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Article(id=1208795424199144130, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208795418612339683, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2021.10.06, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1623859200000, receivedDateStr=2021-06-17, revisedDate=1631376000000, revisedDateStr=2021-09-12, acceptedDate=null, acceptedDateStr=null, onlineDate=1766128887461, onlineDateStr=2025-12-19, pubDate=1635350400000, pubDateStr=2021-10-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766128887461, onlineIssueDateStr=2025-12-19, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766128887461, creator=13701087609, updateTime=1766128887461, updator=13701087609, issue=Issue{id=1208795418612339683, tenantId=1146029695717560320, journalId=1189873630562394117, year='2021', volume='46', issue='10', pageStart='955', pageEnd='1060', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1766128886129, creator=13701087609, updateTime=1766128956061, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1208795711982924071, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208795418612339683, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1208795711982924072, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1208795418612339683, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=989, endPage=996, ext={EN=ArticleExt(id=1208795426921247446, articleId=1208795424199144130, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Clinical characters and influence factors of immune checkpoint inhibitor related thyroiditis, columnId=1190310109000602400, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Clinical Research, runingTitle=null, highlight=null, articleAbstract=

Objective To investigate the clinical characters and influence factors of immune-related thyroiditis(irT) brought by the immune checkpoint inhibitors (ICI) in treatment of malignant tumor. Methods The clinical data were retrospectively analyzed of 286 certificated patients treated with ICI in the Department of Oncology, the First Medical Center of Chinese PLA General Hospital during 2019-2020. The patients were divided into irT group (n=83) and non-irT group (n=203)according to the occurrence of thyroid dysfunction, and the differences between the two groups were compared of age, gender,tumor origin, previous treatment history and ICI types. Then the patients were divided into different subgroups according to the clinical manifestations or severity of irT, then the time of thyroid injury occurrence, auto-antibody level and recovery degree of thyroid dysfunction were compared and analyzed among different subgroups. Results Of the 286 certificated patients, 83 patients(29.0%) developed irT, those with lower age and history of radiotherapy had greater incidence rate. The clinical manifestation of irT included hyperthyroidism (n=28, 33.7%), hypothyroidism (n=48, 57.8%) and transient thyroiditis with normal thyroid function(n=7, 8.4%). All the 83 irT patients, 76 patients (91.6%) only developed mild irT, while 7 patients (8.4%) were severe. In the 28 patients initially diagnosed as immune-related hyperthyroidism, 7 patients (25%) progressed to secondary hypothyroidism in the later course with faster evolution rate than the patients with primary thyroiditis. There was no statistical difference in irT incidence among the patients treated with 4 frequently used PD-1 inhibitors (Pembrolizumab, Nivolumab, Sintilimab and Toripalimab).Among the 83 irT patients, the serum thyroid auto-antibodies levels were often elevated in irT patients. The thyroglobulin antibody(TGAb) was elevated in 23 patients (29.5%) and the thyroid peroxidase antibody (TPOAb) were elevated in 14 patients (12.8%).The TGAb and TPOAb levels were significantly higher in severe irT patients than that in mild patients. The symptoms in most irT patients were reversible and the treatment was tolerable. Only 3 patients (3.6%) stopped ICI treatment due to intolerable symptoms. Conclusions The incidence of irT during immunotherapy was relatively high and its clinical manifestations progressed rapidly.Continuously monitoring the thyroid function should be done during ICI treatment. The clinicians should treat the irT patients promptly according to their clinical stages and symptoms.

, correspAuthors=Shun-Chang Jiao, authorNote=null, correspAuthorsNote=
*E-mail:
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目的 探讨在恶性肿瘤治疗中免疫检查点抑制剂(ICI)引起的免疫相关甲状腺炎(irT)的临床特点及其影响因素。方法 回顾性分析2019—2020年在解放军总医院第一医学中心肿瘤内科接受ICI治疗，符合纳入标准的286例恶性肿瘤患者的临床资料。根据患者甲状腺不良反应的发生情况，将患者分为irT组(n=83)与非irT组(n=203)，对比两组患者年龄、性别、肿瘤来源、既往治疗史及所用ICI药物之间的差异，并根据irT患者的临床表现及严重程度分为不同亚组，对比分析不同亚组患者甲状腺损伤的发生时间、自身抗体水平及恢复情况等。结果 入组患者中83例(29.0%)出现了irT，年龄低及有放疗史的患者irT发生率高。irT患者中临床表现为甲亢28例(33.7%)、甲减48例(57.8%)、甲状腺功能正常的甲状腺炎7例(8.4%)。83例irT患者中76例(91.6%)为轻症，重症仅7例(8.4%)。28例甲亢型irT患者中7例(25%)在病程后期转化为甲减型，其演变速度较原发性甲状腺炎快。4种临床常用ICI药物(帕博利珠单抗、纳武利尤单抗、信迪利单抗、特瑞普利单抗)的irT发生率差异无统计学意义。83例irT患者中，23例(29.5%)甲状腺球蛋白抗体(TGAb)、14例(12.8%)过氧化物酶抗体(TPOAb)存在异常，重症者的TGAb、TPOAb明显高于轻症者。在患者转归方面，经过治疗后irT的症状普遍可以缓解，仅3例(3.6%)因不可耐受的症状中断了免疫治疗。结论 irT的发生率高且变化快，行免疫治疗的患者应注意监测甲状腺功能，以发现irT并及早干预。

, correspAuthors=焦顺昌, authorNote=null, correspAuthorsNote=
焦顺昌，E-mail：
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杨子仲，硕士研究生，住院医师，主要从事肿瘤免疫治疗方面的研究

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杨子仲，硕士研究生，住院医师，主要从事肿瘤免疫治疗方面的研究

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杨子仲，硕士研究生，住院医师，主要从事肿瘤免疫治疗方面的研究

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J Transl Autoimmun, 2020, 3: 100038., articleTitle=Latent autoimmune thyroid disease, refAbstract=null)], funds=[Fund(id=1209111236558590859, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, awardId=2018ZX09201013, language=EN, fundingSource=Major Special Projects Foundation of the "13th Five-Year Plan" of China(2018ZX09201013), fundOrder=null, country=null), Fund(id=1209111236629894029, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, awardId=2018ZX09201013, language=CN, fundingSource=国家“十三五”重大专项课题(2018ZX09201013), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1209111231491871524, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, xref=1, ext=[AuthorCompanyExt(id=1209111231496065829, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, companyId=1209111231491871524, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1School of Medicine, Nankai University, Tianjin 300071, China), AuthorCompanyExt(id=1209111231508648742, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, companyId=1209111231491871524, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=1南开大学医学院，天津 300071)]), AuthorCompany(id=1209111231584146215, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, xref=2, ext=[AuthorCompanyExt(id=1209111231592534824, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, companyId=1209111231584146215, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2Department of Oncology, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, China), AuthorCompanyExt(id=1209111231600923433, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, companyId=1209111231584146215, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2解放军总医院第一医学中心肿瘤内科，北京 100853)]), AuthorCompany(id=1209111231655449386, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, xref=3, ext=[AuthorCompanyExt(id=1209111231659643691, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, companyId=1209111231655449386, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3Department of Endocrinology, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, China), AuthorCompanyExt(id=1209111231668032300, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, companyId=1209111231655449386, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=3解放军总医院第一医学中心内分泌科，北京 100853)])], figs=[ArticleFig(id=1209111234264306547, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, language=EN, label=Fig. 1, caption=Characteristics of the occurrence time of immune related thyroiditis, figureFileSmall=x2zdMxBurxHo6oKkGkU93Q==, figureFileBig=ZAYgiCuCjeqnJokXf7ENMQ==, tableContent=null), ArticleFig(id=1209111234339804021, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, language=CN, label=图1, caption=免疫相关甲状腺炎发生的时间特点

A. 甲亢型与甲减型irT发生时间的对比；B. 不同严重程度分级的irT发生时间对比；C. 甲亢向甲减转化的irT患者治疗时间与促甲状腺素(TSH)水平之间的关系

, figureFileSmall=x2zdMxBurxHo6oKkGkU93Q==, figureFileBig=ZAYgiCuCjeqnJokXf7ENMQ==, tableContent=null), ArticleFig(id=1209111234411107191, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, language=EN, label=Fig. 2, caption=The ultrasound imaging of immune related thyroiditis (irT), figureFileSmall=+9gb6WlEK/+HEHI355P6ag==, figureFileBig=PynLzO0woFQxLw408onsgg==, tableContent=null), ArticleFig(id=1209111234499187577, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, language=CN, label=图2, caption=免疫相关甲状腺炎(irT)的超声影像

A. 可见甲状腺体积稍缩小，实质回声不均；B. 甲状腺弥漫病变

, figureFileSmall=+9gb6WlEK/+HEHI355P6ag==, figureFileBig=PynLzO0woFQxLw408onsgg==, tableContent=null), ArticleFig(id=1209111234595656571, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, language=EN, label=Tab. 1, caption=

Comparison of the general data, type of ICI drugs and baseline level of thyroid hormone between the patients in irT and non-irT group

, figureFileSmall=null, figureFileBig=null, tableContent=
基线临床数据irT组(n=83)非irT组(n=203)t/χ2P
年龄(岁，$\bar{x}±s$)55.5±13.958.9±11.42.1440.033
性别[例(%)]3.3580.067
 男56(67.5)158(77.8)
 女27(32.5)45(22.2)
Karnofsky(KPS)评分[例(%)]
 >70分73(88.0)176(86.7)0.0820.775
 ≤70分10(12.0)27(11.3)
BMI[例(%)]  0.1210.728
 <24kg/m253(63.9)134(66.0)
 ≥24kg/m230(36.1)69(34.0)
肿瘤来源[例(%)]  5.4040.714
 非小细胞肺癌33(39.8)77(37.9)
 食管鳞癌8(9.6)31(15.3)
 胃癌7(8.4)15(7.4)
 小细胞肺癌5(6.0)13(6.4)
 结肠癌6(7.2)8(3.9)
 胰腺癌1(1.2)9(4.4)
 尿路上皮癌2(2.4)6(3.0)
 胆囊癌/胆管癌3(3.6)4(2.0)
 其他(1)18(21.7)40(19.7)
药物过敏史[例(%)]  0.0010.983
 有13(15.7)32(15.8)
 无70(84.3)171(84.2)
手术史[例(%)]  1.5390.215
 有41(49.4)84(41.4)
 无42(50.6)119(58.6)
化疗史[例(%)]  0.2440.621
 有76(91.6)182(89.7)
 无7(8.4)21(10.3)
放疗史[例(%)]  5.5190.023
 有32(38.6)51(25.1)
 无51(61.4)152(74.9)
靶向治疗史[例(%)]  0.8730.350
 有52(62.7)115(56.7)
 无31(37.3)88(43.3)
药物种类[例(%)]  10.810.228
 帕博利珠单抗26(31.3)49(24.1)
 信迪利单抗17(20.5)48(23.6)
 特瑞普利单抗22(26.5)37(18.2)
 纳武利尤单抗(单药)11(13.3)40(19.7)
 替雷利珠单抗0(0)7(3.4)
 卡瑞利珠单抗1(1.2)5(2.5)
 阿替利珠单抗3(3.6)3(1.5)
 度伐利尤单抗1(1.2)3(1.5)
 纳武利尤单抗+伊匹木单抗2(2.4)11(5.4)
治疗前甲状腺激素水平($\bar{x}±s$)
 FT3 (pmol/L)4.438±0.8684.349±0.6740.9280.354
 FT4 (pmol/L)14.78±2.81514.60±1.9300.6200.536
 TSH (mU/L)2.203±1.2461.938±1.0421.8330.068
), ArticleFig(id=1209111234683736957, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, language=CN, label=表1, caption=

免疫相关甲状腺炎(irT)组与非irT组免疫治疗患者的一般资料、ICI药物类型及基线甲状腺激素水平比较

, figureFileSmall=null, figureFileBig=null, tableContent=
基线临床数据irT组(n=83)非irT组(n=203)t/χ2P
年龄(岁，$\bar{x}±s$)55.5±13.958.9±11.42.1440.033
性别[例(%)]3.3580.067
 男56(67.5)158(77.8)
 女27(32.5)45(22.2)
Karnofsky(KPS)评分[例(%)]
 >70分73(88.0)176(86.7)0.0820.775
 ≤70分10(12.0)27(11.3)
BMI[例(%)]  0.1210.728
 <24kg/m253(63.9)134(66.0)
 ≥24kg/m230(36.1)69(34.0)
肿瘤来源[例(%)]  5.4040.714
 非小细胞肺癌33(39.8)77(37.9)
 食管鳞癌8(9.6)31(15.3)
 胃癌7(8.4)15(7.4)
 小细胞肺癌5(6.0)13(6.4)
 结肠癌6(7.2)8(3.9)
 胰腺癌1(1.2)9(4.4)
 尿路上皮癌2(2.4)6(3.0)
 胆囊癌/胆管癌3(3.6)4(2.0)
 其他(1)18(21.7)40(19.7)
药物过敏史[例(%)]  0.0010.983
 有13(15.7)32(15.8)
 无70(84.3)171(84.2)
手术史[例(%)]  1.5390.215
 有41(49.4)84(41.4)
 无42(50.6)119(58.6)
化疗史[例(%)]  0.2440.621
 有76(91.6)182(89.7)
 无7(8.4)21(10.3)
放疗史[例(%)]  5.5190.023
 有32(38.6)51(25.1)
 无51(61.4)152(74.9)
靶向治疗史[例(%)]  0.8730.350
 有52(62.7)115(56.7)
 无31(37.3)88(43.3)
药物种类[例(%)]  10.810.228
 帕博利珠单抗26(31.3)49(24.1)
 信迪利单抗17(20.5)48(23.6)
 特瑞普利单抗22(26.5)37(18.2)
 纳武利尤单抗(单药)11(13.3)40(19.7)
 替雷利珠单抗0(0)7(3.4)
 卡瑞利珠单抗1(1.2)5(2.5)
 阿替利珠单抗3(3.6)3(1.5)
 度伐利尤单抗1(1.2)3(1.5)
 纳武利尤单抗+伊匹木单抗2(2.4)11(5.4)
治疗前甲状腺激素水平($\bar{x}±s$)
 FT3 (pmol/L)4.438±0.8684.349±0.6740.9280.354
 FT4 (pmol/L)14.78±2.81514.60±1.9300.6200.536
 TSH (mU/L)2.203±1.2461.938±1.0421.8330.068
), ArticleFig(id=1209111234796983167, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, language=EN, label=Tab. 2, caption=

The clinical characteristics of immune related thyroiditis

, figureFileSmall=null, figureFileBig=null, tableContent=
临床特征数值
最初的临床分型[例(%)]
 甲状腺功能亢进11(13.3)
 亚临床甲亢17(20.5)
 甲减29(34.9)
 亚临床甲减19(22.9)
 甲状腺激素正常的甲状腺炎7(8.4)
严重程度分级[例(%)]
 1级44(53.0)
 2级32(38.6)
 3级6(7.2)
 4级1(1.2)
 5级0
主要临床表现[例(%)]
 乏力疲劳10(12.0)
 甲状腺疼痛8(9.6)
 甲状腺肿2(2.4)
 烦躁4(4.8)
 心律失常(1)2(2.4)
 皮肤水肿1(1.2)
 甲状腺减退危象1(1.2)
甲状腺激素水平(pmol/L，$\bar{x}±s$)
 甲亢期最高FT38.871±3.553
 甲亢期最高FT428.43±11.81
 甲减期最低FT32.748±1.859
 甲减期最低FT49.471±4.669
合并其他2级以上irAE[例(%)]
 是32(38.6)
 否51(61.4)
超声影像学异常[例(%)]
 有5(9.6)
 无78(90.4)
干预措施[例(%)]
 低碘饮食6(7.2)
 应用甲巯咪唑2(2.4)
 应用左甲状腺素12(14)
 应用糖皮质激素(2)1(1.2)
), ArticleFig(id=1209111235971388289, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, language=CN, label=表2, caption=

免疫相关甲状腺炎(irT)的临床特征

, figureFileSmall=null, figureFileBig=null, tableContent=
临床特征数值
最初的临床分型[例(%)]
 甲状腺功能亢进11(13.3)
 亚临床甲亢17(20.5)
 甲减29(34.9)
 亚临床甲减19(22.9)
 甲状腺激素正常的甲状腺炎7(8.4)
严重程度分级[例(%)]
 1级44(53.0)
 2级32(38.6)
 3级6(7.2)
 4级1(1.2)
 5级0
主要临床表现[例(%)]
 乏力疲劳10(12.0)
 甲状腺疼痛8(9.6)
 甲状腺肿2(2.4)
 烦躁4(4.8)
 心律失常(1)2(2.4)
 皮肤水肿1(1.2)
 甲状腺减退危象1(1.2)
甲状腺激素水平(pmol/L，$\bar{x}±s$)
 甲亢期最高FT38.871±3.553
 甲亢期最高FT428.43±11.81
 甲减期最低FT32.748±1.859
 甲减期最低FT49.471±4.669
合并其他2级以上irAE[例(%)]
 是32(38.6)
 否51(61.4)
超声影像学异常[例(%)]
 有5(9.6)
 无78(90.4)
干预措施[例(%)]
 低碘饮食6(7.2)
 应用甲巯咪唑2(2.4)
 应用左甲状腺素12(14)
 应用糖皮质激素(2)1(1.2)
), ArticleFig(id=1209111236059468675, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, language=EN, label=Tab. 3, caption=

Comparison of the immune related thyroiditis induced by different types of immune checkpoint inhibitors

, figureFileSmall=null, figureFileBig=null, tableContent=
项目帕博利珠单抗(n=75)信迪利单抗(n=65)特瑞普利单抗(n=59)纳武利尤单抗(n=51)合计(n=286)
发生irT[例(%)]26(34.7)17(26.2)21(35.6)11(21.6)83(29.0)
发生2-4级irT[例(%)]11(14.7)7(10.8)12(20.3)7(13.7)39(13.6)
irT的中位发生时间[d，M(Q1，Q3)]154(84，253)55.5(30，129)91(44，153)65(35，190)92(36，170)
), ArticleFig(id=1209111236143354756, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, language=CN, label=表3, caption=

不同免疫检查点抑制剂(ICI)所致免疫相关甲状腺炎(irT)的发生情况比较

, figureFileSmall=null, figureFileBig=null, tableContent=
项目帕博利珠单抗(n=75)信迪利单抗(n=65)特瑞普利单抗(n=59)纳武利尤单抗(n=51)合计(n=286)
发生irT[例(%)]26(34.7)17(26.2)21(35.6)11(21.6)83(29.0)
发生2-4级irT[例(%)]11(14.7)7(10.8)12(20.3)7(13.7)39(13.6)
irT的中位发生时间[d，M(Q1，Q3)]154(84，253)55.5(30，129)91(44，153)65(35，190)92(36，170)
), ArticleFig(id=1209111236260795270, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, language=EN, label=Tab. 4, caption=

The outcome of patients with immune related thyroiditis (n)

, figureFileSmall=null, figureFileBig=null, tableContent=
分型症状恢复甲状腺激素恢复促甲状腺激素恢复自身抗体恢复中断治疗复发
甲亢(n=11)772010
甲减(n=29)10113323
), ArticleFig(id=1209111236374041481, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1208795424199144130, language=CN, label=表4, caption=

免疫相关甲状腺炎(irT)患者的转归情况(例)

, figureFileSmall=null, figureFileBig=null, tableContent=
分型症状恢复甲状腺激素恢复促甲状腺激素恢复自身抗体恢复中断治疗复发
甲亢(n=11)772010
甲减(n=29)10113323
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免疫检查点抑制剂相关甲状腺炎的临床特点及其影响因素分析
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杨子仲 1, 2 , 张国庆 2 , 秦博宇 2 , 张静 2 , 孙琼 2 , 李彬琦 1, 3 , 焦顺昌 2, *
解放军医学杂志 | 论著 2021,46(10): 989-996
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解放军医学杂志 | 论著 2021, 46(10): 989-996
免疫检查点抑制剂相关甲状腺炎的临床特点及其影响因素分析
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杨子仲1, 2, 张国庆2, 秦博宇2, 张静2, 孙琼2, 李彬琦1, 3, 焦顺昌2, *
作者信息
  • 1南开大学医学院，天津 300071
  • 2解放军总医院第一医学中心肿瘤内科，北京 100853
  • 3解放军总医院第一医学中心内分泌科，北京 100853

    • 杨子仲，硕士研究生，住院医师，主要从事肿瘤免疫治疗方面的研究

通讯作者:

焦顺昌，E-mail：
Clinical characters and influence factors of immune checkpoint inhibitor related thyroiditis
Zi-Zhong Yang1, 2, Guo-Qing Zhang2, Bo-Yu Qin2, Jing Zhang2, Qiong Sun2, Bin-Qi Li1, 3, Shun-Chang Jiao2, *
Affiliations
  • 1School of Medicine, Nankai University, Tianjin 300071, China
  • 2Department of Oncology, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
  • 3Department of Endocrinology, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
出版时间: 2021-10-28 doi: 10.11855/j.issn.0577-7402.2021.10.06
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摘要
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目的 探讨在恶性肿瘤治疗中免疫检查点抑制剂(ICI)引起的免疫相关甲状腺炎(irT)的临床特点及其影响因素。方法 回顾性分析2019—2020年在解放军总医院第一医学中心肿瘤内科接受ICI治疗，符合纳入标准的286例恶性肿瘤患者的临床资料。根据患者甲状腺不良反应的发生情况，将患者分为irT组(n=83)与非irT组(n=203)，对比两组患者年龄、性别、肿瘤来源、既往治疗史及所用ICI药物之间的差异，并根据irT患者的临床表现及严重程度分为不同亚组，对比分析不同亚组患者甲状腺损伤的发生时间、自身抗体水平及恢复情况等。结果 入组患者中83例(29.0%)出现了irT，年龄低及有放疗史的患者irT发生率高。irT患者中临床表现为甲亢28例(33.7%)、甲减48例(57.8%)、甲状腺功能正常的甲状腺炎7例(8.4%)。83例irT患者中76例(91.6%)为轻症，重症仅7例(8.4%)。28例甲亢型irT患者中7例(25%)在病程后期转化为甲减型，其演变速度较原发性甲状腺炎快。4种临床常用ICI药物(帕博利珠单抗、纳武利尤单抗、信迪利单抗、特瑞普利单抗)的irT发生率差异无统计学意义。83例irT患者中，23例(29.5%)甲状腺球蛋白抗体(TGAb)、14例(12.8%)过氧化物酶抗体(TPOAb)存在异常，重症者的TGAb、TPOAb明显高于轻症者。在患者转归方面，经过治疗后irT的症状普遍可以缓解，仅3例(3.6%)因不可耐受的症状中断了免疫治疗。结论 irT的发生率高且变化快，行免疫治疗的患者应注意监测甲状腺功能，以发现irT并及早干预。

免疫检查点抑制剂  /  免疫相关不良反应  /  桥本甲状腺炎  /  免疫相关甲状腺炎

Objective To investigate the clinical characters and influence factors of immune-related thyroiditis(irT) brought by the immune checkpoint inhibitors (ICI) in treatment of malignant tumor. Methods The clinical data were retrospectively analyzed of 286 certificated patients treated with ICI in the Department of Oncology, the First Medical Center of Chinese PLA General Hospital during 2019-2020. The patients were divided into irT group (n=83) and non-irT group (n=203)according to the occurrence of thyroid dysfunction, and the differences between the two groups were compared of age, gender,tumor origin, previous treatment history and ICI types. Then the patients were divided into different subgroups according to the clinical manifestations or severity of irT, then the time of thyroid injury occurrence, auto-antibody level and recovery degree of thyroid dysfunction were compared and analyzed among different subgroups. Results Of the 286 certificated patients, 83 patients(29.0%) developed irT, those with lower age and history of radiotherapy had greater incidence rate. The clinical manifestation of irT included hyperthyroidism (n=28, 33.7%), hypothyroidism (n=48, 57.8%) and transient thyroiditis with normal thyroid function(n=7, 8.4%). All the 83 irT patients, 76 patients (91.6%) only developed mild irT, while 7 patients (8.4%) were severe. In the 28 patients initially diagnosed as immune-related hyperthyroidism, 7 patients (25%) progressed to secondary hypothyroidism in the later course with faster evolution rate than the patients with primary thyroiditis. There was no statistical difference in irT incidence among the patients treated with 4 frequently used PD-1 inhibitors (Pembrolizumab, Nivolumab, Sintilimab and Toripalimab).Among the 83 irT patients, the serum thyroid auto-antibodies levels were often elevated in irT patients. The thyroglobulin antibody(TGAb) was elevated in 23 patients (29.5%) and the thyroid peroxidase antibody (TPOAb) were elevated in 14 patients (12.8%).The TGAb and TPOAb levels were significantly higher in severe irT patients than that in mild patients. The symptoms in most irT patients were reversible and the treatment was tolerable. Only 3 patients (3.6%) stopped ICI treatment due to intolerable symptoms. Conclusions The incidence of irT during immunotherapy was relatively high and its clinical manifestations progressed rapidly.Continuously monitoring the thyroid function should be done during ICI treatment. The clinicians should treat the irT patients promptly according to their clinical stages and symptoms.

immune checkpoint inhibitor  /  immune-related adverse effect  /  Hashimoto's thyroiditis  /  immune-related thyroiditis
杨子仲, 张国庆, 秦博宇, 张静, 孙琼, 李彬琦, 焦顺昌. 免疫检查点抑制剂相关甲状腺炎的临床特点及其影响因素分析. 解放军医学杂志, 2021 , 46 (10) : 989 -996 . DOI: 10.11855/j.issn.0577-7402.2021.10.06
Zi-Zhong Yang, Guo-Qing Zhang, Bo-Yu Qin, Jing Zhang, Qiong Sun, Bin-Qi Li, Shun-Chang Jiao. Clinical characters and influence factors of immune checkpoint inhibitor related thyroiditis[J]. Medical Journal of Chinese People’s Liberation Army, 2021 , 46 (10) : 989 -996 . DOI: 10.11855/j.issn.0577-7402.2021.10.06
正文
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免疫检查点抑制剂(immune checkpoint inhibitors，ICI)是一类新型抗肿瘤药物，主要通过阻断程序性死亡受体1(PD-1)/程序性死亡配体1(PD-L1)等信号通路来增强人体的抗肿瘤免疫反应。既往研究证实，免疫治疗较传统疗法缓解率更高，生存获益更大[1]。目前，ICI已广泛应用于肺癌、泌尿上皮癌及消化道肿瘤等的治疗。一般认为，免疫治疗具有较好的安全性和耐受性，国外有研究报道，严重的免疫相关不良反应(irAE)发生率仅为0.5%~13.0%[2]。然而，由于ICI影响自身免疫的特点，其造成的不良反应形式多样，可累及多种组织器官。目前，关于irAE的研究主要集中于肺[3]、心脏[4]、脑[5]等主要脏器，对于ICI所致的免疫相关甲状腺炎(immune-related thyroiditis，irT)关注甚少。免疫治疗的甲状腺损伤主要包括免疫相关性甲亢和免疫相关性甲减。在既往的药物临床试验报道中，irT的发生率较其他irAE略高，其临床表现与对应的原发性甲状腺疾病类似[6]。而药物性甲状腺损害严重影响患者，尤其是长期生存患者的生活质量。严重甲状腺毒性会造成免疫治疗推迟和中止，使患者再次暴露在肿瘤进展的风险之中。同时CheckMate141的亚组分析也显示亚洲人群免疫相关内分泌不良反应的发生率高于全球平均水平[7]，但国内目前尚未见多药物、多癌种中irT发生特点的回顾性研究。本研究对在解放军总医院第一医学中心接受免疫治疗的恶性肿瘤患者irT的发生情况和影响因素进行分析，以期对免疫治疗不良反应的预防和管理提供经验。
1 资料与方法
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1.1 一般资料
选取2019年1月1日—2020年12月31日于解放军总医院第一医学中心肿瘤内科住院接受ICI治疗的恶性肿瘤患者312例进行回顾性分析。本研究经解放军总医院第一医学中心伦理委员会批准(S2018-092-01)，所有患者在开始接受ICI治疗前均签署知情同意书。免疫相关甲亢和甲减的诊断标准参考2020年版美国国家综合癌症网络(NCCN)的免疫相关毒性管理指南[8]。甲状腺功能正常型甲状腺炎的诊断参考2019年版英国国家卫生与临床优化研究所(NICE)甲状腺疾病的评估和管理指南[9]：甲状腺弥漫肿大伴甲状腺球蛋白抗体(TGAb)、甲状腺过氧化物酶抗体(TPOAb)升高，而血清游离三碘甲腺原氨酸(FT3)、游离四碘甲腺原氨酸(FT4)、促甲状腺素(TSH)水平正常，并排除可能造成甲状腺肿大及疼痛的其他疾病。纳入标准为：(1)患有经病理学确诊的恶性实体肿瘤；(2)接受过至少2个周期规范的ICI治疗；(3)具有可分析的临床病历资料。排除标准：(1)合并甲状腺疾病、接受过甲状腺手术或患有自身免疫性疾病；(2)ICI治疗开始前存在FT3、FT4、TSH水平异常；(3)可证实为毒性甲状腺肿所致的甲状腺功能异常；(4)所患恶性肿瘤为甲状腺癌或甲状腺转移癌；(5)同时接受免疫细胞治疗；(6)接受过甲状腺区放疗。最终排除26例，共纳入286例。
1.2 方法
1.2.1 资料收集
通过电子病历系统收集所有患者的临床资料，包括ICI治疗开始时的年龄、性别、身高、体重、肿瘤来源，既往接受的抗肿瘤治疗史，所用的ICI类型等。所有患者均通过每2个周期(相当于5~6周)ICI治疗后评估甲状腺功能(包括血清FT3、FT4、TSH水平)，对于怀疑甲状腺损伤者进行甲状腺超声及甲状腺自身抗体(TGAb、TPOAb)检测。T3、T4、TSH、TPOAb、TGAb均通过电化学发光法(罗氏Cobase 601化学发光仪)检测；甲状腺彩色超声检查由解放军总医院第一医学中心介入超声科进行。
1.2.2 irT的分类
根据甲状腺功能将甲状腺损伤分为以下5类[10]。(1)临床甲亢型：FT3或FT4水平升高、TSH正常或低于正常；(2)亚临床甲亢型：FT3、FT4正常，但TSH水平低于正常，且无典型症状；(3)临床甲减型：FT3或FT4水平减低，TSH水平正常或高于正常；(4)亚临床甲减型：FT3、FT4正常，但TSH高于正常，且无典型症状；(5)甲状腺激素正常的甲状腺炎：FT3、FT4正常，但存在甲状腺肿大等临床表现及甲状腺自身抗体阳性，可伴有超声下甲状腺形态异常，符合甲状腺炎的表现。
1.2.3 irT的严重程度
irT的严重程度分级参考美国癌症中心不良事件报告术语(CTCAE5.0)进行，根据患者的临床表现分为5级[11]。1级：仅为临床或诊断所见，无需治疗；2级：具有轻度的临床症状，需要局部或非侵入性治疗，日常活动轻度受限；3级：严重或者具重要医学意义但不会立即危及生命，导致住院或者延长住院时间或致残；自理性日常生活活动受限；4级：危及生命，需要紧急治疗；5级：AE相关的死亡。如患者在治疗过程中出现多次irT，则按照严重程度等级最高的一次进行分析。
1.2.4 患者分组
根据患者是否发生irT将患者分为irT组(n=83)与非irT组(n=203)。再将irT组患者根据甲状腺功能异常情况分为甲亢组(n=28)、甲减组(n=48)及甲状腺功能正常的甲状腺炎组(n=7)三个亚组；根据irT的严重程度分为轻症组(CTCAE分级1-2级，n=76)与重症组(CTCAE分级3级及以上，n=7)两个亚组。
1.2.5 指标分析
比较irT组与非irT组患者的基线临床资料(包括年龄等一般情况、肿瘤的来源及治疗史、基线甲状腺激素水平)的差异，再对irT组患者甲状腺损伤的分型、严重程度分级、甲状腺激素水平、合并症等临床特征进行统计描述；对比分析不同严重程度、不同临床分型irT亚组患者的发生时间，所用的ICI药物种类，甲状腺自身抗体(TPOAb、TGAb)水平的特点和差异，并分析irT患者的转归情况。
1.3 统计学处理
采用SPSS 22.0和R 4.02软件进行统计分析。正态分布的计量资料以$\bar{x}±s$表示，irT组与非irT组基线甲状腺激素水平的比较采用独立样本t检验；甲状腺自身抗体等非正态计量资料以M(Q1，Q3)表示，组间比较采用秩和检验；计数资料以例(%)表示，组间比较采用χ2检验或Fisher精确概率法校正；采用Kaplan-Meier法分析不同亚组中irT发生的时间差异；甲状腺自身抗体TGAb与TPOAb的相关性采用Spearman相关分析。P<0.05(双侧)为差异有统计学意义。
2 结果
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2.1 一般资料比较
在所有纳入的患者中，男性(n=214)多于女性(n=72)，接受ICI治疗的患者平均年龄为57.9(20~85)岁。纳入患者的原发肿瘤种类较多，主要包括非小细胞肺癌(n=110)、食管鳞癌(n=39)及胃癌(n=22)，但也纳入了部分纤维肉瘤、血管肉瘤等少见恶性肿瘤患者，多数患者在接受ICI治疗前曾接受过手术、化疗、放疗或分子靶向等治疗。在应用的ICI药物类型方面，入组患者主要接受PD-1免疫治疗，其中应用最多的四种药物为帕博利珠单抗(n=75)、信迪利单抗(n=65)、特瑞普利单抗(n=59)、纳武利尤单抗(n=51)，也有少数患者参加临床试验而接受PD-L1或联合细胞毒性T淋巴细胞相关蛋白4(CTLA-4)抗体进行免疫治疗。
286例患者中，83例治疗后出现了irT，发生率为29.0%。对两组患者进行对比发现，不同性别患者irT发生率差异无统计学意义(P=0.067)，irT组患者年龄低于非irT组(P=0.033)。在肿瘤的来源方面，两组中不同癌种irT的发生率差异无统计学意义(P=0.714)。在既往治疗史方面，接受过放疗的患者irT发生率明显高于非放疗患者(P=0.023)，而既往接受过化疗、手术及靶向治疗对于irT的发生无明显影响。总体上，不同ICI药物irT的发生率差异无统计学意义(P=0.228)。在基线甲状腺激素水平上，两组患者治疗前FT3、FT4、TSH水平均在正常范围内，用药前两组FT3及FT4水平相近，irT组基线TSH水平稍高于非irT组，但差异无统计学意义(P=0.068)(表1)。
2.2 irT的临床特征
甲状腺不良反应主要表现为甲状腺功能的亢进和减退，其中表现为甲亢者11例，亚临床甲亢者17例，甲减者29例，亚临床甲减者19例，另有7例患者出现一过性甲状腺疼痛不适及自身抗体阳性，但T3、T4、TSH水平持续正常，考虑为甲状腺激素正常的甲状腺炎。76例(91.6%)患者为1或2级的轻度不良反应，乏力、甲状腺疼痛是常见的临床表现，仅6例发生严重影响生活的3级不良反应，1例患者出现意识障碍、水肿及合并其他严重不良反应，考虑为甲减危象(4级)。发生临床型甲亢的患者，病程中最高FT3和FT4平均值分别为8.871 pmol/L、28.43 pmol/L；而甲减患者的甲状腺激素变化则较为明显，病程中最低FT3、FT4平均值为2.748 pmol/L、9.471 pmol/L。32例(38.6%)irT患者在发生甲状腺不良反应的同时合并其他免疫损伤，包括免疫相关的间质性肺炎、自身免疫性肝损伤、心肌炎以及免疫性肠炎等。多数irT患者不需临床干预，11例甲亢患者中6例接受了低碘饮食治疗，2例需加用抗甲状腺药物治疗。29例甲减患者中，有12例接受了甲状腺素替代治疗，发生甲减危象的1例患者接受了糖皮质激素治疗(表2)。
2.3 irT患者发生甲状腺功能异常的时间特点
患者从第一次接受ICI药物治疗到出现甲状腺功能异常的中位时间为92(36，170) d，但存在较大个体差异，最长者可达591 d，最短者仅3 d。其中甲减型irT发生的中位时间为120 d(95%CI 56.9~183.1)，甲亢型irT为52 d(95%CI 41.9~60.1)，甲亢型irT发生的中位时间明显早于甲减型(P=0.015，图1A)。CTCAE分级1级、2级与3级及以上irT发生的中位时间分别为76 d(95%CI 33.2~118.8)、100 d(95%CI 82.4~117.6)、92 d(95%CI 0~197.2)，不同严重程度患者的中位发生时间差异无统计学意义(P=0.693，图1B)。值得注意的是，最初诊断为甲亢的28例患者中，有7例(25%)随病程发展为甲状腺素水平降低，并最终出现甲减(图1C)，其病程类似伴有一过性甲亢的桥本甲状腺炎。这些患者甲亢期TSH达到最低值的中位时间为53(27，55) d，甲减期TSH达到最高值的中位时间为179(125，216) d，从甲亢期到甲减期的转化过程持续125(100，161) d，7例患者中有5例患者在甲减期接受了甲状腺素替代治疗。
2.4 不同ICI所致irT的发生情况比较
为了对比应用不同种类ICI药物的患者间irT发生情况的差异，本研究选取了四种应用较多的ICI进行对比，结果见表3。四种药物的irT发生率和总体发生率相接近，差异无统计学意义(P=0.279)，其中发生率最低的是纳武利尤单抗(21.6%)，最高的是特瑞普利单抗(35.6%)。在需要临床干预的2-4级不良反应方面，特瑞普利单抗的发生率略高于其他药物(20.3%vs. 11.9%，P=0.134)。不同药物的中位irT时间差距也较大，最短的为信迪利单抗(55.5 d)，最长的为帕博利珠单抗(154 d)。
2.5 irT患者的TGAb和TPOAb抗体水平及甲状腺超声表现
在发生了irT的83例患者中，78例检测了血TPOAb及TGAb水平，其中26例(33.3%)存在甲状腺抗体水平异常，包括TGAb异常23例(29.5%)，TPOAb异常14例(12.8%)，同时异常者11例(14.1%)。TGAb与TPOAb水平呈正相关(r=0.464，P<0.001)。从分型上看，发生甲亢和甲减的患者，其TGAb[16.8(15.0，32.0) U/ml vs. 15.5(15.1，47.4) U/ml，P=0.495]和TPOAb[30.4(28.1，51.6) U/ml vs. 33.6(28.0，54.9) U/ml，P=0.592]水平差异无统计学意义。在甲状腺抗体与不良反应严重程度的关系上，发生3-4级irT者TGAb[251.7(100.6，310.2) U/ml vs. 15.2(14.0，27.8) U/ml，P<0.001]和TPOAb[350.1(53.1，500.0) U/ml vs. 30.7(<26.0，46.3) U/ml，P<0.001]水平较发生1-2级irT者明显升高。值得注意的是，本研究7例发生严重甲状腺损伤者的TGAb水平均异常升高。83例irT患者甲状腺B超中仅有5例出现明显异常，irT的超声表现类似桥本甲状腺炎(图2)，主要包括累及双侧的甲状腺密度不均、弥漫性低回声伴有较丰富的血流信号(n=5)及甲状腺体积增大(n=2)。
2.6 irT患者的转归情况
甲状腺不良反应的转归情况见表4。总体上irT患者的预后良好，7例甲亢、10例甲减患者症状完全恢复，7例甲亢和11例甲减患者甲状腺激素恢复正常水平，但TSH自身抗体异常多持续存在；因irT影响免疫治疗者少见，仅1例甲亢和2例甲减患者因irT而中断过ICI用药；治疗后好转的10例患者中，有3例在随后的ICI治疗中再次出现甲减症状，但复发的严重等级均不高于首次发生的等级。
3 讨论
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irT是免疫治疗中一类独特的现象，早在CheckMate 037研究[12]中就报道了纳武利尤单抗引起的内分泌不良反应。而ICI发明之前，肿瘤患者发生药物相关甲状腺炎则相对罕见，主要由干扰素、白细胞介素-2(IL-2)及酪氨酸激酶抑制药引起[13]。国内进行的ORIENT-1[14]、POLARIS-02[15]等临床试验中也有甲状腺损伤的报道，然而既往研究主要集中于比较不同药物irT的发生率，很少报道irT发生的影响因素及临床特点。而对免疫治疗患者的甲状腺不良反应发生情况进行回顾性分析，有助于理解免疫相关甲状腺毒性的机制，提高免疫治疗的安全性。
魏芬芬等[16]对38例患者的回顾性分析结果提示，免疫治疗患者irT的发生率为42.37%，较本研究(29.0%)高。尽管结果存在差异，但均明显高于药物临床试验Meta分析所报道的irT发生率(4.8%~23.9%)[13]，提示真实世界中患者irT发生率可能被低估。本研究发现多种肿瘤的免疫治疗中均可发生irT，包括纵隔纤维肉瘤等罕见恶性肿瘤，此类疾病可用方案有限且对治疗常不敏感，如因irT停药将对患者造成更严重的影响，故在罕见肿瘤治疗中更应注意预防irT等不良反应的发生。本研究结果显示年龄是irT的危险因素，而Mizuno等[17]和Fukihara等[18]对免疫相关肝炎、肺炎的研究均提示发生irAE的患者较非irAE患者年龄更小，这可能与低龄者对ICI药物更加敏感有关，年轻患者在获得更好疗效的同时也可能面临更高的irAE风险。
尽管本研究纳入的患者未接受过可能直接损伤甲状腺的颈部放疗，但其中接受过其他部位放疗的患者irT的发生率仍高于未接受过放疗者，提示非甲状腺区放疗也可能增加甲状腺免疫不良反应的发生风险，放疗对irT的影响可能与射线引发的炎症提高细胞因子水平、增强抗原呈递有关，其具体机制仍有待进一步研究。
irT起病时多为轻症甲状腺功能异常且缺乏典型症状，故患者极少因irT主动就诊，而对irT进行预防性低碘饮食、免疫调节并及时开始甲状腺替代治疗可减轻症状、保护甲状腺功能，故irT的早期发现尤为重要。目前，我国免疫治疗常以日间治疗等短期住院的方式进行，系统复查较为困难。因而笔者建议接受ICI治疗者均应监测T3、T4、TSH水平，对疑似irT的患者可增加TGAb、TPOAb及甲状腺超声检查以辅助早期诊断和干预，尤其对于甲减型的irT，未经干预时可能出现严重的甲状腺激素水平减低并引发甲减危象，具有潜在的致命性，更值得临床关注。对于影响生活的严重甲状腺毒症及甲减，NCCN指南推荐暂停ICI治疗直至症状缓解[7]，本研究中7例重症患者在接受治疗后irT均得到了控制，仅3例暂时中止了免疫治疗。因此，irT多不影响免疫治疗计划，但病情严重者需及时应用药物控制症状。
部分irT的临床经过类似于桥本甲状腺炎，表现为甲状腺免疫破坏所致的一过性甲状腺毒症和继发性甲减[19]。然而，原发性桥本甲状腺炎一过性甲亢的发生率很低(约5%)[20]，而本研究中irT发生一过性甲亢的比例则较高，首诊为甲亢或亚临床甲亢的28例患者中7例(25%)后期出现了继发性甲减。在甲状腺功能变化的时间特点上，本研究中irT患者甲亢期较桥本甲状腺炎稍短，TSH达到最低值的中位时间仅53 d，而转化过程则相对较慢，可达125 d，与国外的相关研究结果一致[21]，提示对初诊为甲亢的irT应长期监测其甲状腺功能变化；对于irT抗甲状腺药物的应用需谨慎，病情稳定后应及时停药，避免造成严重的继发性甲减。
本研究对比了四种临床常用的PD-1抗体，发现irT的发生率差异并不明显，提示这四种PD-1 ICI在甲状腺毒性方面的安全性相近。但随着免疫治疗药物的不断丰富，PD-L1、CTLA-4、Tim-3抗体等新的ICI的应用也给irT的管理带来了挑战。既往研究认为，免疫检查点CTLA-4在桥本甲状腺炎的发生中起关键作用[22]，国外研究也提示联合应用CTLA-4和PD-1制剂较PD-1单药的irT发生风险更高[23]，但是目前国内CTLA-4类ICI获批较晚，针对CTLA-4抑制剂所致irT的报道也较少。本研究由于样本量的限制，并未观察到PD-1/PD-L1单药与联合CTLA-4药物治疗irT的发生率存在统计学差异，因此，CTLA-4抗体引发irT的特点是否与PD-1抗体有所区别，仍有待进一步大样本研究。
TGAb和TPOAb广泛应用于免疫性甲状腺损伤的诊断中。Inaba等[23]曾证实，需要持续治疗的irT相对于一过性irT其TGAb水平更高。Kimbara等[24]则发现，治疗前甲状腺抗体基础水平升高是纳武利尤单抗引发irT的危险因素。本研究发现重症irT的自身抗体水平明显高于轻症irT，提示抗体水平高者可能存在更大的风险，更值得临床关注。在TGAb和TPOAb的比较中，既往研究认为TPOAb在自身免疫性甲状腺炎的诊断中具有更好的效能。而在本研究中，尽管两者的表达水平明显相关，但irT患者TGAb的阳性率更高。3-4级的irT全部伴有TGAb升高，而TPO的阳性率仅为71.4%，提示与其他甲状腺疾病相比，ICI所致的甲状腺毒性中TGAb可能起着更重要的作用[25]。然而，本研究目前只检测了发生irT患者的抗体水平，其诊断价值仍有待进一步验证。甲状腺超声检查在irT中阳性率较低且缺乏特异性，但对于甲状腺功能正常或处于甲状腺功能转化期而存在症状的患者，超声检测可能起到提示作用，未来的研究可以着眼于结合CT、甲状腺核素扫描等放射检查方法以早期发现irT的影像学特征。
综上所述，本研究通过分析ICI治疗后患者发生甲状腺不良反应的特点，发现年龄小、放疗史可能增加irT的发生风险；甲亢型irT患者存在向甲减转化的可能，其演变较非ICI药物性甲状腺炎更快；重症irT患者的TGAb和TPOAb水平明显高于轻症患者，且TGAb的异常更加明显。在临床工作中，尽管多数甲状腺毒性并不影响ICI治疗的进行，但对甲状腺功能进行定期监测和及时干预，可改善患者的生活质量，预防严重不良反应的发生。
基金
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  • 国家“十三五”重大专项课题(2018ZX09201013)
文献
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2021年第46卷第10期
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doi: 10.11855/j.issn.0577-7402.2021.10.06
  • 接收时间：2021-06-17
  • 首发时间：2025-12-19
  • 出版时间：2021-10-28
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  • 收稿日期：2021-06-17
  • 修回日期：2021-09-12
基金
Major Special Projects Foundation of the "13th Five-Year Plan" of China(2018ZX09201013)
国家“十三五”重大专项课题(2018ZX09201013)
作者信息
    1南开大学医学院，天津 300071
    2解放军总医院第一医学中心肿瘤内科，北京 100853
    3解放军总医院第一医学中心内分泌科，北京 100853

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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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