Immunologic basis for allopurinol-induced severe cutaneous adverse reactions: HLA-B*58:01-restricted activation of drug-specific T cells and molecular interaction

Lin, Chia Hsien; Chen, Jung Kuei; Ko, Tai‐Ming; Chi, Chun‐Wei; Wu, Jer Yuarn; Chung, Wen Hung; Chen, Shih Yang; Liao, Yuxiang; Hung, Shuen Iu; Chen, Yuan Tsong

doi:10.1016/j.jaci.2014.09.041

Cited by 42 publications

(54 citation statements)

References 6 publications

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“…HLA‐B*58:01 differs to HLA‐B*57:01 , which does not present allopurinol, by only 4 amino acids, 45 (Thr/Met), 46 (Glu/Ala), 97 (Arg/Val), and 103 (Leu/Val). Site‐directed mutagenesis studies suggested that Arg97, between the E and C pocket of HLA‐B*58:01 , may be a key contact residue for oxypurinol . These data are consistent with molecular modelling studies which indicate that oxypurinol should make van der Waals interactions with residues surrounding the F pocket and established a hydrogen bond with Arg97 in HLA‐B*58:01 .…”

Section: Hla and Im‐adrs: Representative Examplessupporting

confidence: 81%

HLAs: Key regulators of T‐cell‐mediated drug hypersensitivity

Redwood

Pavlos

White

et al. 2017

HLA

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Adverse drug reactions (ADR) can be broadly categorised as either on-target or off-target. On-target ADRs arise as a direct consequence of the pharmacological properties of the drug and are therefore predictable and dose dependant. On-target ADRs comprise the majority (>80%) of ADRs, relate to the drug’s interaction with its known pharmacological target and are a result of a complex interplay of genetic and ecologic factors. In contrast off-target ADRs, including immune mediated ADRs (IM-ADRs), are due to unintended pharmacological interactions such as inadvertent ligation of host cell receptors or non-pharmacological interactions mediated through an adaptive immune response. IM-ADRs can be classified according to the primary immune cell involved and include B cell-mediated (Gell-Coombs type I-III reactions) and T cell-mediated (Gell-Coombs type IV or delayed hypersensitivity) reactions. IM-ADRs mediated by T cells are associated with phenotypically distinct clinical diagnoses and can vary from a mild delayed rash to a life threatening cutaneous, systemic or organ disease, such as Stephen Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and drug-induced liver disease (DILI). T-cell mediated ADRs are strongly linked to the carriage of particular HLA risk alleles which in the case of abacavir hypersensitivity and HLA-B*57:01 has led to translation into the clinic as a routine screening test. In this review, we will discuss the immunogenetics and pathogenesis of IM-ADRs and how HLA associations inform both pre-drug screening strategies and mechanistic understanding.

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Section: Hla and Im‐adrs: Representative Examplessupporting

confidence: 81%

HLAs: Key regulators of T‐cell‐mediated drug hypersensitivity

Redwood

Pavlos

White

et al. 2017

HLA

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“…These recommendations also did not mention systematic HLA-B*5801 screening before the initiation of allopurinol. This haplotype is the strongest risk factor for allopurinol-induced SCARs,187 and oxypurinol, the serum levels of which are increased in patients with renal failure,164 can preferentially bind to the peptide binding groove of HLA-B*58:01 and dose-dependently activate T cells 188 189. The association between carriage of this allele and increased risk of SCARs has been mainly observed in certain ethnic populations, including Han Chinese, Thai and Korean patients, showing high allele frequency 187.…”

Section: Discussionmentioning

confidence: 99%

2016 updated EULAR evidence-based recommendations for the management of gout

et al. 2016

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BACKGROUND:\ud New drugs and new evidence concerning the use of established treatments have become available since the publication of the first European League Against Rheumatism (EULAR) recommendations for the management of gout, in 2006. This situation has prompted a systematic review and update of the 2006 recommendations.\ud METHODS:\ud \ud The EULAR task force consisted of 15 rheumatologists, 1 radiologist, 2 general practitioners, 1 research fellow, 2 patients and 3 experts in epidemiology/methodology from 12 European countries. A systematic review of the literature concerning all aspects of gout treatments was performed. Subsequently, recommendations were formulated by use of a Delphi consensus approach.\ud RESULTS:\ud \ud Three overarching principles and 11 key recommendations were generated. For the treatment of flare, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular steroids or a combination are recommended. In patients with frequent flare and contraindications to colchicine, NSAIDs and corticosteroids, an interleukin-1 blocker should be considered. In addition to education and a non-pharmacological management approach, urate-lowering therapy (ULT) should be considered from the first presentation of the disease, and serum uric acid (SUA) levels should be maintained at<6 mg/dL (360 µmol/L) and <5 mg/dL (300 µmol/L) in those with severe gout. Allopurinol is recommended as first-line ULT and its dosage should be adjusted according to renal function. If the SUA target cannot be achieved with allopurinol, then febuxostat, a uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be considered. For patients with refractory gout, pegloticase is recommended.\ud CONCLUSIONS:\ud These recommendations aim to inform physicians and patients about the non-pharmacological and pharmacological treatments for gout and to provide the best strategies to achieve the predefined urate target to cure the disease

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“…Therefore, it is not unreasonable to assume that the repertoire of T cells is the determinant for the development of SCARs. It is evident that allopurinol-specific T cells could be generated from patients with allopurinol-induced SCARs but not from those who tolerate allopurinol, even though all these subjects bear the HLA-B*58:01 allele [99]. However, it is still not known if the types or clones of T cells being activated are the major factor in determining which type of SCAR a given patient develops.…”

Section: Pathomechanismsmentioning

confidence: 99%

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): An Interplay among Drugs, Viruses, and Immune System

Cho

Yang

Chu

2017

IJMS

188

276

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Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe multiorgan hypersensitivity reaction mostly caused by a limited number of eliciting drugs in patients with a genetic predisposition. Patients with DRESS syndrome present with characteristic but variable clinical and pathological features. Reactivation of human herpesviruses (HHV), especially HHV-6, is the hallmark of the disease. Anti-viral immune responses intertwined with drug hypersensitivity make the disease more complicated and protracted. In recent years, emerging studies have outlined the disease more clearly, though several important questions remain unresolved. In this review, we provide an overview of DRESS syndrome, including clinical presentations, histopathological features, pathomechanisms, and treatments.

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Immunologic basis for allopurinol-induced severe cutaneous adverse reactions: HLA-B*58:01-restricted activation of drug-specific T cells and molecular interaction

Cited by 42 publications

References 6 publications

HLAs: Key regulators of T‐cell‐mediated drug hypersensitivity

HLAs: Key regulators of T‐cell‐mediated drug hypersensitivity

2016 updated EULAR evidence-based recommendations for the management of gout

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): An Interplay among Drugs, Viruses, and Immune System

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