WO2020223867A1 - 评估疾病调节抗风湿药物引发严重皮肤药物不良反应风险的方法、其检测试剂盒及其用途 - Google Patents

评估疾病调节抗风湿药物引发严重皮肤药物不良反应风险的方法、其检测试剂盒及其用途 Download PDF

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WO2020223867A1
WO2020223867A1 PCT/CN2019/085639 CN2019085639W WO2020223867A1 WO 2020223867 A1 WO2020223867 A1 WO 2020223867A1 CN 2019085639 W CN2019085639 W CN 2019085639W WO 2020223867 A1 WO2020223867 A1 WO 2020223867A1
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hla
drug
disease
risk
adverse
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PCT/CN2019/085639
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French (fr)
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钟文宏
洪舜郁
王壮维
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长庚医疗财团法人林口长庚纪念医院
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Priority to CA3137521A priority Critical patent/CA3137521A1/en
Priority to US17/604,847 priority patent/US20220259655A1/en
Priority to KR1020217035887A priority patent/KR20210149135A/ko
Priority to PCT/CN2019/085639 priority patent/WO2020223867A1/zh
Priority to JP2021563076A priority patent/JP7334263B2/ja
Priority to CN201980044664.9A priority patent/CN112513294A/zh
Priority to SG11202111473UA priority patent/SG11202111473UA/en
Publication of WO2020223867A1 publication Critical patent/WO2020223867A1/zh

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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
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    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6881—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for tissue or cell typing, e.g. human leukocyte antigen [HLA] probes
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
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    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/172—Haplotypes

Definitions

  • the present invention provides a method for assessing the risk of skin drug reactions (Cutaneous Adverse Drug Reactions) caused by disease-regulating anti-rheumatic drugs, especially Sulfasalazine, Mesalazine, Sulfapyridine , Olsalazine (Olsalazine) and other methods that cause the risk of adverse skin drug reactions.
  • Skin drug reactions especially Sulfasalazine, Mesalazine, Sulfapyridine , Olsalazine (Olsalazine) and other methods that cause the risk of adverse skin drug reactions.
  • Cutaneous Adverse Drug Reactions have always been a major clinical problem, and their manifestations are very diverse, ranging from mild papules (MPE), fixed drug rash (fixed drug eruption, FDE) to severe skin drugs Adverse reactions (severe cutaneous adverse drug reactions, SCARs), including: drug rash with eosinophilia and systemic symptoms (DRESS), Stevens Johnson Syndrome, SJS ) And toxic epidermal necrolysis (TEN) and so on.
  • MPE mild papules
  • FDE fixed drug rash
  • SCARs severe skin drugs
  • DRESS drug rash with eosinophilia and systemic symptoms
  • SJS Stevens Johnson Syndrome
  • TEN toxic epidermal necrolysis
  • SJS Stevenson-Johnson Syndrome
  • TEN Toxic Epidermal Necrosis
  • DRESS drug eruption with eosinophilia and systemic symptoms
  • fever fever
  • skin rash increase in blood eosinophilic leukocytes
  • lymphadenopathy and internal organ invasion.
  • the most common and most severely invaded organ is the liver, which may be complicated by explosive hepatitis, which becomes the most common cause of death for patients.
  • Others include nephritis, myocarditis, pneumonia, and thyroid inflammation.
  • HLA-A has about 300 genotypes
  • HLA-B has about 600 genotypes. Therefore, it is difficult to find out the immune mechanism that causes adverse drug reactions.
  • Sulfasalazine (Sulfasalazine, C 18 H 14 N 4 O 5 S, Formula I) (trade name: Salazine enteric-coated tablets, Salazine or or ) Is a drug with immune system adjustment and anti-inflammatory effects. It was approved by the U.S. Food and Drug Administration (FDA) in 1950 to treat inflammatory bowel diseases and various inflammatory arthritis, such as rheumatoid arthritis Arthritis, ankylosing spondylitis, psoriatic arthritis and juvenile chronic arthritis.
  • FDA Food and Drug Administration
  • Sulfasalazine and its metabolites such as Mesalazine (Mesalazine, C 7 H 7 NO 3 , Formula II) and Sulfapyridine (C 11 H 11 N 3 O 2 S, Formula III), and Mesalazine Qin's dimer Olsalazine (Olsalazine, C 14 H 10 N 2 O 6 , formula IV) has anti-inflammatory, immunosuppressive and antibacterial effects. It is used in the treatment of inflammatory arthritis, in addition to reducing joint pain and In addition to swelling, it can also reduce the chance of permanent damage to the joints and cause disability.
  • the present invention provides a method for assessing the risk of severe skin drug reactions caused by the development of disease-regulating antirheumatic drugs in patients.
  • the severe skin drug reactions include: Stevens Johnson Syndrome (SJS) and toxic epidermal necrosis Symptoms (toxic epidermal necrolysis, TEN) or drug rash with eosinophilia and systemic symptoms (drug rash with eosinophilia and systemic symptoms, DRESS).
  • SJS Stevens Johnson Syndrome
  • TEN toxic epidermal necrosis Symptoms
  • drug rash with eosinophilia and systemic symptoms drug rash with eosinophilia and systemic symptoms, DRESS.
  • HLA-B*1502, HLA-B*3802 or its allele combinations, HLA-B*1301 and HLA-B*3901 allele combinations are related to serious adverse skin drug reactions caused by disease-regulating anti-rheumatic drugs.
  • the present invention provides a method for assessing the risk of a patient developing severe skin drug reactions due to disease-modulating antirheumatic drugs, including determining the presence of at least one allele selected from: HLA-B*1502 , HLA-B*3802, or a combination of HLA-B*1301 and HLA-B*3901, in which the presence of at least one allele is an indicator of the risk of severe skin drug reactions.
  • the drug is disease-modifying anti-rheumatic drugs (DMARDs).
  • Disease-modulating anti-rheumatic drugs include (but are not limited to) Sulfasalazine, Mesalazine, Sulfapyridine or Olsalazine.
  • Serious skin drug adverse reactions include at least one adverse reaction selected from the following: Stevens Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN) or drug eruption with eosinophilia Symptoms and systemic symptoms (drug rash with eosinophilia and systemic symptoms, DRESS).
  • SJS Stevens Johnson Syndrome
  • TEN toxic epidermal necrolysis
  • DRESS drug eruption with eosinophilia Symptoms and systemic symptoms (drug rash with eosinophilia and systemic symptoms, DRESS).
  • the patient carries the HLA-B*1502 allele.
  • the patient carries the HLA-B*3802 allele.
  • the patient has HLA-B*1502 and HLA-B*3802 alleles.
  • the patient has HLA-B*1301 and HLA-B*1502, HLA
  • the present invention provides reagents for detecting the alleles of HLA-B*1502, HLA-B*3802, or HLA-B*3901 and HLA-B*1301 combination, which are used in the evaluation of disease-regulating anti-rheumatic drugs causing serious adverse skin drug reactions
  • the kit includes a reagent for detecting at least one allele selected from the group consisting of: HLA-B*1502, HLA-B*3802, or HLA-B*1301 and HLA- B*3901 combination.
  • HLA-B*1502, HLA-B*3802, HLA-B*1301 and HLA-B*3901, HLA-B*1502 and HLA-B*3802, HLA-B*1301 and HLA-B*3802 and HLA-B*3901 and HLA-B*3802 and HLA-B*3901 alleles means that the patient is better than HLA-B*1502, HLA-B*3802, HLA- B*1301 and HLA-B*3901, HLA-B*1502 and HLA-B*3802, HLA-B*1301 and HLA-B*3802 and HLA-B*3901 or HLA-B*1301 and HLA-B* 1502 and HLA-B*3802 and HLA-B*3901 alleles are not present in patients with more than one time, more than two times, more than three times, more than four times, more than five times , Higher than six times, higher than seven times
  • the presence of an allele can be detected by any method known in the relevant technology, such as (but not limited to): the use of oligonucleotides that specifically hybridize with the nucleic acid encoding the allele, serotyping or microscopy Toxicity method is used to determine the cDNA, RNA or protein products of alleles [Kenneth D. McClatchey. Clinical Laboratory Medicine. 2002].
  • the nucleic acid-specific hybridization oligonucleotide assay uses DNA prepared from the peripheral blood of the patient.
  • the specific oligonucleotide can target the most variable of HLA-B*1301 and/or HLA-B*1502 and/or HLA-B*3802 and/or HLA-B*3901 alleles Sequence design.
  • the forward primer oligonucleotide sequence used for detecting the presence of HLA-B*1502 is 5'-ATGGCGCCCCGGG-3' (sequence 1)
  • the reverse primer sequence is 5'-TAGTAGCCGCGCAGGTTCC-3' (sequence 2)
  • probe 1 (probe 1) sequence is 5'-AACACACAGATCTACAAGG-3' (sequence 3)
  • probe 2 (probe 2) sequence is 5'-AACACACAGATCTCCAAGA-3' ( Sequence 4).
  • the forward primer oligonucleotide sequence used to detect the presence of HLA-B*3802 is 5'-GCCGCGAGTCCGAGAGA-3' (sequence 5), and the reverse primer sequence is 5'-GTGCGCAGGTTCTCTCGGTA-3' (sequence 6), probe 1 (probe 1) sequence is 5'-CCGGAGTATTGGGAC-3' (sequence 7) and probe 2 (probe 2) sequence is 5'-CCGGAATATTGGGAC-3'( Sequence 8).
  • the forward primer oligonucleotide sequence used for detecting the presence of HLA-B*1301 is 5'-AGCCCCGCTTCATCACC-3' (sequence 9)
  • the reverse primer sequence (reverse primer) Is 5'-TCCTTGCCGTCGTAGGCTAA-3' (sequence 10)
  • probe 1 (probe 1) sequence is 5'-CACATCATCCAGAGGAT-3' (sequence 11)
  • probe 2 (probe 2) sequence is 5'-ACACTTGGCAGACGAT-3' (Sequence 12).
  • the forward primer oligonucleotide sequence used to detect the presence of HLA-B*3901 is 5'-GCGAGTCCGAGAGAGGAGC-3' (sequence 13), and the reverse primer sequence (reverse primer) 5'-TAGTAGCCGCGCAGGTTCC-3' (sequence 14), probe 1 (probe 1) sequence is 5'-TCCAATTCACAGACTGA-3' (sequence 15) and probe 2 (probe 2) sequence is 5'-CAACACACAGACTGA-3' (Sequence 16).
  • the present invention provides a detection kit for assessing the risk of disease-regulating antirheumatic drugs causing serious adverse skin drug reactions.
  • the detection kit includes a reagent that can detect at least one allele selected from: HLA-B* 1502; HLA-B*3802 or a combination of HLA-B*1301 and HLA-B*3901, wherein the presence of the at least one allele means that the patient has a higher rate than the patient without the at least one allele High risk of severe skin drug reactions caused by disease regulating antirheumatic drugs.
  • the severe skin drug adverse reaction includes at least one adverse reaction selected from the group consisting of Stevenson-Jonson syndrome, toxic epidermal necrosis or drug eruption with eosinophilia and systemic symptoms.
  • the present invention provides a method for reducing the incidence of serious skin drug adverse reactions caused by disease regulating antirheumatic drugs or for treatment.
  • the present invention also provides a method for assessing the risk of disease-modulating antirheumatic drugs causing adverse drug reactions and treating the adverse drug reactions, including the following steps: (a) detecting at least one allele selected from the following alleles in a patient sample: HLA -B*1502, HLA-B*3802 or a combination of HLA-B*1301 and HLA-B*3901, (b) if there is at least one of the following alleles in the sample: HLA-B*1502, HLA-B* 3802 or the combination of HLA-B*1301 and HLA-B*3901 can identify that the patient has an adverse drug reaction caused by a disease-modulating antirheumatic drug and (c) administer the drug to treat the adverse drug reaction.
  • the method of treating adverse drug reactions is to administer a drug including (but not limited to) liquid, steroid, immunoglobulin, cyclosporine, anti-TNF- ⁇ agent or plasma Replacement.
  • a drug including (but not limited to) liquid, steroid, immunoglobulin, cyclosporine, anti-TNF- ⁇ agent or plasma Replacement.
  • the present invention also relates to a method for assessing the risk of adverse drug reactions caused by disease-regulating antirheumatic drugs and reducing the incidence of adverse drug reactions, including the following steps: (a) detecting at least one allele selected from the following in a patient sample : HLA-B*1502, HLA-B*3802 or the presence of a combination of HLA-B*1301 and HLA-B*3901, (b) if there is at least one of the following alleles in the sample: HLA-B*1502
  • the combination of HLA-B*3802 or HLA-B*1301 and HLA-B*3901 can identify that the patient has an increased risk of adverse drug reactions and (c) the patient is not given disease-modulating antirheumatic drugs.
  • invention and "present invention” used in the present invention are intended to broadly refer to all the application objects and claims of the present invention. Statements containing these terms should be understood as not limited to the application objectives described herein or limited to the meaning or scope of the claims of the invention.
  • embodiments of the invention covered by the present invention are defined by the claims rather than the content of the present invention.
  • the summary of the present invention is a high-level overview of various aspects of the present invention, and introduces some concepts that are further described in the following embodiment section.
  • the content of the present invention is not intended to confirm the key or essential features of the claimed application target, nor is it intended to be used alone to determine the scope of the claimed application target.
  • the application goal should be understood by referring to any or all drawings of the entire specification and appropriate parts of each claim.
  • HLA-B*1502 5 out of 11 SJS/TEN patients had this genotype (45.45%), and only 87 out of 941 normal healthy controls had this genotype ( 9.25%), showing that HLA-B*1502 is associated with SJS/
  • SCAR severe skin drug reaction
  • Sulfasalazine disease-modulating anti-rheumatic drug sulfasalazine

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Abstract

一种评估疾病调节抗风湿药物引发严重皮肤药物不良反应（Severe Cutaneous Adverse Drug Reactions，SCARs）风险的方法，其中严重皮肤药物不良反应包括但不限于：史帝文生－琼森症候群（Stevens Johnson Syndrome，SJS）、毒性表皮坏死症（toxic epidermal necrolysis，TEN）、药物疹合并嗜伊红血症及全身症状（drug rash with eosinophilia and systemic symptoms，DRESS）。亦提供一种用于评估患者发展出皮肤药物不良反应风险之检测试剂盒，包括测定特定HLA等位基因之试剂盒及使用此检测试剂盒评估患者发展出皮肤药物不良反应风险。

Description

评估疾病调节抗风湿药物引发严重皮肤药物不良反应风险的方法、其检测试剂盒及其用途 技术领域
本发明系提供一种评估疾病调节抗风湿药物引发皮肤药物不良反应(Cutaneous Adverse Drug Reactions)风险的方法，尤指柳氮磺吡啶(Sulfasalazine)、美色拉秦(Mesalazine)、磺胺比啶(Sulfapyridine)、奥色拉秦(Olsalazine)等引发皮肤药物不良反应风险的方法。
先前技术
皮肤药物不良反应(Cutaneous Adverse Drug Reactions，CADRs)一直以来为临床重大问题，其表现非常多样化，从轻微之丘疹(maculopapular eruption，MPE)、固定型药疹(fixed drug eruption，FDE)至严重皮肤药物不良反应(severe cutaneous adverse drug reactions，SCARs)，包含：药物疹合并嗜伊红血症及全身症状(drug rash with eosinophilia and systemic symptoms，DRESS)、史帝文生-琼森症候群(Stevens Johnson Syndrome，SJS)及毒性表皮坏死症(toxic epidermal necrolysis，TEN)等。史帝文生-琼森症候群(SJS)及毒性表皮坏死症(TEN)在发病前期常常出现一些类似感冒的症状，包括发烧、喉咙痛、唇部肿胀等症状，接着急遽发展出全身性红斑、水泡、眼睛、口腔、生殖器黏膜发炎及溃烂，严重时有如全身烫伤的病人。两者最大分别只是在表皮分离的范围若低于体表面积10％时称为SJS，超过30％则为TEN。药物疹合并嗜伊红血症及全身症状(DRESS)临床上主要特征包括发烧、皮肤疹、血中嗜伊红性白血球增加、淋巴结肿大和内部器官的侵犯。最常见且最严重侵犯的器官是肝脏，可能会并发猛爆性肝炎，而成为病人最常见的死因，其他的还有肾炎、心肌炎、肺炎、甲状腺发炎等。
药物不良反应常和免疫反应有关，然而免疫机制非常复杂，如：HLA-A约有300多种基因型；HLA-B约有600多种基因型。因此找出造成药物不良反应之免疫机制困难重重。
疾病调节抗风湿药物柳氮磺吡啶(Sulfasalazine，C 18H 14N 4O 5S，式I)(商品名为撒乐肠溶锭，Salazine或
Figure PCTCN2019085639-appb-000001
或
Figure PCTCN2019085639-appb-000002
)是一种具有调整免疫系统及抗发炎作用的药物，于1950年被美国食品药物管理局(FDA)获准使用，可用于治疗发炎性肠道疾病及各种发炎性关节炎，如：类风湿性关节炎、僵直性脊椎炎、干癣性关节炎及幼年型慢性关节炎等。柳氮磺吡啶及其代谢物，如美色拉秦(Mesalazine，C 7H 7NO 3，式II)和磺胺比啶(Sulfapyridine，C 11H 11N 3O 2S，式III)，及美色拉秦之二聚体奥色拉秦(Olsalazine，C 14H 10N 2O 6，式IV)，具有抗发炎、免疫抑制及抗菌作用，用在治疗发炎性关节炎时，除了可以减轻关节的疼痛及肿胀之外，还可减少关节发生永久性破坏，造成残障的机率。
Figure PCTCN2019085639-appb-000003
Figure PCTCN2019085639-appb-000004
疾病调节抗风湿药物虽然可应用于治疗多种发炎性疾病，然而却因为其在临床上有较高发生不良反应的频率而限制其被使用。约25％的患者使用柳氮磺吡啶会出现明显的副作用，包括：食欲不振、恶心、头痛、白血球降低、肝脏问题、肾脏问题及皮肤药物不良反应(Cutaneous Adverse Drug Reactions，CADRs)等，其中皮肤药物不良反应占副作用中的第二大比例。因此对于疾病调节抗风湿药物引起严重皮肤药物不良反应(包括：SJS、TEN及DRESS)的风险评估之需求仍然存在。本发明解决此需要。
发明内容
本发明提供一种评估患者发展出疾病调节抗风湿药物引发严重皮肤药物不良反应风险的方法，其中严重皮肤药物不良反应包括：史帝文生－琼森症候群(Stevens Johnson Syndrome，SJS)、毒性表皮坏死症(toxic epidermal necrolysis，TEN)或药物疹合并嗜伊红血症及全身症状(drug rash with eosinophilia and systemic symptoms，DRESS)。HLA-B*1502、HLA-B*3802或其等位基因组合，HLA-B*1301与HLA-B*3901等位基因组合与疾病调节抗风湿药物所引发之严重皮肤药物不良反应有关。
明确言之，本发明提供一种评估患者因疾病调节抗风湿药物而发展出严重皮肤药物不良反应之风险的方法，包括测定选自以下之至少一种等位基因之存在：HLA-B*1502，HLA-B*3802，或HLA-B*1301与HLA-B*3901组合，其中至少一种等位基因之存在为严重皮肤药物不良反应风险之指标。在一具体实例中，该药物为疾病调节抗风湿药物(Disease-modifyinganti-rheumatic drugs，DMARDs)。疾病调节抗风湿药物包括(但不限于)柳氮磺吡啶(Sulfasalazine)、美色拉秦(Mesalazine)、磺胺比啶(Sulfapyridine)或奥色拉秦(Olsalazine)。严重皮肤药物不良反应包括至少一种选自以下之不良反应：史帝文生－琼森症候群(Stevens Johnson Syndrome，SJS)、毒性表 皮坏死症(toxic epidermal necrolysis，TEN)或药物疹合并嗜伊红血症及全身症状(drug rash with eosinophilia and systemic symptoms，DRESS)。在一具体实例中，患者带有HLA-B*1502等位基因。在一具体实例中，患者带有HLA-B*3802等位基因。在一具体实例中，患者带有HLA-B*1502与HLA-B*3802等位基因。在一具体实例中，患者带有HLA-B*1301与HLA-B*3802与HLA-B*3901等位基因。在一具体实例中，患者带有HLA-B*1301与HLA-B*1502与HLA-B*3802与HLA-B*3901等位基因。
本发明提供检测HLA-B*1502、HLA-B*3802或HLA-B*3901与HLA-B*1301组合之等位基因的试剂在制备用于评估疾病调节抗风湿药物引发严重皮肤药物不良反应的风险试剂盒中的用途，该试剂盒包括用于侦测选自以下之至少一种等位基因之试剂：HLA-B*1502，HLA-B*3802，或HLA-B*1301与HLA-B*3901组合。
HLA-B*1502、HLA-B*3802、HLA-B*1301与HLA-B*3901、HLA-B*1502与HLA-B*3802、HLA-B*1301与HLA-B*3802与HLA-B*3901或HLA-B*1301与HLA-B*1502与HLA-B*3802与HLA-B*3901等位基因之存在代表该患者比HLA-B*1502、HLA-B*3802、HLA-B*1301与HLA-B*3901、HLA-B*1502与HLA-B*3802、HLA-B*1301与HLA-B*3802与HLA-B*3901或HLA-B*1301与HLA-B*1502与HLA-B*3802与HLA-B*3901等位基因不存在之患者具有高于一倍以上、高于二倍以上、高于三倍以上、高于四倍以上、高于五倍以上、高于六倍以上、高于七倍以上、高于八倍以上、高于九倍以上、高于十倍以上、高于十一倍以上、高于十二倍以上、高于十三倍以上、高于十四倍以上、高于十五倍以上、高于十六倍以上、高于十七倍以上、高于十八倍以上、高于十九倍以上、高于二十倍以上、高于三十倍以上、高于四十倍以上、高于五十倍以上、高于一倍至高于十四倍药物过敏反应之风险。
等位基因之存在可采用相关技术上已知任何方法检测，例如(但不限于)：使用与编码该等位基因之核酸专一性杂交之寡核苷酸测定，血清定型法或显微细胞毒性法来测定等位基因之cDNA、RNA或蛋白质产物[Kenneth D.McClatchey.Clinical Laboratory Medicine.2002]。在一具体实例中，核酸专一性杂交之寡核苷酸测定使用来自患者周边血液所制成之DNA进行测定。其中具专一性之寡核苷酸可针对HLA-B*1301及/或HLA-B*1502及/或 HLA-B*3802及/或HLA-B*3901等位基因中最具变异性之序列进行设计。在一具体实例中，检测HLA-B*1502存在所使用的正向引物(forward primer)寡核苷酸序列为5’-ATGGCGCCCCGGG-3’(序列1)，反向引物序列(reverse primer)为5’-TAGTAGCCGCGCAGGTTCC-3’(序列2)，探针1(probe 1)序列为5’-AACACACAGATCTACAAGG-3’(序列3)及探针2(probe 2)序列为5’-AACACACAGATCTCCAAGA-3’(序列4)。在一具体实例中，检测HLA-B*3802存在所使用的正向引物(forward primer)寡核苷酸序列为5’-GCCGCGAGTCCGAGAGA-3’(序列5)，反向引物序列(reverse primer)为5’-GTGCGCAGGTTCTCTCGGTA-3’(序列6)，探针1(probe 1)序列为5’-CCGGAGTATTGGGAC-3’(序列7)及探针2(probe 2)序列为5’-CCGGAATATTGGGAC-3’(序列8)。在另一具体实例中，检测HLA-B*1301存在所使用的正向引物(forward primer)寡核苷酸序列为5’-AGCCCCGCTTCATCACC-3’(序列9)，反向引物序列(reverse primer)为5’-TCCTTGCCGTCGTAGGCTAA-3’(序列10)，探针1(probe 1)序列为5’-CACATCATCCAGAGGAT-3’(序列11)及探针2(probe 2)序列为5’-ACACTTGGCAGACGAT-3’(序列12)。在另一具体实例中，检测HLA-B*3901存在所使用的正向引物(forward primer)寡核苷酸序列为5’-GCGAGTCCGAGAGAGGAGC-3’(序列13)，反向引物序列(reverse primer)为5’-TAGTAGCCGCGCAGGTTCC-3’(序列14)，探针1(probe 1)序列为5’-TCCAATTCACAGACTGA-3’(序列15)及探针2(probe 2)序列为5’-CAACACACAGACTGA-3’(序列16)。
本发明提供用于评估疾病调节抗风湿药物引发严重皮肤药物不良反应的风险的检测试剂盒，此检测试剂盒包含一试剂可检测选自以下之至少一种等位基因之试剂：HLA-B*1502；HLA-B*3802或HLA-B*1301与HLA-B*3901组合，其中该等至少一种等位基因之存在代表该患者比该等至少一种等位基因不存在之患者具有较高疾病调节抗风湿药物造成之严重皮肤药物不良反应之风险。在一具体实例中，所述严重皮肤药物不良反应包括至少一种选自以下之不良反应：史帝文生－琼森症候群、毒性表皮坏死症或药物疹合并嗜伊红血症及全身症状。
本发明提供降低疾病调节抗风湿药物引发严重皮肤药物不良反应的发生率或是治疗的方法。
本发明亦提供一种评估疾病调节抗风湿药物引发药物不良反应的风险和治疗此药物不良反应的方法，包括以下步骤：(a)检测一患者样本中选自以下至少一种等位基因：HLA-B*1502、HLA-B*3802或HLA-B*1301与HLA-B*3901组合，(b)若该样本中存在以下至少一种等位基因：HLA-B*1502、HLA-B*3802或HLA-B*1301与HLA-B*3901组合，可鉴定该患者有疾病调节抗风湿药物引发之药物不良反应及(c)给药以治疗此药物不良反应。
在一具体实例中，治疗药物不良反应的方法为施予一种药物包括(但不限于)液体，类固醇、免疫球蛋白、环孢素、抗肿瘤坏死因子制剂(anti-TNF-αagent)或血浆置换。
本发明还涉及一种评估疾病调节抗风湿药物引发药物不良反应的风险和降低药物不良反应发生率的方法，包括以下步骤：(a)检测一患者样本中选自以下之至少一种等位基因：HLA-B*1502、HLA-B*3802或HLA-B*1301与HLA-B*3901组合之存在，(b)若该样本中存在以下至少一种等位基因：HLA-B*1502、HLA-B*3802或HLA-B*1301与HLA-B*3901组合，可鉴定出该患者具有增加发生药物不良反应的风险及(c)不给予该患者疾病调节抗风湿药物。
使用于本发明的用语“发明”及“本发明”旨在广泛地指本发明的所有申请目标，以及权利要求书。含有这些术语的陈述应被理解为不限于本文所述的申请目标或限于发明的权利要求书的含义或范畴。被本发明所涵盖的发明之实施例藉由权利要求书而非本发明内容所定义。本发明内容为本发明的各种态样的高层次概述，并介绍在下面的实施方式部分中进一步描述的一些概念。本发明内容并不旨在确认所要求保护的申请目标之关键或必要特征，也不旨在单独地使用以决定所要求保护的申请目标之范畴。申请目标应藉由参照整份说明书任何或所有图式及每项权利要求的适当部分而理解。
实施方式
在以下实施例中，我们收集32位使用疾病调节抗风湿药物柳氮磺吡啶(Sulfasalazine)引发严重皮肤药物不良反应之患者(包括11位SJS/TEN和21位DRESS患者)进行HLA定型并与941位一般健康人对照组进行比较分析。结 果显示HLA-B*1301、HLA-B*1502、HLA-B*3802、HLA-B*3901、HLA-B*1301与HLA-B*3901、HLA-B*1502与HLA-B*3802、HLA-B*1301与HLA-B*3802与HLA-B*3901或HLA-B*1301与HLA-B*1502与HLA-B*3802与HLA-B*3901等位基因与柳氮磺吡啶引起之严重皮肤药物不良反应具有相关性(如表1)。在HLA-B*1301等位基因分布情形中，21位DRESS患者中有8位带有此基因型(38.10％)，941位一般健康人对照组中只有114位带有此基因型(12.11％)，显示HLA-B*1301与柳氮磺吡啶引起之DRESS具有关联性(DRESS vs.健康人对照组：P＝2.59×10 -3，胜算比(Odds Ratio or OR)＝4.5(1.8-11.0)，敏感度：38.10％，特异性：87.89％)。在HLA-B*3802等位基因分布情形中，11位SJS/TEN患者中有6位带有此基因型(54.54％)，941位一般健康人对照组(General population)中只有71位带有此基因型(7.55％)，显示HLA-B*3802与柳氮磺吡啶引起之SJS/TEN具有关联性(SJS/TEN vs.健康人对照组：P＝7.72×10 -5，胜算比(Odds Ratio or OR)＝14.7(4.4-49.4)，敏感度：54.54％，特异性：92.45％)。进一步将HLA-B*1301及HLA-B*3901合并分析，结果显示合并后与柳氮磺吡啶引起DRESS的相关性及敏感性显著提高(DRESS vs.健康人对照组：P＝4.27×10 -8，胜算比＝13.1(5.0-34.2)，敏感度：71.43％，特异性：83.95％)。在HLA-B*1502等位基因分布情形中，11位SJS/TEN患者中有5位带有此基因型(45.45％)，941位一般健康人对照组中只有87位带有此基因型(9.25％)，显示HLA-B*1502与柳氮磺吡啶引起之SJS/TEN具有关联性(SJS/TEN vs.健康人对照组：P＝2.19×10 -3，胜算比＝8.2(2.4-27.4)，敏感度：45.45％，特异性：90.75％)。在HLA-B*3901等位基因分布情形中，21位DRESS患者中有8位带有此基因型(38.10％)，941位一般健康人对照组中只有43位带有此基因型(4.57％)，显示HLA-B*3901与柳氮磺吡啶引起之DRESS具有关联性(DRESS vs.健康人对照组：P＝4.30×10 -6，胜算比(Odds Ratio or OR)＝12.2(4.6-32.5)，敏感度：38.10％，特异性：95.43％)。进一步将HLA-B*1502及HLA-B*3802合并分析，结果显示合并后与柳氮磺吡啶引起SJS/TEN的相关性及敏感性亦显著提高(SJS/TEN vs.健康人对照组：P＝5.98×10 -5，胜算比＝13.7(3.6-52.4)，敏感度：72.72％，特异性：83.74％)。若进一步将HLA-B*1301及HLA-B*3802及HLA-B*3901合并分析，结果显示合并后与柳氮磺吡啶引起严重皮肤药物不良反应(SCAR)的相关性及敏感性显著提高(SCAR vs.健康人对照组： P＝3.21×10 -8，胜算比＝7.6(3.4-17.1)，敏感度：68.75％，特异性：78.32％)。再进一步将HLA-B*1301及HLA-B*1502及HLA-B*3802及HLA-B*3901合并分析，结果显示合并后与柳氮磺吡啶引起严重皮肤药物不良反应(SCAR)的相关性及敏感性显著提高(SCAR vs.健康人对照组：P＝2.67×10 -7，胜算比＝7.1(3.0-16.9)，敏感度：75.00％，特异性：60.35％)。由以上结果得知检测HLA-B*1301、HLA-B*1502、HLA-B*3802、HLA-B*3901、HLA-B*1301与HLA-B*3901、HLA-B*1502与HLA-B*3802、HLA-B*1301与HLA-B*3802与HLA-B*3901或HLA-B*1301与HLA-B*1502与HLA-B*3802与HLA-B*3901等位基因存在与否可以被用来评估抗癫痫药物拉莫三嗪引发皮肤药物不良反应之风险。
表一、32位疾病调节抗风湿药物柳氮磺吡啶(Sulfasalazine)严重皮肤药物不良反应患者与941位一般健康人对照组之HLA-B*1301及/或HLA-B*1502及/或HLA-B*3802及/或HLA-B*3901基因型分析比较。
Figure PCTCN2019085639-appb-000005
Figure PCTCN2019085639-appb-000006
前文系针对本发明之优选实施例为本发明之技术特征进行具体之说明；惟，熟悉此项技术之人士当可在不脱离本发明之精神与原则下对本发明进行变更与修改，而该等变更与修改，皆应涵盖于如下申请专利范围所界定之范畴中。

Claims (12)

  1. 一种评估患者发展出皮肤药物不良反应风险之方法，该方法包括测定该患者中选自以下之至少一种等位基因：
    (a)HLA-B*1502；
    (b)HLA-B*3802；或
    (c)HLA-B*1301与HLA-B*3901组合，
    其中该等至少一种等位基因之存在代表该患者比该等至少一种等位基因不存在之患者具有较高疾病调节抗风湿药物造成之严重皮肤药物不良反应之风险。
  2. 如权利要求1所述之方法，其中该严重皮肤药物不良反应包括至少一种选自以下之不良反应：史帝文生－琼森症候群(Stevens Johnson Syndrome，SJS)、毒性表皮坏死症(toxic epidermal necrolysis，TEN)或药物疹合并嗜伊红血症及全身症状(drug rash with eosinophilia and systemic symptoms，DRESS)。
  3. 如权利要求1所述之方法，其中HLA-B*1502、HLA-B*3802或HLA-B*1301与HLA-B*3901等位基因之测定系采用来自患者周边血液之DNA、RNA、蛋白质、细胞或血清制备之样品进行测定。
  4. 如权利要求1所述之方法，其中疾病调节抗风湿药物为柳氮磺吡啶(Sulfasalazine)、美色拉秦(Mesalazine)、磺胺比啶(Sulfapyridine)或奥色拉秦(Olsalazine)。
  5. 一种评估患者发展疾病调节抗风湿药物造成之皮肤药物不良反应风险之检测试剂盒，该试剂盒包括用于侦测患者之检测样本中选自以下之至少一种等位基因之试剂：
    (a)HLA-B*1502；
    (b)HLA-B*3802；或
    (c)HLA-B*1301与HLA-B*3901组合疾病调节抗风湿药物。
  6. 如权利要求5所述之检测试剂盒，其中该严重皮肤药物不良反应包括至少一种选自以下之不良反应：史帝文生－琼森症候群、毒性表皮坏死症、药物疹合并嗜伊红血症及全身症状。
  7. 如权利要求5所述之检测试剂盒，其中该试剂盒包括与等位基因之核酸 专一性杂交之寡核苷酸。
  8. 如权利要求5所述之试剂盒，其中疾病调节抗风湿药物为柳氮磺吡啶(Sulfasalazine)、美色拉秦(Mesalazine)、磺胺比啶(Sulfapyridine)或奥色拉秦(Olsalazine)。
  9. 检测HLA-B*1502、HLA-B*3802或HLA-B*3901与HLA-B*1301组合之等位基因的试剂在制备用于评估疾病调节抗风湿药物引发严重皮肤药物不良反应的风险的试剂盒中的用途。
  10. 如权利要求9所述之用途，其中该严重皮肤药物不良反应包括至少一种选自以下之不良反应：史帝文生－琼森症候群、毒性表皮坏死症、药物疹合并嗜伊红血症全身症状。
  11. 如权利要求9所述之用途，其中该试剂盒包括与等位基因之核酸专一性杂交的寡核苷酸。
  12. 如权利要求9所述之用途，其中疾病调节抗风湿药物为柳氮磺吡啶(Sulfasalazine)、美色拉秦(Mesalazine)、磺胺比啶(Sulfapyridine)或奥色拉秦(Olsalazine)。
PCT/CN2019/085639 2019-05-06 2019-05-06 评估疾病调节抗风湿药物引发严重皮肤药物不良反应风险的方法、其检测试剂盒及其用途 WO2020223867A1 (zh)

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JP2021563076A JP7334263B2 (ja) 2019-05-06 2019-05-06 疾患修飾性抗リウマチ薬によって誘発される重度の皮膚副作用を発症するリスクを評価するための方法、その検出キットおよびその使用
CN201980044664.9A CN112513294A (zh) 2019-05-06 2019-05-06 评估疾病调节抗风湿药物引发严重皮肤药物不良反应风险的方法、其检测试剂盒及其用途
SG11202111473UA SG11202111473UA (en) 2019-05-06 2019-05-06 Methods for assessing the risk of developing severe cutaneous adverse drug reactions induced by disease-modifying antirheumatic drugs, detection kit thereof and uses thereof

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CN101454462A (zh) * 2006-05-11 2009-06-10 中央研究院 与药物不良反应相关的hla等位基因及其检测方法
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