RÉSUMÉ
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 (<20 μg/L, n=42) and non-deficiency group (≥20 μg/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 ( χ2=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 ( χ2=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 ( χ2=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.
RÉSUMÉ
Objective:To investigate the relationship between polymorphisms and haplotypes of cyclin-dependent kinase inhibitor 2B antisense RNA 1 ( CDKN2 B- AS1) gene and the risk of ulcerative colitis (UC). Methods:From January 2012 to January 2021, a total of 534 UC patients diagnosed at the Department of Gastroenterology, the Second Affiliated Hospital of Wenzhou Medical University (Yuying Children′s Hospital) and during the same period 560 gender- and age-matched healthy controls were selected. Genotypes of CDKN2 B- AS1 (rs1063192, rs10757274, rs10757278, rs1333048, rs2383207) in venous blood were determined by matrix assisted laser desorption ionization time-of-flight mass spectrometry technique. Unconditional logistic regression was used to analyze the difference in the distribution of CDKN2 B- AS1 gene polymorphisms between UC patients and healthy controls, as well as the influence on the clinicopathologic characteristics of UC patients. Software Haploview 4.2 was used to analyze the linkage disequilibrium and haplotype. Chi-square test was used for statistical analysis. Results:The frequencies of variant genotype (AG+ GG) and variant allele (G) of rs1063192 in UC patients were higher than those in healthy controls (32.4%, 173/534 vs. 24.8%, 139/560; 18.1%, 193/1 068 vs. 13.7%, 153/1 120), and the differences were statistically significant ( OR=1.45 and 1.40, 95% confidence interval(95% CI) 1.12 to 1.89 and 1.11 to 1.77, P=0.006 and 0.004, corrected P=0.030 and 0.020). The frequency of variant allele (G) of rs10757274 in UC patients was lower than that in healthy controls (34.7%, 371/1 068 vs. 39.5%, 442/1 120), and the difference was statistically significant ( OR=0.82, 95% CI 0.69 to 0.98, P=0.025). However, the difference was not significant after Bonferroni correction (corrected P>0.05). According to the Montreal classification, the frequency of homozygous variant genotype (GG) of rs1063192 in the patients with extensive colitis was higher than that in patients with proctitis plus left-sided colitis (6.6%, 14/211 vs. 1.9%, 6/323), and the difference was statistically significant ( OR=3.92, 95% CI 1.47 to 10.42, P=0.006, corrected P=0.030). There was linkage disequilibrium among rs10757274, rs2383207, rs10757278 and rs1333048 of CDKN2 B- AS1 gene. The frequency of haplotype GGGC in UC patients was lower than that in healthy controls (33.3%, 355.5/1 068 vs. 37.8%, 423.4/1 120), and the frequency of haplotype AGGC in UC patients was higher than that in healthy controls (6.7%, 71.7/1 068 vs. 3.6%, 40.3/1 120), and the differences were statistically significant ( χ2=4.81 and 11.16, P=0.028 and<0.001). Conclusions:The variation of rs1063192 in CDKN2 B- AS1 gene may increase the risk of UC. The risk of extensive colitis in patients carrying homozygous variant genotype (GG) of rs1063192 may rise. Among the haplotypes composed of rs10757274, rs2383207, rs10757278 and rs1333048, the risk of UC may decrease in the individuals carrying haplotype GGGC. However, the risk of UC may increase in the individuals carrying haplotype AGGC. The correlation between the variation of 10757274 and the risk of UC still needs to be further verified by expanding the sample size.