5-Aminosalicylates Reduce the Risk of Colorectal Neoplasia in Patients with Ulcerative Colitis: An Updated Meta-Analysis

Background

Although the chemopreventive effect of 5-aminosalicylates on patients with ulcerative colitis has been extensively studied, the results remain controversial. This updated review included more recent studies and evaluated the effectiveness of 5-aminosalicylates use on colorectal neoplasia prevention in patients with ulcerative colitis.

Methods

Up to July 2013, we searched Medline, Embase, Web of Science, Cochrane CENTRAL, and SinoMed of China for all relevant observational studies (case-control and cohort) about the effect of 5-aminosalicylates on the risk of colorectal neoplasia among patients with ulcerative colitis. The Newcastle-Ottawa Scale was used to assess the quality of studies. Adjusted odds ratios (ORs) were extracted from each study. A random-effects model was used to generate pooled ORs and 95% confidence intervals (95%CI). Publication bias and heterogeneity were assessed.

Results

Seventeen studies containing 1,508 cases of colorectal neoplasia and a total of 20,193 subjects published from 1994 to 2012 were analyzed. 5-aminosalicylates use was associated with a reduced risk of colorectal neoplasia in patients with ulcerative colitis (OR 0.63; 95%CI 0.48–0.84). Pooled OR of a higher average daily dose of 5-aminosalicylates (sulfasalazine ≥ 2.0 g/d, mesalamine ≥ 1.2 g/d) was 0.51 [0.35–0.75]. Pooled OR of 5-aminosalicylates use in patients with extensive ulcerative colitis was 1.00 [0.53–1.89].

Conclusion

Our pooled results indicated that 5-aminosalicylates use was associated with a reduced risk of colorectal neoplasia in patients with ulcerative colitis, especially in the cases with a higher average daily dose of 5-aminosalicylates use. However, the chemopreventive benefit of 5-aminosalicylates use in patients with extensive ulcerative colitis was limited.     

溃疡性结肠炎对凝血-纤溶系统激活现象的探讨

目的:通过对活动期和缓解期溃疡性结肠炎(UC)患者凝血和纤溶系统各指标的检测和对比,探讨肠炎对凝血-纤溶系统的激活作用。方法:以20名缓解期溃疡性结肠炎患者为对照,检测20名活动期溃疡性结肠炎患者体内凝血和纤溶系统各指标,包括血小板计数、活化部分凝血活酶时间(APTT)、凝血酶时间(TT)、凝血酶原时间(PT)、凝血因子Ⅻ、Ⅺ、Ⅹ、Ⅸ、Ⅷ、Ⅶ、Ⅴ、Ⅱ,纤维蛋白原和D二聚体(D-D)。结果:活动期溃疡性结肠炎患者体内凝血因子Ⅺ、Ⅹ、Ⅸ、Ⅷ、Ⅴ、Ⅱ因子以及血浆纤维蛋白原、D-二聚体水平显著高于非活动期患者,其他指标没有显著差别。结论:活动期溃疡性结肠炎患者凝血-纤溶系统处于激活状态,提示肠炎可以激活凝血-纤溶系统。     

Reliability of Physical Signs in Patients with Severe Attacks of Ulcerative Colitis

A series of observer variation studies in a small group of patients suffering from severe acute ulcerative colitis is reported. Seventy-two separate assessments of the patients'' physical signs and clinical progress were made by three independent observers.The results of this investigation suggest that there is difficulty in eliciting general physical signs such as anaemia or dehydration in these patients. By contrast, local abdominal signs such as tenderness and distension were relatively reliably elicited. The results also suggest that there are considerable problems in evaluating these clinical signs in terms of the patient''s immediate subsequent progress.     

Health-Related Quality of Life in Chinese Patients with Mild and Moderately Active Ulcerative Colitis

Background

Ulcerative colitis (UC) impairs the health-related quality of life (HRQOL). The difference in HRQOL between patients with mild and moderately active UC is not well-defined. Few studies have been conducted to explore the factors that influence HRQOL in Chinese patients. Our study aims were to (1) compare HRQOL of mildly active UC patients with moderate patients; (2) explore the factors that influence HRQOL in Chinese patients with UC; and (3) analyze demographic and disease characteristics of UC in China.

Methods

A total of 110 mild and 114 moderate patients with UC were enrolled. The demographic and disease characteristics were recorded. HRQOL was measured by the Chinese version of the inflammatory bowel disease questionnaire (IBDQ) between mild and moderate patients, male and female patients, and different disease distributions. Stepwise regression analysis was used to assess factors influencing the IBDQ score.

Results

Patients with moderate UC had significantly lower IBDQ total scores compared to patients with mild UC (P=0.001). The IBDQ total score had a negative correlation with the Mayo score (r=–0.263, P<0.001). Stepwise regression analysis showed that the disease activity index and gender had an influence on the IBDQ total score (P<0.05). The female patients had a lower score than the male patients (P<0.05), especially in the emotional function domain (P=0.002). Different disease distributions were not statistically significant in the IBDQ total score (P=0.183).

Conclusions

UC has a negative influence on HRQOL. HRQOL in patients with moderate UC was lower than HRQOL in patients with mild UC, as measured by the IBDQ. UC disease activity has a negative correlation with HRQOL. Gender and the disease activity index are important factors involved in the impairment of HRQOL in Chinese patients with UC. Chinese females may benefit from increased psychological care as part of UC therapy.     

Integrated miRNA and mRNA Expression Profiling in Inflamed Colon of Patients with Ulcerative Colitis

Background

Ulcerative colitis (UC) is associated with differential colonic expression of genes involved in immune response (e.g. IL8) and barrier integrity (e.g. cadherins). MicroRNAs (miRNAs) are regulators of gene expression and are involved in various immune-related diseases. In this study, we investigated (1) if miRNA expression in UC mucosa is altered and (2) if any of these changes correlate with mucosal mRNA expression. Integration of mRNA and miRNA expression profiling may allow the identification of functional links between dysregulated miRNAs and their target mRNA.

Methodology

Colonic mucosal biopsies were obtained from 17 UC (10 active and 7 inactive) patients and 10 normal controls. Total RNA was used to analyze miRNA and mRNA expression via Affymetrix miRNA 2.0 and Affymetrix Human Gene 1.0ST arrays, respectively. Both miRNA and gene expression profiles were integrated by correlation analysis to identify dysregulated miRNAs with their corresponding predicted target mRNA. Microarray data were validated with qRT-PCR. Regulation of IL8 and CDH11 expression by hsa-miR-200c-3p was determined by luciferase reporter assays.

Results

When comparing active UC patients vs. controls, 51 miRNAs and 1543 gene probe sets gave significantly different signals. In contrast, in inactive UC vs. controls, no significant miRNA expression differences were found while 155 gene probe sets had significantly different signals. We then identified potential target genes of the significantly dysregulated miRNAs and genes in active UC vs. controls and found a highly significant inverse correlation between hsa-miR-200c-3p and IL8, an inflammatory marker, and between hsa-miR-200c-3p and CDH11, a gene related to intestinal epithelial barrier function. We could demonstrate that hsa-miR-200c-3p directly regulates IL8 and CDH11 expression.

Conclusion

Differential expression of immune- and barrier-related genes in inflamed UC mucosa may be influenced by altered expression of miRNAs. Integrated analysis of miRNA and mRNA expression profiles revealed hsa-miR-200c-3p for use of miRNA mimics as therapeutics.     

Decrease of Peripheral and Intestinal NKG2A-Positive T Cells in Patients with Ulcerative Colitis

To investigate the role of inhibitory natural killer receptors (iNKRs) in inflammatory bowel disease (IBD), we analyzed the expression of NKG2A, one of the iNKRs, on T cells in a mouse colitis model and human IBD. During the active phase of dextran sulfate sodium (DSS)-induced mouse colitis, the frequency of NKG2A+ T cells was significantly decreased in the peripheral blood, and increased in the intestine, suggesting the mobilization of this T cell subset to the sites of inflammation. Administration of anti-NKG2A antibody increased the number of inflammatory foci in DSS-induced colitis, suggesting the involvement of NKG2A+ T cells in this colitis model. In ulcerative colitis (UC) patients, the frequency of peripheral blood NKG2A+ T cells was significantly decreased, compared with Crohn's disease (CD) patients and healthy controls, regardless of clinical conditions such as treatment modalities and disease activity. Notably, in sharp contrast to the DSS-induced mouse colitis model, the frequency of NKG2A+ cells among intestinal T cells was also decreased in UC patients. These results suggest that inadequate local infiltration of NKG2A+ T cells may be involved in the pathogenesis of UC.     

Long-Term Alteration of Intestinal Microbiota in Patients with Ulcerative Colitis by Antibiotic Combination Therapy

Previous work has demonstrated that intestinal bacteria, such as Fusobacterium varium (F. varium), contribute to the clinical activity in ulcerative colitis (UC); thus, an antibiotic combination therapy (amoxicillin, tetracycline, and metronidazole (ATM)) against F. varium can induce and maintain UC remission. Therefore, we investigated whether ATM therapy induces a long-term alteration of intestinal microbiota in patients with UC. Patients with UC were enrolled in a multicenter, randomized, double-blind, placebo-controlled study. Biopsy samples at the beginning of the trial and again at 3 months after treatment completion were randomly obtained from 20 patients. The terminal restriction fragment length polymorphism (T-RFLP) in mucosa-associated bacterial components was examined to assess the alteration of the intestinal microbiota. Profile changes of T-RFLP in mucosa-associated bacterial components were found in 10 of 12 patients in the treatment group and in none of 8 in the placebo group. Dice similarity coefficients using the unweighted pair group method with arithmetic averages (Dice-UPGMA) confirmed that the similarity of mucosal microbiota from the descending colon was significantly decreased after the ATM therapy, and this change was maintained for at least 3 months. Moreover, at 3 months after treatment completion, the F. varium/β-actin ratio, examined by real-time PCR using nested PCR products from biopsy samples, was reduced less than 40% in 8 of 12 treated patients, which was higher, but not significantly, than in 4 of 8 patients in the placebo group. Together, these results suggest that ATM therapy induces long-term alterations in the intestinal microbiota of patients with UC, which may be associated, at least in part, with clinical effects of the therapy.     

溃疡性结肠炎患者外周血C 反应性蛋白、血清降钙素原及白细胞介素-6 水平及临床意义

目的:分析溃疡性结肠炎(Ulcerative colitis,UC)患者血清降钙素原(Procalcitonin,PCT)、C反应蛋白(C-reactive protein,CRP)及白细胞介素-6(Interleukin-6,IL-6)水平与病情严重程度的关系。方法:选择2013年5月-2015年5月在我院就诊的溃疡性结肠炎患者91例作为研究对象,另选择同期在我院接受健康体检的志愿者69例作为对照组。检测并比较两组研究对象血清降钙素原(PCT)、C反应性蛋白(CRP)及白细胞介素-6(IL-6)的水平,并分析PCT,CRP及IL-6水平与溃疡性结肠炎的相关性。结果:溃疡性结肠炎患者PCT水平为(1.24±0.23)ng/m L,对照组PCT水平为(0.12±0.10)ng/m L,溃疡性结肠炎患者PCT水平显著高于对照组,差异具有统计学意义(P0.05);溃疡性结肠炎患者CRP水平为(105.27±19.93)mg/m L,对照组CRP水平为(7.62±2.97)mg/m L,溃疡性结肠炎患者血清CRP水平显著高于对照组,差异具有统计学意义(P0.05);溃疡性结肠炎患者IL-6水平为(248.15±35.60)ng/m L,对照组IL-6水平为(144.05±20.26)ng/m L,溃疡性结肠炎患者血清IL-6水平显著高于对照组,差异具有统计学意义(P0.05)。溃疡性结肠炎患者血清PCT,IL-6及CRP水平之间均呈正相关关系(r=0.301,0.468,0.413,P0.01)。结论:溃疡性结肠炎患者血清PCT,CRP及IL-6水平均显著高于健康人群,其水平变化与患者病情严重程度有关。因此,我们在临床实践中应予以重视。     

Decreased Plasma Histidine Level Predicts Risk of Relapse in Patients with Ulcerative Colitis in Remission

Ulcerative colitis (UC) is characterized by chronic intestinal inflammation. Patients with UC have repeated remission and relapse. Clinical biomarkers that can predict relapse in UC patients in remission have not been identified. To facilitate the prediction of relapse of UC, we investigated the potential of novel multivariate indexes using statistical modeling of plasma free amino acid (PFAA) concentrations. We measured fasting PFAA concentrations in 369 UC patients in clinical remission, and 355 were observed prospectively for up to 1 year. Relapse rate within 1 year was 23% (82 of 355 patients). The age- and gender-adjusted hazard ratio for the lowest quartile compared with the highest quartile of plasma histidine concentration was 2.55 (95% confidence interval: 1.41–4.62; p = 0.0020 (log-rank), p for trend = 0.0005). We demonstrated that plasma amino acid profiles in UC patients in clinical remission can predict the risk of relapse within 1 year. Decreased histidine level in PFAAs was associated with increased risk of relapse. Metabolomics could be promising for the establishment of a non-invasive predictive marker in inflammatory bowel disease.     

美沙拉嗪颗粒联合美常安胶囊对溃疡性结肠炎患者临床疗效及炎症反应的影响

目的:研究美沙拉嗪颗粒联合美常安胶囊治疗溃疡性结肠炎的临床疗效及对炎症反应的影响。方法:选取本院自2015年1月至2016年1月收治的92例轻、中度溃疡性结肠炎患者,随机分为对照组和治疗组各46例。对照组单独行美沙拉嗪颗粒治疗,治疗组行美沙拉嗪颗粒联合美常安胶囊治疗,总疗程16周。对比观察两组患者治疗后对临床症状、临床症状积分、有效率以及炎症指标的改变。结果:治疗组患者的症状改善情况、总有效率均显著高于对照组(P0.05),治疗组术前术后临床症状评分也明显优于对照组(P0.05);两组患者治疗后红细胞沉降率(ESR)和C-反应蛋白(CRP)均明显降低,且治疗组降低更显著,差异有统计学意义(P0.05)。结论:美沙拉嗪颗粒联合美常安胶囊可有效提高轻、中度溃疡性结肠炎治疗效果,减轻炎症反应,改善患者临床症状,临床效果显著,值得推广和应用。     

Association of Ulcerative Colitis with FUT2 and FUT3 Polymorphisms in Patients from Southeast China

Objectives

Dysbiosis of intestinal microbiota has been implicated in ulcerative colitis (UC). Fucosyltransferase (FUT) 2 and FUT3 determine expression of histo-blood group antigens in the gut and may affect the intestinal microbiota. We investigated the association between FUT2 and FUT3 polymorphisms and UC in Chinese patients.

Methods

We genotyped FUT2 (rs281377, rs1047781 and rs601338) and FUT3 (rs28362459, rs3745635 and rs3894326) in 485 UC patients and 580 healthy controls using SNaPshot. We also evaluated expression of Lewis a and b antigens in the sigmoid colon of 7 UC patients and 7 patients with benign colonic polyps.

Results

The frequencies of mutant allele (A) and genotype (GA+AA) in FUT3 (rs3745635) were higher in UC patients than controls (P = 0.016, 95%CI: 1.339–1.699; P = 0.038, 95%CI: 1.330–1.742, respectively). Stratified analyses revealed that the frequencies of mutant allele (G) and genotype (TG+GG) of FUT3 (rs28362459) were significantly lower in patients with extensive colitis than those with distal colitis (P<0.001, 95%CI: 0.503–0.742; P = 0.001, 95%CI: 0.567–0.786, respectively). Similar conclusions were drawn for the mutant allele (A) and genotype (GA+AA) of FUT3 (rs3745635) in patients with extensive colitis compared to those with distal colitis (P = 0.006, 95%CI: 0.553–0.845; P = 0.011, 95%CI: 0.621–0.900, respectively). Although expression of Lewis b antigen in the sigmoid colon did not differ between UC patients and controls, Lewis a antigen expression was higher in the cryptic epithelium of both inflammatory and non-inflammatory sigmoid colon of UC patients than controls (P = 0.028).

Conclusions

Our findings indicated that polymorphisms in FUT3 and its intestinal expression might be associated with UC pathogenesis.     

葛根芩连汤加蒲公英灌肠治疗溃疡性结肠炎的临床观察

目的:观察中药葛根芩连汤加蒲公英灌肠治疗溃疡性结肠炎的疗效。方法:溃疡性结肠炎患者113例,随机分为治疗组(60例)和对照组(53例),前者用蒲公英葛根芩连汤灌肠,后者用柳氮黄吡啶治疗。结果:治疗组总有效率为90%,对照组总有效率75.5%,差异具有显著性(P<0.01)。结论:中药葛根芩连汤加蒲公英灌肠治疗溃疡性结肠炎疗效好,建议临床推广应用。     

Clinical Implication of UGT1A1 Promoter Polymorphism for Irinotecan Dose Escalation in Metastatic Colorectal Cancer Patients Treated with Bevacizumab Combined with FOLFIRI in the First-line Setting

PURPOSE: This study aimed to identify the efficacy and toxicity of the FOLFIRI regimen (fluorouracil, leucovorin, and irinotecan) with irinotecan dose escalation plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer (mCRC) via UGT1A1 genotyping. METHODS: We administered bevacizumab plus FOLFIRI with irinotecan dose escalation to treat 70 mCRC patients. The UGT1A1 *1/*1 and *1/*28 genotypes started with a 180-mg/m² dose of irinotecan, and UGT1A1 *28/*28 genotype started with a dose of 120 mg/m². The dose of irinotecan was escalated at increasing intervals of 20 to 30 mg/m² until grade 3/4 adverse events (AEs) occurred. The clinical response rate, toxicity, and survival were analyzed. RESULTS: The clinical response and disease control rates of mCRC patients treated with FOLFIRI plus bevacizumab were significantly better in patients with UGT1A1 *1/*1 and *1/*28 genotypes than in patients with UGT1A1 *28/*28 (P = .006 and P < .001, respectively). Grade 3/4 AEs were significantly more common in mCRC patients with the UGT1A1 *28/*28 genotype (P < .001). Progression-free survival was significantly higher in UGT1A1 *1/*1 and *1/*28 patients (P = .002). mCRC patients who underwent metastasectomy achieved better overall survival than those who did not undergo metastasectomy (P = .015). CONCLUSIONS: Our study showed that mCRC patients with UGT1A1 *1/*1 and *1/*28 genotypes could receive escalated doses of irinotecan to obtain a more favorable clinical outcome without significant AEs.     

Altered Plasma Concentrations of Trace Elements in Ulcerative Colitis Patients Before and After Surgery

Ileal pouch-anal anastomosis (IPAA) is a classical surgery for ulcerative colitis patients. However, knowledge on trace element alteration in patients who had undergone this surgery is limited. This study was conducted to assess trace element alteration in patients with ulcerative colitis before and after ileal pouch-anal anastomosis. Preoperative (40) and postoperative (35) ulcerative colitis patients were studied. The dietary assessment of trace element intake was undertaken by a semiquantitative food frequency questionnaire. Patients' trace element status of zinc, copper, manganese, selenium, calcium, iron, and vitamin D₃ was assessed by measuring their blood concentrations. We found that with the similar dietary intake, there was no statistical difference in the concentrations of plasma copper, iron, calcium, and vitamin D₃ in the two groups (P?>?0.05). Compared with preoperative patients, postoperative patients had higher concentrations of plasma zinc (14.51?±?4.75 μmol/l) and manganese (0.21?±?0.11 μmol/l) and lower concentrations of plasma selenium (0.86?±?0.58 μmol/l). Both preoperative and postoperative mean concentrations of plasma calcium and vitamin D₃ were below their reference range, respectively. We conclude that IPAA does not seem to alter patients' abnormal trace elements completely. It is important to monitor and supply some specified trace elements even in postoperative patients.     

IL-6 和IL-23在溃疡性结肠炎患者肠粘膜中的表达及意义

目的:研究溃疡性结肠炎患者炎症粘膜中IL-6及IL-23的表达及其临床意义。方法:选取2013年4月到2014年4月我院收治的溃疡性结肠炎患者60例,根据Sutherland疾病活动指数分为轻度组(11例)、中度组(19例)、重度组(14例)、缓解期组(16例),另选健康志愿者20名为对照组。分别检测各组粘膜细胞因子IL-6及IL-23的表达水平。结果:轻度组、中度组及重度组患者的IL-6和IL-23表达水平逐渐增高,显著高于缓解期组和对照组,差异有统计学意义(P<0.05);缓解期组患者IL-23水平显著高于对照组,差异有统计学意义(P<0.05);而IL-6表达与对照组比较无显著差异(P>0.05)。结论:IL-6和IL-23在溃疡性结肠炎的发生与发展中起重要作用,其表达能够反应溃疡性结肠炎的炎性程度。     

Serum Glycan Markers for Evaluation of Disease Activity and Prediction of Clinical Course in Patients with Ulcerative Colitis

Background

The aims of this study were to determine the change of whole-serum N-glycan profile in ulcerative colitis (UC) patients and to investigate its clinical utility.

Methods

We collected serum from 75 UC patients at the time of admission and the same number of age/sex-matched healthy volunteers. Serum glycan profile was measured by comprehensive quantitative high-throughput glycome analysis and was compared with disease activity and prognosis.

Results

Out of 61 glycans detected, 24 were differentially expressed in UC patients. Pathway analysis demonstrated that highly sialylated multi-branched glycans and agalactosyl bi-antennary glycans were elevated in UC patients; in addition, the glycan ratio m/z 2378/1914, which also increased in UC, showed the highest Area under Receiver Operating Characteristic curve (0.923) for the diagnosis of UC. Highly sialylated multi-branched glycans and the glycan ratio m/z 2378/1914 were higher in the patients with total colitis, Clinical Activity Index >10, Mayo endoscopic score 3, or a steroid-refractory status. In particular, the glycan ratio m/z 2378/1914 (above median) was an independent prognostic factor for the need for an operation (hazard ratio, 2.67; 95% confidence interval, 1.04–7.84).

Conclusions

Whole-serum glycan profiles revealed that the glycan ratio m/z 2378/1914 and highly sialylated multi-branched glycans increase in UC patients, and are correlated with disease activity. The glycan ratio m/z 2378/1914 was an independent predictive factor of the prognosis of UC.     

美沙拉秦对缓解期溃疡性结肠炎患者血清炎症因子的影响

目的:探讨美沙拉秦对缓解期溃疡性结肠炎(UC)患者血清炎性因子水平的影响。方法:收集2013年5月至2016年5月于我院治疗的缓解期UC患者153例,随机分为观察组75例及对照组78例。对照组患者给予常规治疗,观察组在对照组的基础上加用美沙拉秦治疗。观察比较两组治疗前后的血清白细胞介素-6(IL-6)、白细胞介素-8(IL-8)、白细胞介素-17(IL-17)、肿瘤坏死因子-α(TNF-α)水平、疾病活动指数(DAI)评分、临床疗效、病情复发和不良反应的发生情况。结果:治疗后,观察组治疗总有效率为96.0%,明显高于对照组的62.8%(P0.05);观察组的血清IL-6、IL-8、IL-17及TNF-α水平均较治疗前明显降低,且显著低于对照组(P0.05);两组的DAI评分均有明显改善,但观察组的改善幅度明显大于对照组(P0.05);观察组患者的复发率(2.6%)显著低于对照组(21.8%)(P0.05),两组不良反应发生率比较差异无统计学意义(P0.05)。结论:美沙拉秦治疗缓解期溃疡性结肠炎的临床疗效显著,可显著抑制患者的炎症反应,同时可改善患者的临床症状,降低复发率,且安全性高。