Jettanong Klaewsongkram

Objective In addition to the Human Leukocyte Antigen B*58:01(HLA-B*58:01), several non-genetic factors have been associated with allopurinol hypersensitivity syndrome, particularly severe cutaneous adverse drug reactions (SCAR), which are clinically serious. However, the magnitude of the impact of these non-genetic factors on the development of SCAR remains unclear. This study aimed to develop a non-genetic risk prediction model for predicting allopurinol-induced SCAR. Methods This retrospective observational study was performed during the same time period. SCAR cases were collected from tertiary care hospital centers, while the non-SCAR cases were collected from primary and tertiary care hospital centers. Non-genetic factors including sex, age, renal function, concomitant use of diuretics, starting dose of allopurinol, and serum urate (SU) were used for the development of the prediction models. Results Of the 23,294 cases, 209 were SCAR and 23,085 were non-SCAR cases. Three risk stratification models were developed. Models 1A and 1B were applied for patients who did not have and had SU level at the time of starting allopurinol, respectively. Model 2 was applied for patients who had all non-genetic risk factors, started allopurinol within 60 days, but had not yet developed SCAR. The area under the receiver operating characteristic curve for Models 1A, 1B, and 2 was 0.73 (95% CI 0.68–0.77), 0.81 (95% CI 0.75–0.87), and 0.83 (95% CI 0.80–0.86), respectively, indicating good discriminative performance. Conclusions The developed non-genetic prediction model demonstrated good discriminative performance. This prediction score could assist physicians’ decisions in prescribing allopurinol in the areas where HLA-B*58:01 is limited or unavailable. External validation in future studies is warranted. Key Points • A non-genetic risk prediction model for allopurinol-induced Severe Cutaneous Adverse Drug Reactions, NoG-ASCAR Score, is simple to access and apply in real clinical practice. • The performance of the area under the receiver operating characteristic curve for predicting SCAR of each model was good and had an impact on clinical utility. • It could provide confidence to physicians in prescribing allopurinol in the situation where HLA-B*58:01 assessment is limited or unavailable. • The NoG-ASCAR Score should be considered by policymakers when conducting cost-effectiveness analysis prior to recommending routine HLA-B*58:01 testing before allopurinol initiation.

Introduction: Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) are severe cutaneous adverse drug reactions (SCARs) with high morbidity and mortality. Accurate identification of the culprit drug is critical and remains challenging, whereas current in vitro tests such as lymphocyte transformation test (LTT) have limited sensitivity. To evaluate measuring granulysin (Gr) and granzyme B (GZB) secretion from drug‐stimulated peripheral blood mononuclear cells (PBMCs) for identification of culprit drugs and to compare their diagnostic performance with conventional LTT. Materials and Methods: PBMCs from 12 patients with confirmed SJS/TEN were incubated with suspected drugs. LTT and Gr/GZB detection assays were performed on day 3 and 6. Levels of Gr and GZB were quantified from supernatants, and results were normalized as production ratios. Cut‐off values were defined using receiver operating characteristic (ROC) curve analysis with high specificity thresholds. Results: GZB detection on day 3 yielded the highest sensitivity (8/12) compared to LTT (6/12) and Gr detection. Combining GZB and Gr detection improved the positive rate to 10/12. ROC curve analysis demonstrated higher AUCs for cytokine assay than for LTT, particularly for GZB at day 3. Combining GZB and Gr detection with LTT did not significantly increase diagnostic yield. Conclusion: The detection of GZB and Gr production in PBMC cultures provided a more sensitive and specific method than the conventional LTT for identifying culprit drugs in SJS/TEN. In particular, GZB detection at day 3 provided a shorter assay duration, avoided radioactive labeling, and demonstrated superior diagnostic performance. This cytokine‐based approach may represent a practical and safer alternative to enhance drug causality assessment in patients with SCARs.

This report presents a case of pseudoephedrine-induced non-pigmented bullous fixed drug eruption (NBFDE) manifesting as recurrent palmoplantar exfoliation in a scuba diver. It emphasizes the importance of considering drug allergies in the differential diagnosis when divers present with peeling hands and soles. A 38-year-old female scuba diver experiencing recurrent palmoplantar exfoliation underwent a clinical evaluation, patch testing, an interferon-gamma enzyme-linked immunospot (ELISpot) assay, and graded drug challenges with pseudoephedrine and phenylephrine. Patch testing yielded negative results; however, the ELISpot assay indicated a strong immune response to pseudoephedrine. A graded challenge involving pseudoephedrine successfully reproduced the symptoms, confirming a diagnosis of pseudoephedrine-induced NBFDE. Subsequently, a challenge with phenylephrine elicited a milder reaction, suggesting it as a potential alternative medication for the patient. This case highlights NBFDE as a potential cause of skin peeling in scuba divers who are allergic to pseudoephedrine. It emphasizes the importance of considering drug allergies when diagnosing palmoplantar exfoliation in divers and underscores the need for a thorough evaluation of medication use in this group. Alternative medications and management strategies should be considered for divers with a pseudoephedrine allergy to prevent ear barotrauma while minimizing the risk of adverse skin reactions.

Drug reactions with eosinophilia and systemic symptoms (DRESS) and Stevens‐Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are severe cutaneous adverse hypersensitivity reactions with distinct clinical manifestations. Regulatory T (Treg) cells may behave differently in these syndromes, contributing to their diverse clinical features and outcomes. This study compared Treg dynamics between DRESS and SJS/TEN patients during the acute and recovery phases. Flow cytometry quantitatively analysed and defined the immunophenotype of CD4⁺CD25⁺CD127⁻FoxP3⁺ Tregs in blood from DRESS and SJS/TEN patients indicated that Treg percentages were lowest in DRESS patients during the acute phase compared to those in the recovery phase in DRESS patients and the acute phase in SJS/TEN patients. During the acute phase, CTLA‐4 expression in Tregs in both DRESS patients with and without autoimmune sequelae was significantly increased, while only DRESS patients without autoimmune sequelae had elevated OX40 expression compared to the healthy controls. High IL‐10 expression in Tregs during the acute phase in SJS/TEN patients was also observed. The suppressive function of Tregs was lower in DRESS compared to SJS/TEN, which was determined using a suppression assay by co‐culturing autologous Treg and effector T cells. Furthermore, NanoString technology explored mRNA profiles in Tregs. Genes associated with the JAK/STAT pathway were found to be downregulated during the acute phase in DRESS patients who later developed autoimmune sequelae. Our findings evidenced impaired Treg function in DRESS compared to SJS/TEN. The early disturbance of the JAK/STAT pathway may serve as a prognostic marker for autoimmune development in DRESS patients.

In a double‐blind, randomized controlled trial, we investigated the effectiveness of adding antiplatelet drugs to up‐dosing antihistamines for the treatment of chronic spontaneous urticaria (CSU) in patients with elevated D‐dimer levels who had an inadequate response to conventional antihistamine doses. Twenty patients with Urticaria Activity Score over 7 days (UAS7) ≥16 and D‐dimer >500 ng/mL were randomized to receive either antiplatelet therapy (cilostazol 150 mg/day + dipyridamole 50 mg/day) with antihistamine (desloratadine 20 mg/day) or antihistamine alone for 4 weeks. The antiplatelet group demonstrated a greater decrease in UAS7 compared to the control group (28.10 to 8.90 vs. 22.90 to 16.40, p < 0.001 vs. p = 0.054). Both groups experienced improved quality of life (DLQI), but the improvement was greater in the antiplatelet group (p = 0.046). D‐dimer levels decreased only in the antiplatelet group (1133.67 ng/mL to 581.89 ng/mL, p = 0.013) with no significant change observed in the control group. This suggests that combining dipyridamole and cilostazol with up‐dosing antihistamines may be more effective for CSU patients with high D‐dimer levels compared to up‐dosing antihistamines alone. This could be due to a reduction in platelet activation, as evidenced by the decrease in D‐dimer levels observed in the antiplatelet group.