Current Understanding of Immunological Skin Diseases: Atopic Dermatitis, Generalized Anhidrosis, and Drug Hypersensitivity.

Recent dermatological research has progressed, particularly novel technologies and analytical methodologies, providing great advances in the exploration of previously poorly understood interactions between the skin-the outermost surface of humans-and the external environment [...].

Clinical characteristics of itch in cutaneous lupus erythematosus: A prospective, multicenter, multinational, cross-sectional study.

OBJECTIVE: Pruritus is an important symptom frequently accompanying various inflammatory skin conditions and some recent data indicated that it may be associated with autoimmune connective tissue diseases. The aim of this study was to assess the frequency and clinical presentation of itch in CLE. METHODS: A multinational, prospective, cross-sectional study was performed to assess the prevalence, intensity and clinical characteristic of pruritus in various subtypes of CLE. A total of 153 patients with active CLE lesions were included. Their age ranged between 17 and 82 years (mean 49.8 ± 15.4 years), and 115 patients (75.2%) were women. The disease activity and damage were assessed according to the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Pruritus severity was assessed with Numeric Rating Scale (NRS) and the 12-Item Pruritus Severity Scale. Dermatology Life Quality Index and EQ-5D questionnaire were used to measure quality of life. RESULTS: Pruritus was present in 116 (76.8%) of patients of whom half had NRS scoring equal or above 4 points indicating moderate or severe pruritus. Most commonly itch was localized on the scalp, face (excluding ears and nose) and arms (40.5%, 36.2%, 31.9%, respectively). Sensations connected with pruritus were most frequently described as burning, tingling and like ants crawling feeling, but 31.9% patients described it as "pure itch". More than half of patients reported that pruritus was present every day, and it was most frequent during the evenings. The pruritus scoring and the CLASI activity score were significantly correlated (r = 0.42, p = 0.0001), while no correlation was found with the CLASI damage score (p = 0.16). Both the maximum and average itch intensity were correlated with systemic lupus erythematosus (SLE) activity measured with the Systemic Lupus Erythematosus Disease Activity Index. CONCLUSIONS: Pruritus is a common, but frequently overlooked symptom of CLE. Its intensity correlates with the activity of CLE, but not with the skin damage. In more than a half of patients it occurs on a daily basis. The correlation between the intensity of pruritus and the activity of the skin lesions and the systemic involvement indicate that pruritus could be an individual indicator of both SLE and CLE activity.

HLA-DQ and RBFOX1 as susceptibility genes for an outbreak of hydrolyzed wheat allergy.

BACKGROUND: Food allergy is a growing health problem worldwide because of its increasing prevalence, life-threatening potential, and shortage of effective preventive treatments. In an outbreak of wheat allergy in Japan, thousands of patients had allergic reactions to wheat after using soap containing hydrolyzed wheat protein (HWP). OBJECTIVES: The aim of the present study was to investigate genetic variation that can contribute to susceptibility to HWP allergy. METHODS: We conducted a genome-wide association study of HWP allergy in 452 cases and 2700 control subjects using 6.6 million genotyped or imputed single nucleotide polymorphisms. Replication was assessed by genotyping single nucleotide polymorphisms in independent samples comprising 45 patients with HWP allergy and 326 control subjects. RESULTS: Through the genome-wide association study, we identified significant associations with the class II HLA region on 6p21 (P = 2.16 × 10-24 for rs9271588 and P = 2.96 × 10-24 for HLA-DQα1 amino acid position 34) and with the RBFOX1 locus at 16p13 (rs74575857, P = 8.4 × 10-9). The associations were also confirmed in the replication data set. Both amino acid polymorphisms (HLA-DQß1 amino acid positions 13 and 26) located in the P4 binding pockets on the HLA-DQ molecule achieved the genome-wide significance level (P < 5.0 × 10-8). CONCLUSIONS: Our data provide the first demonstration of genetic risk for HWP allergy and show that this genetic risk is mainly represented by multiple combinations of HLA variants.

Repeated Amblyomma testudinarium tick bites are associated with increased galactose-α-1,3-galactose carbohydrate IgE antibody levels: A retrospective cohort study in a single institution.

BACKGROUND: Alpha-gal syndrome is a hypersensitivity reaction to red meat mediated by IgE antibody specific to galactose-α-1,3-galactose carbohydrate (alpha-gal). Amblyomma tick bites are associated with this condition, but the pathophysiology is not understood. OBJECTIVE: To clarify the mechanism of development of alpha-gal syndrome after tick bites. METHODS: We compared alpha-gal antibody levels between patients with and without a history of tick bites and examined histologic stainings of tick bite lesions between patients with and without detectable alpha-gal IgE antibody. RESULTS: Patients who had ≥2 tick bites had higher levels of alpha-gal IgE antibody compared with those with only 1 tick bite or healthy individuals. On histologic investigation, greater numbers of basophils and eosinophils, but not mast cells, were observed infiltrating lesions of patients with ≥2 tick bites compared with those with 1 tick bite. Type 2 cytokine-producing T-cell infiltration was predominantly observed in such patients. LIMITATIONS: The study was conducted at a single institution in Japan. CONCLUSION: In Amblyomma tick bite lesions, basophils; eosinophils; and type 2, cytokine-producing T cells infiltrate the skin and alpha-gal IgE antibodies are produced. These findings provide a potential mechanistic connection between Amblyomma bites and red meat hypersensitivity.

Topical application of a vitamin D3 analogue and corticosteroid to psoriasis plaques decreases skin infiltration of TH17 cells and their ex vivo expansion.

BACKGROUND: Topical combination of a vitamin D3 analogue and corticosteroid is widely used for the treatment of psoriasis, a TH17-mediated disorder, but the underlying mechanism remains unclear. OBJECTIVE: We investigated the effect of this topical applicant, focusing on skin-infiltrating TH17 cells. METHODS: In 10 patients with plaque psoriasis, calcipotriol (Cal), betamethasone dipropionate (Bet), or the calcipotriol and betamethasone dipropionate 2-compound formulation (CB) was applied to 3 different psoriatic plaques with similar severity once a day for 14 days. One nonapplied lesion was used as a control. Four-millimeter biopsy specimens were taken from each site, cut into 2 pieces, and subjected to histologic examination and ex vivo expansion of skin-infiltrating T cells with anti-CD3/CD28 antibodies and IL-2. RESULTS: Clinical, histologic, and IL-17A(+) cell-infiltrate improvement was found in the following order: CB > Cal > Bet > control or CB > Bet > Cal > control. Numbers of ex vivo expanded T cells were decreased by topical application of Bet and CB, and CB exhibited the most suppressive result. Numbers and frequencies of TH17 cells were significantly reduced by CB and Cal, suggesting that Cal has a capacity to preferentially suppress TH17 cells. When the stocked T cells from control samples were stimulated with anti-CD3 antibodies in the presence of Bet, Cal, or both, Cal downmodulated IL-17 and IFN-γ production and tended to upregulate IL-4 and IL-6 without apoptosis, but Bet inhibited production of these cytokines with apoptosis. CONCLUSION: These findings suggest that Cal and Bet have different effects on T cells to normalize psoriatic changes, with decreased TH17 cell expansion in the skin lesions.

Structural changes of layered alkylsiloxanes during the reversible melting-solidification process.

Through various in situ analyses, we have revealed the structural changes that occur during the reversible melting-solidification process of layered alkylsiloxanes (CnLSiloxanes) with carbon numbers (n) of 18 and 16. In situ high-resolution solid-state (13)C nuclear magnetic resonance (NMR) analysis at controlled temperatures indicates drastic conformational changes of the long alkyl chains during the melting-solidification process. A (13)C NMR signal at 33 ppm, which shows the highest intensity at room temperature (RT), is assigned to an inner methylene group with an all-trans conformation. As the temperature increases, the 33-ppm signal intensity decreases while the signal intensity at 30.5 ppm simultaneously increases. The 30.5 ppm signal is assigned to an inner methylene group with a trans-gauche conformation. Subsequently, upon cooling, the signal at 33 ppm recovers, even after CnLSiloxanes have melted. In situ X-ray diffraction measurements at controlled temperatures reveal that the ordered arrangement of the long alkyl chains becomes disordered with elevating temperatures and reordered upon cooling to RT. In situ high-resolution solid-state (29)Si NMR analysis shows that the melting-solidification process progresses without any structural change in siloxane sheets of the CnLSiloxanes. Thus, the in situ analyses show that disordering of the long alkyl chains causes the CnLSiloxanes to melt. Because the majority of long alkyl chains are packed again in the ordered arrangement with the all-trans conformation upon cooling, the CnLSiloxanes are reversibly solidified and the CnLSiloxane structure is recovered.

Adsorption of amino acids by fullerenes and fullerene nanowhiskers.

We have investigated the adsorption of some amino acids and an oligopeptide by fullerene (C60) and fullerene nanowhiskers (FNWs). C60 and FNWs hardly adsorbed amino acids. Most of the amino acids used have a hydrophobic side chain. Ala and Val, with an alkyl chain, were not adsorbed by the C60 or FNWs. Trp, Phe and Pro, with a cyclic structure, were not adsorbed by them either. The aromatic group of C60 did not interact with the side chain. The carboxyl or amino group, with the frame structure of an amino acid, has a positive or negative charge in solution. It is likely that the C60 and FNWs would not prefer the charged carboxyl or amino group. Tri-Ala was adsorbed slightly by the C60 and FNWs. The carboxyl or amino group is not close to the center of the methyl group of Tri-Ala. One of the methyl groups in Tri-Ala would interact with the aromatic structure of the C60 and FNWs. We compared our results with the theoretical interaction of 20 bio-amino acids with C60. The theoretical simulations showed the bonding distance between C60 and an amino acid and the dissociation energy. The dissociation energy was shown to increase in the order, Val < Phe < Pro < Asp < Ala < Trp < Tyr < Arg < Leu. However, the simulation was not consistent with our experimental results. The adsorption of albumin (a protein) by C60 showed the effect on the side chains of Try and Trp. The structure of albumin was changed a little by C60. In our study Try and Tyr were hardly adsorbed by C60 and FNWs. These amino acids did not show a different adsorption behavior compared with other amino acids. The adsorptive behavior of mono-amino acids might be different from that of polypeptides.

Improvement of the Ocular Prognosis of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A National Survey in Japan.

PURPOSE: To investigate the incidence and prognostic factors of ocular sequelae in Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) cases arising between 2016 and 2018 in Japan, and compare the findings with those presented in the previous 2005-2007 survey. DESIGN: Retrospective, national trend survey. METHODS: Dermatologic case report forms (CRFs) (d-CRFs) were sent to 257 institutions that treated at least 1 SJS/TEN case, and 508 CRFs were collected from 160 institutions. Ophthalmologic CRFs (o-CRFs) regarding patient demographic data, onset date, ocular findings (first appearance, day of worst severity, and final follow-up), topical treatment (betamethasone), outcome (survival or death), and ocular sequelae (visual disturbance, eye dryness) were sent to the ophthalmologists in those 160 institutions. The results of this survey were then compared with that of the previous 2005-2007 survey. RESULTS: A total of 240 cases (SJS/TEN: 132/108) were included. The incidence of ocular sequelae incidence was 14.0%, a significant decrease from the 39.2% in the previous survey (SJS/TEN: 87/48). In 197 (82.1%) of the cases, systemic treatment was initiated within 3 days after admission, an increase compared to the previous survey (ie, treatment initiated in 82 [60.7%] of 135 cases). Of the 85 cases with an Acute Ocular Severity Score of 2 and 3, 62 (72.9%) received corticosteroid pulse therapy and 73 (85.9%) received 0.1% betamethasone therapy; an increase compared to the 60.0% and 70.8%, respectively, in the previous survey. Ocular-sequelae-associated risk factors included Acute Ocular Severity Score (P < .001) and specific year in the survey (P < .001). CONCLUSIONS: The ophthalmologic prognosis of SJS/TEN has dramatically improved via early diagnosis, rapid assessment of acute ocular severity, and early treatment.

Detection and visualization of intracutaneous allergic type-specific elements using long-wavelength near-infrared hyperspectral imaging.

BACKGROUND/PURPOSE: This study aimed to develop a method for the assessment of allergic dermatitis by using the long-wavelength near-infrared spectrum (more than 1000 nm) to detect intracutaneous allergic type-specific elements. Such a method was realized by establishing a spectral classifier for the spectra of type I and type IV allergic dermatitis reactions. METHODS: Near-infrared spectral images of histamine-induced cutaneous reaction (type I) and contact hypersensitivity erythema elicited by squaric acid dibutylester (SADBE; type IV) were obtained, and the absorption spectra of normal and inflamed skin were extracted from these spectral images. A spectral classifier was established from these training datasets, and it was then applied to two test cases, red flare by methyl nicotinate (normal) and metal allergy (type IV). RESULTS: The spectral classifier established by canonical discriminant analysis (CDA) achieved very accurate detection (normal: 87.67%, type I: 87.00%, type IV: 98.5%). Furthermore, the test cases were also correctly classified: the red flare induced by methyl nicotinate was categorized as normal skin and the metal allergy was categorized as a type IV allergic reaction. CONCLUSIONS: These results suggest a possible application of near-infrared spectral imaging to the assessment of allergic dermatitis.

Hydrochlorothiazide increases risk of nonmelanoma skin cancer in an elderly Japanese cohort with hypertension: The Shizuoka study.

Background: Hydrochlorothiazide (HCT), a widely used hypertensive drug, has photocarcinogenic potential, leading to concerns about the development of nonmelanoma skin cancers (SCs) after intake. Despite substantial numbers of observational studies, the results remain inconsistent especially among Asian countries. Objective: To assess the incidence of nonmelanoma SCs in hypertensive Japanese HCT users compared with nonusers. Methods: A population-based, cohort nested, propensity score-matched study was conducted using the Shizuoka Kokuho database. All participants were patients aged ≥60 years. Hazard ratios for SC incidence were calculated in the matched cohorts using the propensity scores of potential confounders, sex, age category, comorbidities, and administration of methotrexate, cyclosporin, and statins. Results: The risk of SC was higher in HCT users than in nonusers (hazard ratio, 1.58; 95% confidence interval, 1.04-2.40), with preferential sun-exposed location and a tendency to develop squamous cell carcinoma, but not basal cell carcinoma or Bowen disease. Limitations: No additional information was available from other than medical records. The data were confined to a Japanese population. Conclusion: HCT use increases the risk of SC in Japanese patients with hypertension and a dark skin type, highlighting the increased risk of SC among HCT users in the aging society worldwide.

Risk factors and drugs that trigger the onset of Stevens-Johnson syndrome and toxic epidermal necrolysis: A population-based cohort study using the Shizuoka Kokuho database.

Background: Evidence of factors associated with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) from population-based studies is scarce. Objective: We aimed to identify the incidence, risk factors, and drugs that trigger the development of SJS/TEN in the general population. Methods: A regional, population-based, longitudinal cohort with 2,398,393 Japanese individuals was analyzed using the Shizuoka Kokuho Database from 2012 to 2020. Results: Among 1,909,570 individuals, 223 (0.01%, 2.3 cases/100,000 person-years) patients were diagnosed with SJS/TEN during the observational period of a maximum of 7.5 years. In a multivariable analysis, the risks of SJS/TEN were an older age, and the presence of type 2 diabetes, peripheral vascular disease, and systemic autoimmune diseases. The administration of drugs, such as immune checkpoint inhibitors, insulin, and type 2 diabetes agents, triggered the onset of SJS/TEN. Limitations: The results may apply only to the Japanese population. Conclusion: In this cohort population from a database representing the general population, the risks of developing SJS/TEN were old age and a history of type 2 diabetes, peripheral vascular disease, and systemic autoimmune disease. Furthermore, in addition to previously reported drugs, the administration of immune checkpoint inhibitors, insulin, and type 2 diabetes agents, may trigger the development of SJS/TEN.

Development and Validation of a Novel Score to Predict Mortality in Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: CRISTEN.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening, severe mucocutaneous adverse reactions. Severity prediction at early onset is urgently required for treatment. However, previous prediction scores have been based on data of blood tests. OBJECTIVE: This study aimed to present a novel score that predicts mortality in patients with SJS/TEN in the early stages based on only clinical information. METHODS: We retrospectively evaluated 382 patients with SJS/TEN in a development study. A clinical risk score for TEN (CRISTEN) was created according to the association of potential risk factors with death. We calculated the sum of these risk factors using CRISTEN, and this was validated in a multinational survey of 416 patients and was compared with previous scoring systems. RESULTS: The significant risk factors for death in SJS/TEN comprised 10 items, including patients' age of ≥65 years, ≥10% body surface area involvement, the use of antibiotics as culprit drugs, the use of systemic corticosteroid therapy before the onset, and mucosal damage affecting the ocular, buccal, and genital mucosa. Renal impairment, diabetes, cardiovascular disease, malignant neoplasm, and bacterial infection were included as underlying diseases. The CRISTEN model showed good discrimination (area under the curve [AUC] = 0.884) and calibration. In the validation study, the AUC was 0.827, which was statistically comparable to those of previous systems. CONCLUSION: A scoring system based on only clinical information was developed to predict mortality in SJS/TEN and was validated in an independent multinational study. CRISTEN may predict individual survival probabilities and direct the management and therapy of patients with SJS/TEN.

Is steroid pulse therapy a suitable treatment for drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms? A systematic review of case reports in patients treated with corticosteroids in Japan.

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms is a life-threatening severe cutaneous adverse reaction, characterized by multiple organ involvement and reactivation of herpes viruses. Although the mainstay of treatment is a high dosage of corticosteroids delivered by pulse therapy or conventional oral administration, it remains debatable which mode is better. To clarify this issue, we reviewed publications in Japan of 299 cases of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms treated with corticosteroids, to evaluate safety concerns with regards to these two modes of treatment. As a result, we found that patients treated with pulse therapy more frequently suffered cytomegalovirus reactivation, persistency, and high mortality but less frequently experienced herpesvirus 6 reactivation or type 1 diabetes compared with those undergoing conventional treatment, suggesting that the administration mode may differentially modulate inflammatory responses toward distinct consequences. This is the first statistical analysis revealing that steroid pulse therapy frequently resulted in severe sequelae with high mortality. In terms of the risk of serious consequences, we consider that steroid pulse therapy should be eschewed for the treatment of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms.

Immunoglobulin A vasculitis post-severe acute respiratory syndrome coronavirus 2 vaccination and review of reported cases.

Immunoglobulin (Ig)A vasculitis/nephropathy is a systemic immune complex-mediated vasculitis. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is widely recommended in individuals without specific allergy to the vaccine components, it is arguable whether vaccination is advisable for patients with IgA vasculitis or for predisposed individuals. We and others have presented cases of IgA vasculitis occurring after SARS-CoV-2 vaccination. In total, these 19 cases, including ours, involved predominantly female patients, and half of them were suffering from de novo vasculitis onset. The most frequent manifestation was gross hematuria (89.5%) while skin lesions were relatively infrequent, occurring in only five cases (26.3%), of which three (15.8%) were confirmed to be IgA vasculitis. Taken together, these cases suggest that SARS-CoV-2 vaccination might be a trigger for development/deterioration of IgA vasculitis/nephropathy.

A new susceptibility index to predict the risk of severe herpes zoster-associated pain: A Japanese regional population-based cohort study, the Shizuoka study.

BACKGROUND: Approximately 7-20% of patients with herpes zoster (HZ) develop zoster-associated pain (ZAP). ZAP not only impairs quality of life and psychological well-being, but also can reduce work effectiveness, which has negative economic effects. Reports of ZAP risk factors are inconsistent. OBJECTIVE: To confirm risk factors for the development of severe ZAP in HZ patients in Japan using a large-scale database, the Shizuoka Kokuho Database. METHODS: A population-based cohort study using the Shizuoka Kokuho Database was conducted. Of 792,647 patients, 7491 (0.95%) experienced "severe ZAP" (as defined in this study). We developed a ZAP risk prediction scoring system by identifying risk factors using logistic regression analysis of several candidate risk factors for severe ZAP: age, sex, seasonality, and presence of comorbidities (using the Charlson comorbidity index), excluding HIV/AIDS. RESULTS: We identified peripheral vascular disease and the onset from October to December as novel risk factors for severe ZAP, in addition to the previously reported risk factors of age and comorbidities (cerebral vascular disease, chronic pulmonary disease, rheumatic disease, peptic ulcer, liver disease, diabetes, and malignant neoplasms with/without metastasis). In contrast, dementia was found to reduce ZAP risk. We developed a susceptibility index to predict the risk of ZAP. CONCLUSION: We newly demonstrated that peripheral vascular disease and the onset from October to December are ZAP risk factors. Our comorbidity findings support previous observations. The susceptibility index proposed here provides a new approach to the prevention of ZAP using early intervention for high-risk patients.

Risk factors for sepsis and effects of pretreatment with systemic steroid therapy for underlying condition in SJS/TEN patients: Results of a nationwide cross-sectional survey in 489 Japanese patients.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse reactions (SCARs). Sepsis has been shown to be the main cause of death in SJS/TEN. The European SCAR study reported that 14.8 % of SJS/TEN patients were receiving systemic steroid therapy for their underlying condition prior to onset. However, it remained unclear whether this factor affected the mortality rate. OBJECTIVE: This study was performed to identify risk factors for sepsis in SJS/TEN patients. In addition, we compared patients who had and had not received systemic steroid therapy for their underlying condition. METHODS: A primary survey regarding the numbers of SJS/TEN patients between 2016 and 2018 was sent to 1205 institutions in Japan. A secondary survey seeking more detailed information was sent to institutions reporting SJS/TEN patients. We analyzed 315 SJS patients and 174 TEN patients using a logistic regression model, Wilcoxon's rank-sum test, χ2 test, and Fisher's exact test. RESULTS: Significant risk factors for sepsis included TEN, diabetes, and intensive care unit (ICU) admission. The mortality rate was significantly higher among patients with sepsis. Patients who had received systemic steroid therapy had a lower incidence of fever, and showed a higher mortality rate. CONCLUSION: Based on a nationwide epidemiological survey of SJS/TEN in Japan, we identified risk factors for sepsis and found that patients who had received steroid therapy for their underlying condition had a lower incidence of fever and a higher mortality rate.

Quinolone immediate hypersensitivity due to topical ophthalmic preparations: a case report and review of literature.

Ophthalmic quinolone preparations are widely used for the treatment of eye diseases; however, there are only a few reported cases of immediate hypersensitivity due to such medications. Here, we present a case of immediate hypersensitivity induced by an ophthalmic administration of quinolones in a 20-year-old female with bacterial conjunctivitis. The results of skin prick and basophil activation tests suggest that it involved a type Ib reaction associated with Mas-related G-protein coupled receptor X2. The present case cautions us to be aware of quinolone immediate hypersensitivity caused by topical ophthalmic preparations, which can easily be overlooked, because it may predict severe hypersensitivity reactions to systemic administration.