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.

Monoclonal suppressor factor specific for lactate dehydrogenase B. I. Mechanism of interaction between the factor and its target cells.

Hybridomas secreting a monoclonal T suppressor-effector factor (TseF) were produced by fusion of a lactate dehydrogenase B (LDHB)-specific long-term T suppressor-effector (Tse) cell line with the BW5147 thymoma. A short exposure (4 h) to TseF completely suppresses the antigen-specific and A-restricted proliferation of LDHB-primed Lyt-1+2- [possibly helper (Th)] cells. The action of TseF on Th cells, as that of the Tse cells themselves, is antigen-specific and A-restricted. The interaction of TseF with Th cells involves two binding events, of which one occurs via antigen bridge, and the other represents the recognition of a factor-derived Ak-like moiety by the anti-Ak receptor of Th cells. The Ak-like moiety of the TseF carries the determinants that serve as restriction elements for antigen recognition by Th cells, and additional determinants demonstrable by T cell-specific monoclonal "anti-Ak" antibodies, however, it lacks serologically detectable determinants of the B cell-derived A alpha A beta class II Mhc molecules.

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.

Photosensitivity to piroxicam is induced by sensitization to thimerosal and thiosalicylate.

Piroxicam (PXM), a nonsteroidal anti-inflammatory drug, has been well known to often induce photosensitive eruptions within a few days after its administration. It has been reported that this photosensitivity correlates well with a positive patch-test reaction to thimerosal (TMS) and also to thiosalicylate (TOS), which is an active hapten of TMS. But it has not yet been concluded whether this correlation is caused by a cross-reaction among the drugs or not. In our experiments, animals contact-sensitized with TMS or TOS developed positive photopatch-test reactions to PXM, and those photocontact-sensitized with PXM had positive patch-test reactions to TMS and TOS. Photosensitive reactions were also induced by UVA irradiation (photo test) performed 90 min after perioral administration of PXM in the animals contact-sensitized with TMS or TOS. Analysis of the UVA-treated PXM by nuclear magnetic resonance spectrography and thin-layer chromatography revealed that the high dose of UVA induced photodecomposition of PXM, and generated several other chemicals different from PXM. But the PXM treated with the high dose of UVA could not induce positive patch-test reactions in many of the animals contact-sensitized with TMS or TOS. The cross-reacting hapten generated from PXM by UVA treatment may not be stable in the absence of carrier proteins. These results taken together indicate that the PXM photosensitivity in man is induced by contact-sensitization with TMS, as shown in our animal model, and then is photoallergic in nature. But the identity of the cross-reacting substance remains unknown.

Piroxicam has at least two epitopes for contact photoallergy.

We have demonstrated previously in guinea pigs that the induction of photocontact sensitivity to piroxicam (PXM) also induces a state of cross-reactive contact hypersensitivity to two compounds having structurally related elements, thimerosal (TMS) and thiosalicylate (TOS). The present study was conducted to determine whether oral administration of TOS would desensitize guinea pigs previously photosensitized with PXM. At the same time, the spectrum of reactivities against these compounds and against tenoxicam (TXM) which resembles only piroxicam was assessed by appropriate sensitizing and eliciting protocols. As expected, animals photosensitized to PXM developed reactivities against all four compounds, PXM and TXM (photosensitivity) and TMS and TOS (contact sensitivity). By contrast, photosensitization with TXM induced cross-reactivity only against PXM. Moreover, the induction of contact sensitivity against TMS or TOS induced photosensitive cross-reactivity to PXM, but not to TXM. Finally, the oral administration of TOS produced a transient desensitization only for TMS and TOS. These results suggest that photosensitization with PXM induces two distinct reactivities. The first reactivity cross-reacts with TMS and TOS and is suppressible with orally administered TOS. The second cross-reacts only with TXM and is not suppressible with oral TOS. We conclude that PXM acquires at least two distinct immunogenic epitopes when exposed to UVA irradiation.

A cross-reaction between piroxicam-photosensitivity and thiosalicylate hypersensitivity in lymphocyte proliferation test.

We examined the cross-reaction between photosensitivity to piroxicam (PXM) and contact sensitivity to thiosalicylate (TOS) by a lymphocyte proliferation test (LPT) in guinea pigs. The lymph node cells (LNCs) plus peritoneal exudate cells (PECs) from guinea pigs contact-sensitized with TOS remarkably cross-proliferated to PXM under UVA (4 J/cm2) irradiation. On the other hand, the PXM-photosensitized LNCs+PECs also cross-proliferated to TOS. From these results, the reciprocal cross-reaction between TOS-hypersensitivity and PXM-photosensitivity was reconfirmed by the in vitro LPT, indirectly indicating that the PXM-photosensitivity is a cell (probably T cell)-mediated PXM photoallergy in its nature. The TOS-primed LNCs+PECs did not cross-proliferate to UVA (4 J, 180 J or 500 J/cm2)-pretreated PXM (UVA-PXM) although it is supposed to contain several photoproducts of PXM. Furthermore, the TOS-primed LNCs developed a remarkable proliferative cross-response to the PECs pulsed with PXM under UVA (4 J/cm2) irradiation (photo-PXM-modified PECs), but not to the PECs pulsed with PXM or UVA-PXM. Therefore, it is presumed that the cross-reactive molecule, which is easily formed from PXM under UVA irradiation, is unstable, and that the formation of complete antigen by the generation of this molecule and its photobinding needs the coexistence of PECs, PXM and UVA irradiation at the same time in the culture.

Systemic and local immunological features of atopic dermatitis patients with ocular complications.

AIMS: Clinical factors and data from recent cases of atopic dermatitis (AD) (with or without ocular complications) and non-AD cases were examined to evaluate the mechanism of atopic ocular complications. METHODS: IgE-RAST for eight allergens including rice, egg, and mite and serum total IgE were measured in 216 patients with AD (70 ocular type, 146 non-ocular type) and 69 non-AD individuals. Tear histamine and leukotriene B4 (LTB4) levels were also measured. RESULTS: The serum levels of IgE were significantly increased in AD patients with ocular complications compared with those without ocular complications. The positive rates of IgE-RAST for rice and wheat were significantly higher in ocular type AD than in non-ocular type AD. In ocular type AD, serum IgE was significantly increased in patients with cataract compared with that in those without cataract. Tear histamine and LTB4 levels in AD patients with ocular complications showed significant elevations compared with those in patients with pure AD and controls. CONCLUSIONS: These results suggest that ocular type AD belongs to the most severe end of the spectrum of AD, and that some food antigens may contribute to the pathogenesis of severe AD resulting in ocular complications.

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.

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.

Study of immune-responsiveness to wheat antigen by IgG, IgA, and IgE immunoblotting with sera from patients with atopic dermatitis.

To investigate the immune mechanism underlying the IgE-mediated hypersensitivity to food antigens, wheat-flour proteins were extracted in mild condition, and IgG antibodies were detected by the ELISA method. Atopic dermatitis patients who had high scores for IgE-RAST were shown to have increased levels of IgG antibodies to wheat proteins. To define the allergenic polypeptides or epitopes in wheat proteins, each patient's serum was subjected to determination of IgG, IgA, and IgE antibodies to each protein component, using a highly sensitive immunoblotting method. Low molecular weight polypeptides bind specifically IgG, IgA, and IgE antibodies in serum from atopic dermatitis patients. Thus, there are specific components or epitopes in wheat proteins which are closely related to the disease states.

A probable involvement of rice allergy in severe type of atopic dermatitis in Japan.

1006 patients with typical and atypical lesions of atopic dermatitis (AD) were analysed statistically. The clinical severity was closely correlated to serum IgE values and RAST (radio-allergosorbent test) positivity. The frequency of RAST-positive antigens was significantly correlated with serum IgE values (gamma = 0.712; p < 0.01). The analysis of multiple correlation between the clinical severity and each RAST score for mite, egg white and rice antigens suggested a strong contribution of rice allergy to the development of severe AD. 25 patients with severe AD and positive rice-RAST were treated by rice exclusion diet. The results were as follows: 9 cases remarkably responsive, 10 cases moderately responsive and 6 cases unresponsive. The rice-RAST titre decreased most remarkably in the 1st group. The wheat-RAST titre also decreased in the 1st, in spite of taking wheat foods every day, but increased in the 3rd. A probable role of rice allergy in severe AD in Japan is discussed.

Mass trial of hypoallergenic rice (HRS-1) produced by enzymatic digestion in atopic dermatitis with suspected rice allergy. HRS-1 Research Group.

The clinical usefulness of a hypoallergenic rice (HRS-1) which was produced by enzymatic decomposition of the constituent proteins of original rice was evaluated in a multicentre study in 44 subjects with recalcitrant atopic dermatitis (AD), who were suspected of having rice allergy. The subjects were fed for at least 4 weeks with HRS-1 instead of eliminating both regular rice and wheat from their daily diet. The extent of overall skin lesions was expressed by using the AD affected area and severity index (ADASI). A statistically significant decrease in ADASI was observed at the 2nd and the 4th week readings and at the end of the study. A provocation test with regular rice was carried out in 5 of 44 subjects following the HRS-1 therapy. An obvious increase in ADASI was found in all of these 5 cases just after this procedure. On final evaluation, 77% of the patients tested showed 'moderate' to 'remarkable' improvement, and 59% of the patients a 'moderate' to 'remarkable' reduction in use of the steroid ointment concomitantly used for the treatment. Finally, HRS-1 was evaluated as 'useful' or 'very useful' in 69% of the subjects.

Psoriasiform intradermal test reaction to ABPC in a patient with psoriasis and ABPC allergy.

We experienced a case of psoriasis with ABPC allergy which showed a psoriasiform intradermal test reaction to ABPC. A 22-year-old man with a history of psoriasis since the age of 17 was admitted to our department because he developed erythrodermic psoriasis after oral administration of ABPC. About 1 year later, he again developed erythroderma after administration of ABPC. Intradermal testing with 2% ABPC was performed. We found infiltrating erythema at day 2, followed by a gradually increasing psoriasiform reaction at 6 days on the site of ABPC skin test. We examined the infiltrating cells in the skin test reaction immunohistochemically. Most of the infiltrating cells in the dermis were activated helper/DTH-type T cells. Among the infiltrating cells in the epidermis, we observed more cytotoxic/suppressor-type T cells than helper/DTH-type T cells. A possible role of a DH reaction to ABPC in inducing the psoriatic lesion is discussed in relation to the pathomechanisms of psoriasis.

Lichenoid drug eruptions due to nandrolone furylpropionate (Demelon).

A case of lichenoid drug eruption due to nandrolone furylpropionate (Demelon) is reported. A 71-year-old man with aplastic anemia developed widespread erythema and reticulation with violaceous papules and pigmentation after receiving intramuscular injections of Demelon weekly for 2 months. The eruption gradually resolved after drug withdrawal, leaving reticular pigmentation. A biopsy specimen of the skin lesion showed lichenoid-type reactions including hydropic or colloid degeneration of the basal cells, sometimes with satellite necrosis, and a band-like subepidermal lymphocytic infiltrate. Most of the mononuclear cells stained strongly for helper/inducer T lymphocytes (Leu 3a).

Gold sodium thiomalate (GTM) induces hypersensitivity to thiomalate, the thiol carrier of GTM.

A case of the gold sodium thiomalate (GTM)-induced eruptions with thiomalate (TM) hypersensitivity was reported. A 61-year-old Japanese woman developed lichenoid and seborrheic dermatitis (SD)-like eruptions with alopetia, when the total dosage of GTM administered for rheumatoid arthritis became 110 mg. The eruptions slowly disappeared with pigmentation after discontinuance of the GTM therapy, and the resumption resulted in the development of similar eruptions. She showed a positive reaction to GTM in an intradermal test. She also showed a positive response to TM, which is the thiol carrier of GTM, in the patch test, but a negative one to metallic gold. After administration of auranofin (AF), she also developed the SD-like eruptions with hypersensitivity to metallic gold as well as AF on patch testing, but did not develop the lichenoid ones. Our animal experiments revealed an almost complete cross reaction between GTM and TM, but only a partial one between GTM and aurothioglucose, which have dissmilar structures in the carrier part for gold. Probable roles of hypersensitivity to TM and metallic gold, which are metabolites of GTM, were discussed, respectively, in the genesis of the GTM-induced lichenoid eruptions and the AF-induced SD-like eruptions.

Generalized rash induced by sulfhydryl drug in guinea pigs--a comparative study on it with cephalothin-induced rash in guinea pigs.

Adverse reactions produced by sulfhydryl compounds with active thiol groups have generally formed a distinctive pattern in man when they are viewed as a class. It has been reported that cutaneous SH-induced drug eruptions have a wide variety of clinical presentations; histologically, they show a pattern of eosinophilic necrosis and/or satellite necrosis similar to that seen in cutaneous graft vs host reactions. In the present experiments, guinea pigs were sensitized with cephalothin (CET) and thiol compounds such as tiopronin (TP), D-penicillamine, gold sodium thiomalate or thiomalate, using a method similar to that described previously. In lymphocyte stimulation tests, lymph node cells from the sensitized animals responded positively to spleen cells pulsed with each thiol compound. Intracutaneous tests revealed some positive reactions to each thiol compound; there was a tendency to produce a tuberculin type reaction with indurated erythema rather than the Jones-Mote type seen in CET-induced reactions. The dose-requirements for positive intracutaneous tests and generalized rash (GR) due to thiol compounds were lower than for CET, which required relatively large doses. Histologically, infiltration of basophilic cells was prominent in the skin lesions induced by intracutaneous tests with CET and in those of CET-induced GR. On the other hand, intracutaneous tests with TP following the induction of TP-induced GR revealed eosinophilic degeneration of epidermal cells, which was similar to the eosinophilic necrosis seen in cutaneous GVHR. Intracutaneous tests after the induction of CET-GR did not show any eosinophilic changes in the epidermal cells. These findings are reminiscent of the characteristics of eruptions induced by thiol compounds in man, which differ from the eruptions induced by CET.