Efficacy and Safety of Belimumab, Anifrolumab, and Telitacicept on the Treatment of Systemic Lupus Erythematosus: a Network Meta-analysis

doi:10.12114/j.issn.1007-9572.2023.0864

Abstract

Abstract:

Background

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease. At present, three biological agents have been approved for treating SLE, including belimumab, anifrolumab, and telitacicept. However, a direct comparison of their efficacy and safety is lacking.

Objective

To analyze the clinical efficacy and safety of belimumab, anifrolumab, and telitacicept on the treatment of SLE using network meta-analysis.

Methods

Randomized controlled trials (RCTs) reporting belimumab, anifrolumab, and telitacicept to treat SLE were searched in the databases of PubMed, Web of Science, Cochrane Library, and Embase from the establishment of the databases to August 2023. After screening the relevant literatures and obtaining data from eligible RCTs based on the inclusion and exclusion criteria, direct or network meta-analysis was performed using the RevMan 5.4.1, R language 4.3.1, and Aggregate Data Drug Information System (ADDIS) 1.16.8 software.

Results

After screening, 4 789 SLE patients from 12 RCTs were included, including 2 721 patients in the experimental group and 2 068 patients in the placebo group. The direct meta-analysis results showed that the relief rate of SLE responder index 4 (SRI4) in SLE patients treated with belimumab, anifrolumab, and telitacicept was significantly higher in the experimental group compared with that of the placebo group (OR=1.62, 95%CI=1.40-1.88, P<0.001; OR=2.39, 95%CI=1.70-3.37, P<0.001; OR=6.28, 95%CI=3.20-12.33, P<0.001). Compared with that of the placebo group, the proportion of SLE patients with a reduced oral corticosteroid dosage after belimumab and anifrolumab treatment was significantly higher (OR=1.48, 95%CI=1.09-2.02, P<0.001; OR=2.45, 95%CI=1.69-3.54, P<0.001), and the severe recurrence (SR) rate was significantly lower (OR=0.59, 95%CI=0.49-0.71, P<0.001; OR=0.52, 95%CI=0.39-0.69, P<0.001). The incidence of total adverse events (TAEs) of anifrolumab and telitacicept was significantly higher than that of the placebo group (OR=1.80, 95%CI=1.25-2.59, P=0.001; OR=2.13, 95%CI=1.18-3.83, P=0.01), while the incidence of serious adverse events (SAEs) of anifrolumab was significantly lower (OR=0.67, 95%CI=0.46-0.97, P=0.04). There were no significant differences in the incidence of TAEs (OR=0.89, 95%CI=0.72-1.08, P=0.24) and SAEs (OR=0.82, 95%CI=0.59-1.12, P=0.25) between the belimumab group and placebo group. The results of network meta-analysis showed that the highest SRI4 was detected after the treatment of telitacicept, followed by anifrolumab, subcutaneous injection of belimumab and intravenous injection of belimumab. The highest incidence of TAEs was detected after the treatment of telitacicept, followed by anifrolumab, intravenous injection of belimumaband subcutaneous injection of belimumab.

Conclusion

Aelimumab, anifrolumab, and telitacicept all exhibit good clinical efficacy on the treatment of SLE, especially telitacicept. Although anifrolumab and telitacicept increase the overall incidence of TAEs after treatment, they reduce the incidence of SAEs. Belimumab exhibits the highest safety on treating SLE.

Key words: Systemic lupus erythematosus, Belimumab, Anifrolumab, Telitacicept, Efficacy, Adverse events, Network meta-analysis

摘要：

背景

系统性红斑狼疮（SLE）是一种慢性多系统自身免疫性疾病，目前已有3种生物制剂被批准用于治疗SLE，分别为贝利尤单抗、阿尼鲁单抗和泰它西普，但目前尚缺乏直接比较3种药物疗效及安全性的研究。

目的

通过网状Meta分析探索贝利尤单抗、阿尼鲁单抗和泰它西普治疗SLE的临床疗效及安全性。

方法

检索PubMed、Web of Science、Cochrane Library、Embase中有关贝利尤单抗、阿尼鲁单抗和泰它西普治疗SLE的随机对照试验，检索时间为建库至2023年8月。通过纳入、排除标准筛选文献，获取数据，采用RevMan 5.4.1软件、R语言4.3.1和ADDIS 1.16.8软件对数据进行直接或网状Meta分析。

结果

经过筛选后纳入12项随机对照试验，共计4 789例患者，其中试验组2 721例，安慰剂组2 068例。直接Meta分析结果显示，贝利尤单抗、阿尼鲁单抗和泰它西普SLE应答指数4（SRI4）缓解率均高于安慰剂组（OR=1.62，95%CI=1.40~1.88，P<0.001；OR=2.39，95%CI=1.70~3.37，P<0.001；OR=6.28，95%CI=3.20~12.33，P<0.001）。贝利尤单抗、阿尼鲁单抗口服皮质类固醇剂量减少所占比例高于安慰剂组（OR=1.48，95%CI=1.09~2.02，P<0.001；OR=2.45，95%CI=1.69~3.54，P<0.001），严重复发率（SF）低于安慰剂组（OR=0.59，95%CI=0.49~0.71，P<0.001；OR=0.52，95%CI=0.39~0.69，P<0.001）。阿尼鲁单抗和泰它西普总不良事件（TAEs）发生率高于安慰剂组（OR=1.80，95%CI=1.25~2.59，P=0.001；OR=2.13，95%CI=1.18~3.83，P=0.01）；阿尼鲁单抗严重不良事件（SAEs）发生率低于安慰剂组（OR=0.67，95%CI=0.46~0.97，P=0.04）。与安慰剂组比较，贝利尤单抗和安慰剂组TAEs发生率（OR=0.89，95%CI=0.72~1.08，P=0.24）和SAEs发生率（OR=0.82，95%CI=0.59~1.12，P=0.25）比较，差异无统计学意义。网状Meta分析结果显示，3种生物制剂治疗后的SRI4缓解率的概率排序为泰它西普>阿尼鲁单抗>贝利尤单抗（皮下注射）>贝利尤单抗（静脉注射）；TAEs发生率的概率排序为泰它西普>阿尼鲁单抗>贝利尤单抗（静脉注射）>贝利尤单抗（皮下注射）。

结论

3种药物治疗SLE皆具有良好的临床疗效，其中泰它西普疗效更为显著，阿尼鲁单抗和泰它西普虽然增加了用药后的TAEs发生率，但降低了SAEs发生率，贝利尤单抗在安全性方面更为稳定。

关键词: 系统性红斑狼疮, 贝利尤单抗, 阿尼鲁单抗, 泰它西普, 疗效, 不良事件, 网状Meta分析

CLC Number:

R 593.241

LI Hao,LI Jiangtao,LIU Dan, et al. Efficacy and Safety of Belimumab, Anifrolumab, and Telitacicept on the Treatment of Systemic Lupus Erythematosus: a Network Meta-analysis[J]. Chinese General Practice, 2025, 28(23): 2924-2933. DOI: 10.12114/j.issn.1007-9572.2023.0864.
李浩,李江涛,刘丹等. 贝利尤单抗和阿尼鲁单抗及泰它西普治疗系统性红斑狼疮疗效和安全性的网状Meta分析[J]. 中国全科医学, 2025, 28(23): 2924-2933. DOI: 10.12114/j.issn.1007-9572.2023.0864.

Figures/Tables 22

References 38

[1]	GOMEZ A, ENMAN Y, PARODIS I. Impact of belimumab on patient-reported outcomes in systemic lupus erythematosus：insights from clinical trials and real-world evidence[J]. Patient Relat Outcome Meas，2023，14：1-13. DOI：10.2147/PROM.S369584.
[2]	PONS-ESTEL G J, ALARCÓN G S, SCOFIELD L, et al. Understanding the epidemiology and progression of systemic lupus erythematosus[J]. Semin Arthritis Rheum，2010，39(4)：257-268. DOI：10.1016/j.semarthrit.2008.10.007.
[3]	DANCHENKO N, SATIA J A, ANTHONY M S. Epidemiology of systemic lupus erythematosus：a comparison of worldwide disease burden[J]. Lupus，2006，15(5)：308-318. DOI：10.1191/0961203306lu2305xx.
[4]	DORIA A, ARIENTI S, RAMPUDDA M, et al. Preventive strategies in systemic lupus erythematosus[J]. Autoimmun Rev，2008，7(3)：192-197. DOI：10.1016/j.autrev.2007.11.004.
[5]	DORIA A, ZEN M, CANOVA M, et al. SLE diagnosis and treatment：when early is early[J]. Autoimmun Rev，2010，10(1)：55-60. DOI：10.1016/j.autrev.2010.08.014.
[6]	GATTO M, ZEN M, IACCARINO L, et al. New therapeutic strategies in systemic lupus erythematosus management[J]. Nat Rev Rheumatol，2019，15(1)：30-48. DOI：10.1038/s41584-018-0133-2.
[7]	GATTO M, KISS E, NAPARSTEK Y, et al. In-/ off-label use of biologic therapy in systemic lupus erythematosus[J]. BMC Med，2014，12：30. DOI：10.1186/1741-7015-12-30.
[8]	THONG B, OLSEN N J. Systemic lupus erythematosus diagnosis and management[J]. Rheumatology：Oxford，2017，56(suppl_1)：i3-13. DOI：10.1093/rheumatology/kew401.
[9]	YURKOVICH M, VOSTRETSOVA K, CHEN W J, et al. Overall and cause-specific mortality in patients with systemic lupus erythematosus：a meta-analysis of observational studies[J]. Arthritis Care Res，2014，66(4)：608-616. DOI：10.1002/acr.22173.
[10]	ZONANA-NACACH A, BARR S G, MAGDER L S, et al. Damage in systemic lupus erythematosus and its association with corticosteroids[J]. Arthritis Rheum，2000，43(8)：1801-1808. DOI：10.1002/1529-0131(200008)43:8<1801:AID-ANR16>3.0.CO;2-O.
[11]	ATISHA-FREGOSO Y, TOZ B, DIAMOND B. Meant to B：B cells as a therapeutic target in systemic lupus erythematosus[J]. J Clin Invest，2021，131(12)：e149095. DOI：10.1172/JCI149095.
[12]	DEPASCALE R, GATTO M, ZEN M, et al. Belimumab：a step forward in the treatment of systemic lupus erythematosus[J]. Expert Opin Biol Ther，2021，21(5)：563-573.
[13]	MURIMI-WORSTELL I B, LIN D H, NAB H, et al. Association between organ damage and mortality in systemic lupus erythematosus：a systematic review and meta-analysis[J]. BMJ Open，2020，10(5)：e031850. DOI：10.1136/bmjopen-2019-031850.
[14]	LEE Y H, SONG G G. Anifrolumab for the treatment of active systemic lupus erythematosus：a meta-analysis of randomized controlled trials[J]. Z Rheumatol，2021，80(10)：988-994. DOI：10.1007/s00393-020-00928-7.
[15]	BENGTSSON A A, RÖNNBLOM L. Role of interferons in SLE[J]. Best Pract Res Clin Rheumatol，2017，31(3)：415-428. DOI：10.1016/j.berh.2017.10.003.
[16]	SAMOTIJ D, REICH A. Biologics in the treatment of lupus erythematosus：a critical literature review[J]. Biomed Res Int，2019，2019：8142368. DOI：10.1155/2019/8142368.
[17]	LEE W S, AMENGUAL O. B cells targeting therapy in the management of systemic lupus erythematosus[J]. Immunol Med，2020，43(1)：16-35. DOI：10.1080/25785826.2019.1698929.
[18]	DORIA A, STOHL W, SCHWARTING A, et al. Efficacy and safety of subcutaneous belimumab in anti-double-stranded DNA-positive，hypocomplementemic patients with systemic lupus erythematosus[J]. Arthritis Rheumatol，2018，70(8)：1256-1264. DOI：10.1002/art.40511.
[19]	DEEKS E D. Anifrolumab：first approval[J]. Drugs，2021，81(15)：1795-1802. DOI：10.1007/s40265-021-01604-z.
[20]	MA X Y, FU X Y, CUI B B, et al. Telitacicept for recalcitrant cutaneous manifestations of systemic lupus erythematosus：a case report and review of the literature[J]. Tohoku J Exp Med，2022，258(3)：219-223. DOI：10.1620/tjem.2022.j074.
[21]	WALLACE D J, STOHL W, FURIE R A, et al. A phase Ⅱ，randomized，double-blind，placebo-controlled，dose-ranging study of belimumab in patients with active systemic lupus erythematosus[J]. Arthritis Rheum，2009，61(9)：1168-1178. DOI：10.1002/art.24699.
[22]	NAVARRA S V, GUZMÁN R M, GALLACHER A E, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus：a randomised，placebo-controlled，phase 3 trial[J]. Lancet，2011，377(9767)：721-731. DOI：10.1016/s0140-6736(10)61354-2.
[23]	FURIE R, PETRI M, ZAMANI O, et al. A phaseⅢ，randomized，placebo-controlled study of belimumab，a monoclonal antibody that inhibits B lymphocyte stimulator，in patients with systemic lupus erythematosus[J]. Arthritis Rheum，2011，63(12)：3918-3930. DOI：10.1002/art.30613.
[24]	ZHANG F, BAE S C, BASS D, et al. A pivotal phaseⅢ，randomised，placebo-controlled study of belimumab in patients with systemic lupus erythematosus located in China，Japan and South Korea[J]. Ann Rheum Dis，2018，77(3)：355-363. DOI：10.1136/annrheumdis-2017-211631.
[25]	STOHL W, SCHWARTING A, OKADA M, et al. Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus：a fifty-two-week randomized，double-blind，placebo-controlled study[J]. Arthritis Rheumatol，2017，69(5)：1016-1027.
[26]	FURIE R, KHAMASHTA M, MERRILL J T, et al. Anifrolumab，an anti-interferon-α receptor monoclonal antibody，in moderate-to-severe systemic lupus erythematosus[J]. Arthritis Rheumatol，2017，69(2)：376-386. DOI：10.1002/art.39962.
[27]	FURIE R A, MORAND E F, BRUCE I N, et al.Type Ⅰ interferon inhibitor anifrolumab in active systemic lupus erythematosus（TULIP-1）：a randomised，controlled，phase 3 trial[J]. Lancet Rheumatol，2019，1(4)：e208-219. DOI：10.1016/S2665-9913(19)30076-1.
[28]	WU D, LI J, XU D, et al.A human recombinant fusion protein targeting B lymphocyte stimulator（BlyS）and a proliferation-inducing ligand（APRIL），telitacicept（RC18），in systemic lupus erythematosus（SLE）：results of a phase 2b study[EB/OL].（2019-10-23）[2023-10-16].
[29]	BRUNNER H I, ABUD-MENDOZA C, VIOLA D O, et al.Paediatric Rheumatology International Trials Organisation（PRINTO）and the Pediatric Rheumatology Collaborative Study Group（PRCSG）. Safety and efficacy of intravenous belimumab in children with systemic lupus erythematosus：results from a randomised，placebo-controlled trial[J]. Ann Rheum Dis，2020，79(10)：1340-1348. DOI：10.1136/annrheumdis-2020-217101.
[30]	GINZLER E, GUEDES BARBOSA L S, D'CRUZ D, et al. PhaseⅢ/Ⅳ，randomized，fifty-two-week study of the efficacy and safety of belimumab in patients of black African ancestry with systemic lupus erythematosus[J]. Arthritis Rheumatol，2022，74(1)：112-123. DOI：10.1002/art.41900.
[31]	MORAND E F, FURIE R, TANAKA Y, et al. Trial of anifrolumab in active systemic lupus erythematosus[J]. N Engl J Med，2020，382(3)：211-221. DOI：10.1056/nejmoa1912196.
[32]	WU D, LI J, XU D, et al. Telitacicept，a human recombinant fusion protein targeting B lymphocyte stimulator（BlyS）and a proliferation-inducing ligand（APRIL），in systemic lupus erythematosus（SLE）：results of a phase 3 study[EB/OL].（2022-10-18）[2023-10-16].
[33]	BRUCE I N, O'KEEFFE A G, FAREWELL V, et al. Factors associated with damage accrual in patients with systemic lupus erythematosus：results from the Systemic Lupus International Collaborating Clinics（SLICC）Inception Cohort[J]. Ann Rheum Dis，2015，74(9)：1706-1713. DOI：10.1136/annrheumdis-2013-205171.
[34]	FURIE R, ROVIN B H, HOUSSIAU F, et al. Two-year，randomized，controlled trial of belimumab in lupus nephritis[J]. N Engl J Med，2020，383(12)：1117-1128. DOI：10.1056/NEJMoa2001180.
[35]	FDA approves GSK's BENLYSTA as the first medicine for adult patients with active lupus nephritis in the US[EB/OL]. （2020-12-17）[2023-10-10].
[36]	UROWITZ M B, OHSFELDT R L, WIELAGE R C, et al. Comparative analysis of long-term organ damage in patients with systemic lupus erythematosus using belimumab versus standard therapy：a post hoc longitudinal study[J]. Lupus Sci Med，2020，7(1)：e000412. DOI：10.1136/lupus-2020-000412.
[37]	KALUNIAN K C, FURIE R, MORAND E F, et al. A randomized，placebo-controlled phaseⅢ extension trial of the long-term safety and tolerability of anifrolumab in active systemic lupus erythematosus[J]. Arthritis Rheumatol，2023，75(2)：253-265. DOI：10.1002/art.42392.
[38]	CHATHAM W W, FURIE R, SAXENA A, et al. Long-term safety and efficacy of anifrolumab in adults with systemic lupus erythematosus：results of a phase Ⅱ open-label extension study[J]. Arthritis Rheumatol，2021，73(5)：816-825.

检索步骤	检索式
#1	"Lupus Erythematosus，Systemic"[Mesh]
#2	（（（（Systemic Lupus Erythematosus[Title/Abstract]）OR（Lupus Erythematosus Disseminatus[Title/Abstract]））OR（Libman-Sacks Disease[Title/Abstract]））OR（Disease，Libman-Sacks[Title/Abstract]））OR（Libman Sacks Disease[Title/Abstract]）
#3	#1 OR #2
#4	"belimumab" [Supplementary Concept]
#5	（LymphoStat-B[Title/Abstract]）OR（Benlysta[Title/Abstract]）
#6	#4 OR #5
#7	"anifrolumab" [Supplementary Concept]
#8	（Saphnelo[Title/Abstract]）OR（MEDI-546[Title/Abstract]）
#9	#7 OR #8
#10	"telitacicept" [Supplementary Concept]
#11	"randomized controlled trial"[pt] OR "controlled clinical trial"[pt] OR randomized[tiab] OR placebo[tiab] OR "drug therapy"[sh] OR randomly[tiab] OR trial[tiab] OR groups[tiab]
#12	#6 AND #9 AND #10
#13	#3 AND #11 AND #12

检索步骤	检索式
#1	"Lupus Erythematosus，Systemic"[Mesh]
#2	（（（（Systemic Lupus Erythematosus[Title/Abstract]）OR（Lupus Erythematosus Disseminatus[Title/Abstract]））OR（Libman-Sacks Disease[Title/Abstract]））OR（Disease，Libman-Sacks[Title/Abstract]））OR（Libman Sacks Disease[Title/Abstract]）
#3	#1 OR #2
#4	"belimumab" [Supplementary Concept]
#5	（LymphoStat-B[Title/Abstract]）OR（Benlysta[Title/Abstract]）
#6	#4 OR #5
#7	"anifrolumab" [Supplementary Concept]
#8	（Saphnelo[Title/Abstract]）OR（MEDI-546[Title/Abstract]）
#9	#7 OR #8
#10	"telitacicept" [Supplementary Concept]
#11	"randomized controlled trial"[pt] OR "controlled clinical trial"[pt] OR randomized[tiab] OR placebo[tiab] OR "drug therapy"[sh] OR randomly[tiab] OR trial[tiab] OR groups[tiab]
#12	#6 AND #9 AND #10
#13	#3 AND #11 AND #12

第一作者	发表时间（年）	国家（个）	临床试验（期）	试验组			对照组			疗程（周）	结局指标
第一作者	发表时间（年）	国家（个）	临床试验（期）	样本量（例）	年龄（岁）	干预措施	样本量（例）	年龄（岁）	干预措施	疗程（周）	结局指标
WALLACE^[21]	2009	2	Ⅱ	111	41.8±11.7	B	113	42.2±10.9	A	52	④
NAVARRA^[22]	2011	13	Ⅲ	290	35.4±10.8	B	287	36.2±11.8	A	52	①②③④
FURIE^[23]	2011	19	Ⅲ	273	40.5±11.1	B	275	40.0±11.9	A	52	①②③④
ZHANG^[24]	2017	3	Ⅲ	451	32.3±9.65	B	226	31.7±9.18	A	52	①②③④
STOHL^[25]	2017	30	Ⅲ	556	38.1±12.1	C	280	39.6±12.6	A	52	①②④
FURIE^[26]	2017	14	ⅡB	99	39.1±11.9	D	102	39.3±12.9	A	52	①②③④
FURIE^[27]	2019	18	Ⅲ	180	42.0±12.0	D	184	41.0±12.3	A	52	②③④
WU^[28]	2019	1	ⅡB	63	NA	E	62	NA	A	48	①④
BRUNNER^[29]	2020	10	Ⅱ	53	14.0（12.0，15.0）	B	40	15.0（14.0，16.0）	A	52	①④
GINZLER^[30]	2022	6	Ⅲ/Ⅳ	298	38.6±11.1	B	149	39.3±12.2	A	52	①②③④
MORAND^[31]	2022	16	Ⅲ	180	43.1±12.0	D	182	41.1±11.5	A	52	①②③④
WU^[32]	2022	1	Ⅲ	167	NA	E	168	NA	A	52	①④

第一作者	发表时间（年）	国家（个）	临床试验（期）	试验组			对照组			疗程（周）	结局指标
第一作者	发表时间（年）	国家（个）	临床试验（期）	样本量（例）	年龄（岁）	干预措施	样本量（例）	年龄（岁）	干预措施	疗程（周）	结局指标
WALLACE^[21]	2009	2	Ⅱ	111	41.8±11.7	B	113	42.2±10.9	A	52	④
NAVARRA^[22]	2011	13	Ⅲ	290	35.4±10.8	B	287	36.2±11.8	A	52	①②③④
FURIE^[23]	2011	19	Ⅲ	273	40.5±11.1	B	275	40.0±11.9	A	52	①②③④
ZHANG^[24]	2017	3	Ⅲ	451	32.3±9.65	B	226	31.7±9.18	A	52	①②③④
STOHL^[25]	2017	30	Ⅲ	556	38.1±12.1	C	280	39.6±12.6	A	52	①②④
FURIE^[26]	2017	14	ⅡB	99	39.1±11.9	D	102	39.3±12.9	A	52	①②③④
FURIE^[27]	2019	18	Ⅲ	180	42.0±12.0	D	184	41.0±12.3	A	52	②③④
WU^[28]	2019	1	ⅡB	63	NA	E	62	NA	A	48	①④
BRUNNER^[29]	2020	10	Ⅱ	53	14.0（12.0，15.0）	B	40	15.0（14.0，16.0）	A	52	①④
GINZLER^[30]	2022	6	Ⅲ/Ⅳ	298	38.6±11.1	B	149	39.3±12.2	A	52	①②③④
MORAND^[31]	2022	16	Ⅲ	180	43.1±12.0	D	182	41.1±11.5	A	52	①②③④
WU^[32]	2022	1	Ⅲ	167	NA	E	168	NA	A	52	①④

不良事件	研究数量（篇）	贝利尤单抗组		安慰剂组		I²值（%）	P值	OR（95%CI）	P值
不良事件	研究数量（篇）	事件例数	总例数	事件例数	总例数	I²值（%）	P值	OR（95%CI）	P值
总不良事件	6^{[21,22,23,24,29,30]}	1 298	1 528	981	1 115	0	0.96	0.93（0.73~1.18）	0.55
严重不良事件	5^{[21,22,23,24,30]}	214	1 475	186	1 075	56	0.06	0.82（0.59~1.12）	0.25
上呼吸道感染	6^{[21,22,23,24,29,30]}	239	1 528	199	1 115	32	0.20	0.90（0.73~1.12）	0.35
尿路感染	5^{[21,22,23,24,30]}	154	1 475	118	1 075	0	1.00	1.04（0.80~1.35）	0.78
腹泻	6^{[21,22,23,24,29,30]}	147	1 528	93	1 115	0	0.68	1.28（0.97~1.69）	0.08
头痛	6^{[21,22,23,24,29,30]}	214	1 528	187	1 115	38	0.15	0.95（0.76~1.19）	0.67
关节痛	4^{[21,22,23,30]}	154	1 005	137	840	0	0.99	0.99（0.76~1.28）	0.93
恶心	5^{[21,22,23,24,30]}	137	1 475	104	1 075	65	0.02	1.16（0.88~1.54）	0.28
鼻咽炎	4^{[22,23,24,29]}	128	1 086	81	837	41	0.17	1.22（0.90~1.64）	0.20
鼻窦炎	4^{[21,22,23,30]}	105	1 005	86	840	0	0.71	1.10（0.81~1.49）	0.56