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基线IgM水平对原发性胆汁性胆管炎治疗应答的预测价值
DOI: 10.3969/j.issn.1001-5256.2022.04.015
伦理学声明：本研究方案于2020年5月9日经解放军总医院第五医学中心伦理委员会批准，批号：R2015140DC020。
利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明：韩琳、梁庆升负责课题设计，撰写论文；谢欢、陈英、张明月负责收集数据及资料分析；李保森、赵军负责修改论文；孙颖、董艳丽负责拟定写作思路，指导撰写文章并最后定稿。
Value of baseline IgM level in predicting the treatment response of primary biliary cholangitis
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摘要:
目的 研究基线IgM水平与原发性胆汁性胆管炎(PBC)患者经熊去氧胆酸(UDCA)治疗应答的关系。 方法 回顾性分析2010年1月—2020年1月解放军总医院第五医学中心确诊的637例UDCA初治PBC患者的临床资料。将PBC患者分为UDCA完全应答组(n=436)和UDCA应答不良组(n=201)，比较两组患者的临床基线资料。根据基线指标预测治疗应答不良风险的受试者工作特征曲线下面积(AUC)确定IgM的最佳临界值，将患者分为IgM≥1.5×ULN组与IgM＜1.5×ULN组，分析患者组间基线参数、治疗应答及预后模型评分的差异。符合正态分布的计量资料两组间比较使用t检验，非正态分布的计量资料两组间比较使用Mann-Whitney U检验；计数资料两组间比较使用χ2检验。亚组分析使用Cochran-Mantel-Haenszel检验，并绘制风险值森林图。 结果 UDCA应答不良组患者基线存在肝硬化、TBil、AST、ALP、总胆汁酸、总胆固醇、IgA、IgM水平及抗Gp210阳性率均明显高于完全应答组患者(χ2=4.596，Z值分别为-9.932、-8.931、-8.361、-7.836、-4.694、-3.242、-2.115，χ2=15.931，P值均＜0.05)。Mayo风险评分(MRS)、Globe评分、UK-PBC风险评分在应答不良组均显著高于完全应答组(t=4.092，Z值分别为-10.910、-11.646，P值均＜0.001)。IgM升高组患者AST、ALP、总胆固醇、IgA、IgG水平及抗Gp210阳性率显著高于IgM正常组(Z值分别为-3.774、-5.063、-4.344、-2.051、-6.144，χ2=25.180，P值均＜0.05)。IgM预测UDCA应答不良的AUC为0.552。IgM≥1.5×ULN组患者的AST、ALP、总胆固醇、IgG、抗Gp210阳性率、UDCA应答不良率高于IgM＜1.5×ULN组患者(Z值分别为-4.193、-5.044、-3.250、-5.465，χ2=25.204、8.948，P值均＜0.05)。IgM≥1.5×ULN预测应答不良风险值为1.416 (95%CI：1.129~1.776, P=0.003)。亚组分析中，无肝硬化患者，IgM≥1.5×ULN预测应答不良风险值为1.821(95%CI：1.224~2.711, P=0.003)。 结论 基线IgM水平对于预测UDCA应答具有重要价值，基线IgM水平较高的PBC患者，治疗中应密切监测IgM水平，如持续异常，应及时联合二线药物治疗。 Abstract:Objective To investigate the association between baseline IgM level and treatment response to ursodeoxycholic acid (UDCA) in patients with primary biliary cholangitis (PBC). Methods A retrospective analysis was performed for the clinical data of 637 PBC patients who were diagnosed and treated with UDCA for the first time in The Fifth Medical Center of Chinese PLA General Hospital from January 2010 to January 2020. The PBC patients were divided into UDCA complete response group with 436 patients and UDCA poor response group with 201 patients, and baseline clinical data were compared between the two groups. According to the optimal cut-off value of IgM determined by the area under the ROC curve (AUC) of baseline indices in predicting the risk of poor treatment response, the patients were divided into IgM ≥1.5×ULN group and IgM < 1.5×ULN group, and baseline parameters, treatment response, and prognostic model score were compared between groups. The t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data between two groups. The Cochran-Mantel-Haenszel test was used for subgroup analysis, and forest plots were plotted for related risk values. Results Compared with the UDCA complete response group, the UDCA poor response group had significantly higher proportion of patients with liver cirrhosis, levels of total bilirubin, aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bile acid, total cholesterol (TC), IgA, and IgM, and positive rate of anti-Gp210 antibody at baseline (χ2=4.596, Z=-9.932, -8.931, -8.361, -7.836, -4.694, -3.242, and -2.115, χ2=15.931, all P < 0.05). The UDCA poor response group had significantly higher Mayo Risk Score, Globe score, and UK-PBC risk score than the UDCA complete response group (t=4.092, Z=-10.910 and -11.646, all P < 0.001). Compared with the normal IgM group, the elevated IgM group had significantly higher levels of AST, ALP, TC, IgA, and IgG and a significantly higher positive rate of anti-Gp210 antibody (Z=-3.774, -5.063, -4.344, -2.051, and -6.144, χ2=25.180, all P < 0.05). IgM had an AUC of 0.552 in predicting poor treatment response. Compared with the IgM < 1.5×ULN group, the IgM ≥1.5×ULN group had significantly higher levels of AST, ALP, TC, and IgG, a significantly higher positive rate of anti-Gp210 antibody, and a significantly higher poor UDCA response rate (Z=-4.193, -5.044, -3.250, and -5.465, χ2=25.204 and 8.948, all P < 0.05). IgM ≥1.5×ULN had an odds ratio of 1.416 (95% confidence interval [CI]: 1.129-1.776, P=0.003) in predicting poor response. The subgroup analysis showed that for patients without liver cirrhosis, IgM ≥1.5×ULN had an odds ratio of 1.821 (95%CI: 1.224-2.711, P=0.003) in predicting poor response. Conclusion Baseline IgM level has an important value in predicting UDCA response. IgM level should be closely monitored during treatment in PBC patients with a high baseline IgM level, and second-line drugs should be given in time if the abnormality persists. -
Key words:
- Primary Biliary Cholangitis /
- Cholestasis /
- Immunoglobulin M /
- Therapeutics
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图 1 PBC患者基线指标预测UDCA治疗1年后应答不良的ROC曲线
Figure 1. ROC curves of characteristics at baseline in predicting poor response to UDCA after 1 year of treatment
图 2 IgM≥1.5×ULN相对IgM＜1.5×ULN预测治疗应答情况亚组分析森林图
Figure 2. Forest plot for subgroup analysis by IgM≥1.5×ULN versus IgM < 1.5×ULN in predicting treatment response of UDCA
表 1 PBC患者基线特征及UDCA治疗1年后的应答情况
Table 1. Characteristics of patients with PBC at baseline and biochemical response to UDCA after 1 year of treatment
基线特征 数值 性别[例(%)] 男 126(19.8) 女 511(80.2) 发病年龄(岁) 56(50~66) 肝硬化[例(%)] 487(76.5) PLT(×109/L) 121(77~182) Alb(g/L) 35(31~38) TBil(μmol/L) 20.7(13.8~38.2) ALT(U/L) 53(27~95) AST(U/L) 69(41~105) ALP(U/L) 247(158~432) GGT(U/L) 163(81~374) TBA(μmol/L) 28(12~65) ChE(U/L) 4405(2922~5947) TC(mmol/L) 4.4(3.3~5.8) PT(s) 11.6(10.5~12.9) INR 1.01(0.94~1.12) IgA(g/L) 2.68(1.84~3.87) IgG(g/L) 15.67(12.83~20.41) IgM(g/L) 2.76(1.61~4.43) IgM＞ULN[例(%)] 357(56.0) ANA阳性[例(%)] 469(73.6) 抗Sp100阳性[例(%)] 94(14.8) 抗Gp210阳性[例(%)] 218(34.2) MRS[6] 5.84±1.45 Globe评分[7] 1.21(0.34~2.11) UK-PBC评分[8] 0.037(0.015~0.112) UDCA治疗1年[例(%)] 完全应答 436(68.4) 应答不良 201(31.6) 注：TBA，总胆汁酸；ChE，胆碱酯酶。 
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表 2 UDCA治疗完全应答与应答不良患者基线指标及风险评分差异
Table 2. Differences of baseline characteristics and risk scores between PBC with complete response and poor response to UDCA treatment
指标 UDCA完全应答组(n=436) UDCA应答不良组(n=201) 统计值 P值 性别[例(%)] χ2=3.112 0.078 男 78(17.9) 48(23.9) 女 358(82.1) 153(76.1) 年龄(岁) 57(50~66) 54(49~65) Z=-1.447 0.148 肝硬化[例(%)] 344(78.9) 143(71.1) χ2=4.596 0.032 TBil(μmol/L) 17.5(12.1~26.1) 39.2(20.6~62.7) Z=-9.932 ＜0.001 AST(U/L) 55(38~87) 99(69~135) Z=-8.931 ＜0.001 ALP(U/L) 201(150~340) 390(237~599) Z=-8.361 ＜0.001 TBA(μmol/L) 22(9~43) 54(20~121) Z=-7.836 ＜0.001 TC(mmol/L) 4.2(3.2~5.3) 5.1(3.5~7.1) Z=-4.694 ＜0.001 IgA(g/L) 2.55(1.75~3.61) 3.01(2.01~4.38) Z=-3.242 0.001 IgG(g/L) 15.59(12.63~20.50) 15.73(12.97~20.16) Z=-0.227 0.821 IgM(g/L) 2.60(1.56~4.30) 3.33(1.78~5.02) Z=-2.115 0.034 ANA阳性[例(%)] 313(71.8) 156(77.6) χ2=2.402 0.121 抗Sp100阳性[例(%)] 66(15.1) 28(13.9) χ2=0.159 0.690 抗Gp210阳性[例(%)] 127(29.1) 91(45.3) χ2=15.931 ＜0.001 MRS 5.68±1.45 6.18±1.41 t=4.092 ＜0.001 Globe评分 0.83(0.14~1.66) 2.09(1.29~2.81) Z=-10.910 ＜0.001 UK-PBC评分 0.025(0.012~0.058) 0.128(0.050~0.324) Z=-11.646 ＜0.001
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表 3 IgM升高与IgM正常的PBC患者基线特征及治疗应答差异
Table 3. Differences of baseline characteristics and biochemical response to UDCA treatment between IgM-normal and IgM-elevated PBC
指标 IgM升高组(n=357) IgM正常组(n=280) 统计值 P值 性别[例(%)] χ2=0.525 0.469 男 67(18.8) 59(21.1) 女 290(81.2) 221(78.9) 年龄(岁) 55(49~65) 57(50~67) Z=-1.776 0.076 肝硬化[例(%)] 275(77.0) 212(75.7) χ2=0.151 0.698 TBil(μmol/L) 20.4(14.0~38.2) 21.1(13.6~38.6) Z=-0.066 0.947 AST(U/L) 75(45~106) 55(35~100) Z=-3.774 ＜0.001 ALP(U/L) 275(173~478) 201(144~347) Z=-5.063 ＜0.001 TBA(μmol/L) 29(13~60) 28(11~70) Z=-0.587 0.558 TC(mmol/L) 4.8(3.6~6.2) 4.2(3.1~5.3) Z=-4.344 ＜0.001 IgA(g/L) 2.83(1.96~3.91) 2.53(1.70~3.82) Z=-2.051 0.040 IgG(g/L) 16.88(14.00~21.42) 14.04(11.87~18.50) Z=-6.144 ＜0.001 ANA阳性[例(%)] 270(75.6) 199(71.1) χ2=1.680 0.195 抗Sp100阳性[例(%)] 56(15.7) 38(13.6) χ2=0.558 0.455 抗Gp210阳性[例(%)] 152(42.6) 66(23.6) χ2=25.180 ＜0.001 MRS 5.78±1.46 5.91±1.43 t=-1.071 0.284 Globe评分 1.18(0.29~2.12) 1.27(0.36~2.07) Z=-0.433 0.665 UK-PBC评分 0.038(0.015~0.114) 0.037(0.015~0.108) Z=-0.416 0.677 UDCA治疗1年[例(%)] χ2=2.580 0.108 完全应答 235(65.8) 201(71.8) 应答不良 122(34.2) 79(28.2)
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表 4 PBC患者基线指标预测UDCA治疗1年后应答不良的AUC
Table 4. AUC values of characteristics at baseline in predicting poor biochemical response to UDCA after 1 year of treatment
指标 AUC 95%CI TBil 0.745 0.709~0.778 AST 0.720 0.683~0.755 ALP 0.706 0.669~0.741 TBA 0.693 0.655~0.728 TC 0.615 0.576~0.653 IgA 0.576 0.537~0.615 IgM 0.552 0.512~0.591 IgG 0.505 0.466~0.545
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表 5 不同IgM水平PBC患者基线临床特征及UDCA疗效比较
Table 5. Comparison of baseline characteristics and the outcome of UDCA treatment between PBC with different levels of IgM
指标 IgM≥1.5×ULN组(n=253) IgM＜1.5×ULN组(n=384) 统计值 P值 性别[例(%)] χ2=0.038 0.846 男 51(20.2) 75(19.5) 女 202(79.8) 309(80.5) 年龄(岁) 56(49~65) 56(50~66) Z=-1.077 0.281 肝硬化[例(%)] 195(77.1) 292(76.0) χ2=0.090 0.764 TBil(μmol/L) 21.0(14.3~38.0) 20.5(13.6~39.7) Z=-0.244 0.808 AST(U/L) 78(46~112) 61(38~99) Z=-4.193 ＜0.001 ALP(U/L) 288(179~492) 210(150~358) Z=-5.044 ＜0.001 TBA(μmol/L) 28(13~57) 28(10~70) Z=-0.210 0.834 TC(mmol/L) 4.8(3.6~6.3) 4.3(3.2~5.5) Z=-3.250 0.001 IgA(g/L) 2.81(1.90~3.85) 2.63(1.76~3.87) Z=-1.021 0.307 IgG(g/L) 17.60(14.09~22.10) 14.89(12.15~19.32) Z=-5.465 ＜0.001 ANA阳性[例(%)] 192(75.9) 277(72.1) χ2=1.107 0.293 抗Sp100阳性[例(%)] 44(17.4) 50(13.0) χ2=2.316 0.128 抗Gp210阳性[例(%)] 116(45.8) 102(26.6) χ2=25.204 ＜0.001 MRS 5.71±1.43 5.92±1.46 t=-1.792 0.074 Globe评分 1.17(0.36~2.14) 1.28(0.29~2.07) Z=-0.161 0.872 UK-PBC评分 0.038(0.014~0.119) 0.037(0.015~0.109) Z=-0.481 0.631 UDCA治疗1年[例(%)] χ2=8.948 0.003 完全应答 156(61.7) 280(72.9) 应答不良 97(38.3) 104(27.1)
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