CN-121975929-A - Use of HLA alleles for the preparation of a product for assessing the risk of developing hydroxychloroquine-induced drug eruptions

Abstract

The application relates to the biomedical field, and discloses an application of HLA-B27:04 alleles in preparation of a product for evaluating the risk of drug eruption caused by hydroxychloroquine. The use comprises predicting the risk of administration of a subject by detecting whether the subject carries an HLA-B27:04 allele. The application discovers that HLA-B27:04 alleles are strongly related to hydroxychloroquine drug eruption for the first time, and can be used as a risk genetic marker of hydroxychloroquine drug eruption. In practice, the risk of developing a drug eruption after the subject has been treated with hydroxychloroquine can be predicted by detecting whether the subject in need of hydroxychloroquine carries an HLA-B27:04 allele, wherein the risk of developing a drug eruption after the subject has been treated with hydroxychloroquine is significantly higher than in non-carriers. The detection product provided by the application has high specificity and high positive predictive value, and has good clinical application prospect.

Inventors

• LUO XIAOQUN
• XING QINGHE
• HE PAN
• ZHANG LUYAO
• YANG FANPING

Assignees

• 复旦大学附属华山医院
• 复旦大学

Dates

Publication Date

20260505

Application Date

20251210

Claims (10)

1. Use of an hla-B27:04 allele as a biomarker for the manufacture of a product for assessing the risk of a subject for developing hydroxychloroquine-induced drug eruption.
2. 2. The use according to claim 1, wherein the product comprises a kit.
3. 3. Use of a substance that detects an HLA-B27:04 allele in the manufacture of a product for assessing the risk of a subject for developing hydroxychloroquine-induced drug eruption.
4. 4. The use according to claim 3, wherein the substance for detecting HLA-B27:04 alleles comprises reagents, kits, instruments for detecting whether HLA-B27:04 alleles are carried or not using at least one of DNA specific hybridization, PCR-based HLA sequencing typing and HLA serological typing.
5. 5. Use according to claim 3, wherein the product comprises a kit.
6. 6. A product for assessing the risk of a subject for developing hydroxychloroquine-induced drug eruption, said product comprising a substance for detecting HLA-B27:04 alleles.
7. 7. The product of claim 6, wherein the substance for detecting HLA-B27:04 alleles comprises an HLA-DNA typing reagent or kit.
8. 8. The product according to claim 6, wherein the use of the product comprises any one or more of the following: A) Detecting or evaluating the risk of developing a drug eruption in a subject following administration of hydroxychloroquine; b) Screening high risk groups needing to avoid hydroxychloroquine; c) Providing hydroxychloroquine individual medication suggestion.
9. Use of hla-B27:04 alleles as targets for the manufacture of a medicament for the treatment and/or prophylaxis of hydroxychloroquine induced drug eruptions.
10. 10. The use according to claim 1 or 3 or 9, or the product according to claim 6, wherein the rash comprises eruption type rash, erythema multiforme type rash, urticaria/angioedema type rash, fixed rash, STS/TEN, AGEP, DRESS.

Description

Use of HLA alleles for the preparation of a product for assessing the risk of developing hydroxychloroquine-induced drug eruptions Technical Field The present application relates to the biomedical field, more specifically, it relates to an HLA-BUse of the 27:04 allele in the manufacture of a product for assessing the risk of developing hydroxychloroquine-induced drug eruptions. Background The dermatitis (DERMATITIS MEDICAMENTOSA)/drug eruption (drug eruption) refers to skin and mucous membrane inflammatory lesions induced by the drug entering the body, and comprises various administration routes such as oral administration, injection, inhalation, external application and the like, and belongs to skin drug adverse reactions (cutaneous adverse drug reaction, cADR). Depending on the severity of the condition, the rash can be classified into a general type, which includes eruption type rash (maculopapular exanthems), erythema multiforme type rash (erythema multiforme type Drug eruption), urticaria type/angioedema type rash, fixed rash (fixed Drug eruption), etc., and a severe type, which includes Stevens-Johnson syndrome (SJS), toxic epidermonecrosis lysis (toxic epidermal necrolysis, TEN), acute generalized eruption impetigo (acute generalized exanthematous pustulosis, age), and Drug response with eosinophilia and systemic symptoms (Drug reaction with eosinophilia AND SYSTEMIC symptoms, DRESS, also known as Drug hypersensitivity syndrome (Drug-induced hypersensitivity syndrome, DIHS)). Global cADR is statistically between about 0.3% and 8% and cADR is 1% to 3% of hospitalized patients. In view of the high state of cADR at present, it is of great importance to strengthen the prevention and treatment thereof. The human leukocyte antigen (human leukocyte antigen, HLA) gene system, namely human major histocompatibility complex (major histocompatibility complex class, MHC), has its coding region gene cluster located in the short arm q21.3 segment of chromosome 6, and is composed of multiple closely linked loci, and is the most complex and most polymorphic gene system in human genome, and is mainly involved in presenting various internal and exogenous antigens. The high polymorphism of HLA genes can be mapped to MHC peptide binding groove, thus greatly improving antigen diversity which can be presented to T cells, and playing an important role in physiological processes such as specific immune response, immune regulation and the like and pathological processes such as transplant immune rejection and the like. Initially, HLA-related studies were mainly used for organ transplantation and hematopoietic stem cell transplantation, and after that, they were found to be closely related to individual disease susceptibility, drug efficacy, etc., and gradually used for evaluation of refractory thrombocytopenia, association detection of autoimmune diseases with HLA genes, and pharmacogenomics, etc. It has now been found that a number of specific drug-induced drug eruptions are associated with carrying HLA-susceptible alleles, such as allopurinol and HLA-B58:01, Carbamazepine and HLA-A31:01 And HLA-B15:02, Methylzoxamide-induced SJS/TEN and HLA-BThere is a strong genetic association 59:01. However, genetic markers for hydroxychloroquine-induced drug eruptions are not yet defined, and there is a clinical lack of effective risk prediction means. Hydroxychloroquine (Hydroxychloroquine, HCQ), chemical name 4-amino-7-chloro-4-quinolinecarboxylic acid, a derivative of chloroquine, is also known as hydroxychloroquine, hydroxychloroquine sulfate, which is a typical representative of 4-aminoquinolines, was approved in 1955 for clinical use, was originally used for treating malaria, was subsequently found to have anti-inflammatory, immunomodulatory effects, was gradually widely used for various autoimmune diseases such as systemic lupus erythematosus, primary sjogren's syndrome, rheumatoid arthritis, etc., and was also used for infections, metabolic or neoplastic diseases, and its efficacy was also approved during the epidemic period of the novel coronavirus, and its use amount was continuously increasing. The pharmacological actions of hydroxychloroquine have not been fully elucidated, and it is presently believed that the actions thereof mainly include interaction with sulfhydryl groups, interfering enzyme activities (including phosphatase, NADH-cytochrome C reductase, cholinesterase, protease and hydrolase), binding to DNA, stabilizing lysosomal membranes, inhibiting prostaglandin formation, inhibiting chemotactic action of polymorphonuclear cells and phagocytic action, interfering monocyte interleukin 1 formation, inhibiting neutrophil superoxide release, and the like. The hydroxychloroquine is well absorbed by oral administration, and is mainly generated into the active desethylhydroxychloroquine and the inactive diethyl hydroxychloroquine after being metabolized by cytochrome P450 enzyme system in vivo. Notably, hydroxychloroquine