Clinical observations on delayed pressure urticaria

Repeated pressure tests at regular intervals were carried out on 48 patients with delayed pressure urticaria (DPU). Patients showed a considerable variation in response with periods of positive testing ranging from a few days to months or years. All the DPU patients had had chronic urticaria and/or angio-oedema although sometimes minor and occasional. Pressure tests were also carried out at regular intervals on seven patients with chronic urticaria who had weals at pressure sites but no history of pressure-induced weals (Köbner weals). These weals coincided with positive pressure tests and it seems likely that they all had DPU but only for a short time. Delayed dermographism was studied in eight patients with DPU. There was a good correlation in time and degree between positive pressure tests and delayed dermographism, confirming that delayed dermographism is in fact DPU provoked by a slightly different mode of pressure.     

Markers of systemic inflammation in delayed pressure urticaria

Background We have previously reported, increased plasma IL‐6 concentration in chronic urticaria. In addition, it has been suggested that IL‐6 and C‐reactive protein (CRP) may be useful markers of the disease activity. Aim The aim of this study was to evaluate whether a systemic inflammation is present in delayed pressure urticaria (DPU). Methods Plasma IL‐6 and serum CRP concentrations, biomarkers of acute phase response, were measured in DPU, and the healthy subjects matched by age, gender, and BMI using ELISA method. Results DPU patients showed significantly higher plasma IL‐6 and serum CRP concentrations than the healthy subjects. Conclusions Similarly to the known locally increased IL‐6 activity in DPU lesions, the elevated circulating levels of IL‐6 and CRP have been currently found in DPU. This indicates that the disease induces a systemic inflammatory process, termed the acute phase response.     

Characterization of the inflammatory infiltrate and expression of endothelial cell adhesion molecules in lupus erythematosus tumidus

Lupus erythematosus tumidus (LET) is a disease with characteristic clinical and histopathologic features that has not always been considered a subset of cutaneous lupus erythematosus (CLE). Although LET was first mentioned in the literature in 1930, it has rarely been documented, and immunohistochemical studies have never been performed. The aim of the present study was to characterize the inflammatory infiltrate and to analyze the expression of endothelial cell adhesion molecules in skin specimens from patients with LET and to compare the results with those from patients with other variants of CLE, such as discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE). Cryostat sections of lesional skin specimens from ten patients with LET demonstrated an infiltrate composed of more than 75% CD4+, CD8+, and HLA-DR+ cells. Interestingly, CD45RO+ cells, in contrast to CD45RA+ cells, were the prevailing inflammatory cell population. Compared with skin specimens from patients with DLE and SCLE, the mean expression of CD4+ and CD8+ cells was higher (but not significantly so) in LET, and no differences were observed with the other three antibodies. Furthermore, in contrast to controls, intercellular adhesion molecule-1, vascular adhesion molecule-1, E-selectin, and P-selectin showed the same expression pattern in skin specimens from patients with DLE, SCLE, and LET. In conclusion, the inflammatory infiltrate of LET primarily consists of CD4+/CD8+ lymphocytes. Furthermore, expression of endothelial cell adhesion molecules was equally upregulated in LET compared with the expression in DLE and SCLE, suggesting a similar immunopathomechanism of these subtypes of CLE.     

Effect of high-dose intravenous immunoglobulin in delayed pressure urticaria

BACKGROUND: Delayed pressure urticaria (DPU) is difficult to treat. High-dose intravenous immunoglobulin (IVIG) has been found to be effective in treating patients with autoimmune chronic urticaria. OBJECTIVES: To report the effect of IVIG on eight patients with severe unremitting DPU. METHODS: IVIG was administered at a dose of 2 g kg-1 over 2-3 days on an in-patient basis. The response to treatment was assessed subjectively and recorded as remission, improved or unchanged. An autologous serum skin test (ASST) was performed in seven patients. RESULTS: Three of eight patients achieved remission; two after one infusion and one after three infusions. Two patients improved. Three patients remained unchanged; of these, two declined further treatment after two infusions, and one failed to improve after six infusions at monthly intervals. Four of seven patients had positive ASST; three responded to IVIG. Two developed delayed positive ASST; both responded to IVIG. Of three patients with negative ASST, two responded. CONCLUSIONS: IVIG induced remission or improved symptoms in five of eight patients with DPU with severe unremitting disease who had failed to respond to other therapies or were controlled only with systemic corticosteroids. Those who responded did so with three or fewer infusions. ASST is not a reliable predictor of response to IVIG.     

Immunohistological comparison of granulated cell proteins in induced immediate urticarial dermographism and delayed pressure urticaria lesions

Urticarial dermographism and delayed pressure urticaria are two forms of physical urticaria which are well defined clinically and histologically. Previous studies have shown eosinophil granule protein deposition in urticarial reactions, including chronic urticaria, solar urticaria and delayed pressure urticaria. To evaluate and compare the involvement of granulated inflammatory cells in urticarial dermographism and delayed pressure urticaria, we studied sequential biopsies of induced lesions of urticarial dermographism and delayed pressure urticaria by indirect immunotluorescence, to detect eosinophil granule major basic protein (MBP) and neutrophil granule elastase. Biopsies from dermographic lesions at time 0.5 min, 15 min, 2h and 24 h, showed few infiltrating eosinophils, with minimal extracellular MBP deposition, and a few infiltrating neutrophils, with minimal neutrophil elastase deposition, throughout the evolution of the lesions. Sequential biopsies of delayed pressure urticaria at time 0. 20min. 6. 12 and 24h. showed eosinophil infiltration with extensive MBP deposition beginning at 20 min. and neutrophil infiltration with variable elastase deposition beginning at 20 min. Control tissue specimens from normal volunteers showed neutrophil infiltration and slight degranulation, but no eosinophil infiltrations or degranulation. Comparison of Urticaria dermographism with delayed pressure urticaria showed marked differences in the patterns of infiltration. Delayed pressure urticaria, with eosinophil and neutrophil degranulation, was strikingly similar to the IgE-mediated late phase reaction. In contrast, eosinophil and neutrophil involvement in urticarial dermographism was minimal. Considering the extent of eosinophil granule protein deposition and the biological activities of the eosinophil granule proteins, the findings in delayed pressure urticaria point to an important pathophysiological role of eosinophils in the disease.     

Arachidonic acid transformation is not stimulated in delayed pressure urticaria

Little is known about the molecular mechanisms or inflammatory mediators involved in delayed pressure urticaria (DPU). Pressure sufficient to provoke lesions was applied to the back of six patients with DPU. The levels of products of arachidonic acid transformation in skin exudate from the pressure challenged skin were estimated immediately after pressure was removed and 6 h later when lesions were present. These were compared to levels estimated in a similar way from unchallenged skin in these patients. Levels of leukotriene C4/D4/E4, prostaglandin E2, 12-hydroxyeicosatetraenoic acid and leukotriene B4 were not raised in lesional skin. Our results suggest that arachidonic acid metabolism is not stimulated in DPU.     

Adhesion molecule expression in normal skin and melanocytic lesions

Cell adhesion between surfaces of cells and to extracellular matrices represents a fundamental mechanism in tissue organization and influences the biological behaviour and the architecture of tumors. We investigated the expression of various adhesion molecules in normal skin (n=5), nevi (n=29), and malignant melanoma (n=10) by immunohistochemistry. Special attention was paid to the correlation between adhesion molecule expression and the respective architectural features, e.g. UV-induced morphological changes, and the arrangement of melanocytes in congenital nevi. In nevi, a single erythemagenic close of UV-light did not influence the influence expression of melanocytes, but results in an upregulation of α3β1- and α6β1-integrin within the suprabasal layers of the epidermis. This suprabasal labelling was associated with an increased number of suprabasal melanocytes in UV-irradiated nevi which were detected with HMB-45 antibody. Nine of 10 congenital nevi demonstrated a labelling of α4β1-integrin only in melanocytes of the deeper dermis. This integrin previously has been associated with high tumor thickness and the clinical outcome in melanomas. The integrin profile observed in melanomas differed in part from that seen in nevi with expression of β2-and β3-integrins in some cases. The results may indicate a correlation between adhesion molecule expression and histopathological findings in melanocytic lesions.     

Clinical, pharmacological and immunological aspects of delayed pressure urticaria

We studied the clinical features of thirty-two patients with delayed pressure urticaria, and special laboratory tests were performed in seven patients. Striking clinical features included a long duration of the disease (mean 6 years) and an elevated erythrocyte sedimentation rate in 71%, dermographism in 63% and a leukocytosis in 33% of the patients. There was prolongation of weals in response to histamine, compound 48/80, concanavalin A and NaCl. In some patients, histamine and chemotactic factor levels were increased in suction blisters over skin test and delayed pressure sites. In extracts from pressure weals, chemotactic activity was found for leukotriene B₄, its 20-ω-oxidation products and mono-HETEs. Studies of peripheral blood leukocytes revealed significantly increased intracellular histamine levels and increased release of histamine, and a trend to increased release of chemotactic activity from stimulated patient cells. The response of leukocytes to mitogens was normal.
We conclude that histamine plays a major role in the pathogenesis of PU. Arachidonate-derived chemotactic factors might account for the variably observed leukocytosis and the cellular infiltrate in lesions of pressure urticaria. Additional mediators must be involved in PU in order to explain the unique prolonged wealing response.     

Adhesion molecule expression in polymorphic light eruption.

Endothelial leukocyte adhesion molecule-1 (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) are cytokine-regulated cell-surface leukocyte adhesion molecules. We have investigated the in vivo kinetics and pattern of expression of these adhesion molecules in relation to tissue accumulation of leukocytes in the photodermatosis, polymorphic light eruption (PMLE), which is characterized by dense perivascular leukocytic infiltration. Immunohistology was performed on biopsies taken at varying time points from PMLE lesions induced in 11 subjects by suberythemal solar simulated irradiation. Vascular endothelial ELAM-1 expression was first observed at 5 h, maximal at 24 to 72 h, and remained elevated at 6 d. VCAM-1, minimally expressed in control skin, was induced above background levels on endothelium and some perivascular cells after 24 h and maintained at 6 d. Endothelial cell ICAM-1 expression was increased above control levels at 72 h and 6 d. Keratinocyte ICAM-1 expression, most marked overlying areas of dermal leukocytic infiltration, began at 5 h and was strong at 72 h and 6 d. In addition to lymphocytes, significant numbers of neutrophils but not eosinophils were detected in the dermal leukocytic infiltrate that appeared at 5 h and persisted at 6 d. The pattern of adhesion molecule expression that we have observed is similar to that seen in normal skin during a delayed hypersensitivity reaction. These observations support an immunologic basis for PMLE.     

The effects of topical corticosteroids on delayed pressure urticaria

Six patients with delayed pressure urticaria (DPU) applied clobetasol propionate (0.05%) ointment or its base to predetermined test sites on the right and left thigh as part of a randomized, double-blind study. A pressure challenge was administered to each test site at the initial visit and repeated after 3 days and 6 weeks of treatment and at between 4 and 8 weeks after treatment. The areas of pressure-induced weals were measurd 6 h after each challenge. At the 6-week visit, a 4-mm punch biopsy was taken from pressure-challenged skin on each test site. Sections were stained for mast cells and immunohistochemical labelling was used to demonstrate neutrophils (neutrophil elastase), eosinophils (eosinophil cationic protein), monocytes/ macrophages (EBM 11), cells expressing the beta-2 integrins (CD11/18) and the vascular adhesion molecules, E selectin and intercellular adhesion molecule-1 (ICAM-1). In the steroid-treated sites, there was a significant decrease (P<0.05, Wilcoxon's matched-pairs test) in the size of the pressure weals compared with baseline at 3 days, 6 weeks and at follow-up. Demonstrable mast cells were significantly decreased (P=0.059) in the pressure-challenged areas in the steroid-treated sites compared with the base-treated sites. The histological response to pressure was minimal in both sites perhaps demonstrating an active pharmacological effect of the ointment base. In conclusion, the application of potent topical steroids significantly reduced the clinical response to pressure in patients with DPU, possibly through a reduction in mast cells.     

CD69 expression and tumour necrosis factor-α immunoreactivity in the inflammatory cell infiltrate of halo naevi

It has been suggested that the involution of the pigmented lesions of halo naevus (HN) is mediated by an immune response, with the involvement of specific cytotoxic T lymphocytes. To explore further the pathogenesis of HN. skin biopsies from six patients with this condition were obtained and the characteristics of the infiltrating inflammatory ceils were studied by immunostaining techniques. We found that the cell infiltrate of HN is mainly composed by CD8⁺ T lymphocytes that express the activation molecule CD69. Tumour necrosis factor-α (TNF-α) immunoreactivity was detected on the inflammatory cells, a finding that suggests that the infiltrating T cells of HN are actively synthesizing this cytokine. Our results indicate that the infiltrating cells of HN predominantly have an activated cytotoxic phenotype, and suggest that these cells are indeed involved in the regression of the naevomelanocytic naevus of HN.     

Bullous delayed pressure urticaria; pressure testing may produce a systemic reaction

We report a patient with bullous delayed pressure urticaria (DPU) and chronic idiopathic urticaria (CIU) in whom a systemic reaction occurred. The reaction occurred 18 h after a pressure test had been performed on the right forearm. Blood histamine levels were more elevated in the sample taken from the forearm on which the test had been applied. Skin biopsy revealed both intraepidermal and subepidermal bullae with a sparse dermal inflammatory infiltrate and direct immunofluorescence showed linear deposition of fibrinogen along the epidermodermal basement membrane. As far as we are aware this is only the third case of bullous DPU reported and the first associated with generalized urticaria and angioedema and severe broncho-obstruction. Possible pathophysiological mechanisms are discussed.