Stevens-Johnson syndrome and toxic epidermal necrolysis due to anticonvulsants share certain clinical and laboratory features with drug-induced hypersensitivity syndrome, despite differences in cutaneous presentations.

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is characterized by late disease onset, fever, rash, hepatic dysfunction, haematological abnormalities, lymphadenopathy and often, human herpesvirus (HHV) reactivation. The diagnosis of DIHS is based on the combined presence of these findings. Anticonvulsants are a major cause of DIHS and may also cause Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We examined whether SJS/TEN due to anticonvulsants display similar clinical and laboratory features seen in DIHS. METHODS: Patients diagnosed with SJS or TEN due to anticonvulsants (n = 8) were examined and their clinical features and laboratory findings were compared with patients with anticonvulsant-related DIHS (n = 6). RESULTS: Seven of the eight patients with SJS/TEN developed symptoms > 3 weeks after starting anticonvulsants. Hepatic dysfunction was present in six patients with SJS/TEN and five patients with DIHS. Leucocytosis and/or eosinophilia was noted in seven patients with SJS/TEN and four patients with DIHS. Only one patient in the SJS/TEN group had atypical lymphocytosis; this was present in four patients with DIHS. Reactivation of HHV-6 was detected in one of the four patients tested in the SJS/TEN group, although it was seen in five of the six patients with DIHS. CONCLUSIONS: TSJS/TEN due to anticonvulsants may exhibit some clinical and laboratory features of DIHS. The nature of the cutaneous involvement should be emphasized in the diagnosis of DIHS.

Sweet's syndrome associated with Mycobacterium avium infection.

A 68-year-old woman presented with a 3-month history of nontender, erythematous nodules on the right side of the neck. Subsequently, tender, circinate erythematous plaques appeared on the limbs, accompanied by peripheral leucocytosis. A biopsy specimen obtained from an erythematous plaque revealed diffuse infiltration of neutrophils in the dermis. Treatment with prednisolone improved the erythematous lesions, but upon tapering of prednisolone, numerous areas of indurated erythema with pustules recurred on the face and back accompanied by high fever. Computed tomography of the lung revealed multiple lesions. A smear of gastric juice contained acid-fast bacilli that were identified as Mycobacterium avium by DNA-DNA hybridization. Treatment with multiple antibiotics did not result in a favourable response of the M. avium infection, and dome-shaped, subcutaneous abscesses developed on the limbs and trunk. Sweet's syndrome may thus occur in association with nontuberculous mycobacterial infection.

Serum cytokine levels in atopic dermatitis.

Elevated IgE responses and eosinophilia observed in patients with atopic dermatitis (AD) may reflect increased responses of type 2 T-helper (Th2) cytokines with a concomitant decrease in interferon-gamma (IFN-gamma) production. However, the cross-regulation of Th1/Th2 derivation and function in AD patients are incompletely characterized. Therefore, we investigated serum levels of several cytokines [interleukin (IL)-18, IL-12, IL-10, IL-2 and IFN-gamma] in patients with AD to assess their possible relationships to the severity of disease. Serum IL-18 levels in AD patients were significantly higher than those in healthy controls [207 pg/mL; 95% confidence interval (CI), 172-242 pg/mL vs. 144 pg/mL; 95% CI, 116-178 pg/mL; P = 0.026]. Those IL-18 levels significantly correlated with eosinophil counts and serum soluble IL-2 receptor (sIL-2R) levels, and showed a tendency to correlate with clinical severity scores and serum IgE levels. IL-2 levels showed a significantly inverse correlation with serum IgE levels, and IL-12 levels clearly correlated with IL-10 levels. These results suggest the value of serum IL-18 levels as a parameter of AD activity and may support a possible role for IL-18 in the pathogenesis of AD. The inverse correlation between IgE levels and IL-2 levels suggests that IgE production may be inhibited by IL-2 in patients with AD. Furthermore, the correlation of IL-12 levels with IL-10 levels may support the previous reports that show the induction of IL-10 production by human natural killer cells and/or T cells stimulated with IL-12 in vitro.

Grouping prurigo: report of cases.

Grouping prurigo was reported as a new clinical entity by Ofuji et al. in 1977 and 1988. No further cases have been reported since. Herein we report four cases of grouping prurigo and discuss the possible relationship between this condition and other diseases in the prurigo group, including chronic pruritic papular dermatitis in adult men, which was reported by Chang et al. in 1999. Since grouping prurigo and chronic pruritic papular dermatitis in adult men share approximately the same characteristics in both clinical and histopathological findings, we concluded that these two disorders may be the same entity, characterized by grouped pruritic solid papules on the trunk.

Leukocytoclasis: ultrastructural in situ nick end labeling study in anaphylactoid purpura.

In order to characterize leukocytoclasis of polymorphonuclear neutrophils (PMNs), the method of in situ nick end labeling for DNA breakdown was applied on tissue samples from 36 patients with anaphylactoid purpura at ultrastructural, as well as light microscopic, level. Light microscopic immuno-peroxidase technique showed positively labeled PMNs infiltrating in the dermis of 24 cases in which leukocytoclastic vasculitis was fully developed, suggesting that breakdown of DNA strands is triggered in the PMNs. Electron microscopic immuno-gold technique employed in six patients with the fully developed stage of inflammation identified the DNA breaks in the nuclei of PMNs. Ultrastructure of these cells, however, showed that only a minor population ( approximately 1/60) of PMNs showed the condensed and marginated nuclei, being compatible with typical apoptotic change. However, the majority of immuno-gold-labeled cells showed relatively intact nuclei without margination of condensed heterochromatin and with disintegrated cytoplasmic organelles and plasma membrane, suggesting that apoptotic cell removal mechanism may be incomplete. The immuno-gold-positive nuclear debris scattering in the tissue is most likely the remnants of unsatisfactory disposal by apoptosis of potentially injurious PMNs, resulting in the vascular and perivascular damage in leukocytoclastic vasculitis in anaphylactoid purpura.

Topical dinitrochlorobenzene therapy in the treatment of refractory atopic dermatitis: systemic immunotherapy.

BACKGROUND: Repeated dinitrochlorobenzene (DNCB) application has been proposed as a systemic immunotherapy on the basis of its ability to stimulate T helper 1 (T(H)1) responses, such as those for systemic lupus erythematosus and HIV infection. OBJECTIVE: We report the effect of topical DNCB therapy in an open trial in patients with refractory atopic dermatitis (AD). METHODS: Eight patients with refractory AD received weekly application of 0.2% to 1% DNCB to a 2. 5-cm(2) area on the upper arm after sensitization with 5% DNCB; the position was rotated at each application. Disease activity was monitored by pruritus score, percentage of body involvement, clinical severity score, eosinophil counts, serum IgE levels, and serum soluble interleukin 2 receptor levels. RESULTS: Six of 8 patients (patients 1-6) showed apparent improvement both on clinical scores and laboratory data until 16 weeks after DNCB therapy (week 16). The clinical severity scores of patients 1 to 6 were significantly correlated with eosinophil counts, IgE levels, and serum soluble interleukin 2 receptor levels. One patient did not show clear improvement, and another (patient 8) showed deterioration. DNCB therapy was discontinued at week 12 for patient 8. CONCLUSION: Topical DNCB may systemically stimulate T(H)1 cell responses of patients with AD, resulting in restoration of the T(H)1/T(H)2 imbalance and possible clinical improvement. These results, however, should be interpreted with caution until additional documentation is obtained.

Corticosteroid-induced pancreatitis in patients with autoimmune bullous disease: case report and prospective study.

Corticosteroid pulse therapy using very high doses may produce corticosteroid-induced pancreatitis (CIP) that is unexpected during conventional oral corticosteroid therapy and may sometimes be fatal. Our goal was to evaluate the relation between pulse corticosteroid administration and pancreatitis. A case of CIP is reported, and a prospective study was performed. Corticosteroid pulse therapy followed by 30 mg prednisolone orally was utilized in 7 hospitalized patients with autoimmune bullous disease, and serum pancreatic enzymes were measured during therapy. The case report revealed reproducible pancreatitis in a dose-dependent manner after 2 corticosteroid regimens. In the prospective study, serum pancreatic enzyme levels increased significantly within several days after pulse therapy, then decreased with tapering of the dose of oral prednisolone. Laboratory pancreatic alterations appear to be induced within days after pulse corticosteroid administration in a dose-dependent manner: less than 25 mg of oral prednisolone may be below threshold to alter the pancreatic enzyme level.

Co-localization of urokinase and its receptor on established human umbilical vein endothelial cell.

Vascular endothelial cells possess antithrombotic properties, which are determined by the balance between plasminogen activators (PAs) and PA inhibitors (PAls). A cell line, TKM-33, has been established and cloned from human umbilical vein endothelial cells, was previously reported to produce a large amount of urokinase-type PA (u-PA) and small amounts of tissue-type plasminogen activator (t-PA) and PA inhibitor-1 (PAI-1). Moreover, TKM-33 expressed the u-PA receptor (u-PAR) which plays an important role in the localization of fibrinolytic activity on cell surface. In the present study, we investigated the localization of u-PA, t-PA, PAI-1 and u-PAR in TKM-33 by using immunofluorescence staining technique. The endothelial cells were strongly stained with anti-PAI-1, anti-u-PA and anti-u-PAR IgGs, and slightly with anti-t-PA IgG. The double immunofluorescence staining with mouse anti-u-PA IgG and rabbit anti-u-PAR IgG followed by rhodamine-conjugated anti-mouse IgG and FITC-conjugated anti-rabbit IgG showed the co-localization of u-PA and u-PAR on the same section of endothelial cells. Although u-PA antigen also existed in the cytoplasm of endothelial cells, u-PAR antigen did not. The treatment of endothelial cells with phorbol-myristate-acetate (PMA) upregulated the expression of u-PA and u-PAR antigens. In this stimulation, u-PAR antigen was detected not only on the surface of the cells but also in the cytoplasm. Thus, the binding of u-PA to u-PAR was confirmed by double immunofluorescence staining.

Apoptosis of hair follicle cells in the second-degree burn wound unders hypernatremic conditions.

Progressive burn wound necrosis is an important factor as a cause of delayed healing during clinical therapy of burns. Among the causes of progressive necrosis have been attributed an insufficient blood supply or a dehydration at the zone of stasis just beneath the zone of coagulation. In a previous study evidence was presented that hypernatremia, an osmotic injury, may act to promote progressive tissue or cell death of the superficial dermal wound resulting from a heat injury. To test this hypothesis pathological features of cell death in the second-degree burn wound in the rat with hypernatremia were investigated and evidence for apoptosis in hair follicle cells was observed. Rats in the hypernatremic group were administered 10 ml of hypertonic sodium solution (850 meq 1(-1)) and the control rats were treated with 10 ml of hyponatremic solution (100 meq 1(-1)) to prevent hypernatremia. After 24 h postburn the average incidence of hair follicles (ratio to the normal skin) in the hypernatremic group was 30.1 +/-11.6 per cent and significantly lower when compared with the control group (87.6+/-6.0 per cent). The numbers of hair follicles were studied by haematoxylin and eosin stain, and the apoptotic process was investigated by an immunochemical assay and electron microscopy.

Platelet-activating factor and arachidonic acid metabolites in psoriatic inflammation.

Platelet-activating factor (PAF), as well as PAF acetylhydrolase (PAF-AH) activity in the peripheral blood plasma of patients with psoriasis and palmoplantar pustolosis, was measured with a radioimmunoassay technique, and compared with leukotriene (LT) B4, LTC4, LTD4 and E4 (LTD4/E4), thromboxane (TX) B2 and prostaglandin (PG) E2 levels. In a normal healthy group (n = 12) PAF level was 25.9 +/- 6.5 pg/0.1 ml plasma (mean +/- standard error of the mean: SEM), and this was elevated in patients with psoriasis (68.1 +/- 11.8, n = 25, P < 0.01), without a change in the PAF-AH level. LTB4 showed a similar increase (115.0 +/- 21.6 pg/ml vs. 68.2 +/- 11.8 pg/ml, P < 0.05), while TXB2 and PGE2 showed insignificant (P > 0.05) changes. LTC4 and LTD4/E4 were around the level of the limit of detection. Patients with palmoplantar pustulosis (n = 33) demonstrated similar, but milder and statistically insignificant, increases in PAF, LTB4, TXB2 and PGE2 levels. Modulation of the mediator levels before and after treatment was compared in 16 patients with psoriasis and 11 with palmoplantar pustulosis. PAF in psoriasis significantly decreased after treatment (70.9 +/- 17.1 to 25.1 +/- 5.5, P < 0.05) and this was moderately correlated (r = 0.298) with clinical improvement as indicated by the psoriasis area and severity index (38.5 +/- 7.5 to 10.9 +/- 4.2, P < 0.01). TXB2 (180.2 +/- 100.4 to 34.1 +/- 13.5), PGE2 (3.7 +/- 0.7 to 2.9 +/- 0.5) and LTB4 (120.1 +/- 31.1 to 84.2 +/- 8.2), in psoriasis, mildly decreased without statistical significance. Patients with palmoplantar pustulosis demonstrated a similar decrease in all mediators without statistical significance. The results obtained suggest a role of PAF in psoriasis. As the priming effects of PAF have been shown, for leucocytes and endothelial cells, to enhance their inflammatory response, we assume that PAF has roles in the acute phase of psoriatic and leucotactic inflammation.

Paraneoplastic pemphigus: report of a case.

A 56-year-old male with chronic lymphocytic leukemia developed extensive erosive mucocutaneous lesions with histologic acantholysis. Immunopathologic studies showed IgG deposition at the intercellular space, C3 deposition at both the intercellular space and the dermo-epidermal junction, and reactivity of the serum to rat urinary bladder epithelium. Autoantibodies in the serum to human epidermal proteins of 210 kD and 190 kD were shown by Western blotting and to proteins of 250 kD, 210 kD, and 190 kD by immunoprecipitation. All these data suggest the diagnosis of paraneoplastic pemphigus. Repeated plasmapheresis resulted in re-epithelialization of the mucocutaneous lesions and reduction in antibody titer from 1:1280 to 1:20. Although this mucocutaneous disease was established as a new autoimmune bullous disease by Anhalt et al. (1990), cases have rarely been reported from Japan. The present patient demonstrates the major characteristics of paraneoplastic pemphigus.

Effect of heat shock on the expression of urokinase-type plasminogen activator receptor in human umbilical vein endothelial cells.

We investigated the effect of heat shock on the fibrinolytic potential of human umbilical vein endothelial cells (HUVECs) in culture. When cultured at 43 degrees C, the mRNA for heat shock protein 70 (HSP70) was dramatically induced within 120 min with a maximal induction of more than 90-fold compared with that in HUVECs cultured at 37 degrees C. The level of urokinase-type plasminogen activator (u-PA) receptor (u-PAR) mRNA increased up to 2.2-fold in response to heat shock, which was associated with the increased u-PA binding and cell-surface u-PA activity determined by adding exogenous u-PA to acid-treated HUVECs. The increased u-PAR mRNA returned to normal level when HUVECs were further incubated at 37 degrees C for 180 min, and this decline was not affected in the presence of actinomycin D. Though the secreted antigens for tissue-type plasminogen activator (t-PA) and type 1 plasminogen activator inhibitor (PAI-1) in the conditioned medium (CM) of HUVECs were simultaneously increased at 43 degrees C during this period, the increase in the levels of t-PA (about 26.6-fold at 120 min) was greater than that of PAI-1 (1.8-fold at 120 min). The fibrinolytic activity of CM obtained from HUVECs at 43 degrees C was significantly enhanced up to 3-fold, indicating that heat shock induced hyperfibrinolytic states in HUVECs. The secretion of u-PA into CM was also enhanced by heat shock. These results suggested that human endothelial cells respond to hyperthermia by inducing HSP70 followed by hyperfibrinolytic states with the enhanced expression of u-PAR as well as that of t-PA and u-PA.

Antibody production to heat shock proteins with Mr 65 kD (HSP65) in cutaneous inflammation: a possible relation to focal infection.

In order to correlate the immunomodulatory roles of homologous heat shock proteins with Mr 65 kD (HSP65) to skin diseases, antibody level to recombinant-HSP65 of Mycobacterium leprae was quantified with enzyme-linked immunosorbent assay (ELISA) in the sera of patients. In psoriasis, an insignificant increase was observed in anti-HSP65 IgG (0.111 +/- 0.053, mean +/- SD in 0D492 nm, n = 22), compared with a normal group (0.080 +/- 0.032, n = 9). However, psoriasis of acute guttate-type (PGA), which is often induced after tonsillar infection, showed a significant increase (0.178 +/- 0.032 n = 4, p <0.001), but psoriasis vulgaris did not (PV) (0.101 +/- 0.053, n = 12), nor generalized psoriasis pustulosa (PP) (0.087 +/- 0.025, n = 6). Similarly, patients with palmoplantar pustulosis (PPP) with tonsillar or periodontal infection showed significantly high anti-H5P65 IgG (0.230 +/- 0.065, n = 7, p <0.0001), compared with only a mild increase in PPP without suspected infectious foci (0.139 +/- 0.066, n = 13, p <0.05). Possible staphylococcal infection in the oral cavity was suggested by an additional ELISA assay to staphylococcal antigen: anti-staphylokinase IgG showed a significant increase in PPP with infectious foci (0.110 +/- 0.028 n = 3, p <0.01) compared with the normal group (0.039 +/- 0.014), while PPP without them showed only a mild change (0.060 +/- 0.017, n = 6, p <0.05). We assume that immunoreaction to H5P65 may be involved in psoriatic skin inflammation associated with focal infection.