A whole-genome association study of major determinants for allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe, cutaneous adverse drug reactions that are rare but life threatening. Genetic biomarkers for allopurinol-related SJS/TEN in Japanese were examined in a genome-wide association study in which Japanese patients (n=14) were compared with ethnically matched healthy controls (n=991). Associations between 890 321 single nucleotide polymorphisms and allopurinol-related SJS/TEN were analyzed by the Fisher's exact test (dominant genotype mode). A total of 21 polymorphisms on chromosome 6 were significantly associated with allopurinol-related SJS/TEN. The strongest association was found at rs2734583 in BAT1, rs3094011 in HCP5 and GA005234 in MICC (P=2.44 × 10(-8); odds ratio=66.8; 95% confidence interval, 19.8-225.0). rs9263726 in PSORS1C1, also significantly associated with allopurinol-related SJS/TEN, is in absolute linkage disequilibrium with human leukocyte antigen-B*5801, which is in strong association with allopurinol-induced SJS/TEN. The ease of typing rs9263726 makes it a useful biomarker for allopurinol-related SJS/TEN in Japanese.

Serum periostin levels are correlated with progressive skin sclerosis in patients with systemic sclerosis.

BACKGROUND: Periostin, a matricellular protein, serves as a regulator of wound healing and fibrosis. The role of periostin in the pathogenesis of systemic sclerosis (SSc) is unknown. OBJECTIVE: To determine periostin levels in association with severity of skin fibrosis in patients with SSc. METHODS: Expression of periostin was immunohistochemically examined in skin obtained from patients with SSc and healthy controls. Enzyme-linked immunosorbent assay was performed to evaluate serum periostin levels in association with clinical characteristics in 56 patients with SSc [diffuse cutaneous SSc (dSSc), n=16; and limited cutaneous SSc (lSSc), n=40] and 66 healthy controls. RESULTS: Periostin was strongly expressed in the affected dermis from patients with SSc. Periostin was colocalized in α-smooth muscle actin-positive myofibroblasts and platelet endothelial cell adhesion molecule-1-positive endothelial cells in SSc dermis. Serum levels of periostin in patients with dSSc were markedly elevated compared with those in patients with lSSc and control subjects. Patients with lSSc had increased periostin levels compared with healthy controls. In addition, significantly higher levels of periostin were observed in patients with dSSc with disease duration ≤5 years compared with those with disease duration >5 years. Furthermore, the modified Rodnan total skin thickness score (MRSS) was positively correlated with periostin levels in patients with SSc. Serial analysis revealed a correlation between periostin and MRSS; namely, MRSS decreased in line with decreased periostin levels in some patients with dSSc as the disease progressed. CONCLUSION: An elevated periostin level in patients with SSc is associated with severity of skin sclerosis. Periostin may be a potential biomarker for progressive skin fibrosis in SSc.

Interleukin-18 is elevated in the horny layer in patients with atopic dermatitis and is associated with Staphylococcus aureus colonization.

BACKGROUND: An increase in interleukin (IL)-18 production from epidermal cells has been reported in an atopic dermatitis (AD) mouse model, and subsequent topical application of Staphylococcus aureus results in severe dermatitis. OBJECTIVES: To reveal the relationship between S. aureus colonization of skin lesions and keratinocyte IL-18 production, particularly in AD with relatively low serum IgE levels. We also aimed to establish a simple and noninvasive method of assaying IL-18 produced by epidermal keratinocytes to evaluate local skin inflammation and therapeutic effects in patients with AD. METHODS: IL-18 in the horny layer of the skin was collected via a tape-stripping method and measured in 95 patients with AD and 40 healthy controls by enzyme-linked immunosorbent assay (ELISA). Clinical severity, blood data and S. aureus skin colonization were evaluated before and after treatment. RESULTS: IL-18 levels in the horny layer were significantly higher in the skin lesions of patients with AD than in healthy controls and correlated with SCORAD, levels of serum IL-18, IgE, lactate dehydrogenase, thymus and activation-regulated chemokine, blood eosinophils and transepidermal water loss. In the AD group with serum IgE < 1500 IU mL(-1) , significantly higher IL-18 levels were observed in the horny layer of patients colonized with S. aureus compared with those who were not. CONCLUSIONS: Epidermal IL-18 production was associated with the severity of AD. Staphylococcus aureus colonization seems to contribute to this IL-18 production, especially in the AD group with relatively low IgE production. Tape stripping provides an easy and noninvasive method to assess epidermal IL-18 production by ELISA.

Attitudes of dermatologists toward the Chapel Hill Consensus Conference nomenclature and classification.

This study was designed to explore the attitudes of dermatologists towards the Chapel Hill Consensus Conference (CHCC) nomenclature and classification. We developed a questionnaire to determine the views of chief assistant dermatological professors at 61 Japanese university hospitals. A chi2 analysis of the responses found a close relationship between dermatological facilities that based their evaluations on the CHCC and their likelihood of taking confirmatory skin biopsies from patients with suspected microscopic polyangiitis with cutaneous features. In those facilities, the physicians and pathologists tended to consider cutaneous polyarteritis nodosa and cutaneous leucocytoclastic angiitis as independent disease conditions. We believe that it would be beneficial for dermatologists to take advantage of the CHCC, through which an appropriate early diagnosis of vasculitis can be realized. The present investigation provides a picture of current practices of Japanese dermatologists with reference to the management of vasculitis, including the extent to which biopsies are used to establish the diagnosis.

Two cases of wheat-dependent anaphylaxis induced by aspirin administration but not by exercise.

BACKGROUND: Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to enhance the symptoms of wheat-dependent exercise-induced anaphylaxis (WDEIA). In contrast to many reports on WDEIA, there have been only a few reports of wheat-dependent aspirin-induced anaphylaxis not induced by the combination of wheat and exercise. METHODS: Two patients with wheat-dependent anaphylaxis underwent provocation tests to clarify the cause of their symptoms. Skin-prick testing (SPT) was also performed with and without administration of aspirin. Specific IgE antibody to wheat, gluten, and omega-5 gliadin were examined. RESULTS: In the provocation tests, anaphylactic reactions were not induced by wheat or aspirin alone or by the combination of wheat and exercise, but were induced by the combination of wheat and aspirin. An increase in the blood histamine level was detected after provocation in both patients. Pretreatment with aspirin enhanced the SPT reactions to wheat and gluten in both patients. Specific IgE antibodies to wheat and gluten were expressed in the serum of both patients, and specific omega-5 gliadin IgE antibody was detected in the serum of one patient. CONCLUSIONS: We present two cases of specific wheat-dependent anaphylaxis induced by aspirin but not by exercise. We suggest that pretreatment with aspirin under controlled conditions is useful to confirm the diagnosis of food allergy when a challenge test with food alone or with food and exercise fails to induce positive reactions.

Clinical usefulness of oral itraconazole, an antimycotic drug, for refractory atopic dermatitis.

We investigated the clinical usefulness of oral itraconazole for refractory atopic dermatitis in a crossover study. Patients with refractory atopic dermatitis were divided into two groups: Group A; a combination of itraconazole plus a conventional lactobacillus preparation was administered for 8 weeks, followed by lactobacillus preparation alone for 8 weeks, Group B; lactobacillus preparation alone was administered for 8 weeks, followed by itraconazole plus lactobacillus for 8 weeks. In both groups, a decrease in dose or strength of concomitant topical steroids was observed at the end of the treatment course of itraconazole, and improvement of parameters such as eosinophil count, serum IgE level and specific IgE antibody titers to fungi was also observed after the administration of itraconazole. These results suggest that oral itraconazole is useful for the treatment of intractable atopic dermatitis patients who do not respond to conventional therapeutic approaches.

High positive frequency of antibodies to metallothionein and heat shock protein 70 in sera of patients with metal allergy.

Two principal types of stress protein, heat shock proteins (hsps) and metallothionein (MT), are induced in cells responding to a variety of stresses. They play an important role in protecting cells from these stresses. However, many reports indicate that antibodies to hsps are present in human serum and are associated with several autoimmunity diseases. Metals, which are commonly allergenic to humans, induce both MT and hsp70 (one of the hsps family). Until now, there has been no report of any antibody to MT in human serum. In the present study, serum samples from healthy controls (Group I), and patients suffering from atopic dermatitis without (Group II) or with (Group III) metal allergy, were measured for antibodies to MT and hsp70, using an enzyme-linked immunosorbent assay (ELISA). Metal allergy was confirmed by patch testing. We first found that antibody to MT exists in human serum. We also found a high positive frequency of antibody to MT (51.3%) and to hsp70 (43.6%) in the sera of Group III, compared to those of Group I (3.8% and 5.1%) or Group II (6.4% and 5.1%). Furthermore, there was a strong positive correlation between antibody to MT and antibody to hsp70 in Group III (P = 0.0013), but not in Group I and Group II. Our results indicate that antibody to MT exists in human serum, as do antibodies to hsps, and suggest that elevated levels of MT and hsp70 antibodies are associated with metal allergy in atopic patients.

Food-dependent exercise-induced anaphylaxis: influence of concurrent aspirin administration on skin testing and provocation.

BACKGROUND: Provocation tests in patients with food-dependent exercise-induced anaphylaxis (FDEIA) are often negative, even after a sufficient quantity of the implicated food and exercise have been taken. OBJECTIVES: To investigate the effect of aspirin in provocation tests and in skin prick testing (SPT) of patients with FDEIA. Gluten as a major allergen in wheat-dependent FDEIA was also investigated. METHODS: Provocation tests and SPT with suspected foods were performed in 12 patients with FDEIA. Provocation tests were performed with combinations of foods, exercise and aspirin. Detection of gluten-specific IgE was also performed by the CAP System FEIA radioallergosorbent test, SPT and a histamine release test. RESULTS: The SPT reaction was enhanced by pretreatment with oral aspirin in five of eight (62.5) patients. Aspirin facilitated provocation in five of seven (71%) patients tested. Ingestion of wheat and aspirin without exercise provoked symptoms in two patients. Aspirin provoked symptoms even with a small amount of wheat and exercise in one patient. Only the combination of aspirin, wheat and exercise provoked anaphylaxis in one patient. Specific IgE, SPT and/or the histamine release test with gluten were positive in nine of 11 patients with wheat-dependent FDEIA. CONCLUSIONS: Aspirin enhances symptoms of FDEIA, and prior ingestion of aspirin under controlled conditions can be used to confirm FDEIA. In practice, such patients should avoid aspirin ingestion. Gluten appears to be the major allergen in these patients with wheat-dependent FDEIA.

Frequency of food-dependent, exercise-induced anaphylaxis in Japanese junior-high-school students.

BACKGROUND: Food-dependent, exercise-induced anaphylaxis (FEIAn) is classified among the physical allergies. The pathophysiology of FEIAn remains unknown, as does the frequency of FEIAn in the general population. OBJECTIVE: We sought to study the epidemiology of FEIAn, especially its frequency in junior-high-school students in Yokohama, Japan. METHODS: A questionnaire asking about the occurrence of FEIAn in school students was sent to all 145 public junior-high-school nurses in Yokohama. RESULTS: One hundred thirty-two junior-high-school nurses responded to the questionnaire, and 13 (11 boys and 2 girls) cases of FEIAn among 76,229 junior-high-school students were reported. In addition, 24 (12 boys and 12 girls) subjects with exercise-induced anaphylaxis (EIAn) were detected. From this survey, the frequency of FEIAn was 0.017% in this population, and its frequency was significantly higher in boys than in girls (P < .05). The frequency of EIAn was 0.031%, and there was no difference according to sex. Only one third of junior-high-school nurses had any knowledge of FEIAn. We also performed provocation tests in 5 of the 13 cases with FEIAn after obtaining informed consent from the students and their parents and were able to confirm the diagnosis. CONCLUSION: This study showed that FEIAn and EIAn are relatively rare diseases among junior-high-school students in Yokohama. To avoid serious outcomes, we believe it is important that not only physicians but also school nurses and teachers of physical education be aware of these diseases.

Autoimmune vesicles on the face and neck. A variant of Brunsting-Perry type localized bullous pemphigoid?

We report a case of blistering disease presenting a unique distribution of vesiculobullous lesions on the face and neck which is similar to Brunsting-Perry type of localized bullous pemphigoid (BP). Histopathology of a lesional skin biopsy demonstrated a subepidermal blister. Direct immunofluorescence demonstrated a strong linear deposition of IgG and IgA to the basement membrane zone, and a faint staining for C3. However, circulating antibodies were not detected by indirect immunofluorescence and immunoblotting. And the patient did not develop atrophic scars and was a relatively young woman. This case might be a variant of Brunsting-Perry type of localized BP or localized epidermolysis bullosa acquisita, presenting the clinical heterogeneity of subepidermal blistering diseases.

The necessity for dual food intake to provoke food-dependent exercise-induced anaphylaxis (FEIAn): a case report of FEIAn with simultaneous intake of wheat and umeboshi.

BACKGROUND: Food-dependent exercised-induced anaphylaxis (FEIAn) is classified among the physical allergies. Many different food allergens have been reported, but the pathophysiology of FEIAn remains unknown. Furthermore, provocation tests with a suspected food do not always succeed in patients with FEIAn. OBJECTIVE: We sought to clarify and investigate causative foods and mechanisms of FEIAn in a 14-year-old boy. In addition, we tested in vivo and in vitro effects of cromolyn sodium in the same patient. METHODS: We used open challenge tests for the provocation of FEIAn and measured changes in plasma histamine levels and FEV1. In addition, we investigated the mechanism of FEIAn in this case with in vitro histamine release testing. RESULTS: The patient was diagnosed as having FEIAn by provocation testing with a simultaneous intake of wheat and umeboshi, but not when each food was eaten singly, followed by exercise. In addition, his plasma histamine level increased transiently and forced expiratory volume 1, expressed as a percentage change from baseline, decreased significantly. A synergistic effect on in vitro histamine release testing with 2 kinds of the causative foods was shown. Administration of cromolyn sodium proved to be effective on both the in vitro and in vivo tests. CONCLUSION: This is the first report of FEIAn provoked by the test with a simultaneous intake of 2 kinds of food. This case might in part explain negative challenge test results in patients with FEIAn.

Anticonvulsant hypersensitivity syndrome associated with reactivation of cytomegalovirus.

Recently, it has been proposed that viral infection is involved in the pathogenesis of hypersensitivity syndrome. Cytomegalovirus (CMV), one of the aetiological agents of infectious mononucleosis, has never been reported as an organism associated with hypersensitivity syndrome. We describe a 64-year-old man with severe phenytoin-induced hypersensitivity syndrome associated with CMV infection. Twenty-five days after the patient was started on phenytoin, he developed high fever and a generalized erythematous rash followed by jaundice, renal failure and disseminated intravascular coagulopathy (DIC). CMV-specific IgG antibodies were significantly increased 7 weeks after the onset of clinical symptoms and the increase was associated with the appearance of CMV-specific IgM. CMV DNA was detected in the serum of the patient. Coinfection with other viruses, such as Epstein-Barr virus and human herpesviruses 6 and 7, could be excluded because antibody titres to those viruses did not increase during the clinical course of his illness. We suggest that reactivation of CMV may contribute, at least in some cases, to the development of hypersensitivity syndrome.

Contact urticaria from rice.

A 30-year-old man with atopic dermatitis had had erythema and itching of the hands after washing rice in water, though he had always eaten cooked rice without problems. Handling test with water used to wash regular rice was performed on abraded hands, and produced urticarial erythema after several minutes. Applications of water used to wash allergen-reduced rice were negative for urticarial reaction. Prick test with water used to wash regular rice was +++. However prick test reaction with water used to wash allergen-reduced rice was +. Histamine-release test of regular rice-washing water was grade 3 and that of allergen-reduced rice grade 1. In immunoblotting analysis with regular rice washing water, there were no bands with this patient. These results suggest that the allergen responsible for contact urticaria in this patient might be water-soluble, heat-unstable, and not contained in allergen-reduced rice.

Effect of IL-12 encoding plasmid administration on tight-skin mouse.

The tight-skin (Tsk/+) mutant mice, a putative murine model of scleroderma, are characterized by the excessive deposition of collagen and the presence of antinuclear antibodies. Type 2 cytokines, such as IL-4 and IL-6, are capable of regulating the synthesis of various matrix molecules, including type I collagen, by fibroblasts. IL-12 is well known to induce type 1 cytokine production and to reduce type 2 activity. Here, we examined the effect of IL-12 encoding plasmid (pCAGGSIL-12) on the disease progression of Tsk/+ mice. pCAGGSIL-12 plasmid or pCAGGS parental vector was injected intramuscularly 7 times at 3 week intervals into Tsk/+ mice. One week after the last injection, pCAGGSIL-12 administered Tsk/+ mice exhibited a marked decrease in the skin thickness compared with the mice treated with pCAGGS vector. The serum levels of antinuclear antibodies were diminished in pCAGGSIL-12 treated mice. IL-4 production by spleen cells from pCAGGSIL-12 plasmid treated mice was significantly lower than that from vector treated mice. These results indicate that pCAGGSIL-12 administration into Tsk/+ mice had beneficial effects in preventing the collagen accumulation in the skin and suppressing the autoimmunity via improvement of Th1/Th2 balance. The present study suggests that the IL-12 encoding plasmid administration might have a therapeutic effect on systemic sclerosis.

[Atopic dermatitis at 18-months physical examination].

In order to know the prevalence rate and severity of atopic dermatitis, and to compare them to those previously done for 4-month-old infants, the authors examined atopic dermatitis of 18-month-old children at regular health checks at a health center. Among 769 children examined, 69 were diagnosed as having atopic dermatitis, giving a prevalence rate of 9.0%. Most of cases were mild, and no severe cases were observed. In contrast to the location of eruptions on head, face, and trunk at 4-month-old, the eruptions were seen mainly on the trunk and extremities. The prevalence rate in summer and autumn was significantly lower than that in winter and spring. Among 501 children whom we could examine both at 4-month and 18-month-old, 102 cases were diagnosed as having atopic eruptions at 4 months. The eruptions, however, were disappeared in 83 cases when they were 18-month-old. The severity of atopic dermatitis also came to be mild when they grew up. Altogether, a quarter of children had atopic eruptions either at 4 months or 18 months, or both. It will be of interest to observe the transition of atopic dermatitis in childhood and we are planning to follow them at next physical examination at 3-year-old.

[Immunological and clinical features of vernal keratoconjunctivitis between persons with and without systemic atopic dermatitis].

PURPOSE: The aim of this study was to evaluate whether there exists immunological or clinical difference between patients with vernal keratoconjunctivitis(VKC), which is characterized by conjunctival proliferative changes belonging to the serious spectrum of allergic conjunctival diseases, complicated by atopic dermatitis(AD) and those without AD. MATERIALS AND METHODS: The study population consisted of 52 patients with VKC (33 patients with AD, 19 without AD). Clinical severity was determined on the basis of clinical scores of conjunctival, corneal, and limbal lesions. The serum level of total IgE, the proportion of eosinophils in peripheral blood, antigen specific IgE antibodies (radioallergo sorbent test, RAST), and tear levels of interleukin (IL)-4 and IL-5 were measured. RESULTS: The serum level of total IgE and the number of positive RAST antigens were significantly higher in VKC patients with AD than in those without AD. No significant difference was observed in the proportion of peripheral blood eosinophils, distribution of clinical types of VKC, or clinical severity between VKC patients with and without AD. Although tear IL-4 level in VKC patients with AD was significantly higher than in those without AD, no difference was observed in tear level of IL-5 between these groups. CONCLUSIONS: These results indicate that clinical features are similar or identical in VKC regardless of the presence of AD. However, it is suggested that there may be a different immunological background between VKC patients with AD and those without AD.

Digestibility of allergens extracted from natural rubber latex and vegetable foods.

BACKGROUND: Several cross-reactive allergens are now known to be involved in the defense responses of higher plants. Such proteins are drawing the attention of plant breeders because of their antimicrobial or stress-alleviating activities. Plants genetically modified to express defense-related proteins are being developed. The current concern is focused on the allergenicity of these intentionally expressed proteins. OBJECTIVE: It is believed that food allergens are proteins resistant to digestion. Digestibility tests have been accepted as an appropriate method for evaluating the allergenicity of newly introduced proteins. In this study we investigated the usefulness of this method for detecting allergens from natural rubber latex and vegetable foods. METHODS: Proteins were extracted from rubber latex, potato, and 5 kinds of fruits. Simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) were used for the digestibility test. An aliquot of each digest was periodically withdrawn and analyzed. Allergens were detected with pooled sera from individuals with latex allergy or patients given a diagnosis of oral allergy syndrome. RESULTS: Most latex and vegetable food proteins were digested by the SGF within 4 minutes. Numerous allergens were also decomposed by the SGF within 8 minutes. Although vegetable food allergens were relatively stable in the SIF, kiwi allergens were substantially degraded by the SIF within 16 hours. CONCLUSION: The pronounced lability of the plant-derived allergens was thought to reflect the discrete sensitization and elicitation processes of patients with latex-fruit syndrome or oral allergy syndrome. These results indicate that the allergenicity of a newly expressed protein should be carefully evaluated according to not only its digestibility but also other important properties.