Masafumi Iijima

Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population

An anticonvulsant, carbamazepine (CBZ), is known to show incidences of cutaneous adverse drug reactions (cADRs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS). To identify a gene(s) susceptible to CBZ-induced cADRs, we conducted a genome-wide association study (GWAS) in 53 subjects with the CBZ-induced cADRs, including SJS, TEN and DIHS, and 882 subjects of a general population in Japan. Among the single nucleotide polymorphisms (SNPs) analyzed in the GWAS, 12 SNPs showed significant association with CBZ-induced cADRs, and rs1633021 showed the smallest P-value for association with CBZ-induced cADRs (P = 1.18 × 10⁻¹³). These SNPs were located within a 430 kb linkage disequilibrium block on chromosome 6p21.33, including the HLA-A locus. Thus, we genotyped the individual HLA-A alleles in 61 cases and 376 patients who showed no cADRs by administration of CBZ (CBZ-tolerant controls) and found that HLA-A*3101 was present in 60.7% (37/61) of the patients with CBZ-induced cADRs, but in only 12.5% (47/376) of the CBZ-tolerant controls (odds ratio = 10.8, 95% confidence interval 5.9-19.6, P = 3.64 × 10⁻¹⁵), implying that this allele has the 60.7% sensitivity and 87.5% specificity when we apply HLA-A*3101 as a risk predictor for CBZ-induced cADRs. Although DIHS is clinically distinguished from SJS and TEN, our data presented here have indicated that they share a common genetic factor as well as a common pathophysiological mechanism. Our findings should provide useful information for making a decision of individualized medication of anticonvulsants.

Functional Characterization of IL-17F as a Selective Neutrophil Attractant in Psoriasis

IL-17F is known to be involved in many inflammatory diseases, but its role in skin diseases has not been fully examined. Because IL-8 is involved in many skin diseases such as psoriasis, we investigated the production of IL-8 in normal human epidermal keratinocytes (NHEKs) stimulated by IL-17F, tumor necrosis factor-alpha (TNF-alpha), IL-17A, and control using real-time PCR and ELISA. The results showed that IL-17F induced production of IL-8 in NHEKs in a time-dependent manner. Interestingly, the amounts of IL-8 stimulated by IL-17F were much higher than those stimulated by TNF-alpha or IL-17A. Next, we confirmed that selective mitogen-activated protein kinase kinase inhibitors significantly inhibited IL-17F-induced IL-8 production. Moreover, mouse skin intradermally injected with IL-17F expressed high level of IL-8 mRNA and induced ERK1/2 phosphorylation. Histological examination of mouse skin that was injected with IL-17F revealed marked neutrophilia in dermis and the infiltration was significantly inhibited by anti-IL-8 antibody. Finally, IL-17F expression in skin biopsy samples from psoriasis patients were examined by western blotting and ELISA. IL-17F was upregulated in lesional psoriatic skin compared with nonlesional skin. These results indicate that IL-17F may be involved in psoriasis via, in part, the activation of ERK1/2 and the induction of IL-8 in keratinocytes.

Enhancing Effect of Ultraviolet A on Ornithine Decarboxylase Induction and Dermatitis Evoked by 12-o-Tetradecanoylphorbol-13-Acetate and Its Inhibition by Curcumin in Mouse Skin

BACKGROUND Previous studies have demonstrated appreciable tumor induction in mouse skin by daily irradiation with high-power long-wavelength ultraviolet A (UVA). OBJECT The aim of the present study was to examine the enhancing effects of UVA on changes in mouse skin mediated by the tumor promoter 12-o-tetradecanoylphorbol-13-acetate (TPA) by measurement of ornithine decarboxylase (ODC) activity and morphometric analysis. In addition, we examined the inhibitory effects of curcumin, a component of turmeric, on these changes. METHOD ODC activity in the epidermis of CD-1 mice was determined by the method of Russell and Snyder. Epidermal and dermal thickness, and the number of dermal infiltrating inflammatory cells were quantified using a computer-assisted image analyzer. RESULTS A combination of topical TPA application and UVA irradiation produced a greater increment of ODC activity at 4 h than TPA alone (p < 0.05). Histopathologically, TPA plus UVA tended to increase the dermal infiltrating inflammatory cells in contrast to TPA alone. Pretreatment of mice with curcumin significantly abrogated the TPA-induced changes in ODC activity and the dermal infiltrating inflammatory cells as well as the TPA plus UVA-mediated enhancement of these changes. CONCLUSION Our data indicate that UVA irradiation (18.72 J/cm2) significantly enhances ODC induction at an early stage (4-6 h) after topical application of TPA, and aggravates the dermatitis elicited by TPA. Pretreatment with curcumin significantly inhibits these enhancing effects.

Multiple Fixed Drug Eruption Caused by Iomeprol (Iomeron®), A Nonionic Contrast Medium

Most cases of drug eruption caused by nonionic contrast media (NICM) reported to date have been of the erythema multiforme type. Herein we report the first case of multiple fixed drug eruption (FDE) caused by iomeprol (Iomeron®). A 67-year-old woman developed multiple pea-sized erythematous papules on the trunk and extremities 4 days after receiving 100 ml of iomeprol for a computed tomography examination. Some of the papules coalesced, forming 7 large plaques on the limbs. Six months later, the patient was mistakenly administered iomeprol again. On the following morning, erythematous plaques admixed with vesicles recurred at the same sites as during the previous episode. In both episodes, the lesions cleared leaving pigmentation that faded with 6 weeks. Both patch testing and an intradermal test with iomeprol on lesional pigmented skin were positive. The present case indicates that NICM may cause multiple FDE and that repeated administration of the causative agent may increase the severity of the eruption.

Inhibitory effect of catechin against the superantigen staphylococcal enterotoxin B (SEB)

Staphylococcal superantigens (SsAgs) have gained attention as one of the factors aggravating atopic dermatitis (AD) and several potential mechanisms of AD aggravation by SsAgs have been reported. Tea catechin has been found to have many unique antimicrobiological activities such as antibacterial, antiviral, antifungal and antitoxic effects. In the present study, we investigated the inhibitory effect of the green tea catechin extract, Polyphenon, and (−)-epigallocatechin gallate (EGCg) on staphylococcal enterotoxin B (SEB) and its mechanisms of action, and we also discuss the possibility of therapeutic benefits for AD patients of tea catechin. Polyphenon inhibited the lethal toxicity of SEB and the SEB-induced production of TNF-α, IFN-γ and IL-4 following its intraperitoneal administration to BALB/c mice. Although Polyphenon is composed of several isomers among which EGCg is approximately 50% of the total, we considered that most of the inhibitory effect of Polyphenon in mice could be attributed to EGCg. EGCg was immediately bound to SEB molecules and neutralized SEB in a dose- and incubation time-dependent manner without molecular weight alteration of the SEB molecule. Furthermore, EGCg inhibited SEB-induced TNF-α and IFN- γ production and IL-2, IFN- γ, IL-10 and IL-12 p40 mRNA expression in human PBMCs from normal donors in a dose-dependent manner. Inhibition of SsAg-induced T-cell activation by catechin was observed in both in vivo and in vitro studies, suggesting that catechin may be useful in the treatment of AD.

Comparative study of direct polymerase chain reaction, microscopic examination and culture-based morphological methods for detection and identification of dermatophytes in nail and skin samples.

The positive rates of dermatophytes isolated and identified by conventional methods are rather low. Moreover, clinical isolates sometimes show atypical morphology, and in such cases microscopic methods are not applicable for identification. The present study was performed to assess the utility of specific polymerase chain reaction (PCR)‐based methods for Trichophyton rubrum and Trichophyton mentagrophytes as diagnostic tools for dermatophytoses. Both conventional morphological identification and specific PCR methods based on the nuclear ribosomal internal transcribed spacer (ITS)1 DNA sequence were performed to identify dermatophyte species from clinical specimens of patients who visited Kawasaki Social Insurance Hospital between 16 May and 17 August 2005. Specific PCR methods were also directly applied to clinical specimens, and the results of the two methods were compared. The clinical samples examined consisted of 126 skin scale specimens and 80 nail specimens. The positive rates of culture isolation from clinical specimens were 67% and 33% for skin scale and nail specimens, respectively. In contrast, PCR analysis yielded a positive rate of 100% for clinical isolates from both skin scales and nails, and rates of 95% and 99% were obtained by direct application to clinical specimens. The results of the present study indicated that specific PCR is highly advantageous as a diagnostic tool for detection and identification of dermatophytes on direct application to skin scale or nail specimens.

Occupational trichloroethylene hypersensitivity syndrome with human herpesvirus-6 and cytomegalovirus reactivation.

Patients having a generalised rash with severe liver dysfunction associated with exposure to trichloroethylene (TCE) have been reported mainly in Asian countries. However, no case has been reported in Japan since the 1990s. Here, we describe a case of hypersensitivity syndrome (HS) caused by TCE in a 30-year-old Japanese man. The patient developed a rash, fever and liver dysfunction 21 days after he had been exposed to TCE at his workplace. Serum human herpesvirus (HHV)-6 and cytomegalovirus (CMV) DNA were detected 4 and 7 weeks, respectively, after the onset; the IgG antibody titres to HHV-6 and CMV were significantly elevated 6 and 9 weeks, respectively, after the onset. Patch testing was positive for the metabolites of TCE (i.e. trichloroethanol, trichloroacetic acid and chloral hydrate) but not for TCE itself; these results suggest that the TCE metabolites induced this disease. Human leucocyte antigen-B*1301, which has been reported to be strongly associated with TCE-induced HS, was identified in this patient. In addition, the clinical findings, laboratory data and period of virus reactivation after onset were quite similar to those of drug-induced hypersensitivity syndrome (DIHS). We also review TCE-induced HS from the viewpoint of the similarity to DIHS in this article.

Predictive Factors Associated With Acute Ocular Involvement in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

PURPOSE To suggest an objective score for grading the acute ocular severity of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), and to determine predictive factors for severe acute ocular involvement such as ocular surface epithelial defect and/or pseudomembrane formation. DESIGN Retrospective cohort study. METHODS The medical records of SJS (n = 87) and TEN (n = 48) patients between 2005 and 2007 were reviewed. An acute ocular severity score was determined on a scale from 0 to 3 (none, mild, severe, and very severe) according to the existence of hyperemia, corneal or conjunctival epithelial defect, and pseudomembrane formation. The associations between the severe acute ocular involvement and factors such as patient age, exposed drugs, systemic severity, and the prevalence of ocular sequelae were examined. RESULTS The number of cases with score grade 0, 1, 2, and 3 was 19 (21.8%), 31 (35.6%), 22 (25.3%), and 15 (17.2%) in 87 SJS cases and 12 (25.0%), 11 (22.9%), 17 (35.4%), and 8 (16.7%) in 48 TEN cases. Multivariate logistic regression analysis revealed that patient age (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.96-0.99; P = .007) and nonsteroidal anti-inflammatory drugs NSAIDs or cold remedies (OR, 2.58; 95% CI, 1.26-5.29; P = .010) were predictive factors for severe acute ocular involvement. The prevalence of visual disturbance and eye dryness increased according to the increase of acute ocular severity (P = .001 and P = .007 in SJS; P = .007 and P = .014 in TEN, respectively). CONCLUSIONS At the onset of SJS/TEN, strict attention should be paid to ocular involvement in young patients and in patients exposed to NSAIDs or cold remedies.

Identification of thymus and activation-regulated chemokine (TARC/CCL17) as a potential marker for early indication of disease and prediction of disease activity in drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS).

BACKGROUND Drug-induced hypersensitivity syndrome (DIHS)/drug rash with eosinophilia and systemic symptoms (DRESS) is a serious acute drug reaction with fever, cutaneous eruption, lymphadenopathy, and several visceral dysfunctions. Eosinophilia is a common hematological abnormality in DIHS/DRESS suggesting that the Th2-type immune response is involved. Thymus and activation-regulated chemokine (TARC/CCL17) is a family of CC chemokines known to play an important role in Th2-mediated immune-inflammatory processes. OBJECTIVE We investigated the pathogenic role of TARC in patients with DIHS. METHODS Sera were obtained from 8 patients with DIHS, 7 patients with Stevens-Johnson syndrome/Toxic epidermal necrolysis (SJS/TEN), and 14 patients with drug-induced maculopapular exanthema (MPE). Serum TARC levels were measured by ELISA. TARC levels were then compared with clinical symptoms and various hematological parameters. In addition, a biopsy was taken from the lesional skin of patients with DIHS and stained with anti-TARC Ab and anti-CD11c Ab. RESULTS Serum TARC levels in patients with DIHS were significantly higher than those in patients with SJS/TEN and MPE during the acute phase. Serum TARC levels in DIHS patients correlated with skin eruptions, serum sIL-2R levels, eosinophil counts, and serum IL-5 levels. Immunohistochemical staining revealed that TARC was mainly expressed on CD11c+ dermal dendritic cells in patients with DIHS. CONCLUSION Serum TARC levels may be associated with the initial presentation of DIHS as well as disease activity during the course. Thus, they could be useful as an indicator for early diagnosis and assessment of disease activity in DIHS. CD11c+ dendritic cells may be the main source of TARC in patients with DIHS.

Adult-onset xanthogranuloma appearing symmetrically on the ear lobes

Clinical backgrounds of patients with adult-onset xanthogranuloma are somewhat different from those of patients with juvenile xanthogranuloma, but the histologic findings of both forms of the disease are identical. The lesions of the adult form are usually asymmetric. We describe a patient with adult-onset xanthogranuloma that appeared symmetrically on the ear lobes. This case suggests a possible role for mechanical stimuli (e.g., earrings) in the pathogenesis of adult-onset xanthogranuloma.