[A boy with small lumps on his shoulder]. / Een jongen met bultjes op zijn schouder.

A 17-year-old boy presented with small papules on his right shoulder and was diagnosed with syringocystadenoma papilliferum.

Investigation on a novel and specific leukotriene B4 receptor antagonist in the treatment of stable plaque psoriasis.

The aim of the present study was to investigate the efficacy and clinical tolerability of the specific leukotriene B4 receptor antagonist VML295 in the treatment of stable plaque psoriasis. Immunohistochemical and flow cytometrical methods were used to assess the effects on inflammation and epidermal proliferation. VML295 in the treatment of chronic plaque psoriasis was shown to be safe and well tolerated. After treatment, there was a statistically significant difference between patients treated with VML295 and patients treated with placebo with respect to the leukotriene B4-induced CD11b up-regulation on the cell surface of polymorphonuclear leukocytes derived from peripheral blood. Ex vivo CD11b up-regulation in the VML295-treated group was completely inhibited after 7 days of treatment (P = 0.001). This effect persisted until the end of the treatment period (P = 0.004 on day 15 and P < 0.0001 after 4 weeks), whereas CD11b up-regulation in the placebo group remained unaffected. There was no statistically significant difference in the median psoriasis area and severity index between the treatment groups at the end of the treatment period. During treatment, no significant histological changes were observed in the markers for cutaneous inflammation and epidermal proliferation. Although not statistically significant, a tendency for the increased expression of some markers of cutaneous inflammation and epidermal proliferation was observed after 1 week of treatment with VML295, and a decreased expression of these markers was seen after 4 weeks of treatment with VML295. This observation could indicate anti-inflammatory effects of VML295 appearing between 2 and 4 weeks after the start of treatment.

Effects of systemic treatment with liarozole on cutaneous inflammation, epidermal proliferation and differentiation in extensive plaque psoriasis.

Liarozole is a novel inhibitor of the enzyme cytochrome P450 which has inhibitory effects on the 4-hydroxylation of retinoic acid. Previous studies have shown that liarozole is effective in the treatment of psoriasis. We performed an immunohistochemical study on the lesional skin from 7 patients with extensive plaque psoriasis, who were treated with systemic liarozole 75 mg BID for a period of at least 2 months. The effects of liarozole treatment on clinical and histological parameters were investigated. In particular, the effect of liarozole on the integrin markers CD11b and CD18 was studied. For immunohistochemistry, three consecutive biopsies were taken: before treatment, after 4, and after 8 weeks of treatment. Clinical scores and side effects were recorded before and during treatment. The medication was well tolerated and only mild side effects were reported, which were comparable with hypervitaminosis A. After 2 months of treatment a statistically significant decrease of the extent of body involvement was observed. In the psoriatic plaque, markers for epidermal proliferation and cutaneous inflammation decreased, and markers for epidermal differentiation increased to values comparable to normal skin. The first therapeutic effects in the psoriatic plaque occurred after 4 weeks of treatment, and consisted of a decreased induration, accompanied by a decrease of the total number of inflammatory infiltrate cells and a decreased epidermal ICAM-1 expression. Already after 4 weeks of treatment, a decrease of CD11b-positive cells was observed. Subsequently, after 8 weeks of treatment recruitment of cycling epidermal cells and the number of involucrin-positive cell layers decreased. The present study demonstrates that liarozole treatment of psoriasis results in a reduction of aspects of cutaneous inflammation and subsequently a reduction of epidermal proliferation and promotion of differentiation. After 4 weeks of treatment, effects are observed on the epidermal ICAM-1 expression and on the CD11b-positive cell population.

Expression of endoglin in the transition between psoriatic uninvolved and involved skin.

Endoglin is a glycoprotein which is predominantly expressed on endothelial cells. It is upregulated under inflammatory conditions as well as in skin lesions where endothelial cell proliferation occurs. Endoglin has the capacity to bind transforming growth factor beta (TGF-beta) and can reduce the bioavailability of TGF-beta. TGF-beta has a growth-inhibiting effect on keratinocytes and a restraining influence on the extravasation of peripheral white blood cells. In order to find out how endoglin is expressed in the margin zone of psoriatic plaques and how it correlates with the appearance of an inflammatory infiltrate, punch biopsies were taken from the margin zone of actively spreading psoriatic plaques in 8 patients. Indirect immunoperoxidase staining was performed using PAL-E (vascular endothelium), PN-E2 (anti-endoglin) and T11 (T-lymphocytes). In all patients it was found that the appearance of parakeratosis correlated with a clear increase of PN-E2 expression. PAL-E and PN-E2 expression was assessed, using a 5-point scale. Thus a tendency to decreased PN-E2 expression in uninvolved skin compared to PAL-E expression was found within the margin zone (1.6 +/- 0.4 and 2.2 +/- 0.4, respectively), whereas in involved skin PN-E2 expression and PAL-E expression were in agreement (2.6 +/- 0.5 and 2.6 +/- 0.5 respectively), suggesting that in the overt plaque all endothelium is in a so-called activated state. Also correlating with PN-E2 expression was the appearance of a huge dermal lymphocytic infiltrate and epidermal T-lymphocytic expression. The present study lends further support for a permissive role of endoglin expression in the development of the psoriatic lesion.

The CD11b/CD18-integrin in the pathogenesis of psoriasis.

The aim of the present investigation was to study the distribution of CD11b, CD18, and ICAM-1 over the various cell populations present in the margin zone of the actively spreading psoriatic lesion and distant uninvolved psoriatic skin. This study was performed in order to obtain more insight in the relevance of these receptor molecules in the early phase of psoriatic plaque development. Skin biopsies were taken and inflammation markers were assessed using immunohistochemical techniques. All dermal changes in the margin zone preceded those in the epidermis. In the margin zone the most peripheral change was a decrease in dermal ICAM-1-expression, followed by an increase in dermal CD11b-expression. CD11b-positive cells showed a different tissue distribution from polymorphonuclear leukocytes and were more abundantly present, suggesting significant amounts of CD11b-bearing cell populations other than polymorphonuclear leukocytes in the early phase of psoriasis. Decreased numbers of CD18-positive cells in distant uninvolved skin suggest the existence of a selective modulating mechanism altering the trafficking of myeloid subpopulations. Polymorphonuclear leukocytes appeared to invade the skin well after the appearance of CD11b- and CD18-positive cells.

The effects of oral liarozole on epidermal proliferation and differentiation in severe plaque psoriasis are comparable with those of acitretin.

The imidazole derivative liarozole is a potent inhibitor of cytochrome P450-dependent 4-hydroxylation of endogenous all-trans retinoic acid, thereby increasing the levels of all-trans retinoic acid in both plasma and skin. As part of a large, double-blind, randomized clinical study, we investigated the cell biological alterations in uninvolved and lesional skin of 20 patients with severe plaque psoriasis, who were treated with either liarozole or acitretin. The extent and severity of the skin lesions, as recorded by the Psoriasis Area and Severity Index score, was significantly reduced (P

Epicutaneous application of leukotriene B4 induces patterns of tenascin and a heparan sulfate proteoglycan epitope that are typical for psoriatic lesions.

Application of leukotriene B4 (LTB4) to normal human skin induces changes similar to those found in psoriatic skin, and it has proved to be a useful model for studying the pathogenesis and treatment of psoriasis. We studied the expression patterns of molecules that have recently been shown to be altered in lesional psoriatic skin, including the extracellular matrix protein tenascin (TN) and the basement membrane and cell surface-associated heparan sulfate proteoglycans (HSPGs). During 72-h the expression of these markers was studied immunohistochemically and the expression of TN was correlated with epidermal proliferation and influx of inflammatory cells. Following the peak influx of polymorphonuclear leukocytes, a marked increase in TN expression was noted in the papillary dermis 72 h after LTB4 application. The expression patterns of basal membrane-associated epitopes of HSPG remained unaltered, whereas the expression of cell surface-associated HSPG disappeared 72 h after LTB4 application. A significant correlation was found between dermal TN expression and epidermal hyperproliferation, and between TN expression and the presence of dermal T cells. These findings indicate that the model of LTB4-induced acute cutaneous inflammation displays many characteristics of early psoriatic lesions and could serve as a model to study some of the cell biological changes in this disease.

The regulation of CD11b integrin levels on human blood leukocytes and leukotriene B4-stimulated skin by a specific leukotriene B4 receptor antagonist (LY293111).

CD11b is part of the beta2-integrin Mac-1 and plays an important role in neutrophil adhesion. Leukotriene B4 (LTB4) is an active upregulator of neutrophil CD11b-expression, acts as a potent chemoattractant to neutrophils and is also known to upmodulate epidermal proliferation. We performed a placebo-controlled study on LY293111, an oral LTB4 receptor antagonist. Twenty healthy male volunteers were randomised over three treatment groups that received placebo, 48 mg, or 200 mg drug twice daily for 10 days. Before and after treatment, flow cytometrical CD11b assessment was performed on in vitro LTB4-stimulated peripheral blood neutrophils. Additionally, skin biopsies were taken at 24 and 72 h after epicutaneous LTB4 application, before and after treatment. The effects on skin were assessed immunohistochemically using various markers. All observed effects were dose related. CD11b upregulation on blood neutrophils was significantly suppressed in both treatment groups compared to placebo. In skin, a significant suppression of inflammation and hyperproliferation occurred. Pronounced inhibition was observed on neutrophil migration into the epidermis and the inflammatory infiltrate was decreased. A similar but weaker response was seen in the dermis. The number of cycling cells as well as suprabasal keratin-16 expression were decreased in both treatment groups. LY293111 proved to be a potent inhibitor of LTB4-induced cutaneous inflammation and hyperproliferation. The potent antiinflammatory effect in vivo and the fact that in the present study the compound showed no clinically significant side effects make it an interesting drug in the future treatment of inflammatory conditions predominated by neutrophils.

Response of the clinically uninvolved skin of psoriatic patients to tape stripping during acitretin treatment.

The aromatic retinoids etretinate and acitretin are widely used in the systemic treatment of severe psoriasis. The purpose of the present investigation was to further elucidate the mode of action of acitretin on abnormal keratinization and epidermal hyperproliferation in an in vivo model. Studies on the interference of acitretin with epidermal hyperproliferation and abnormal keratinization in psoriatic plaques are difficult to interpret, as acitretin-induced changes might be due to direct effects of acitretin or be the indirect effect of retinoid-induced modulation of cutaneous inflammation. Using an immunohistochemical assessment, we examined the in vivo effect of systemic acitretin ( > 35 mg daily) on the expression of filaggrin, involucrin, and on the recruitment of cycling epidermal cells, in the tape-stripped uninvolved skin of psoriatic patients, a model which provides the opportunity to study epidermal regeneration in the absence of significant accumulation of T-lymphocytes. During acitretin therapy and 3 weeks after withdrawal of acitretin, we took biopsies from uninvolved skin following tape-stripping in 6 patients with psoriasis. Six patients with psoriasis who had never used acitretin served as controls. We did not observe a Koebner response in our patients after tape stripping. Filaggrin expression was decreased, while the recruitment of cycling epidermal cells and the involucrin expression were increased in the biopsies taken from patients who did not use acitretin. During acitretin treatment, however, the filaggrin expression was similar, whereas the Ki-67 positive nuclei and the involucrin expression showed a statistically significant decrease compared to those parameters in the patients who did not use acitretin. Our findings indicate that epidermal hyperproliferation and abnormal keratinization are modulated directly by acitretin.