The usefulness of reflectance spectrophotometric measurements during psoralens and ultraviolet A therapy for psoriasis

Reflectance spectrophotometry was used to obtain indices of the hemoglobin and melanin content of psoriatic lesions and adjacent clinically normal skin in thirteen patients undergoing photochemotherapy. The pretreatment lesional hemoglobin index was 2.8 times greater than that of adjacent uninvolved skin. With therapy, this index decreased rapidly initially, and during the second or third week approached that of the uninvolved skin. The ratio of lesional and uninvolved skin hemoglobin indices decreased to approximately 1.3, and continuation of PUVA treatment failed to reduce it further. Termination of treatment at this stage, which occurs before clinical resolution, resulted in subsequent clearance of psoriasis. The decrease in the lesional hemoglobin index and the clearance time appeared to be dose-dependent, and, indeed, a more aggressive regimen resulted in approximately 50% reduction in both the number of treatments and the cumulative dose required to achieve a stable hemoglobin index ratio and subsequent clinical clearance.     

Dual wavelength (532 and 633 nm) laser Doppler imaging of plaque psoriasis

BACKGROUND: Increased blood flow occurs in plaques of psoriasis, and an increase in blood flow has been shown to occur in uninvolved skin adjacent to the active edge. OBJECTIVES: In order to gain more insight into the pathophysiology of the active edges of plaques of psoriasis, we investigated different components of the microcirculation in the lesional and nonlesional skin of patients with psoriasis, using dual wavelength laser Doppler imaging (LDI). METHODS: The cutaneous blood flow in 23 plaques on the forearms of 20 patients with chronic plaque psoriasis was recorded using dual wavelength LDI. Perfusion was determined within the plaque (P), in uninvolved skin adjacent to the plaque (A) and in nonadjacent skin (U). RESULTS: Perfusion in plaques was increased as imaged by either 633 nm (red wavelength) or 532 nm (green wavelength) compared with both adjacent and nonadjacent uninvolved skin: median (interquartile range) P/A(RED) = 3.7 (2.5-4.9), P/A(GREEN) = 1.3 (1.2-1.6), P/U(RED) = 4.2 (2.7-6.1), P/U(GREEN) = 1.5 (1.3-1.9). CONCLUSIONS: Vascular perfusion is increased within plaques of psoriasis compared with adjacent and nonadjacent uninvolved skin. The results suggest an area of increased perfusion in skin adjacent to plaques, when compared with nonadjacent skin, for both deeper (large) and superficial (small) vessels (imaged by 633 and 532 nm, respectively). We believe that this dual wavelength tool may be a suitable and useful way of assessing pathophysiology and treatment response in psoriasis.     

Lack of evidence for activation of the hedgehog pathway in psoriasis

Recent reports have suggested that the hedgehog (Hh) pathway is activated in lesional psoriatic skin, and that treatment with the Hh pathway antagonist cyclopamine may lead to rapid resolution of the disease. To assess Hh pathway activity in psoriasis, we isolated RNA from lesional and uninvolved skin of 58 psoriatic patients, and from 63 normal control subjects, and subjected these samples to global gene expression profiling on Affymetrix HU133 Plus 2.0 gene arrays. We were especially interested in Hh target genes (PTCH1 and GLI1), whose expression is elevated in response to Hh signaling. The microarray data demonstrated downregulation of PTCH1 expression in uninvolved and lesional skin (1.1-fold and 2-fold, respectively; P<0.0001). Additionally GLI1 mRNA was downregulated in lesional skin (1.7 fold; P<0.05). No significant changes were observed between lesional and uninvolved skin for the Hh ligands or Smoothened. Quantitative PCR confirmed these findings. In situ hybridization for GLI1 and PTCH1 was positive in basal cell carcinoma tumor cells, but was negligible in uninvolved or lesional psoriatic skin. The absence of elevated Hh target gene expression in lesional psoriatic skin indicates that the Hh pathway is not activated in this disease, raising questions regarding the proposed use of Hh antagonists as antipsoriatic agents.     

Blood flow in psoriatic skin lesions: the effect of treatment

Laser Doppler velocimetry (LDV) was used to assess the effect of treatment upon cutaneous blood flow in psoriatic skin lesions. The resolution of two separate plaques in each of seven subjects was followed. Six of the subjects received the Goeckerman regimen, the seventh was treated with psoralen-ultraviolet A (PUVA) therapy. Control LDV readings were taken from uninvolved skin sites during the treatment period. Cutaneous blood flow in the psoriatic lesions of the Goeckerman-treated patients decreased to levels comparable to those in uninvolved skin early in the course of treatment and significantly preceeded the observed clinical resolution from 4 to 8 days after initiation of therapy (P less than 0.05). Visible flare-ups sometimes appeared when patients were untreated (over a weekend, for example) and these eruptions were accompanied by a transient elevation of LDV readings. Perfusion of the lesions of the PUVA-treated patient remained consistently higher than perfusion of uninvolved skin despite clinical healing. In a separate series of experiments, blood flow at the extensor surface of the forearm was measured in the skin of normal subjects, the uninvolved skin of psoriatic patients and the untreated lesional skin of psoriatic patients. While the lesional skin had significantly higher perfusion levels than uninvolved psoriatic or normal control skin (P less than 0.01), there was no significant difference between blood flow to the uninvolved psoriatic skin of psoriatics and that to the skin of healthy controls.     

Immunopathological investigations in purpura pigmentosa chronica

We studied the cell infiltrates and antigenic characteristics of keratinocytes in biopsies from purpura pigmentosa chronica (PPC), with eleven monoclonal antibodies against several cell surface markers of effector and/or accessory cells of the immune system and compared the reactivity patterns with those in biopsies from uninvolved skin. Immunohistochemical staining revealed a predominance of activated helper T lymphocytes in the cutaneous inflammatory infiltrate. In contrast to uninvolved skin, lesional keratinocytes were found to express HLA-DR, OKM5, Leu-8 and Leu-11b (CD16) antigens in all biopsies from the involved skin. We demonstrate here for the first time the in vivo expression of several effector and/or accessory cell markers on lesional keratinocytes and infiltrate cells in PPC.     

Detection of nitric oxide and nitric oxide synthases in psoriasis

Biopsies from psoriasis lesions and clinically uninvolved skin of eight patients and five normal subjects were studied by immunocytochemistry with computerized image analysis for the presence of endothelial, neuronal and inducible isoforms of nitric oxide synthase. Endothelial nitric oxide synthase was expressed in the endothelium and weakly in some keratinoctyes. Its expression was not significantly different in psoriasis. Inducible nitric oxide synthase, however, was absent from normal skin but was significantly upregulated in psoriatic lesional skin, focally in keratinocytes but to the greatest extent in the papillary dermis and to a lesser extent in clinically uninvolved psoriatic skin. Inducible nitric oxide synthase staining was greatest in the more severe lesions and correlated with the inflammatory infiltrate (CD3-positive cells) and with keratinocyte proliferation (Ki-67-positive cells). In normal skin, neuronal nitric oxide synthase was expressed only in keratinocytes in the granular layer and eccrine sweat glands. However, in psoriasis and clinically uninvolved skin the neuronal form was present through all levels of the epidermis. Direct measurement of nitric oxide production from the skin surface revealed a tenfold increase in the lesions of 16 psoriatic patients compared with their nonlesional skin, and this nitric oxide production was inhibited by topical betamethasone. Received: 4 March 1996     

Moisturisers for psoriatic skin--do gross morphological differences matter?

Studies suggest that moisturisers have a beneficial effect on psoriasis, and their use in preventive or adjuvant dermatological therapy is therefore of considerable clinical interest, although no classification of these products exists to guide their use. We have previously suggested a classification based on the ability of moisturisers to induce mechanical changes in normal skin. In psoriasis patients obvious objective differences exist between plaques and clinically uninvolved skin. This study was undertaken to investigate if these differences influence the mechanical response to moisturisers. Skin mechanics distension and hysteresis, Dermaflex as well as capacitance Corneometer 812 CM and moisturiser absorption were measured on psoriasis plaques and adjacent clinically uninvolved skin of 17 psoriasis patients. Three commonly available moisturisers, a barrier cream and a gel were tested. Baseline distensibility and capacitance were significantly lower for plaques (p < 0.0001), and all moisturisers increased distensibility in both lesions and adjacent skin. Hysteresis was generally affected to a greater degree by Locobase. The gel caused greater increases in hysteresis outside plaques. Capacitance was significantly increased in plaques, except for areas treated with Locobase, while only Decubal appeared to cause significant increases in uninvolved skin. Locobase showed better absorption in plaques than in control areas. No objective differences were found in the effects of moisturisers between psoriatic plaques and adjacent clinically uninvolved skin, suggesting that the significant clinical differences between lesional and paralesional skin do not influence the efficacy of moisturisers.     

Platelet activating factor (PAF) and lyso-PAF in psoriasis

Previous studies have shown that scale from lesional psoriatic skin contains substantial amounts of platelet activating factor (PAF). In this study, PAF and its immediate precursor, lyso-PAF, were measured in exudates from abrasions on lesional and uninvolved psoriatic skin, and from skin of healthy subjects. The mean amounts of PAF recovered from lesional and uninvolved psoriatic skin (n=13) and from healthy skin (n=14) were not significantly different (range 0.05–2.14 pmol/sample). Mean recoveries of lyso-PAF from lesional psoriatic skin (n=9) and skin of healthy subjects (n=13) were also similar (9.5 ± 1.9 and 11.0 ± 1.9 pmol/sample, respectively), but significantly less lyso-PAF was found in exudates from the uninvolved psoriatic skin (n=9; 3.1 ± 0.4 pmol/sample; P<0.01 relative to both lesional psoriasis and healthy skin). The finding of reduced lyso-PAF in uninvolved psoriatic skin was unexpected because increased phospholipase-A₂ activity is associated with psoriasis. These results do not support the hypothesis that extracellular PAF contributes significantly to the inflammation associated with psoriasis.     

Erythemal and therapeutic response of psoriasis to PUVA using high-dose UVA

In PUVA treatment of psoriasis, clinical observation suggests that uninvolved skin is more susceptible to PUVA erythema than lesions of psoriasis. If this is the case, then the efficacy of PUVA treatment might be increased by using localized high-dose UVA restricted to lesional skin. We have therefore studied the erythemal and therapeutic response of psoriasis to PUVA using high-dose UVA and, for comparison, the erythemal response to UVB. In 14 patients, an area of psoriasis and adjacent uninvolved skin were exposed to a series of UVA doses (350 ± 30 nm, 1–16 J/cm²), using an irradiation monochromator. Six other patients were similarly phototested with a series of UVB doses (300 ± 5 nm, 20–112 mJ/cm²) to both uninvolved and lesional skin. Erythema was judged visually at 72 h for psoralen–UVA, and at 24 h for UVB, and measured using a scanning laser–Doppler velocimeter. In 10 patients, PUVA therapy using high-dose UVA was subsequently given to lesional skin (8–16 J/cm² twice weekly) in addition to conventional whole-body PUVA. For psoralen–UVA, the minimal phototoxic dose within psoriasis was increased by a factor of 4 compared with non-lesional skin (P < 0.01, Wilcoxon signed-rank test). For UVB, the minimal erythema dose within psoriasis was higher than that for non-lesional skin (medians > 112 and 28 respectively, P < 0.05). Laser–Doppler measurements confirmed that the reduced erythemal sensitivity was not due to masking of response by pre-existing increased blood flux within psoriasis. In six patients, the sites subsequently treated twice weekly with PUVA, using high-dose UVA, cleared faster (median number of treatments 3), but with a similar cumulative UVA dose, compared with adjacent lesional skin treated with conventional PUVA (median number of treatments 12). This study demonstrates that psoriasis may clear rapidly, without burning, using high-dose UVA. Availability of a suitable irradiation apparatus would allow rapid and effective PUVA treatment to be used for localized, resistant disease.     

Stratum corneum hydration and skin surface pH in patients with atopic dermatitis

Atopic dermatitis (AD) is a chronically relapsing skin disease with genetic predisposition, which occurs most frequently in preschool children. It is considered that dryness and pruritus, which are always present in AD, are in correlation with degradation of the skin barrier function. Measurement of hydration and pH value of the stratum corneum is one of the noninvasive methods for evaluation of skin barrier function. The aim of the study was to assess skin barrier function by measuring stratum corneum hydration and skin surface pH of the skin with lesions, perilesional skin and uninvolved skin in AD patients, and skin in a healthy control group. Forty-two patients were included in the study: 21 young and adult AD patients and 21 age-matched healthy controls. Capacitance, which is correlated with hydration of stratum corneum and skin surface pH were measured on the forearm in the above areas by SM810/CM820/pH900 combined units (Courage AND Khazaka, Germany). The mean value of water capacitance measured in AD patients was 44.1 ± 11.6 AU (arbitrary units) on the lesions, 60.2 ± 12.4 AU on perilesional skin and 67.2 ± 8.8 AU on uninvolved skin. In healthy controls, the mean value was 74.1 ± 9.2 AU. The mean pH value measured in AD patients was 6.13 ± 0.52 on the lesions, 5.80 ± 0.41 on perilesional skin, and 5.54 ± 0.49 on uninvolved skin. In control group, the mean pH of the skin surface was 5.24 ± 0.40. The values of both parameters measured on lesional skin were significantly different (capacitance decreased and pH increased) from the values recorded on perilesional skin and uninvolved skin. The same held for the relation between perilesional and uninvolved skin. According to study results, the uninvolved skin of AD patients had significantly worse values of the measured parameters as compared with control group. The results of this study suggested the skin barrier function to be degraded in AD patients, which is specifically expressed in lesional skin.     

Reticular erythematous mucinosis syndrome with an infiltration of factor XIIIa+ and hyaluronan synthase 2+ dermal dendrocytes

We report a patient with reticular erythematous mucinosis (REM) syndrome. Content of hyaluronan in lesional skin was approximately 2.9-fold higher than in the patient's uninvolved skin, but its synthetic activity in fibroblasts explanted from lesional skin remained unchanged. Immunohistochemical study using antifactor XIIIa (anti-FXIIIa) antibody demonstrated that the number of FXIIIa+ cells in the lesional skin was significantly increased compared with those in the patient's uninvolved skin and in normal control skin samples (P < 0.01). As hyaluronan is considered to be synthesized by hyaluronan synthase (HAS), which is composed of three genetically distinct isoforms (HAS1, HAS2 and HAS3), the cells responsible for the accumulation of hyaluronan in lesional skin were immunohistochemically examined using antibodies for HAS1, HAS2 and HAS3. The specific antibody for HAS2 was found to react with some populations of FXIIIa+ cells in the involved skin, and the number of HAS2+ cells was significantly increased in the involved skin (P < 0.01). The results suggest that accumulation of hyaluronan in REM may be related to populations of FXIIIa+/HAS2+ dermal dendrocytes rather than to dermal fibroblasts.     

Diagnostic, prognostic and pathogenic value of the direct immunofluorescence test in cutaneous leukocytoclastic vasculitis

BACKGROUND: No precise studies have been performed on cutaneous leukocytoclastic vasculitis (LV) to establish whether it is better to obtain a skin biopsy from lesional or from perilesional skin for direct immunofluorescence (DIF). There is no agreement on the immunoglobulins most frequently detected and the value of DIF for the classification of cutaneous vasculitis. METHODS: A prospective study of DIF in lesional and perilesional skin was performed in 50 leukocytoclastic vasculitis patients and 15 nonvasculitis patients. RESULTS: We detected a higher level of positivity in involved skin than in uninvolved skin for IgG, IgA, IgM, C3 and fibrinogen but not for C1q. In vasculitic patients, IgA was the immunoglobulin most frequently detected in lesional (82%) and perilesional skin (68%), followed by IgM (56 and 34%, respectively) and IgG (20 and 8%, respectively). Only IgA deposits were associated with the diagnosis of vasculitis, with a sensitivity of 82% in lesional and 68% in perilesional skin, and with a specificity of 73 and 66.7%, respectively. The presence of IgA in lesional skin was associated with renal involvement but there was no association with severity. The presence of IgG or IgM, or the absence of IgA in perilesional skin was related to the presence of cryoglobulins. The absence of IgA in lesional and perilesional skin was also related to hepatitis C virus infection. CONCLUSIONS: DIF findings in involved skin are more closely related to the diagnosis of vasculitis and can give more information about overall renal involvement than findings in uninvolved skin. However, findings in uninvolved skin are more closely related to the pathogenic factors that trigger the development of vasculitis.     

Leukotriene B4 fails to induce penetration of lymorphonuclear leukocytes into psoriatic lesions

The intraepidermal accumulation of polymorphonuclear leukocytes following the epicutaneous application of leukotriene B4 (LTB4) was studied in lesional and clinically uninvolved skin of five patients with chronic stable plaque psoriasis. The lesions were found to be wholly unresponsive to LTB4, doses of 100 ng failing to produce either micropustules or exocytosis. This phenomenon was sharply localized; the response immediately adjacent to the lesion being identical to that in more distant uninvolved skin. We speculate that both the reduced response to LTB4 in the psoriatic patient and also the tolerance to LTB4 seen after repeated applications, result from the induction of a P450-linked hydroxylase.     

Interleukin-6 in the epidermis of patients with psoriasis before and during PUVA treatment

Biopsies from lesional and unaffected skin of 6 patients with psoriasis, taken before and during treatment with psoralen plus UVA (PUVA) were examined immunohistologically, using partially purified polyclonal antibodies to crude supernatants of activated human blood monocytes. By absorption with recombinant derived human monokines, we were able to demonstrate that interleukin-6 (IL-6) (but not IL-1 alpha or IL-1 beta) was located in a laminar and granular pattern in stratum corneum, and on epidermal cell membranes in the viable cellular epidermis. Before PUVA treatment, the intensity and the extension of staining for IL-6 were both markedly increased in lesional skin compared with uninvolved skin. A weaker staining for IL-6 was observed in lesional skin, simultaneous with the clinical improvement of psoriasis. The staining patterns for IL-6 in biopsies from cleared lesional skin and uninvolved psoriatic skin were identical at the conclusion of therapy.     

Over-expression of Mn-superoxide dismutase as a marker of oxidative stress in lesional skin of chronic idiopathic urticaria

We studied the involvement of oxidative stress in chronic idiopathic urticaria (CIU), assessing the activities of superoxide dismutase (SOD) and glutathione and the levels of malondialdeyde (MDA), a marker of lipid peroxidation, in samples taken from lesional skin (n = 16) and nonlesional skin (n = 11) of CIU patients. The activity of SOD and glutathione and the levels of MDA were markedly increased in lesional skin as compared with skin of healthy subjects, whereas no differences were detected between nonlesional skin of CIU patients and control samples. Immuno-dot blot assay revealed an up-regulation of Mn-SOD expression in lesional skin. These findings show that oxidative stress is crucially involved in CIU. The evidence of lipid peroxidation and compensatory increase of Mn-SOD and glutathione activities in lesional skin, in the absence of any alteration in uninvolved skin, suggests that oxidative stress is secondary to the development of inflammation.     

Sj?gren-Larsson syndrome: microscopic and scanning electron microscopic findings in replicas of the skin

Replicas of the skin below the cubital fossa were made in 29 SLS patients with an age range of 8 days to 69 years. The skin surface patterns differed from those in healthy controls. The papillomatosis observed in most SLS replicas seemed to appear during the first year or years of life and to increase in some patients with increasing age, but seemed to diminish again in middle-aged and older SLS patients. Other common features were the occurrence of longitudinal and transverse furrows. All these findings in SLS patients could, at least in part, represent an exaggeration of the normal skin surface pattern. The use of replicas for diagnostic purposes is commented on.     

Suction blister fluid histamine in fixed drug eruption.

The histamine concentration was measured from suction blister fluid obtained from normal and lesional skin of 8 patients with fixed drug eruption (FDE) caused by phenazone salicylate and from that of 2 healthy control subjects. In blister fluid samples obtained before peroral challenge with phenazone salicylate, the histamine concentrations were below 5 nmol/l both in uninvolved skin and in sites of previous FDE lesion (sample 0). After challenge, samples were taken from the incipient reaction that was visible after an average of 155 min. Histamine levels were significantly elevated in the blister fluid of 2 out of 8 FDE lesions (200 and 640 nmol/l) but in none of the uninvolved skin (sample 1). Two hours later (sample 2) the histamine levels were elevated in both uninvolved (mean 51.4 nmol/l) and lesional skin (mean 168 nmol/l). After 24 h (sample 3) the corresponding mean value was 25.4 nmol/l for uninvolved skin and 108 nmol/l for lesional skin. The histamine values in the blister fluid from FDE lesions in samples 2 and 3 were significantly higher (p less than 0.05) than those in the control blisters of uninvolved skin. An elevation of histamine levels comparable to that in the uninvolved skin of FDE patients was seen in the 2 healthy control subjects studied. The present study provides direct evidence of early release of histamine from mast cells or basophils in FDE and suggests that histamine is one of the mediators of clinical symptoms of FDE.     

银屑病皮损区和非皮损区AgNOR的定量观察

应用核仁组成区银染蛋白（ＡｇＮＯＲ）染色方法，对１２例银屑病患者皮损区和非皮损区表皮细胞进行了观察。并和非银屑病患考的正常皮肤及慢性皮炎类皮损各１２例进行了比较。结果显示银屑病患者皮损区和非皮损区ＡｇＮＯＲ值均数均明显高于正常皮肤和慢性皮炎类皮损，而后两者相类似。作者认为ＡｇＮＯＲ在组织学上可能有助于银屑病和一些慢性皮炎类疾病的鉴别。     

Expression of the T-cell activation antigens CD27 and CD28 in normal and psoriatic skin

Activated T lymphocytes are thought to be involved in the pathogenesis of psoriasis. From studies with peripheral blood T lymphocytes it is known that T cells show a decrease in membrane expression of CD27 molecules during continuous antigenic stimulation. The T-cell activation molecule CD28 is thought to be involved in the transduction of an antigen-non-specific costimulatory signal. Therefore, in order to elucidate further the pathogenesis of psoriasis we studied the expression of CD27 and CD28, together with CD4, CD8 and CD45RA in this benign inflammatory dermatological disease. We used immunohistochemical techniques to determine absolute numbers of T lymphocytes and expression of these T-cell activation and T-subset-specific molecules in normal (n= 7), uninvolved perilesional (n= 7) and lesional psoriatic (n= 7) skin. We found that not only lesional but also clinically uninvolved perilesional skin showed an increased number of T cells. Further, immunohistochemical studies showed that CD27 is expressed by a minority of normal skin T cells, while in lesional psoriatic skin, expression was even lower, and almost absent in perilesional skin sections. In contrast to normal skin, both perilesional and lesional psoriatic skin contained no CD28 positive T cells. In lesional psoriatic skin, however, T cells showed predominantly the CD4 phenotype, while in perilesional skin CDS positive T cells were dominant. Two conclusions were reached: first, the absolute number of T cells, their CD27, CD28 and CD45RA expression, and the influx of CD8 positive T cells, indicate that perilesional psoriatic skin is different from normal and lesional psoriatic skin; and secondly, the data on CD27 and CD28 suggest that not only lesional but also perilesional psoriatic skin is subject to continuous antigenic stimulation, thus leading to decreased CD27 and CD28 expression on skin T cells.