质子泵抑制剂导致的急性泛发性发疹性脓疱病：基于真实世界的药物警戒研究

赵喆; 王涛; 唐彦; 陈晓光; 赵彬

doi:10.12290/xhyxzz.20200262

质子泵抑制剂导致的急性泛发性发疹性脓疱病：基于真实世界的药物警戒研究

doi: 10.12290/xhyxzz.20200262

赵喆^{1, 2},
王涛³,
唐彦¹,
陈晓光²,
赵彬^1, ,

1.
中国医学科学院北京协和医学院北京协和医院药剂科，北京 100730
2.
中国医学科学院北京协和医学院药物研究所，北京 100050
3.
中国医学科学院北京协和医学院北京协和医院皮肤科，北京 100730

详细信息

通讯作者:
赵彬电话：010-69156513，E-mail：zhaobin@pumch.cn

中图分类号: R753.1
计量
- 文章访问数: 457
- HTML全文浏览量: 160
- PDF下载量: 46
- 被引次数: 0
出版历程
- 收稿日期: 2020-10-15
- 录用日期: 2020-11-30
- 网络出版日期: 2021-06-28
- 刊出日期: 2021-11-30

Acute Generalized Exanthematous Pustulosis Caused by Proton Pump Inhibitors: A Real-World Pharmacovigilance Study

ZHAO Zhe^{1, 2},
WANG Tao³,
TANG Yan¹,
CHEN Xiaoguang²,
ZHAO Bin^{1
, ,}

1.
Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
2.
Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China
3.
Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

More Information

Corresponding author: ZHAO Bin Tel: 86-10-69156513, E-mail: zhaobin@pumch.cn

摘要

摘要: 目的探讨不同质子泵抑制剂(proton pump inhibitors, PPIs)与急性泛发性发疹性脓疱病(acute generalized exanthematous pustulosis, AGEP)的关联性及特点。方法检索2004年1月至2020年6月美国食品药品监督管理局不良事件报告系统(Food and Drug Administration's adverse events reporting system, FAERS)数据库中PPIs/AGEP相关报告，采用比例失衡测量法及贝叶斯法对不同PPIs导致的AGEP进行关联性分析，并比较其发病时间及预后。结果共检索到此期间PPIs导致的AGEP病例报告162例。应用的PPIs药物主要为奥美拉唑(33.95%，55/162)，其次为埃索美拉唑(29.63%，48/162)、泮托拉唑(26.54%，43/162)。以泮托拉唑与AGEP的关联性最强，其次为奥美拉唑和兰索拉唑，埃索美拉唑与AGEP的关联性较弱。PPIs导致AGEP发病时间的中位数为6(2，12)d，60.00%~83.33%的患者于用药后10 d内发病(除雷贝拉唑外)。3例(1.86%)AGEP患者死亡，128例(79.50%)需住院治疗。以埃索美拉唑导致的AGEP患者住院比率最高(91.49%，43/47)，其次为泮托拉唑(88.37%，38/43)、兰索拉唑(85.71%，12/44)，奥美拉唑(61.82%，34/55)最低。结论基于对FAERS数据库的药物警戒研究，揭示不同PPIs导致AGEP的风险及特点，可为临床合理用药提供依据。
- 质子泵抑制剂 /
- 急性泛发性发疹性脓疱病 /
- 不良反应 /
- 数据挖掘
Abstract: Objective To explore and compare the associations of different proton pump inhibitors (PPIs) with acute generalized exanthematous pustulosis (AGEP). Methods Data were obtained from the database of Food and Drug Administration's adverse event reporting system (FAERS) from January 2004 to June 2020. Non-proportional analysis and Bayesian analysis were utilized to analyze the signs of AGEP caused by different PPIs. The onset time and prognosis of PPIs-related AGEP were also analyzed. Results A total of 162 cases of AGEP caused by PPIs were reported. The most frequently used PPI was omeprazole (33.95%, 55/162), followed by esomeprazole (29.63%, 48/162) and pantoprazole (26.54%, 43/162). Pantoprazole showed the strongest correlation with AGEP, followed by omeprazole and lansoprazole, while esomeprazole appeared to have a weaker association with AGEP than other PPIs. The median time to the onset of AGEP was 6 (2, 12) days after PPI treatment, and 60.00%-83.33% of patients developed symptoms within 10 days after the medication (except rabeprazole). PPI-associated AGEP generally led to a fatality of 1.86% (3 cases) and a hospitalization rate of 79.50% (128 cases). The hospitalization rate of AGEP patients caused by omeprazole was the highest (91.49%, 43/47), followed by that of pantoprazole (88.37%, 38/43), lansoprazole (85.71%, 12/44), and omeprazole (61.82%, 34/55). Conclusions Our pharmacovigilance study based on the FAERS database demonstrated in detail the risks and characteristics of AGEP caused by different PPIs, which could provide a theoretical basis for rational clinical drug use.
- proton pump inhibitors /
- acute generalized exanthematous pustulosis /
- adverse reactions /
- data mining
注释:

作者贡献：赵喆负责数据分析及论文撰写; 赵彬负责研究设计及数据挖掘; 王涛、唐彦负责数据资料整理; 陈晓光负责部分图表绘制。

利益冲突：无

HTML全文

图 1 FAERS数据库中PPIs导致AGEP病例筛选流程图

DEMO：人口统计信息; DRUG：药物信息; REAC：不良事件; FAERS：美国食品药品监督管理局不良反应报告系统; PPIs、AGEP：同表 1

下载: 全尺寸图片幻灯片

图 2 PPIs导致的AGEP患者年龄分布特征

PPIs、AGEP：同表 1

下载: 全尺寸图片幻灯片

图 3 PPIs导致的AGEP患者报告年份分布折线图

PPIs、AGEP：同表 1

下载: 全尺寸图片幻灯片

图 4 不同PPIs导致的AGEP患者发病时间分布

PPIs、AGEP：同表 1

下载: 全尺寸图片幻灯片

表 1 PPIs与AGEP关联性评估的算法公式及信号检测标准

算法	公式	信号检测标准
ROR	ROR=(a/b)/(c/d)	95% CI＞1，N≥2
	95% CI=e^{ln(ROR)±1.96(1/a+1/b+1/c+1/d)^0.5}
PRR	PRR=[a/(a+c)]/[b/(b+d)]	PRR≥2, χ²≥4, N≥3
	χ²=Σ[(O-E)2/E]，[O=a，E=(a+b)(a+c)/(a+b+c+d)]
BCPNN	IC=log₂a(a+b+c+d)/[(a+c)(a+b)]	IC025＞0
	IC025=e^{ln(IC)-1.96(1/a+1/b+1/c+1/d)^0.5}
MGPS	EBGM=a(a+b+c+d)/[(a+c)(a+b)]	EBGM05＞2，N＞0
	EBGM05=e^{ln(EBGM)-1.64(1/a+1/b+1/c+1/d)^0.5}
PPIs：质子泵抑制剂; AGEP：急性泛发性发疹性脓疱病; ROR：报告比值比; 95% CI：95%置信区间; PRR：比例报告比值比; BCPNN：贝叶斯置信传播神经网络法; IC：信息成分; IC025：信号组分的95%双侧置信区间下限; MGPS：多项伽玛泊松分布缩减法; EBGM：经验贝叶斯几何平均数; EBGM05：EBGM的90%单侧置信区间的下限; a：同时包含可疑药物和可疑药物不良反应的报告数量; b：包含与其他药物(目标药物除外)相关的可疑不良反应的报告数量; c：包含目标药物相关的其他药物不良反应的报告数量(目标不良事件除外); d：包含其他药物和其他药物不良反应的报告数量; N：同时出现的次数

下载: 导出CSV

表 2 PPIs导致的AGEP患者临床基本特征

指标	例数[n(%)]
报告地区
欧洲	104(64.20)
北美洲	28(17.28)
非洲	2(1.23)
亚洲	16(9.88)
未知	12(7.41)
报告者
医务人员	139(85.80)
患者	6(3.70)
未知	17(10.49)
PPIs药物
奥美拉唑	55(33.95)
埃索美拉唑	48(29.63)
泮托拉唑	43(26.54)
兰索拉唑	14(8.64)
雷贝拉唑	2(1.23)
PPIs用药指征
胃食管反流病	23(14.20)
预防用药	18(11.11)
腹痛	10(6.17)
反流性胃炎	9(5.56)
不明确	102(62.96)
PPIs、AGEP：同表 1

下载: 导出CSV

表 3 不同PPIs与AGEP的关联性

药物	例数(n)	ROR(95%CI)	PRR(χ²)	IC(IC025)	EBGM(EBGM05)
泮托拉唑	43	6.19(4.58~8.36)^*	6.18(184.67)^*	2.61(1.94)^*	6.12(4.76)^*
奥美拉唑	55	5.69(4.36~7.43)^*	5.68(209.40)^*	2.49(1.91)^*	5.62(4.50)^*
兰索拉唑	14	1.93(1.14~3.25)^*	1.92(6.20)	0.94(0.56)^*	1.92(1.24)
雷贝拉唑	2	3.50(0.87~14.02)	3.50(3.57)	1.81(0.45)^*	3.50(1.10)
埃索美拉唑	48	1.17(0.88~1.56)	1.17(1.17)	0.22(0.17)^*	1.17(0.92)
PPIs、AGEP、ROR、PRR、IC、IC025、EBGM、EBGM05：同表 1;^*阳性信号

下载: 导出CSV

参考文献(27)

[1]	Shin JM, Cho YM, Sachs G. Chemistry of covalent inhibition of the gastric (H⁺, K⁺)-ATPase by proton pump inhibitors[J]. J Am Chem Soc, 2004, 126: 7800-7811. doi: 10.1021/ja049607w
[2]	Yu LY, Sun LN, Zhang XH, et al. A Review of the Novel Application and Potential Adverse Effects of Proton Pump Inhibitors[J]. Adv Ther, 2017, 34: 1070-1086. doi: 10.1007/s12325-017-0532-9
[3]	Sidoroff A. Acute generalized exanthematous pustulosis[J]. Chem Immunol Allergy, 2012, 97: 139-148. doi: 10.1159/000335625
[4]	Dewerdt S, Vaillant L, Machet L, et al. Acute generalized exanthematous pustulosis induced by lansoprazole[J]. Acta Derm Venereol, 1997, 77: 250. http://europepmc.org/abstract/MED/9188895
[5]	Nantes Castillejo O, Zozaya Urmeneta JM, Valcayo Peñalba A, et al. Acute generalized exanthematous pustulosis induced by omeprazole[J]. Gastroenterol Hepatol, 2008, 31: 295-298. doi: 10.1157/13119883
[6]	Schmitz B, Sorrells T, Glass JS. Acute generalized exanthematous pustulosis caused by pantoprazole[J]. Cutis, 2018, 101: E22-E23. http://www.onacademic.com/detail/journal_1000040410316010_32f7.html
[7]	中国临床医学真实世界研究施行规范专家委员会. 中国临床医学真实世界研究施行规范[J]. 中华实验和临床感染病杂志(电子版), 2017, 11: 521-525. Academic Committee of Chinese Practice Algorithm on Real World Study of Clinical Medicine. Chinese practice algorithm on real world study of clinical medicine[J]. Zhonghua Shiyan He Linchuang Ganranbing Zazhi (Dianziban), 2017, 11: 521-525.
[8]	Gargoloff PD, Corral R, Herbst L, et al. Effectiveness of agomelatine on anhedonia in depressed patients: an outpatient, open-label, real-world study[J]. Hum Psychopharmacol, 2016, 31: 412-418. doi: 10.1002/hup.2557
[9]	Quackenbush D, Allen JG, Fowler JC. Comparison of Attachments in Real-World and Virtual-World Relationships[J]. Psychiatry, 2015, 78: 317-327. doi: 10.1080/00332747.2015.1092854
[10]	Evans SJ, Waller PC, Davis S. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports[J]. Pharmacoepidemiol Drug Saf, 2001, 10: 483-486. doi: 10.1002/pds.677
[11]	Sakaeda T, Tamon A, Kadoyama K, et al. Data mining of the public version of the FDA Adverse Event Reporting System[J]. Int J Med Sci, 2013, 10: 796-803. doi: 10.7150/ijms.6048
[12]	Van Puijenbroek EP, Bate A, Leufkens HG, et al. A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions[J]. Pharmacoepidemiol Drug Saf, 2002, 11: 3-10. doi: 10.1002/pds.668
[13]	Natsch S, Vinks MH, Voogt AK, et al. Anaphylactic reactions to proton-pump inhibitors[J]. Ann Pharmacother, 2000, 34: 474-476. doi: 10.1345/aph.19235
[14]	Bose S, Guyer A, Long A, et al. Evaluation and manage-ment of hypersensitivity to proton pump inhibitors[J]. Ann Allergy Asthma Immunol, 2013, 111: 452-457. doi: 10.1016/j.anai.2013.08.022
[15]	Lin CY, Wang CW, Hui CR, et al. Delayed-type hypersensitivity reactions induced by proton pump inhibitors: A clinical and in vitro T-cell reactivity study[J]. Allergy, 2018, 73: 221-229. doi: 10.1111/all.13235
[16]	Britschgi M, Steiner UC, Schmid S, et al. T-cell involve-ment in drug-induced acute generalized exanthematous pustulosis[J]. J Clin Invest, 2001, 107: 1433-1441. doi: 10.1172/JCI12118
[17]	Sidoroff A, Dunant A, Viboud C, et al. Risk factors for acute generalized exanthematous pustulosis (AGEP)-results of a multinational case-control study (EuroSCAR)[J]. Br J Dermatol, 2007, 157: 989-996. doi: 10.1111/j.1365-2133.2007.08156.x
[18]	Schaerli P, Britschgi M, Keller M, et al. Characterization of human T cells that regulate neutrophilic skin inflammation[J]. J Immunol, 2004, 173: 2151-2158. doi: 10.4049/jimmunol.173.3.2151
[19]	Kakeda M, Schlapbach C, Danelon G, et al. Innate immune cells express IL-17A/F in acute generalized exanthematous pustulosis and generalized pustular psoriasis[J]. Arch Dermatol Res, 2014, 306: 933-938. doi: 10.1007/s00403-014-1488-0
[20]	Kabashima R, Sugita K, Sawada Y, et al. Increased circulating Th17 frequencies and serum IL-22 levels in patients with acute generalized exanthematous pustulosis[J]. J Eur Acad Dermatol Venereol, 2011, 25: 485-488. doi: 10.1111/j.1468-3083.2010.03771.x
[21]	Sidoroff A, Halevy S, Bavinck JN, et al. Acute generalized exanthematous pustulosis (AGEP)--a clinical reaction pattern[J]. J Cutan Pathol, 2001, 28: 113-119. doi: 10.1034/j.1600-0560.2001.028003113.x
[22]	Ahrens D, Chenot JF, Behrens G, et al. Appropriateness of treatment recommendations for PPI in hospital discharge letters[J]. Eur J Clin Pharmacol, 2010, 66: 1265-1271. doi: 10.1007/s00228-010-0871-9
[23]	Ying J, Li LC, Wu CY, et al. The status of proton pump inhibitor use: a prescription survey of 45 hospitals in China[J]. Rev Esp Enferm Dig, 2019, 111: 738-743. http://www.ncbi.nlm.nih.gov/pubmed/31373505
[24]	Thienvibul C, Vachiramon V, Chanprapaph K. Five-Year Retrospective Review of Acute Generalized Exanthematous Pustulosis[J]. Dermatol Res Pract, 2015, 2015: 260928. http://www.onacademic.com/detail/journal_1000040466855610_13cb.html
[25]	Li XQ, Andersson TB, Ahlström M, et al. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities[J]. Drug Metab Dispos, 2004, 32: 821-827. doi: 10.1124/dmd.32.8.821
[26]	Roujeau JC, Bioulac-Sage P, Bourseau C, et al. Acute generalized exanthematous pustulosis. Analysis of 63 cases[J]. Arch Dermatol, 1991, 127: 1333-1338. doi: 10.1001/archderm.1991.01680080069004
[27]	Patek TM, Teng C, Kennedy KE, et al. Comparing Acute Kidney Injury Reports Among Antibiotics: A Pharmacovigilance Study of the FDA Adverse Event Reporting System (FAERS)[J]. Drug Saf, 2020, 43: 17-22. doi: 10.1007/s40264-019-00873-8

施引文献

资源附件(0)

访问统计

点击查看大图

图(4) / 表(3)

计量

文章访问数: 457
HTML全文浏览量: 160
PDF下载量: 46
被引次数: 0

姓名
邮箱
手机号码
标题
留言内容
验证码

地址：	北京市东城区帅府园1号北京协和医院老楼7号楼 3层302室《协和医学杂志》编辑部
电话：	010-69154261/4262
E - mail：	medj@pumch.cn mjpumch@126.com
期刊网站版权所有：	《协和医学杂志》编辑部京ICP备 11002662

留言板

质子泵抑制剂导致的急性泛发性发疹性脓疱病：基于真实世界的药物警戒研究

doi: 10.12290/xhyxzz.20200262

通讯作者:
赵彬电话：010-69156513，E-mail：zhaobin@pumch.cn

计量

Acute Generalized Exanthematous Pustulosis Caused by Proton Pump Inhibitors: A Real-World Pharmacovigilance Study

Corresponding author: ZHAO Bin Tel: 86-10-69156513, E-mail: zhaobin@pumch.cn

计量

目录

留言板

质子泵抑制剂导致的急性泛发性发疹性脓疱病：基于真实世界的药物警戒研究

doi: 10.12290/xhyxzz.20200262

通讯作者: 赵彬 电话：010-69156513，E-mail：zhaobin@pumch.cn

计量

出版历程

Acute Generalized Exanthematous Pustulosis Caused by Proton Pump Inhibitors: A Real-World Pharmacovigilance Study

Corresponding author: ZHAO Bin Tel: 86-10-69156513, E-mail: zhaobin@pumch.cn

计量

出版历程

目录

通讯作者:
赵彬电话：010-69156513，E-mail：zhaobin@pumch.cn