Influence of pharmacogenomic polymorphisms on allopurinol-induced cutaneous adverse drug reactions in Thai patients.

BACKGROUND: Allopurinol has been causing substantial morbidity and mortality particularly in Asian population by producing cutaneous adverse drug reactions (cADRs). Nonetheless, there are no data describing whether other genetics are a valid marker for prediction of allopurinol-induced cADRs patients in addition to HLA-B*58:01 allele. The goal of this study was to identify suitable single nucleotide polymorphisms (SNPs) for allopurinol induced cADRs among Thai patients. METHODS: We conducted a case-control association study after enrolling 57 Thai patients with allopurinol induced cADRs and 101 allopurinol-tolerant controls. The genetic biomarkers and associated SNPs located on chromosome 6p21 were examined by TaqMan® SNP genotyping assays in both the cases and the controls. RESULTS: Out of fifteen SNPs in nine genes, we found four combined SNPs (rs3099844 of HCP5, rs9263726 of PSORS1C1, rs9263733 of POLR2LP, and rs9263745 of CCHCR1) were significantly associated with allopurinol-induced cADRs compared to the tolerant controls (OR 73.2; 95% CI 24.2-266.8; P = 1.9 × 10- 24). The overall sensitivity, specificity, positive predictive value and negative predictive value of these combinations were 84%, 94%, 9%, and 100%, respectively. However, the variant alleles of these SNP combinations were detected in 89.5% (51/57) of the cases. Moreover, the HLA-B*58:01 allele was observed in 86.0% of patients with allopurinol-induced cADRs, but only in 4.0% of tolerant controls (OR: 137.2; 95% CI: 38.3-670.5 and p-value = 1.7 × 10- 27). CONCLUSIONS: Thus, this research confirms the association between the specific HLA-B*58:01 allele and all phenotypes of allopurinol-induced cADRs in Thais. Furthermore, there was found the combined four SNPs (rs3099844, rs9263726, rs9263733, and rs9263745) could be used as alternative novel biomarkers for predicting cADRs in patients taking allopurinol.

IFN-γ ELISpot-enabled machine learning for culprit drug identification in nonimmediate drug hypersensitivity.

BACKGROUND: Diagnosing drug-induced allergy, especially nonimmediate phenotypes, is challenging. Incorrect classifications have unwanted consequences. OBJECTIVE: We sought to evaluate the diagnostic utility of IFN-γ ELISpot and clinical parameters in predicting drug-induced nonimmediate hypersensitivity using machine learning. METHODS: The study recruited 393 patients. A positive patch test or drug provocation test (DPT) was used to define positive drug hypersensitivity. Various clinical factors were considered in developing random forest (RF) and logistic regression (LR) models. Performances were compared against the IFN-γ ELISpot-only model. RESULTS: Among the 102 patients who had 164 DPTs, most patients had severe cutaneous adverse reactions (35/102, 34.3%) and maculopapular exanthems (33/102, 32.4%). Common suspected drugs were antituberculosis drugs (46/164, 28.1%) and ß-lactams (42/164, 25.6%). Mean (SD) age of patients with DPT was 52.7 (20.8) years. IFN-γ ELISpot, fixed drug eruption, Naranjo categories, and nonsteroidal anti-inflammatory drugs were the most important features in all developed models. The RF and LR models had higher discriminating abilities. An IFN-γ ELISpot cutoff value of 16.0 spot-forming cells/106 PBMCs achieved 94.8% specificity and 57.1% sensitivity. Depending on clinical needs, optimal cutoff values for RF and LR models can be chosen to achieve either high specificity (0.41 for 96.1% specificity and 0.52 for 97.4% specificity, respectively) or high sensitivity (0.26 for 78.6% sensitivity and 0.37 for 71.4% sensitivity, respectively). CONCLUSIONS: IFN-γ ELISpot assay was valuable in identifying culprit drugs, whether used individually or incorporated in a prediction model. Performances of RF and LR models were comparable. Additional test datasets with DPT would be helpful to validate the model further.

Skin manifestations and biophysical changes following weight reduction induced by bariatric surgery: A 2-year prospective study.

Skin manifestations and biophysical changes are observed in patients with morbid obesity. However, reports of changes after significant weight loss, particularly through post-bariatric surgery (BaS), are limited. The aim of this 2-year prospective study was to evaluate the prevalence of skin signs and their changes in patients with morbid obesity who underwent BaS. Thirty-one patients were recruited for the study, with a mean age of 38.35 (SD 10.61) years and a male preponderance (male = 19 [61.29%], female = 12 [38.71%]). Patients were scheduled for multiple visits at months 0, 3, 6, 12, 18, and 24 post-BaS. Each subject had a thorough skin examination, biophysical measurements, and laboratory tests at each visit. Striae, acanthosis nigricans (AN), and plantar hyperkeratosis were the most common skin findings (n = 30 [96.77%], 29 [93.55%], 29 [93.55%], respectively). BaS provided improvements in many skin manifestations, namely striae, AN, acrochordons, plantar hyperkeratosis, hirsutism, lymphedema, pruritus, acne, finger pebbles, and chronic venous insufficiency with varied cumulative rates of improvements. However, acute telogen effluvium was observed in 17 (54.84%) patients. Regarding skin biophysical properties, transepidermal water loss, skin hydration, and pH did not change, while sebum production on the face significantly decreased at months 3 and 6, and elasticity decreased at months 6 and 24. In conclusion, weight reduction by BaS provided improvements in various skin signs, although telogen effluvium was a common sequelae.

Correlations between histopathologic findings, serum biomarker levels, and clinical outcomes in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN).

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe dermatological emergencies. The role of cytokines and chemokines in the pathogenesis, progression of the disease, and histopathologic features is not fully elucidated. To address this gap, we conducted a retrospective study examining the associations between 42 serum biomarkers, histopathologic findings, and clinical outcomes in SJS/TEN patients. We reviewed the medical records of 23 patients diagnosed with SJS/TEN. Regarding histopathology, our study did not reveal any significant associations between the degree of epidermal necrosis, dermal mononuclear cell infiltration, and clinical outcomes. However, an intriguing observation was made regarding the degree of dermal infiltration of CD8 + cells, which showed a negative correlation with the severity of acute ocular complications. Notably, serum levels of IFN-γ positively correlated with the number of CD8 + cells in dermal infiltration. Additionally, higher serum levels of myeloperoxidase were associated with greater degrees of epidermal necrosis, while serum Fas ligand and stem cell factor levels were elevated in individuals with increased dermal mononuclear cell infiltration. Furthermore, the levels of S100A8/A9 were significantly correlated with the SCORTEN and mortality rate. These findings provide insights into the intricate pathogenesis of the disease.

Key factors predicting the in-hospital mortality of patients with severe cutaneous adverse reactions in Thailand.

BACKGROUND: At present, no predictive models are available to determine the probability of in-hospital mortality rates (HMRs) in all phenotypes of severe cutaneous adverse reactions (SCARs). OBJECTIVES: Our study explored whether simple clinical and laboratory assessments could help predict the HMRs in any phenotypes of SCAR patients. METHODS: Factors influencing HMRs in 195 adults diagnosed with different SCAR phenotypes were identified, and their optimal cut-offs were determined by Youden's index. Predictive equations for HMRs for all SCAR patients and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) patients were determined using the exact logistic regression models. RESULTS: Acute generalized exanthematous pustulosis (AGEP) patients were significantly older, with a short time from drug exposure to reaction, and higher neutrophil count compared to SJS/TEN and drug reaction with eosinophilia and systemic symptoms (DRESS, p < 0.001). Peripheral blood eosinophilia, atypical lymphocytosis and elevated liver transaminase enzymes were significantly higher in DRESS. SJS/TEN phenotype, age ≥ 71.5 years, neutrophil-to-lymphocyte ratio ≥ 4.08 (high NLR) and systemic infection were factors predicting in-hospital mortality in all SCAR subjects. The ALLSCAR model developed from these factors demonstrated high-diagnostic accuracy for predicting HMRs in all SCAR phenotypes (area under the receiver-operator curve (AUC) = 0.95). The risk of in-hospital death was significantly increased in SCAR patients with high NLR after adjusting for systemic infection. The model derived from high NLR, systemic infection and age yielded higher accuracy than SCORTEN (AUC = 0.77) for predicting the HMRs in SJS/TEN patients (AUC = 0.97). CONCLUSIONS: Being older, having systemic infection, having a high NLR and SJS/TEN phenotype increases ALLSCAR scores, which in turn increases the risk of in-hospital mortality. These basic clinical and laboratory parameters can easily be obtained in any hospital setting. Despite its simple approach, further validation of the model is warranted.

Exosomal microRNAs from PBMCs stimulated with culprit drugs enhanced keratinocyte cell death in Stevens-Johnson syndrome/toxic epidermal necrolysis.

BACKGROUND: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reactions with eosinophilia and systemic symptoms (DRESS) are both severe cutaneous adverse reactions. Keratinocyte death is much more prominent in SJS/TEN compared to DRESS. OBJECTIVE: This study aimed to investigate the role of exosomal miRNAs on keratinocyte death in SJS/TEN. METHODS: Peripheral blood mononuclear cells (PBMCs) from SJS/TEN and DRESS patients were stimulated with the culprit drugs. The exosomes released in cell supernatants were co-incubated with HaCaT cells to study the cytotoxic effects on keratinocytes. Exosomal miRNA sequencing analysis was performed to compare the expression patterns between SJS/TEN and DRESS subjects. HaCaT cells were then transfected with miRNA mimics and inhibitors to explore the functions of miRNAs on keratinocyte cell death. RESULTS: Cytotoxic effects of PBMC-derived exosomes on keratinocytes were demonstrated in SJS/TEN and could be neutralized with exosome inhibitors. Cytotoxic effects of PBMC-derived exosomes from SJS/TEN subjects were higher after incubating PBMCs with the culprit drugs than those incubating with irrelevant drugs and unstimulated controls. The sequencing data revealed differential expressions of 61 exosomal miRNAs between SJS/TEN and DRESS. Exosomal miR-4488 was upregulated while miR-486-5p, miR-96-5p and miR-132-3p were downregulated in SJS/TEN compared to DRESS as determined by quantitative real-time PCR. The increased percentage of apoptotic cells upon transfection of HaCat cells was 36.3% and 34.9% with miR-4488 mimic and miR-96-5p inhibitor, respectively. CONCLUSION: This study illustrated the regulatory functions of exosomal miRNAs in controlling keratinocyte death in SJS/TEN. Exosome inhibitors might have a therapeutic role in SJS/TEN.

Skin testing might have a diagnostic role in immune complex-mediated hypersensitivity reactions.

Clinical applications of skin testing are known to help diagnose IgE-mediated and T-cell-mediated delayed cutaneous reactions. By contrast, drug-induced immune complex-mediated vasculitis is primarily diagnosed based on medical history, clinical setting and laboratory evidence of immune-complex formation, as there are no proven methods to identify the suspect culprit. We report three cases of drug- or biologic-induced immune complex-mediated vasculitis, in which the culprit agents could be confirmed by a positive intradermal test with later reading (between 12 and 24 h after the test), with verification by immunohistochemical or immunofluorescent results. The findings of our study suggest that skin tests with a delayed reading could have a potential role in diagnosing some instances of immune complex-mediated hypersensitivity reactions.

Efficacy of antimalarial agents to prevent the progression of discoid lupus erythematosus to systemic lupus erythematosus: A retrospective cross-sectional study.

BACKGROUND: Discoid Lupus Erythematosus (DLE) patients have the potential to developing Systemic Lupus Erythematosus (SLE) at a later time. The prescription of antimalarial agents might be beneficial to prevent this progression but the validated data is still lacking. OBJECTIVE: Our study aimed to explore whether antimalarial agent could slow progression to SLE in DLE patients, adjusting for other potential confounders. METHODS: We retrospectively studied 65 patients who were diagnosed as DLE and attended the outpatient clinic at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between January 1, 2017 and December 31, 2020. We reviewed medical records including history of DLE, SLE signs and symptoms, laboratory findings and treatment options. RESULTS: Over a total of 458.73 person years (PY), 19 patients (29.23%) eventually progressed to SLE within approximately 1 year. Of these, 15 patients had widespread lesions whereas only 4 patients presented with localized form. The prescription of antimalarial drug was associated with delayed SLE progression in our cohort. Other parameters such as generalized form (IRR 6.243 (95% CI 1.450-26.872); P = 0.014), joint involvement (IRR 5.005 (95% CI 1.931-12.969); P = 0.001) and LE specific skin lesions (IRR 3.799 (95% CI 1.220-11.825); P = 0.021) were considered as strong risk factors in SLE development. CONCLUSIONS: Our study suggested that an antimalarial drug could postpone the SLE development in DLE patients.

Delayed urticaria after BNT162b2 booster vaccination at previous intradermal test site with severe acute respiratory syndrome-coronavirus-2 spike protein.

Urticaria is a common cutaneous adverse event from coronavirus disease 2019 vaccination. Previous studies hypothesized that excipients as polyethylene glycol in BNT162b2 vaccine and polysorbate in ChAdOx1 nCoV-19 vaccine are allergens. A 28-year-old woman had urticaria after a booster vaccination with BNT162b2 at the site of previous intradermal injection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) spike protein. This reaction emphasized that delayed urticaria may not be an allergic reaction to excipient but rather to the immunogen as such as SARS-CoV-2 spike protein.

Drug-Induced Severe Cutaneous Adverse Reactions: Insights Into Clinical Presentation, Immunopathogenesis, Diagnostic Methods, Treatment, and Pharmacogenomics.

SCARs are rare and life-threatening hypersensitivity reactions. In general, the increased duration of hospital stays and the associated cost burden are common issues, and in the worst-case scenario, they can result in mortality. SCARs are delayed T cell-mediated hypersensitivity reactions. Recovery can take from 2 weeks to many months after dechallenging the culprit drugs. Genetic polymorphism of the HLA genes may change the selection and presentation of antigens, allowing toxic drug metabolites to initiate immunological reactions. However, each SCARs has a different onset latency period, clinical features, or morphological pattern. This explains that, other than HLA mutations, other immuno-pathogenesis may be involved in drug-induced severe cutaneous reactions. This review will discuss the clinical morphology of various SCARs, various immune pathogenesis models, diagnostic criteria, treatments, the association of various drug-induced reactions and susceptible alleles in different populations, and the successful implementation of pharmacogenomics in Thailand for the prevention of SCARs.

Lupus band test for diagnostic evaluation in systemic lupus erythematosus.

BACKGROUND: The lupus band test (LBT) using a sample of clinically normal skin was proposed as a useful diagnostic test for systemic lupus erythematosus (SLE). It is mostly performed to help diagnosing SLE in patients with insufficient clinical and serological profiles. However, most published studies on its utility are outdated and the results remain controversial. OBJECTIVES: To determine the diagnostic performance of LBT on non-lesion sun-protected (NLSP) and sun-exposed (NLSE) skin for SLE. METHODS: Consecutively presenting patients with clinical and serological suspicion of SLE who had LBT performed on non-lesion skin during January 2012 to August 2021 were retrospectively studied. LBT performed on either NLSE or NLSP skin biopsies were all included. Laboratory characteristics, number, types and patterns of deposited immunoreactants and disease activity were also assessed. RESULTS: LBT was performed in 57 patients with suspected SLE. LBT was positive in 18/57, 9/28 and 6/21 patients in overall non-lesion, NLSE and NLSP, respectively. Of all patients, 23 patients were diagnosed with SLE and 34 patients with other diseases. Overall, the sensitivity and specificity of LBT on non-lesion skin was 56.5% and 88.2%, respectively. The ability of the test to discriminate between those with and without SLE, assessed by the area under the Receiver-Operating Characteristic curve, was 0.72 (0.61-0.84). The sensitivity and specificity of LBT on NLSE skin was 58.3% and 87.5% while those of NLSP skin, were 57.1% and 85.7%, respectively. We found no significant correlation between the positivity of LBT and overall disease activity. Types, number and pattern of deposited immunoreactants also showed no correlation with disease activity (all p > 0.05). CONCLUSIONS: Used as a diagnostic adjunct, non-lesion LBT is still of value for diagnosing SLE in inconclusive cases.

Red light emitting diode as an adjuvant treatment for epidermal growth factor receptor inhibitors-induced paronychia.

We evaluated the efficacy and safety of red light LED as an adjuvant treatment for epidermal growth factor receptor inhibitor-induced paronychia. Eight patients were recruited in this randomized, single-blinded controlled trial. They were randomized to receive red-light on one hand or foot 2-3 times/week for 6 weeks while the contralateral side served as controls. The standard treatments were continued. Erythema and lesion elevation observed by Anthera® 3D, severity and pain scores were obtained at weeks 0, 2, 4, 6, and 8. The red light group showed significantly lower erythema, severity, and pain scores at weeks 4, 6, and 8. The elevation was significantly lower in the red light group at every follow-up visit. No adverse events occurred. Red light therapy may be an option as adjunctive treatment for EGFRi-induced paronychia.

Role of antimicrobial peptides in atopic dermatitis.

Host defense peptides (HDPs) or antimicrobial peptides (AMPs) are short cationic amphipathic peptides of divergent sequences, which are part of the innate immune system and produced by various types of cells and tissues. The predominant role of HDPs is to respond to and protect humans against infection and inflammation. Common human HDPs include defensins, cathelicidin, psoriasin, dermcidin, and ribonucleases, but these peptides may be dysregulated in the skin of patients with atopic dermatitis (AD). Current evidence suggests that the antimicrobial properties and immunomodulatory effects of HDPs are involved in AD pathogenesis, making HDPs research a promising area for predicting disease severity and developing novel treatments for AD. In this review, we describe a potential role for human HDPs in the development, exacerbation, and progression of AD and propose their potential therapeutic benefits.

The Role of In Vitro Detection of Drug-Specific Mediator-Releasing Cells to Diagnose Different Phenotypes of Severe Cutaneous Adverse Reactions.

PROPOSE: The purpose of this study was to investigate panels of enzyme-linked immunospot assays (ELISpot) to detect drug-specific mediator releasing cells for confirming culprit drugs in severe cutaneous adverse reactions (SCARs). METHODS: Frequencies of drug-induced interleukin-22 (IL-22)-, interferon-gamma (IFN-γ)-, and granzyme-B (GrB)-releasing cells were measured by incubating peripheral blood mononuclear cells (PBMCs) from SCAR patients with the culprit drugs. Potential immunoadjuvants were supplemented to enhance drug-induced mediator responses. RESULTS: Twenty-seven patients, including 9 acute generalized exanthematous pustulosis (AGEP), 10 drug reactions with eosinophilia and systemic symptoms, and 8 Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) were recruited. The average frequencies of drug-induced IL-22-, IFN-γ-, and GrB-releasing cells were 35.5±16.3, 33.0±7.1, and 164.8±43.1 cells/million PBMCs, respectively. The sensitivity of combined IFN-γ/IL-22/GrB ELISpot was higher than that of IFN-γ ELISpot alone for culprit drug detection in all SCAR subjects (77.8% vs 51.9%, P < 0.01). The measurement of drug-induced IL-22- and IFN-γ releasing cells confirmed the culprit drugs in 77.8% of AGEP. The measurement of drug-induced IFN-γ- and GrB-releasing cells confirmed the culprit drugs in 62.5% of SJS/TEN. Alpha-galactosylceramide supplementation significantly increased the frequencies of drug-induced IFN-γ releasing cells. CONCLUSION: The measurement of drug-induced IFN-γ-releasing cells is the key for identifying culprit drugs. The additional measurement of drug-induced IL-22-releasing cells enhances ELISpot sensitivity to identify drug-induced AGEP, while the measurement of drug-induced GrB-releasing cells could have a role in SJS/TEN. ELISpot sensitivity might be improved by supplementary alpha-galactosylceramide. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02574988.

Clinical parameters and biological markers associated with acute severe ocular complications in Stevens-Johnson syndrome and toxic epidermal necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions with high mortality rates. Its sequelae, such as blindness, persist even after recovery. Patients with SJS/TEN should be accurately diagnosed and receive appropriate treatment as soon as possible. Therefore, identifying the factors for severity prediction is necessary. We aimed to clarify the clinical parameters and biological markers that can predict acute severe ocular complications (SOCs) in SJS/TEN. This retrospective cross-sectional study enrolled 47 patients with SJS/TEN who were divided into two groups according to ocular severity at acute onset: non-severe ocular complications group (n = 27) and severe ocular complications group (n = 20). Multivariate logistic regression analysis revealed that disease severity (body surface area detachment ≥ 10%) was a predictive factor for acute SOCs, and older age (≥ 60 years) was marginally significantly predictive of SOCs. Serum biomarker levels of S100A8/A9 and granulysin were marginally significant and tended to increase in the SOC group. Therefore, during the early acute stage, focusing on disease severity, patient age, and serum inflammatory biomarkers (S100A8/A9 and granulysin) might help predict SOC progression in patients with SJS/TEN who need prompt and aggressive ocular management to prevent severe ocular sequelae.

Spectrum of cutaneous adverse reactions to aromatic antiepileptic drugs and human leukocyte antigen genotypes in Thai patients and meta-analysis.

Aromatic antiepileptic drugs (AEDs)-induced cutaneous adverse drug reactions (cADRs) add up to the limited use of the AEDs in the treatment and prevention of seizures. Human leukocyte antigen-B (HLA-B) alleles have been linked to AEDs-induced cADRs. We investigated the association between cADRs (including Stevens-Johnson syndrome; SJS/toxic epidermal necrolysis; TEN, drug reaction with eosinophilia and systemic symptoms; DRESS, and Maculopapular eruption; MPE) caused by AEDs (phenytoin, carbamazepine, lamotrigine, phenobarbital and oxcarbazepine) and HLA-B alleles in Thai population. Through the case-control study, 166 patients with AEDs-induced cADRs, 426 AEDs-tolerant patients (AEDs-tolerant controls), and 470 healthy subjects (Thai population) were collected. The HLA genotypes were detected using the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. We also performed a meta-analysis with these data and other populations. The carrier rate of HLA-B*15:02 was significantly different between AEDs-induced cADRs group and AEDs-tolerant group (Odds ratio; OR 4.28, 95% Confidence interval; CI 2.64-6.95, p < 0.001), AEDs-induced cADRs group and Thai population (OR 2.15, 95%CI 1.41-3.29, p < 0.001). In meta-analysis showed the strong association HLA-B*15:02 with AEDs-induced cADRs (OR 4.77, 95%CI 1.79-12.73, p < 0.001). Furthermore, HLA-B*15:02 was associated with SJS/TEN induced by AEDs (OR 10.28, 95%CI 6.50-16.28, p < 0.001) Phenytoin (OR 4.12, 95%CI 1.77-9.59, p = 0.001) and carbamazepine (OR 137.69, 95%CI 50.97-371.98, p < 0.001). This study demonstrated that genetic association for AEDs-induced cADRs was phenotype-specific. A strong association between HLA-B*15:02 and AEDs-induced SJS/TEN was demonstrated with an OR of 10.79 (95%CI 5.50-21.16, p < 0.001) when compared with AEDs-tolerant group. On the other hand, the carrier rates of HLA-B*08:01, HLA-B*13:01, and HLA-B*56:02 were significantly higher in the DRESS group compared with the AEDs-tolerant group (p = 0.029, 0.007, and 0.017, respectively). The HLA-B*15:02 allele may represent a risk factor for AEDs-induced cADRs.