Carbamazepine Induces Focused T Cell Responses in Resolved Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Cases But Does Not Perturb the Immunopeptidome for T Cell Recognition.

Antiseizure medications (ASMs) are frequently implicated in T cell-mediated drug hypersensitivity reactions and cause skin tropic pathologies that range in severity from mild rashes to life-threatening systemic syndromes. During the acute stages of the more severe manifestations of these reactions, drug responsive proinflammatory CD8+ T cells display classical features of Th1 cytokine production (e.g. IFNγ) and cytolysis (e.g. granzyme B, perforin). These T cells may be found locally at the site of pathology (e.g. blister cells/fluid), as well as systemically (e.g. blood, organs). What is less understood are the long-lived immunological effects of the memory T cell pool following T cell-mediated drug hypersensitivity reactions. In this study, we examine the ASM carbamazepine (CBZ) and the CBZ-reactive memory T cell pool in patients who have a history of either Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) from 3-to-20 years following their initial adverse reaction. We show that in vitro drug restimulation of CBZ-reactive CD8+ T cells results in a proinflammatory profile and produces a mainly focused, yet private, T cell receptor (TCR) usage amongst human leukocyte antigen (HLA)-B*15:02-positive SJS or TEN patients. Additionally, we show that expression of these CBZ-reactive TCRs in a reporter cell line, lacking endogenous αßTCR, recapitulates the features of TCR activation reported for ASM-treated T cell lines/clones, providing a useful tool for further functional validations. Finally, we conduct a comprehensive evaluation of the HLA-B*15:02 immunopeptidome following ASM (or a metabolite) treatment of a HLA-B*15:02-positive B-lymphoblastoid cell line (C1R.B*15:02) and minor perturbation of the peptide repertoire. Collectively, this study shows that the CBZ-reactive T cells characterized require both the drug and HLA-B*15:02 for activation and that reactivation of memory T cells from blood results in a focused private TCR profile in patients with resolved disease.

Economic evaluation of HLA-B*15:02 screening for carbamazepine-induced severe adverse drug reactions in Thailand.

PURPOSE: There is strong evidence of an association between the presence of the human leukocyte antigen (HLA)-B*15:02 and two severe adverse drug reactions-Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)-in patients taking carbamazepine (CBZ), a common treatment for patients with epilepsy and neuropathic pain. As a result, there are calls for all patients that are due to undergo CBZ therapy to be screened for this genetic marker before commencing their therapy. This study aims to determine the value for money of HLA-B*15:02 screening compared to the following: (1) administering CBZ therapy without conducting patient screening, and (2) not prescribing CBZ but alternative drugs that are less likely to result in severe reactions, but that come at a higher cost. METHOD: An economic evaluation was carried out by using a decision tree and Markov models to examine the cost-utility of providing HLA-B*15:02 screening for all patients with either newly diagnosed epilepsy or neuropathic pain in the Thai setting. All transitional probabilities were derived from the national and international literature. The majority of the data on direct medical care costs were collected from 10 community, provincial, and regional hospitals throughout Thailand. Direct non-medical cost and health-related quality of life (HRQoL) data were obtained from interviews that were conducted with 33 patients, some of whom had experienced severe drug reactions. KEY FINDINGS: The incremental cost-effectiveness ratio (ICER) of adopting a universal HLA-B*15:02 screening policy was estimated at 222,000 Thai baht, THB/quality-adjusted life year (QALY) gained for epilepsy patients and 130,000 THB/QALY gained for patients with neuropathic pain. Furthermore, we found that 343 patients need to be tested for HLA-B*15:02 allele to prevent one case of SJS/TEN. SIGNIFICANCE: Universal HLA-B*15:02 screening represents good value for the money in terms of preventing SJS/TEN in CBZ-treated patients with neuropathic pain at the Thai ceiling ratio of 120,000 THB/QALY gained. However, the prevalence of CBZ-induced SJS/TEN in the Thai population and the positive predictive value (PPV) are major factors that influence the cost-effectiveness of HLA-B*15:02 screening. Therefore, an active surveillance system to make a more accurate assessment of the prevalence CBZ-induced SJS/TEN in the Thai population would enhance the generalizability of the results.

Cost minimization of HLA-B*1502 screening before prescribing carbamazepine in Thailand.

BACKGROUND: Carbamazepine (CBZ) is broadly used for the treatment of epilepsy, neuropathic pain and other neurological diseases, owing to its effectiveness and low price. CBZ can induce Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). There are several studies that found an association between HLA-B*1502 and CBZ-induced SJS/TEN, especially in people of Thai origin. In Thailand the prevalence of HLA-B*1502 was found to be in the range 8.1-14 %. OBJECTIVE: This study aimed to determine if screening for HLA-B*1502 in Thai patients who were to receive CBZ is cost effective. Setting Srinagarind Hospital, Khon Kaen University, Thailand. METHOD: A comparison between treatment cost of CBZ induced SJS/TEN and the HLAB*1502 screening costs in the Thai population. MAIN OUTCOME MEASURE: Comparison of the costs of treatment of CBZ induced SJS/TEN and costs of HLA-B*1502 screening test. Results When persons having the HLA-B*1502 allele receive CBZ, the chance of developing SJS/TEN is as high as 88.1 %, while persons without the HLA-B*1502 allele do not develop SJS/TEN. Therefore, a model was calculated to compare the cost of treatment between HLA-B*1502 testing before giving CBZ and if the patients were not tested for HLAB*1502. It was found that screening 100 patients before giving CBZ would save an amount of 98,549.94 baht per 100 cases of CBZ-prescribed patients. CONCLUSION: The screening for HLA-B*1502 allele before giving carbamazepine is cost effective. The results of the present study may also apply to other populations if the HLA-B*1502 frequency is high enough.

Genetic determinants of 21-hydroxylase autoantibodies amongst patients of the Type 1 Diabetes Genetics Consortium.

BACKGROUND: Autoantibodies to 21-hydroxylase (21OH-AA) precede the onset of autoimmune Addison's disease (AD) and are found in 1.5% of individuals with type 1 diabetes mellitus (T1DM). The greatest genetic risk for both disorders is found in the major histocompatibility complex (MHC), suggesting a common pathophysiology between AD and T1DM. Screening for 21OH-AA in newly diagnosed T1DM patients is a valuable prognostic tool, made stronger when MHC genotype is considered. METHODS: The Type 1 Diabetes Genetics Consortium has collected genotype data in T1DM subjects with tissue-specific autoantibody typing. Genotype and phenotype data in individuals positive and negative for 21OH-AA are compared. RESULTS: Major genetic risk for 21OH-AA is in the MHC haplotypes DRB1*04-DQB1*0302 (primarily DRB1*0404) and DRB1*0301-DQB1*0201. Protective effects in class II MHC haplotypes DRB1*0101-DQB1*0501 and DRB1*0701-DQB1*0202 also were detected. There is no difference in the presence of HLA-B15 and little difference in the presence of HLA-B8 (after class II effects are accounted for) in T1DM patients with 21OH-AA compared with known associations (HLA-B8 positive and HLA-B15 negative) in AD. CONCLUSIONS: In 21OH-AA(+) subjects, genetic risk is found mainly in MHC class II haplotypes DR3 and DR4 but not class I alleles (HLA-B8 or HLA-B15). This suggests a difference between autoantibody formation (class II dependent) and progression to overt disease (class I dependent) in AD.