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Specific human leukocyte antigen (HLA) polymorphisms combined with certain drug administration strongly correlate with skin eruption. Abacavir hypersensitivity (AHS), which is strongly associated with HLA-B*57:01, is one of the most representative examples. Conventionally, HLA transmits immunological signals via interactions with T cell receptors on the cell surface. This study focused on HLA-mediated intracellular reactions in keratinocytes that might determine the onset of skin immunotoxicity by drug treatments. Abacavir exposure resulted in keratinocytes expressing HLA-B*57:01 exhibiting endoplasmic reticulum (ER) stress responses, such as immediate calcium release into the cytosol and enhanced HSP70 expression. In contrast, keratinocytes expressing HLA-B*57:03 (closely related to HLA-B*57:01) did not show these changes. This indicated that HLA-B*57:01 has a specific intracellular response to abacavir in keratinocytes in the absence of lymphocytes. Furthermore, abacavir exposure in HLA-B*57:01-expressing keratinocytes elevated the expression of cytokines/chemokines such as interferon-γ, interleukin-1β, and CCL27, and induced T lymphoblast migration. These effects were suppressed by ER stress relief using 4-phenylbutyrate (4-PB). HLA-B*57:01-transgenic mice also exhibited ER stress in epidermal areas following abacavir administration, and abacavir-induced skin toxicity was attenuated by the administration of 4-PB. Moreover, abacavir bound to HLA-B*57:01 within cells and its exposure led to HLA-B*57:01 protein aggregation and interaction with molecular chaperones in the ER of keratinocytes. Our results underscore the importance of HLA-mediated intracellular stress responses in understanding the onset of HLA-B*57:01-mediated AHS. We provide the possibility that the intracellular behavior of HLA is crucial for determining the onset of drug eruptions.

Several patients with cutaneous adverse drug reactions exhibit extracutaneous organ damages, and it becomes severe in a few patients resulting in death due to multiorgan failure. Understanding the sequential changes in various organs in patients with cutaneous eruption following drug administration will help understand disease onset and progression, aiding the development of prevention strategies and interventions. Therefore, we aimed to understand the effects of abacavir (ABC) on various organs in patients with ABC-induced eruptions by evaluating its effects in a mouse model. We found pathological changes in various organs of HLA-B*57:01 transgenic mice (B*57:01-Tg) following oral administration of ABC (20 mg/body/day). B*57:01-Tg exhibited a significant body weight decrease from day 1 of ABC administration, and reddening of the auricle was observed from day 5, and approximately 2/3 mice died by day 7. Histopathological examination revealed severe thymic atrophy after day 3, infiltration of inflammatory cells, predominantly lymphocytes with neutrophils, not only in the skin but also in the liver, kidney, and lung after day 5, and an increased number of lymphocytes with enlarged nuclei and granulocytic hematopoiesis were observed in the spleen after day 5. Blood chemistry revealed that albumin/globulin ratio was below 1.0 on day 5, reflecting a systemic inflammatory response, and the aspartate aminotransferase concentration rose to 193 ± 93.0 U/L on day 7, suggesting that cell damage may have occurred in various organs including liver accompanying inflammatory cell infiltration. These examinations of a mouse model of ABC-induced skin eruption show that disorders in various organs other than the skin should be considered and provide insights into the unexpected early systemic responses dependent on HLA-B*57:01.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s43188-023-00220-1.

Background. Fixed drug eruption and Rowell syndrome stand as intriguing entities with overlapping clinical and pathological features. Case Presentation. A 32-year-old female patient presented with a tender and pruritic rash on the left upper chest for 3 days. Clinical examination revealed a flaring rash on the chest, under her left eye, tongue, and lips. The patient had a significant past medical history of systemic lupus erythematous with positive (ANA, Sm, dsDNA, ribosomalP, RNP) antibodies, hypocomplementemia, inflammatory arthritis, discoid lupus, leukopenia, thrombocytopenia, and immune thrombocytopenic purpura, and avascular necrosis affecting both hips and her right knee. At the time of presentation, the patient was on azathioprine 150 mg daily and hydroxychloroquine 200 mg twice daily. Skin biopsy of the left upper chest revealed interface dermatitis with necrotic keratinocytes at the dermal-epidermal junction. Superficial and, in some areas, deep perivascular and peri adnexal lymphocytic infiltrates were observed, accompanied by eosinophils. CD123 staining highlighted 16% of the inflammatory cells. Direct Immunofluorescence for IgG, IgA, IgM, C3, and fibrinogen revealed positive linear basement membrane staining for IgG and fibrinogen, with no significant staining for the remaining immunoreactants. Considering the patient\'s history of medicine usage, and negative SS-A and SS-B antibody, a fixed drug eruption was favored. Discussion. This article discusses the clinical presentations, pathophysiological mechanisms, and diagnostic criteria for fixed drug eruption and Rowell syndrome. Conclusion. Awareness of the distinct clinical and histopathologic features of fixed drug eruption and Rowell syndrome, particularly when sharing cutaneous manifestations, underscores the importance of a comprehensive diagnostic approach and laboratory testing.

UNASSIGNED: Blood eosinophilia is often associated with various dermatoses, such as atopic eczema, urticaria, drug eruption, bullous pemphigoid, and hypereosinophilic syndrome (HES). Differential diagnosis is very challenging due to the similarities of clinical and pathological characteristics.
UNASSIGNED: To investigate and analyze the clinical characteristics of dermatoses associated with blood eosinophilia (DABE) to further optimize disease management.
UNASSIGNED: We conducted a retrospective analysis on 397 DABE patients with blood absolute eosinophil count (AEC) greater than or equal to 0.5×109/L. Clinical characteristics, laboratory values, treatment course, and associated diagnoses were evaluated. All DABE patients were grouped based on the severity of eosinophilia as mild group (0.5 ≤ AEC×109/L < 1.5), moderate group (1.5 ≤ AEC×109/L < 3), and severe group (AEC×109/L ≥ 3).
UNASSIGNED: Our study revealed three distinct patterns: (1) Mild eosinophilia associated with localized skin lesions, atopic history, mildly elevated total serum IgE level, diagnosed with eczema/dermatitis, and frequent antihistamines use. (2) Moderate eosinophilia has the characteristics of both mild group and severe group. (3) The severe eosinophilia group had a high proportion of elderly people without atopic history, but with acute onset, generalized skin lesions, and high level of lactate dehydrogenase, and the majority of them were diagnosed with systemic diseases (HES or tumor).
UNASSIGNED: We summarize the clinical rules of dermatoses associated with blood eosinophilia, hoping to facilitate the diagnosis and treatment for patients.

Graves\' disease (GD) and drug eruption are closely associated and frequently observed in the clinical setting. However, it remains unclear whether a causal relationship exists between these two conditions. The aim of the study is to investigate whether GD is causal to drug eruptions using two-sample Mendelian randomization.
We launched a two-sample MR to investigate whether GD is causal to drug eruption using Genome-wide association study (GWAS) summary data from Biobank Japan and FinnGen. Genetic variants were used as instrumental variables to avoid confounding bias. Statistical methods including inverse variance weighted (IVW), weighted median, MR-Egger, and MR-PRESSO were conducted to identify the robustness of the causal effect.
Genetically predicted GD may increase the risk of drug eruption by 30.3% (OR=1.303, 95% CI 1.119-1.516, p<0.001) in the Asian population. In European populations, GD may increase the generalized drug eruption by 15.9% (OR=1.159, 95%CI 0.982-1.367, p=0.080).
We found GD is potentially causal to drug eruption. This finding expanded the view of the frequently observed co-existence of GD and adverse drug reactions involving the skin. The mechanism remains for further investigation.

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Apalutamide is an antiandrogen used to treat prostate cancer. Although it sometimes induces mild cutaneous adverse events and occasionally severe ones, clinical differences between severe and mild cases remain unclear. To assess the risks in patients experiencing apalutamide-related cutaneous adverse events (ARCAEs), we aimed to characterize severe and mild ARCAEs in terms of onset time and lymphocyte transformation test (LTT) for apalutamide. We reviewed 41 ARCAE cases: 24 from our institute and 17 from the literature, comprising (i) eight severe cases including six with toxic epidermal necrolysis, one with acute generalized exanthematous pustulosis, and one with drug reaction with eosinophilia and systemic symptoms, and (ii) 33 mild cases. Patients with evere cases developed ARCAEs significantly earlier than patients with mild cases (5.2 vs 9.6 weeks). No severe cases appeared ≥8 weeks after initiation of apalutamide. LTTs showed positive results in two of seven mild cases (28.6%) and four of four severe cases (100.0%). In conclusion, we found that severe ARCAEs are characterized by earlier onset and LTT positivity. Dermatologists and urologists should pay special attention to patients who develop ARCAEs <8 weeks after initiating apalutamide and/or show positive LTT results.

Stevens-Johnson syndrome is a type of severe drug eruption, which is characterized by rapid onset and rapid progress. If not treated in time, it can develop into toxic epidermal necrolysis, even life-threatening. Common sensitizing drugs include sulfa, carbamazepine, etc. In China, reports and studies of carbamazepine causing Stevens-Johnson syndrome mainly focus on the HLA-B * 1502 gene, and there are no reports of HLA-A * 3101 gene positive. We reported a patient who got Stevens-Johnson syndrome with HLA-A * 3101 gene positive caused by carbamazepine. She took carbamazepine for trigeminal neuralgia and had never taken the drug before. After 2 weeks, papules and edematous target-like erythema gradually appeared on the trunk and limbs, surface blisters and scabs, and the oral, eyes, and vulvar mucosa appeared erosion, accompanied by fever and pain, with an area of about 3% exfoliation. She was diagnosed with Stevens-Johnson syndrome and admitted to Peking University Third Hospital on March 24, 2020. After admission, in order to identify the sensitizing drugs, We performed a genetic test on her for carbamazepine-related drugs. The results showed that the HLA-A * 3101 gene was positive, and the HLA-B * 1502 and HLA-B * 5801 genes were negative. In terms of treatment, the patient was systematically given a single intravenous infusion of 300 mg of infliximab, and symptomatic treatment and care of the oral, eye, and vulvar mucosa. After 6 days, the rash on the trunk and limbs subsided, and the mucosa returned to normal and was discharged from the hospital. Retrieving domestic and foreign literature, it is not uncommon to report that carbamazepine causes drug eruption, including severe drug eruption, and there are obvious ethnic differences in the pathogenicity of HLA genotyping. In China and Asia, stu-dies on carbamazepine causing Stevens-Johnson syndrome emphasized that the adverse reactions were strongly related to the HLA-B * 1502 gene. However, there is a strong correlation with HLA-A * 3101 gene in people suffering from the disease in Europe and Japan. In this case report, the HLA-B * 1502 gene was negative and the HLA-A * 3101 gene was positive. This is the first domestic report that carba-mazepine causes HLA-A * 3101 positive for Stevens-Johnson syndrome. This report reminds that HLA-A * 3101 gene testing should be taken seriously besides HLA-B * 1502 gene.

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