补充维生素D对乌司奴单抗治疗克罗恩病临床疗效影响的回顾性分析

Effects of vitamin D supplementation on the clinical efficacy of Crohn′s disease treated with ustekinumab:a retrospective analysis

目的回顾性分析补充维生素D对乌司奴单抗(UST)治疗克罗恩病患者临床疗效的影响。方法通过检索温州医科大学附属第二医院临床资料数据库,收集2021年5月至2023年2月接受UST一线治疗的71例中、重度活动期克罗恩病患者资料。采用哈维-布拉德肖指数(HBI)评估克罗恩病疾病活动度,简化克罗恩病内镜评分(SES-CD)评估克罗恩病肠道炎症严重度。依据UST治疗的同时是否补充维生素D(400 U/d)将克罗恩病患者分为补充组(41例)和未补充组(30例)。再依据基线血清25-羟维生素D[25(OH)D]水平,将克罗恩病患者分为维生素D缺乏组(<20μg/L,42例)和不缺乏组(≥20μg/L,29例)。主要观察终点是UST治疗第24周时补充组与未补充组之间临床缓解(HBI评分≤4分)率和黏膜愈合(SES-CD评分≤2分)率的差异。次要观察终点是UST治疗第8周时补充组与未补充组之间临床应答(HBI评分较第0周下降≥3分)率和生物化学缓解[C反应蛋白(CRP)≤5 mg/L]率的差异。采用多元线性回归模型分析血清25(OH)D水平与克罗恩病患者临床病理特征的关系,采用多因素二元logistic回归分析第8周和第24周UST临床疗效的影响因素。两组间比较采用独立样本t检验、Mann-Whitney U检验、卡方检验。UST治疗前后计量资料的比较采用配对t检验。结果多元线性回归分析发现克恩罗病患者基线血清25(OH)D水平是基线CRP水平[β=-0.33,95%置信区间(95%CI)-0.41~-0.08,P=0.041]和基线HBI评分(β=-0.52,95%CI-0.68~-0.33,P=0.027)的独立影响因素。第8周与第0周比较,补充组血清25(OH)D水平升高[(17.18±5.46)μg/L比(13.71±7.73)μg/L],差异有统计学意义(t=-7.81,P<0.001);未补充组血清25(OH)D水平[(14.85±3.92)μg/L比(15.69±5.48)μg/L]差异无统计学意义(P>0.05)。第8周时,补充组的HBI评分和CRP均低于未补充组[(5.71±1.88)分比(8.34±2.27)分、10.83 mg/L(3.95 mg/L,21.07 mg/L)比16.17 mg/L(6.91 mg/L,35.48 mg/L),t=0.48、Z=2.87,P<0.001、=0.001],而临床应答率和生物化学缓解率均高于未补充组[68.3%(28/41)比40.00%(12/30)、43.9%(18/41)比13.33%(4/30)],差异均有统计学意义(χ^(2)=5.64、6.21,P=0.018、0.013)。第24周与第0周比较,补充组血清25(OH)D水平[(24.73±8.34)μg/L]升高,差异有统计学意义(t=-6.83,P<0.001),而未补充组血清25(OH)D水平[(15.59±7.24)μg/L比(15.69±5.48)μg/L]差异无统计学意义(P>0.05)。第24周时,补充组的HBI评分降幅和SES-CD评分降幅均大于未补充组[第24周与第0周差值(-8.96±1.45)分比(-5.33±0.59)、-7.00分(-10.00分,-3.00分)比-2.00分(-2.50分,-1.50分),t=-5.64、Z=-3.27,P<0.001、=0.039];临床缓解率和黏膜愈合率均高于未补充组[65.9%(27/41)比26.7%(8/30)、61.0%(25/41)比30.0%(9/30)],差异均有统计学意义(χ^(2)=10.64、6.66,P=0.001、0.010)。第24周时,在维生素D缺乏组中分析发现,接受补充维生素D治疗的患者临床缓解率和黏膜愈合率均高于未接受补充维生素D治疗的患者[69.0%(20/29)比3/13、58.6%(17/29)比2/13],差异均有统计学意义(χ^(2)=4.43、5.14,P=0.035、0.023)。补充维生素D是UST治疗克罗恩病第8周临床应答率、生物化学缓解率,以及第24周临床缓解率、黏膜愈合率的独立影响因素[OR(95%CI)为5.83(1.15~7.59)、4.91(3.67~6.98)、5.13(2.88~9.44)、7.01(1.16~20.97),P<0.001、<0.001、<0.001、=0.036]。结论补充维生素D可能有助于改善UST治疗克罗恩病患者的临床疗效,尤其对于维生素D缺乏患者。

Objective To retrospectively analyze the effects of vitamin D supplementation on the clinical efficacy of ustekinumab(UST)in treatment of patients with Crohn′s disease(CD).Methods Seventy-one patients with moderate to severe active CD who received the first-line treatment UST from May 2021 to February 2023 were collected by searching the clinical database of the Second Affiliated Hospital of Wenzhou Medical University.The disease activity of CD was evaluated by Harvey-Bradshaw index(HBI)and intestinal inflammation was assessed by simplified endoscopic score for Crohn′s disease(SES-CD).The CD patients were divided into supplementary group(n=41)and non-supplementary group(n=30)based on whether vitamin D supplementation(400 U/d)was performed during UST treatment.According to the baseline serum 25(OH)D level,the patients were divided into vitamin D deficiency group(<20μg/L,n=42)and non-deficiency group(≥20μg/L,n=29).The main end points were the differences in the clinical remission(HBI score≤4)rate and mucosal healing(SES-CD score≤2)rate between supplementary group and non-supplementary group at week 24 of UST treatment.The secondary end points were the differences in the clinical response(the reduction of HBI score≥3 compared to week 0)rate and biochemical remission(C-reactive protein(CRP)≤5 mg/L)rate between supplementary group and non-supplementary group at week 8 of UST treatment.A multiple linear regression analysis was performed to investigate the relation between serum 25(OH)D levels and the clinicopathological characteristics of CD patients.Multivariate binary logistic regression models were used to analyze the factors affecting the clinical efficacy of UST at week 8 and 24.Independent sample t test,Mann-Whitney U test,Chi-square test and Fisher′s exact test were used for comparisons between the two groups.Paired t test was used to analyze the differences before and after UST treatment.Results The results of multiple linear regression analysis for 71 CD patients showed that the baseline serum 25(OH)D level was independent influencing factor for the baseline CRP level(β=-0.33,95%confidence interval(95%CI)-0.41 to-0.08,P=0.041)and baseline HBI score(β=-0.52,95%CI-0.68 to-0.33,P=0.027).Compared with week 0,the serum 25(OH)D level of supplementary group increased at week 8((17.18±5.46)μg/L vs.(13.71±7.73)μg/L),and the difference was statistically significant(t=-7.81,P<0.001),however,there was no significant difference of serum 25(OH)D in non-supplementary group((14.85±3.92)μg/L vs.(15.69±5.48)μg/L,P>0.05).At week 8,the HBI score and median CRP level of supplementary group were both lower than those of non-supplementary group(5.71±1.88 vs.8.34±2.27,10.83 mg/L(3.95 mg/L,21.07 mg/L)vs.16.17 mg/L(6.91 mg/L,35.48 mg/L)),and the diffierences were statistically significant(t=0.48,Z=2.87;P<0.001 and=0.001).However,the clinical response rate and biochemical remission rate were both higher than those of non-supplementary group(68.3%,28/41 vs.40.00%,12/30 and 43.9%,18/41 vs.13.3%,4/30),and the differences were statistically significant(χ^(2)=5.64 and 6.21,P=0.018 and 0.013).Compared with week 0,the serum 25(OH)D level of supplementary group increased((24.73±8.34)μg/L)at week 24,and the difference was statistically significant(t=-6.83,P<0.001),however,there was no statistically significant difference in the serum 25(OH)D level of non-supplementary group((15.59±7.24)μg/L vs.(15.69±5.48)μg/L,P>0.05).At week 24,the decrease of HBI score and SES-CD score of supplementary group were both greater than those of non-supplementary group(difference between week 24 and week 0-8.96±1.45 vs.-5.33±0.59,-7.00(-10.00,-3.00)vs.-2.00(-2.50,-1.50),and the differences were statisticalcy significant(t=-5.64 and Z=-3.27,P<0.001 and=0.039).Moreover,the clinical remission rate and mucosal healing rate were both higher than those of non-supplementary group(65.9%,27/41 vs.26.7%,8/30,and 61.0%,25/41 vs.30.0%,9/30),and the differences were statistically significant(χ^(2)=10.64 and 6.66,P=0.001 and 0.010).At week 24,the analysis of non-supplementary group indicated that the clinical remission rate and mucosal healing rate of patients received vitamin D supplementary therapy were both higher than those of patients without vitamin D supplementary therapy(69.0%,20/29 vs.3/13,and 58.6%,17/29 vs.2/13),and the differences were statistically significant(χ^(2)=4.43 and 5.14,P=0.035 and 0.023).Vitamin D supplementing therapy was an independent influencing factor of clinical response rate and biochemical remission rate at week 8,clinical remission rate and mucosal healing rate at week 24 for UST treatment of CD(OR(95%CI)were 5.83(1.15 to 7.59),4.91(3.67 to 6.98),5.13(2.88 to 9.44),7.01(1.16 to 20.97),respectively;P<0.001,<0.001,<0.001,=0.036).Conclusion Vitamin D supplementation may help to improve the clinical efficacy of UST treatment in CD patients,especially in patients with vitamin D deficiency.