to avoid inclusion of lower‐quality data in the review. Qualitative review of the abstracted data was performed and reviewed at a meeting of all of the content and evidence‐based medicine experts.Results While systemic exposure to these topical agents does occur, physiological changes appear to be uncommon and systemic complications rare and have only been found with use of topical corticosteroids.Conclusions Based on the data that are available the overall safety of AD therapies appears to be good with the only documented systemic side‐effects of therapy those occasionally seen with use of topical corticosteroids.

De Berker, D.; McGregor, J.M.; Hughes, B.R.; ,

doi: 10.1111/j.1365-2133.2006.07692.xpmid: 17223860

SummaryThese guidelines stemmed from a consensus meeting held by the British Photobiology Group (BPG) in 1999. Following this meeting one of the authors (J.M.M.) was invited to draw up guidelines for the management of actinic keratoses by the British Association of Dermatologists Therapy Guidelines and Audit Subcommittee. Relevant evidence was sought using the search terms ‘solar keratosis’ and ‘actinic keratosis’ in Medline from 1966 onwards. Additional and earlier literature was reviewed on the basis of references within post‐1966 publications. All articles of apparent relevance were reviewed independently of the nature of the publication. The quality of the evidence elicited has been indicated. The National Ambulatory Medical Care Survey (U.S.A.) was used for further data on topical chemotherapy. Papers were reviewed and discussed by the contributors to the BPG Workshop (see Acknowledgments). Recommendations are evidence based where possible. Strength of recommendation is coupled with quality of evidence. Strength of recommendation includes consideration of apparent cost‐benefit and practical considerations. Quality of evidence reflects the nature of the trial structure that provides data of efficacy.

Breternitz, M.; Flach, M.; Präßler, J.; Elsner, P.; Fluhr, J.W.

doi: 10.1111/j.1365-2133.2006.07632.xpmid: 17223861

SummaryBackground Tape stripping is an established procedure in stratum corneum (SC) physiology research. Adhesive films are pressed to the surface of the skin and then removed. The superficial layers of the SC adhere to the film and are accessible for further investigations. Although this method is widely used, only scant information about standardization is known. Various protocols are used but are difficult to compare.Objectives The aim of the present study was to investigate the effects of the type of tape, pressure, time, anatomical site and type of applied pressure.Methods Twelve healthy volunteers (age range 20–31 years) were entered in a randomized, controlled study with sequential tape stripping at the volar forearm, upper arm, cheek and back. Different methods (roller, stamp, thumb, stretched skin), total duration of applied pressure (2 s, 10 s), degrees of pressure (2 N stamp, 7 N stamp) and different tapes (D‐Squame®, Corneofix, Blenderm) were investigated and the impact on barrier function assessed by transepidermal water loss measurements. Furthermore, measurements of SC hydration, skin colour and skin surface pH were performed. Spectroscopic measurements and a Bradford protein assay to determine the mass of removed SC were carried out in parallel.Results The degree of barrier disruption, irritation and SC cohesion is influenced by the character of adhesive tapes, total duration of applied pressure (2 s, 10 s; 2 N, 7 N), the kind of method for pressure application (roller, stamp, thumb, stretched skin), anatomical site and condition before stripping (occlusion vs. nonocclusion). The spectroscopic assessment and Bradford protein assay determination showed a significant correlation (P < 0·0001; r = 0·7041).Conclusions The present study showed significant differences between different factors on controlled barrier disruption. The results indicate the importance of defining these factors when a study is initiated and when results of different studies should be compared. Based on our data we propose using a 2 N stamp for a duration of 2 s on 15 sequential D‐Squame® tape strips on the volar forearm and then discarding the first and second strips. This approach allows the performance of a standardized study with a reasonable amount of resources.

Takano, N.; Sakurai, T.; Ohashi, Y.; Kurachi, M.

doi: 10.1111/j.1365-2133.2006.07636.xpmid: 17223862

SummaryBackground Nerve growth factor (NGF) is an important substance in the skin, where it modulates nerve maintenance and repair. However, the direct link between NGF and pruritic diseases such as atopic dermatitis is not yet fully understood. Our previous study showed that NGF plays an important role in the pathogenesis of atopic dermatitis‐like skin lesions in NC/Nga mice. NGF mediates its effects by binding to two classes of transmembrane receptors, a high‐affinity receptor (tropomyosin‐related kinase A, TrkA) and a low‐affinity receptor (p75).Objectives To determine the significance of NGF receptors in the pathogenesis of atopic dermatitis, the effects of TrkA inhibitors AG879 and K252a on the symptoms of NC/Nga mice were evaluated.Methods Male NC/Nga mice with severe skin lesions were used. AG879 or K252a was applied to the rostral part of the back of mice five times a week. The dermatitis score for the rostral back was assessed once a week. The scratching behaviour was measured using an apparatus, MicroAct (Neuroscience, Tokyo, Japan). Immunofluorescence examinations were made in the rostral back skin for nerve fibres, NGF and TrkA receptor.Results Repeated applications of AG879 or K252a significantly improved the established dermatitis and scratching behaviour, and decreased nerve fibres in the epidermis. NGF was observed more weakly in keratinocytes, and a lower expression of TrkA was observed in stratum germinativum of the epidermis of mice treated with AG879 or K252a compared with those treated with vehicle.Conclusions We suggest that NGF plays an important role in the pathogenesis of atopic dermatitis‐like skin lesions via the high‐affinity NGF receptor. These findings provide a new potential therapeutic approach for the amelioration of symptoms of atopic dermatitis.

Harrison, C.A.; Layton, C.M.; Hau, Z.; Bullock, A.J.; Johnson, T.S.; MacNeil, S.

doi: 10.1111/j.1365-2133.2006.07641.xpmid: 17223863

SummaryBackground The transglutaminase (TG) family consists of eight distinct isoforms. TG types 1, 3 and 5 play a major role in normal skin development, with TG2 also being elevated during dermal wounding. TG1, 3 and 5 are responsible for the cross‐linking of keratin precursors and formation of the cornified envelope during keratinocyte differentiation. TG2 may play a role in keratinocyte basement membrane cross‐linking. Abnormal TG expression has been demonstrated in Darier disease, Netherton syndrome, psoriasis and lamellar ichthyosis. During a recent investigation of skin contraction in tissue‐engineered skin, transglutaminase inhibitors were found to produce hyperproliferation and parakeratosis.Objectives Accordingly, this study was designed to study the effect of pan‐transglutaminase inhibition on morphology of tissue‐engineered skin and expression of keratinocyte differentiation and proliferation‐associated antigens.Methods We used a tissue‐engineered model of human skin, based on de‐epidermized acellular human dermis, seeded with normal keratinocytes and dermal fibroblasts and cultured at an air–liquid interface. The pan‐transglutaminase inhibitors putrescine, NTU283 (1‐dimethyl,2‐[(oxopropyl)thio]imidazolium) and NTU285 (N‐benzyloxycarbonyl‐l‐glutaminyl‐6‐dimethylsulfonium‐5‐oxo‐l‐norleucine) were added to the culture medium. After 28 days, histology and immunohistochemistry for collagen IV, involucrin and cytokeratins 6, 10 and 16 were performed.Results Keratinocyte hyperproliferation and parakeratosis were seen in response to transglutaminase inhibition. Inhibition of transglutaminase also resulted in loss of basement membrane collagen IV. Involucrin and cytokeratins 6 and 16 were confined to the basal layers in control composites but expressed throughout the epidermis in response to transglutaminase inhibition. A distinct band of expression of cytokeratin 10 was seen in the upper stratum granulosum of control composites but only patchy expression was seen after transglutaminase expression.Conclusions Pan‐transglutaminase inhibition inhibits terminal differentiation of keratinocytes, leading to a hyperproliferative epidermis with parakeratosis and enhanced expression of involucrin and cytokeratins 6 and 16. Expression of the differentiation‐associated cytokeratin, cytokeratin 10, is reduced. Basement membrane integrity is also lost as a result of transglutaminase inhibition.

Griffiths, C.E.M.; Christophers, E.; Barker, J.N.W.N.; Chalmers, R.J.G.; Chimenti, S.; Krueger, G.G.; Leonardi, C.; Menter, A.; Ortonne, J.‐P.; Fry, L.

doi: 10.1111/j.1365-2133.2006.07675.xpmid: 17223864

Bovenschen, H.J.; Otero, M.E.; Langewouters, A.M.G.; Van Vlijmen‐Willems, I.M.J.J.; Van Rens, D.W.A.; Seyger, M.M.B.; Van De Kerkhof, P.C.M.

doi: 10.1111/j.1365-2133.2006.07660.xpmid: 17223865

SummaryBackground The novel systemic all‐trans retinoic acid metabolism blocking agent (RAMBA) R115866 (RambazoleTM; Barrier Therapeutics, Geel, Belgium; further referred to as rambazole) increases intracellular levels of endogenous all‐trans retinoic acid (RA). Well‐known effects of RA are normalization of aberrant epithelial growth and differentiation. Hence, rambazole might be beneficial in the treatment of plaque psoriasis.Objectives The dynamics of epidermal proliferation, keratinization, lesional T‐cell subsets and cells expressing natural killer (NK)‐receptors in plaque psoriasis were assessed during treatment with rambazole, as part of a phase IIa open‐label clinical trial.Methods Six patients were treated with rambazole, 1 mg, once daily, for 8 weeks. At weeks 0, 2 and 8, psoriatic plaque severity scores (SUM) and biopsies from a target lesion were assessed. Epidermal proliferation (Ki67), keratinization markers (K10, K13, K19), T‐cell subsets (CD3, CD4+, CD8+, CD45RO+, CD45RA+, CD2+, CD25+, GITR+) and cells expressing NK‐receptors (CD94, CD161) were immunohistochemically stained and quantified with image analysis.Results At week 2 the mean SUM‐score was virtually equal to baseline, which was accompanied immunohistochemically by equal epidermal hyperproliferation, a nonsignificant decrease in K10 positive epidermis and, overall, a nonsignificant increase in immunocyte subsets. At week 8, in contrast, plaque severity was reduced by 34% from baseline (P < 0·05). Improvements were also detected for epidermal proliferation (−63%; P < 0·01) and K10 expression (+29%; P < 0·01), compared with baseline. No induction of retinoid‐specific keratinization (K13, K19) was observed. A nonsignificant reduction of all pathogenic T‐cell subsets and cells expressing NK‐receptors was observed at week 8 of treatment (P > 0·05).Conclusions Clinical efficacy of rambazole is primarily the result of restoring proliferation (Ki67) and differentiation (K10) of epidermal keratinocytes. Secondly, relevant T‐cell subsets and cells expressing NK‐receptors showed nonsignificant reductions after 8 weeks of treatment with rambazole.

Ludwig, R.J.; Herzog, C.; Rostock, A.; Ochsendorf, F.R.; Zollner, T.M.; Thaci, D.; Kaufmann, R.; Vogl, T.J.; Boehncke, W‐H.

doi: 10.1111/j.1365-2133.2006.07562.xpmid: 17223866

SummaryBackground Psoriasis is a chronic inflammatory skin disorder affecting about 2% of white‐skinned individuals. Epidemiological data on the prevalence and degree of coronary artery calcification (CAC) as an indicator for cardiovascular diseases in patients with psoriasis are contradictory.Objectives To study the prevalence and degree of CAC as an indicator for cardiovascular diseases in 32 patients with psoriasis matched for age, sex and risk factors to an equally sized control population.Methods Noncontrast‐enhanced 16‐row spiral computed tomography was performed in patients and controls.Results We found a significantly increased prevalence (59·4% vs. 28·1%, P = 0·015) and severity (CAC score according to Agatston 3·7 vs. 0·0, P = 0·019) of CAC in patients with psoriasis. Multiple linear regression calculations identified psoriasis as a likely independent risk factor for CAC.Conclusions Our results point towards the potentially systemic nature of the inflammatory processes underlying the pathogenesis of psoriasis, which may therefore be considered a potentially severe systemic disease.

Santonocito, C.; Capizzi, R.; Concolino, P.; Lavieri, M.M.; Paradisi, A.; Gentileschi, S.; Torti, E.; Rutella, S.; Rocchetti, S.; Di Carlo, A.; Di Stasio, E.; Ameglio, F.; Zuppi, C.; Capoluongo, E.