Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS): An update in 2019.

Novel genetic and epigenetic factors of importance for inter-individual differences in drug disposition, response and toxicity

Adverse drug reactions (ADRs) are a common cause of hospital admissions (up to 19%), with the majority of cases due to off-target predictable drug effects (type A reactions). However, idiosyncratic drug-induced immune activated (type B) reactions contribute to a range of hypersensitivity reactions, with T-cell-mediated type IV hypersensitivity reactions mainly manifesting as cutaneous ADRs (cADRs). Aromatic antiepileptic drugs (AEDs), used in the treatment of epilepsy as well as bipolar disorder or neuropathic pain, have been implicated as culprit drugs in a spectrum of pathologies ranging from mild maculopapular exanthema (MPE) to severe and life-threatening conditions including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These AED-induced cADRs are unpredictable based on pharmacological and clinical factors alone, thereby prompting investigations into genomic contributors mediating risk of pathology. The most strongly associated risk genes identified are from the human leukocyte antigen (HLA) class I alleles, which play a critical role in adaptive immunity by flagging either infected or aberrant cells for recognition by surveying T-cells. In the setting of drug hypersensitivity, the immunogenicity of HLA molecules and their peptide cargo can be modulated by interactions with small drug molecules that drive inappropriate T-cell responses. This review discusses the current understanding of HLA class I molecules in modifying risk of AED-induced cADRs.

/pdf/hla-associated-antiepileptic-drug-induced-cutaneous-adverse-4krixvrbcn.pdf

HLA-associated antiepileptic drug-induced cutaneous adverse reactions.

Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to eva ...

/pdf/shared-genetic-risk-factors-across-carbamazepine-induced-3t2epgaexv.pdf

Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions

Severe cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS), are idiosyncratic and unpredictable drug-hypersensitivity reactions with a high-mortality rate ranging from 10% to over 30%, thus causing a major burden on the healthcare system. Recent pharmacogenomic studies have revealed strong associations between SCAR and the genes encoding human-leukocyte antigens (HLAs) or drug-metabolizing enzymes. Some of pharmacogenetic markers have been successfully applied in clinical practice to protect patients from SCAR, such as HLA-B*15:02 and HLA-A*31:01 for new users of carbamazepine, HLA-B*58:01 for allopurinol, and HLA-B*57:01 for abacavir. This article aims to update the current knowledge in the field of pharmacogenomics of drug hypersensitivities or SCAR, and its implementation in the clinical practice.

/pdf/pharmacogenetic-testing-for-prevention-of-severe-cutaneous-29vlwx60u7.pdf

Pharmacogenetic Testing for Prevention of Severe Cutaneous Adverse Drug Reactions

BACKGROUND With the ageing of the general population, demand has grown for measures to prevent hospitalization for dementia, which can exacerbate problems associated with activities of daily living in elderly individuals. Anticholinergic medication has been shown to cause falls, delirium, and cognitive impairment in aged patients. However, the risk of hospitalization associated with the administration of anticholinergics is unclear. METHODS We analyzed the records of 61 outpatients (26 men, 35 women; mean age: 78 ± 7 years; mean follow-up period: 420 days) diagnosed with dementia (Alzheimer's disease: n = 45; dementia with Lewy bodies: n = 3; undifferentiated n = 13) and prescribed anti-dementia drugs between May 2013 and December 2014. Medication history was noted, and the patients were divided into two groups according to the Anticholinergic Risk Scale: with risk (n = 13) and without risk (n = 48). Outcome was judged based on an end-point of hospitalization or death. Kaplan-Meier survival and Cox proportional hazard analyses were performed. RESULTS Eight patients with anticholinergic risk and 12 without anticholinergic risk reached the end-point (P < 0.005). Analysis with a proportional hazard model showed that anticholinergic medication administration was related to a higher risk for reaching the end-point (crude hazard ratio: 3.62, 95% confidence interval: 1.45-9.04, P < 0.01; adjusted hazard ratio: 4.54, 95% confidence interval: 1.03-20.0, P < 0.05). In contrast, Mini-Mental State Examination score, Charlson Comorbidity Index, and the number of drugs were not major risk factors for hospitalization in patients with dementia. CONCLUSION The Anticholinergic Risk Scale findings were shown to be a strong predictor of hospitalization for patients with dementia. We should evaluate the anticholinergic burden before initiating anti-dementia therapy.

Risk of hospitalization associated with anticholinergic medication for patients with dementia

BACKGROUND Phantom boarder symptom (PBS) is classified as a delusional misidentification syndrome, and is often encountered in elderly individuals who have mild or major neurocognitive disorders. With the ageing of society, patients presenting with PBS are increasing in Japan. This retrospective study was conducted to examine the aetiology and identify significant predictors of PBS. METHODS The records of 511 consecutive patients who visited our hospital with suspicion of dementia between September 2013 and September 2019 were retrospectively examined. From those, 16 patients who presented with PBS (1 male, 15 females; mean age 79.9 ± 4 years) were selected and case features were investigated in detail. Clinical symptoms, background factors, and final diagnoses were noted. PBS was most common in patients affected by dementia with Lewy bodies (DLB). Predictive factors were evaluated using multiple logistic regression analysis. RESULTS The final diagnosis of the 16 subjects was DLB in 7, Alzheimer's disease in 3, delusional disorder in 3, unspecified dementia in 2, and vascular dementia in 1. Analysis limited to DLB cases showed that a low Mini-Mental State Examination (MMSE) score and living alone were related to higher risk for PBS. CONCLUSION Various types of dementia, especially DLB, as well as cognitive impairment and living alone were found to be strong predictors of PBS.

Phantom boarder symptom in elderly Japanese.

Importance Carbamazepine, a commonly used antiepileptic drug, is one of the most common causes of cutaneous adverse drug reactions (cADRs) worldwide. The allele HLA-A*31:01 is reportedly associated with carbamazepine-induced cADRs in Japanese and European populations; however, the clinical utility of HLA-A*31:01 has not been evaluated. Objective To assess the use of HLA-A*31:01 genetic screening to identify Japanese individuals at risk of carbamazepine-induced cADRs. Design, Setting, and Participants This cohort study was conducted across 36 hospitals in Japan from January 2012 to November 2014 among 1202 patients who had been deemed suitable to start treatment with carbamazepine. Preemptive HLA-A*31:01 genetic screening was performed for 1187 participants. Patients who did not start treatment with carbamazepine or alternative drugs were excluded. Participants were interviewed once weekly for 8 weeks to monitor the development of cADRs. Data analysis was performed from June 8, 2015, to December 27, 2016. Exposures Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLA-A*31:01 and alternative drugs for those who tested positive for HLA-A*31:01. Main Outcomes and Measures Incidence of carbamazepine-induced cADRs. Results Of the 1130 included patients who were prescribed carbamazepine or alternative drugs, the mean (range) age was 37.4 (0-95) years, 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Expert dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cADRs, of which 4 patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for 3 patients, maculopapular eruption for 9 patients, erythema multiforme for 5 patients, and an undetermined type of cADR for 6 patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis. Compared with historical controls, the incidence of carbamazepine-induced cADRs was significantly decreased (for BioBank Japan data: incidence, 3.4%; odds ratio, 0.60; 95% CI, 0.36-1.00;P = .048; for the Japan Medical Data Centre claims database: incidence, 5.1%; odds ratio, 0.39; 95% CI, 0.26-0.59;P  Conclusions and Relevance Preemptive HLA-A*31:01 genetic screening significantly decreased the incidence of carbamazepine-induced cADRs among Japanese patients, which suggests that it may be warranted in routine clinical practice.

/pdf/association-of-hla-a-31-01-screening-with-the-incidence-of-14d2bxu5t2.pdf

Association of HLA-A*31:01 Screening With the Incidence of Carbamazepine-Induced Cutaneous Adverse Reactions in a Japanese Population.

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Risk of hospitalization associated with anticholinergic medication for patients with dementia

Phantom boarder symptom in elderly Japanese.

Association of HLA-A*31:01 Screening With the Incidence of Carbamazepine-Induced Cutaneous Adverse Reactions in a Japanese Population.