HLA‐associated antiepileptic drug‐induced cutaneous adverse reactions

Abstract

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.

Diagnostic Test Criteria for HLA Genotyping to Prevent Drug Hypersensitivity Reactions: A Systematic Review of Actionable HLA Recommendations in CPIC and DPWG Guidelines

“…To our knowledge, this is the first overview of the diagnostic test criteria of drug-HLA interactions for the actionable CPIC and/or DPWG guidelines. A review by Mullan et al (2019) provides diagnostic test criteria but is limited to four AEDs. A strength of our study is that we calculated the diagnostic test criteria using the original data of genotyping results in cases and controls instead of only reporting diagnostic criteria if they were reported in the original studies.…”

Trigeminal Neuralgia: Basic and Clinical Aspects

“…It is important to highlight that carbamazepine use has been associated with a variety of hypersensitivity reactions, ranging from mild maculopapular exanthemas to hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, Stevens‐Johnson syndrome, and toxic epidermal necrolysis; the latter four phenotypes are referred to as serious cutaneous adverse reactions [ 106 , 107 ]. Frequently, these reactions require the discontinuation of carbamazepine, due to the discomfort caused to patients or due to its severity and life-threatening character [ 108 ].…”

“…Two genetic risk variants for carbamazepine‐induced hypersensitivity reactions have been identified: HLA‐B*15:02 and HLA‐A*31:01, but the precise mechanism of how carrying each variant results in an increased risk of hypersensitivity to the drug remains to be elucidated [ 108 ]. It is estimated that the incidence of Stevens‐Johnson syndrome is 1 in 1000 in the general population, with an alarming incidence of 1 in 400 at-risk populations [ 107 , 109 , 110 ]. Thus, testing is recommended for HLA‐B*15:02 and HLA‐A*31:01 alleles in patients with Asian ancestry before starting carbamazepine therapy [ 108 ].…”

Facial paralysis associated with drug reaction with eosinophilia and systemic symptoms (DRESS) with oxcarbazepine and reactivation of human herpesvirus 6 (HHV‐6)

“…1,6 HLA-B * 15: 02 and HLA-A * 31:01 are considered HLA at risk for DRESS under carbamazepine. 6 HLA-A * 31:01 has also been reported with OXC. 7 The prevalence of HLA-A * 31:01 in Northern Europe is 2-5%.…”

“…OXC-induced DRESS cases have been reported in the literature. [5][6][7] DRESS syndrome has been associated with specific HLA (human leukocyte antigen) groups, in some ethnic groups, and for some causal drugs. 1,6 HLA-B * 15: 02 and HLA-A * 31:01 are considered HLA at risk for DRESS under carbamazepine.…”