Clearing of psoriasis documented by laser Doppler perfusion imaging contrasts remaining elevation of dermal expression levels of CD31.

BACKGROUND: Vascular modifications represent a key feature in psoriatic plaques. Previous research with Laser Doppler Perfusion Imaging (LDPI) revealed a remarkable heterogeneity in the cutaneous perfusion within homogenous-appearing psoriatic lesions. Insights in the relation between perfusion during treatment and related biological changes are lacking. OBJECTIVES: To study the effect of calcipotriol-betamethasone dipropionate ointment on the microcirculation and the expression levels of immunohistochemical markers in psoriatic lesions compared to the distant uninvolved skin. METHODS: Psoriatic lesions of fourteen patients were treated once a day during 8 weeks. Clinical SUM scores and the perfusion intensity by means of LDPI were assessed every 2 weeks. After 8 weeks, a biopsy from the target lesion and one from the distant uninvolved skin were taken and stained for psoriasis-related markers, like IL-17 and CD31. RESULTS: After 8 weeks, seven patients reached a SUM score of 0 or 1, and were classified as good-responders. The other patients were classified moderate-responders. The perfusion intensity decreased in all lesions during therapy. In the good-responders, all investigated psoriasis-related proteins within the treated lesions reached the expression level found within the distant uninvolved skin. The expression of CD31, however, was significantly higher in the treated lesions as compared to the distant uninvolved skin (p = 0.0156). In the moderate responders, almost all expression levels remained significantly elevated compared to the uninvolved skin. CONCLUSIONS: In the skin of good-responders the expression of dermal CD31(+) endothelium remains significantly elevated within the treated lesions compared with the distant uninvolved skin, whereas a marked reduction in the perfusion intensity and SUM score was found. This indicates that clinical improvement might outrun endothelial changes.

The effect of adalimumab on key drivers in the pathogenesis of psoriasis.

BACKGROUND: The use of recently introduced biologics targeting specific immune mechanisms has identified crucial steps in the pathogenesis of psoriasis. Studying the dynamics of changes of these target mechanisms in sequential skin biopsies during treatment with biologics may reveal potential biomarkers. Correlation between clinical parameters and the expression of specific genes during treatments may identify markers indicative of treatment response. OBJECTIVES: This observational open-label study aimed to provide an overview of important cell biological changes in lesional skin during treatment with adalimumab, and their relationship to clinical improvement. METHODS: Ten patients with moderate-to-severe plaque psoriasis were included and treated with adalimumab for 16 weeks. At baseline, and after 10 days and 16 weeks of treatment clinical scores were assessed and biopsies were taken to examine gene expression at the mRNA and protein level. RESULTS: The expression of marker genes for innate immunity, and epidermal differentiation and proliferation was rapidly restored to normal levels, whereas genes of the adaptive immune system showed a delayed decrease. The static and dynamic course of CD1a+ Langerhans cells and Ki67+ nuclei showed a significant strong correlation to the Psoriasis Area and Severity Index score. No correlation between interleukin-17 expression and clinical scores was found. CONCLUSIONS: The innate immune system is affected during adalimumab treatment well before the changes in the adaptive immune system become apparent. We may speculate that the addition of a treatment with an early effect on adaptive immunity to adalimumab may result in superior effectiveness compared with monotherapies.

Cutaneous application of leukotriene B4 as an in vivo model of psoriasis-like skin inflammation: an immunohistological study.

BACKGROUND: Research has revealed new insights into the pathogenesis of psoriasis, leading to new therapeutic options. So far the order of changes in the pathogenesis of psoriasis is unclear. The responses to cutaneous leukotriene B4 (LTB4) application have been studied in the past as an in vivo model for inflammation. The aim of the present study is to find out the order of changes of key steps in inflammation, which all have been shown to be involved in mature psoriatic lesions. OBJECTIVE: To study the dynamics of the consecutive stages of inflammation in challenged skin as a reflection of a psoriasis-like inflammatory response. METHODS: We examined the dynamics of epidermal growth control and the key representatives of the innate and acquired immune system during the first 72 h after challenging the skin by LTB4 application. RESULTS: Interleukin 17-positive (IL-17+) cells dominate the acute phase of inflammation, whereas T-Bet+ cells seem to increase gradually during the entire observation period. This indicates a more important role for IL-17 in the unstable phase of inflammation and a more prominent role for T-Bet+ cells within the chronic phase. CONCLUSION: The present model is highly reproducible and is useful in studying the dynamics of a psoriasis-like inflammation with respect to key components of immunity. It could provide a useful tool to study the immediate biological effects of new therapies like anti-IL-17 drugs on IL-17 production and effects on cutaneous inflammation and epidermal proliferation in vivo.

Efficacy and safety of combinations of first-line topical treatments in chronic plaque psoriasis: a systematic literature review.

BACKGROUND: Most psoriasis patients suffering from mild to moderate disease are treated with first-line topical treatments, including corticosteroids, vitamin D analogues, topical retinoids and calcineurin inhibitors. Although evidence-based guidelines on combinations are lacking, the majority of patients will be treated with combinations of these popular topicals at some point during their life-long treatment. OBJECTIVES: We intended to systematically review all available literature on the efficacy and safety of combinations of first-line topicals in chronic plaque psoriasis, and ultimately, to propose recommendations for combined regimens concerning first-line treatments. METHODS: Databases used as data sources were PubMed, EMBASE and the Cochrane Controlled Clinical Trial Register. According to standardized procedures, literature searches were performed and a level of evidence was determined. RESULTS: In total, 2918 publications on topical combination therapy were revealed, of which 45 articles on first-line combinations were included. The combination of potent and superpotent corticosteroids with vitamin D analogues provides an improvement of psoriasis within 2 weeks, reaching a maximal improvement after 4 weeks in the majority of patients. The two-compound product permits once-daily treatment and therefore is a good solution for chronic plaque psoriasis including scalp psoriasis. Combinations of corticosteroids, with tazarotene or with calcineurin inhibitors do not provide an advantage above corticosteroid monotherapy. CONCLUSION: The combination of potent corticosteroids with calcipotriol has been studied most extensively and should be regarded as an efficacious and safe treatment option with the two-compound products as the most practical solution.

Combinations of classical time-honoured topicals in plaque psoriasis: a systematic review.

BACKGROUND: Despite the availability of newer topical treatments, classical topical treatments for chronic plaque psoriasis still have an important position for selected patient populations. The vast majority of patients are treated with a combination of topicals. The question arises: what is the evidence behind these approaches? OBJECTIVES: To systematically review all available literature on efficacy and safety of combinations of classical topical treatments in chronic plaque psoriasis, including all combinations with dithranol, coal tar and penetration enhancers, and ultimately, to propose recommendations for combination treatment. METHODS: Standardized literature searches in PubMed, EMBASE and the Cochrane Controlled Clinical Trial Register, and allocation of the degree of evidence was carried out. RESULTS: In total 2918 publications on topical combination therapy were revealed, of which 48 articles on combinations of classical treatments. In this article, the results concerning the 19 included publications are stated. The majority of combination regimens is at least as effective as monotherapies, and is generally well tolerated. CONCLUSIONS: Methods of classical treatments are not standardized and different protocols in different treatment settings are used. Therefore the interpretation of study results cannot be generalized. Most evidence was found to recommend the use of a combination regimen of topical corticosteroids and salicylic acid, above monotherapy with either component. Also, the combinations of dithranol with superpotent corticosteroids or with coal tar may be preferred above both monotherapies. In case first-line treatments and systemic therapies are not effective or contraindicated, combinations of classical topicals may provide an important opportunity.