Differential cytokine profiles produced by anti-epileptic drug re-exposure of peripheral blood mononuclear cells derived from severe anti-epileptic drug patients and non-allergic controls.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reactions with eosinophilia and systemic symptoms (DRESS) are the most common severe cutaneous adverse drug reactions (SCARs). Anti-epileptic drugs are one of the most common drugs causing SCARs. Cytokine profiles of SCARs during culprit drug exposure have never been characterized. This study aimed to identify cytokine patterns between SCARs and non-SCARs in epilepsy patients and the patterns of DRESS and SJS/TEN. Epilepsy patients that showed allergic responses to anti-epileptic drugs that manifested as SJS/TEN or DRESS were recruited. Epilepsy patients with no drug allergy symptoms and healthy people were also recruited as control groups. Peripheral blood mononuclear cells (PBMCs) were isolated and co-cultured with assigned anti-epileptic drugs according to the lymphocyte transformation test (LTT). LTT and measurement of cytokine levels in supernatants were performed on day six of cell cultivation. This study identified different cytokine expression patterns between SCAR and non-SCAR in epilepsy patients. Significant levels of IL-10, IL-12, IL-17, and GM-CSF were detected in non-SCAR epilepsy. However, the levels of IL-2, IL-5, IL-13, and IFN-gamma were significantly higher in supernatants of PBMCs of DRESS cultivated with AEDs relative to those of SJS/TEN. These cytokine levels were positively correlated with the cell proliferation index. Production of IL-5 and IL-13 was a unique characteristic of DRESS PBMCs. This study was the first to demonstrate distinct differences in cytokine levels between SCAR and non-SCAR PBMCs in epilepsy, which could help explain the immune-pathomechanism of drug hypersensitivity in SCARs. Different patterns of cytokine production and cell proliferation between DRESS and SJS/TEN in AED hypersensitivity were also demonstrated. Production of IL-5 and IL-13 might be a promising marker to define drug hypersensitivity in DRESS.

Evaluation of a lymphocyte transformation test and cytokine detection assay to identify phenytoin and carbamazepine provoked DRESS or SJS/TEN in epilepsy patients.

Phenytoin (PHE) and carbamazepine (CBZ) are first rank causative drugs that can induce drug rash with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Identification of anti-epileptic drugs as a culprit drug has been problematic; hence, in vitro tests could be promising methods to define causative drugs without clinical risk. The aim of this study is to evaluate the efficacy of lymphocyte transformation tests (LTT) and cytokine detection assays in identifying PHE and CBZ as culprit drugs. Peripheral blood mononuclear cells were collected from normal, PHE/CBZ tolerance and PHE/CBZ hypersensitivity cohorts and utilized for cell-culture assays. LTT was performed and culture supernatants were subjected to multiple cytokine detection assays. Our study showed that LTT correlated with outcomes of Naranjo's assessment with statistical significance (r = 0.614). Various sensitivities of LTT and cytokine detection assays were demonstrated. Although both assays provided excellent specificity, LTT yielded higher sensitivity as compared to those of cytokine detection assays in both DRESS and SJS/TEN. Regardless whether specificity is, this is the first report to demonstrate that IL-4 detection assay could enhance sensitivity to identify culprit drug when it was combined with LTT for SJS/TEN patients or it was combined with IL-2/IFN-γ detection assays for DRESS ones.