Hiroyuki Niihara

Exercise and aspirin increase levels of circulating gliadin peptides in patients with wheat-dependent exercise-induced anaphylaxis.

Background Food‐dependent exercise‐induced anaphylaxis (FDEIA) is an allergic reaction characteristically induced by intense exercise combined with the ingestion of causative food. Recent reports have shown that aspirin intake is a contributing factor in some patients with FDEIA. Wheat is known to be the most frequent causative food, and the IgE‐binding epitopes of a major wheat allergen (ω‐5 gliadin) in wheat‐dependent exercise induced anaphylaxis (WDEIA) have already been clarified. However, the mechanism of eliciting the symptom in WDEIA remains not fully understood.

Specific IgE Determination to Epitope Peptides of ω-5 Gliadin and High Molecular Weight Glutenin Subunit Is a Useful Tool for Diagnosis of Wheat-Dependent Exercise-Induced Anaphylaxis

Wheat ω-5 gliadin and a high m.w. glutenin subunit (HMW-glutenin) have been reported as major allergens in wheat-dependent exercise-induced anaphylaxis. A simultaneous detection of specific IgE to epitope sequences of both proteins is considered to be a reliable method for diagnosis of wheat-dependent exercise-induced anaphylaxis. However, the IgE-binding epitope of HMW-glutenin remains unknown. The aim of this study was to determine the IgE-binding epitopes of HMW-glutenin to establish a useful system of identifying patients with wheat-dependent exercise-induced anaphylaxis. For determination of IgE-binding epitopes of HMW-glutenin overlapping peptides were synthesized and reactivities of IgE Abs in the sera of patients to those peptides were analyzed. Three IgE-binding epitopes, QQPGQ, QQPGQGQQ, and QQSGQGQ, were identified within primary sequence of HMW-glutenin. Epitope peptides, which include IgE-binding sequences of ω-5 gliadin and a HMW-glutenin, were synthesized and peptide-specific IgE Abs were measured by CAP-System fluorescent enzyme immunoassay. Twenty-nine of 30 patients with wheat-dependent exercise-induced anaphylaxis had specific IgE Abs to these epitope peptides. None of the 25 sera from healthy subjects reacted to both epitope peptides. Twenty-five patients with atopic dermatitis who had specific IgE to wheat and/or gluten had very low or nonexistent levels of epitope peptide-specific IgE Abs. These results indicated that measurement of IgE levels specific to epitope peptides of ω-5 gliadin and HMW-glutenin is useful as an in vitro diagnostic method for the assessment of patients with wheat-dependent exercise-induced anaphylaxis.

Stratum corneum TARC level is a new indicator of lesional skin inflammation in atopic dermatitis.

To cite this article: Morita E, Takahashi H, Niihara H, Dekio I, Sumikawa Y, Murakami Y, Matsunaka H. Stratum corneum TARC level is a new indicator of lesional skin inflammation in atopic dermatitis. Allergy 2010; 65: 1166–1172.

Fluorescence navigation with indocyanine green for detecting sentinel nodes in extramammary Paget's disease and squamous cell carcinoma.

The radioisotope navigation method, which has usually been used for identification of sentinel nodes, is less useful in locating sentinel nodes close to primary lesions in cases of extramammary Pagets disease because of overlapping radioactivity from the primary site. We applied fluorescence navigation with indocyanine green (ICG) in two patients with skin cancer to cover this defect. The use of a charge‐coupled device camera enabled real‐time visualization of dynamic lymph flow without skin incision. The inguinal skin over the identified sentinel node with a handheld gamma probe was in accordance with the point detected by ICG fluorescence in a patient with squamous cell carcinoma of the foot. Sentinel node biopsy using fluorescence navigation with ICG proved to be easy and reliable.

HLA-A31 strongly associates with carbamazepine-induced adverse drug reactions but not with carbamazepine-induced lymphocyte proliferation in a Japanese population

Carbamazepine (CBZ) is the most frequent culprit drug for severe cutaneous adverse drug reactions (ADR), such as Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug‐induced hypersensitivity syndrome (DIHS). A strong association between human leukocyte antigen (HLA)‐B*1502 and CBZ‐induced SJS/TEN has been reported in Han Chinese, Thai, Malaysian and Indian populations, but not in Caucasian or Japanese populations. Recent studies showed an association between HLA‐A*3101 and CBZ‐induced ADR in Caucasian and Japanese populations. We conducted a case–control study to determine HLA genotyping of patients with CBZ‐induced ADR in a Japanese population. Fifteen patients with CBZ‐induced ADR and 33 subjects who had taken CBZ for more than 3 months without evidence of any ADR as a control were enrolled. In addition, the results of a CBZ‐induced lymphocyte stimulation test were compared between the groups. A strong association was found between HLA‐A31 and CBZ‐induced ADR (P < 0.001), and a weak association was found between HLA‐A11 and HLA‐B51 with CBZ‐induced ADR. No HLA‐B*1502 was found in either patients or control subjects. The mean CBZ‐induced lymphocyte stimulation index was significantly high in patients with CBZ‐induced ADR compared with CBZ‐tolerant patients (P < 0.001); however, no significant difference was seen between HLA‐A31‐positive subjects and HLA‐A31‐negative subjects in either group. These findings suggest that HLA‐A31 is strongly associated with CBZ‐induced ADR in the Japanese, but does not determine CBZ‐induced lymphocyte proliferation.

Serum Gliadin Monitoring Extracts Patients with False Negative Results in Challenge Tests for the Diagnosis of Wheat-Dependent Exercise-Induced Anaphylaxis*

BACKGROUND Challenge testing with wheat plus exercise and/or aspirin is a gold standard for the diagnosis of wheat-dependent exercise-induced anaphylaxis (WDEIA); however, the test may often yield false-negative results. Our previous study suggested that an increase in serum wheat gliadin levels is required to induce allergic symptoms in patients with WDEIA. Based on this knowledge, we sought to extract the patients with false negative results in the challenge tests of WDEIA. METHODS Thirty-six patients with suspected WDEIA were enrolled. First, group categorizations-Group I, challenge tests were positive; Group II, challenge tests were negative and serum gliadin were undetectable; Group III, challenge tests were negative and serum gliadin were detectable-were given according to the results of wheat plus exercise and/or aspirin challenge testing and serum gliadin levels. Second, diagnoses were made using retests and/or dietary management in Group II and III. RESULTS Positive results for wheat plus exercise and/or aspirin challenge tests gave a diagnosis of definite WDEIA in 17 of 36 patients (Group I). Of the remaining 19 challenge negative patients, serum gliadin was undetectable in ten patients (Group II). Of the ten patients (Group II), three of them were diagnosed as definite WDEIA by retesting and six of them were diagnosed as probable WDEIA using a wheat elimination diet, whereas one patient was non-WDEIA. In the rest of the nine challenge negative patients, serum gliadin was detectable (Group III). No allergic episodes with a normal diet provided a diagnosis of non-WDEIA in seven of the nine patients, whereas the remaining two patients were probable WDEIA or had another food allergy because of repeated episodes. CONCLUSIONS Our study revealed that serum gliadin monitoring during challenge testing is useful.

HLA-B*58:01 strongly associates with allopurinol-induced adverse drug reactions in a Japanese sample population.

[1] Kaplan DH, Barker J. Psoriasis. N Engl J Med 2009;361:496–509. [2] Sonnenberg GF, Fouser LA, Artis D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat ImmuHidehisa Saeki*, Tomomitsu Hirota, Hidemi Nakagawa, Yuichiro Tsunemi, Toyoaki Kato, Sayaka Shibata, Makoto Sugaya, Shinichi Sato, Satoru Doi, Akihiko Miyatake, Kouji Ebe, Emiko Noguchi, Tamotsu Ebihara, Masayuki Amagai, Hitokazu Esaki, Satoshi Takeuchi, Masutaka Furue, Yusuke Nakamura, Mayumi Tamari

Standing posture at work and overweight exacerbate varicose veins: Shimane CoHRE Study

Varicose veins (VV) in legs are commonly observed in the general global population. However, the prevalence of and risk factors for VV in Japan are not clear. This study aimed at clarifying the risk factors for VV in traditional rural areas of Shimane prefecture. Subjects (113 men and 205 women aged ≥45 years) were recruited from health examinations in those areas in 2012. VV were defined as a reflux of blood in the great and/or small saphenous vein and incompetent perforating veins detected by ultrasonography. Risk factors for VV were analyzed using logistic regression models that included various parameters. We also investigated the possible interaction between standing at work and overweight and calculated the synergistic index. VV were found in 20.1% of the subjects (12.4% of men and 24.4% of women). The previously known risk factors of prolonged upright standing posture during work, higher body mass index (BMI), female sex, and age were also significant factors for VV. There was a significant combined effect of overweight (BMI ≥25) and prolonged upright standing posture at work [adjusted odds ratio = 3.42; 95% confidence interval (CI), 1.07–10.89], although the synergistic effect was not significant [synergistic index = 1.3; 95% CI, 0.2–8.7]. The prevalence of VV in the traditional rural area of Shimane prefecture was comparable to that reported previously in European countries. Our results confirm that exposure to both prolonged standing at work and overweight exacerbate VV development. This finding is useful to develop strategies for VV prevention.

Simple and rapid detection of HLA-A*31:01 for prediction of carbamazepine-induced hypersensitivity using loop-mediated isothermal amplification method.

BACKGROUND Carbamazepine (CBZ), which is widely used in management of epilepsy or neuropathic pain, causes fatal severe cutaneous adverse reactions (SCARs). CBZ-induced SCARs are known to occur in strong association with human leukocyte antigen (HLA)-A*31:01 in Japanese and European populations. HLA genotyping is currently used to detect human HLA-A*31:01. OBJECTIVE To establish a simple and rapid screening assay specific for HLA-A*31:01, the loop-mediated isothermal amplification (LAMP) method was employed on a sample Japanese population. METHODS A set of LAMP primers targeting exon 2 of HLA-A*31:01 were designed. Thirty-two clinical samples including the representative HLA-A allele in Japan were used to assess the specificity of LAMP primers in the detection of HLA-A*31:01. RESULTS The HLA-A*31:01-specific LAMP assay showed consistency with polymerase chain reaction reverse sequence-specific oligonucleotide probe (PCR-rSSO) and polymerase chain reaction-sequence based typing (PCR-SBT) results. CONCLUSION High sensitivity and specificity of the HLA-A*31:01 LAMP assay was confirmed. Considering its convenience, the assay can be widely used to screen patients at high genetic risk of CBZ-induced SCARs.

Case of carbamazepine-induced hypersensitivity syndrome associated with human leukocyte antigen-A*3101

modulate the l-opioid receptor making it possible to change the sensorium of pruritus. Pregabalin shows faster treatment response than gabapentin and it does not bind to plasma protein, so has the advantage of use in patients with low plasma protein and hepatic failure. Our study has several limitations. First, this was an open-label uncontrolled study and the effect of pregabalin could be attributed to a placebo effect. Second, we used pregabalin in a fixed dose of 150 mg ⁄ day. It is known that pregabalin may be used in higher doses up to 300 mg ⁄ day within 1 week based on efficacy and tolerability. Third, pregabalin also works for underlying neuropathic pain and anxiety, and so it could affect these accompanying symptoms and may lead to an overall improvement.