Azathioprine in Ulcerative Colitis: Final Report on Controlled Therapeutic Trial

Eighty patients, all of whom were suffering from a frank clinical attack of ulcerative colitis, were admitted to the trial. The attack was treated with a standard course of corticosteroids and the patients were immediately placed on treatment with either azathioprine in a dose of 2·5 mg/kg body weight or dummy tablets. The trial tablets were continued for one year while the patients were maintained under regular clinical, sigmoidoscopic, histological, haematological, and biochemical surveillance. If a patient relapsed during such maintenance treatment he or she was treated with a further course of corticosteroids without interrupting maintenance treatment.In the treatment of an actual attack of ulcerative colitis the results in the attacks which brought the 80 patients into the trial show that no benefit came from the addition of azathioprine to a standard course of corticosteroid therapy.Patients admitted in their first attack of ulcerative colitis showed no benefit from the one-year maintenance treatment with azathioprine, the benefits of which were confined to patients admitted in a relapse of established disease. Even in these the difference between the treated group and the control group failed to reach statistical significance, but the difference was big enough to suggest that there is a prima facie case for regarding azathioprine as of some benefit in this group of patients.     

Randomised controlled trial of azathioprine withdrawal in ulcerative colitis.

OBJECTIVE--To determine whether azathioprine can prevent relapse in ulcerative colitis. DESIGN--One year placebo controlled double blind trial of withdrawal or continuation of azathioprine. SETTING--Outpatient clinics of five hospitals. SUBJECTS--79 patients with ulcerative colitis who had been taking azathioprine for six months or more. Patients in full remission for two months or more (67), and patients with chronic low grade or corticosteroid dependent disease (12) were randomised separately. 33 patients in remission received azathioprine and 34 placebo; five patients with chronic stable disease received azathioprine and seven placebo. MAIN OUTCOME MEASURE--Rate of relapse. Relapse was defined as worsening of symptoms or sigmoidoscopic appearance. RESULTS--For the remission group the one year rate of relapse was 36% (12/33) for patients continuing azathioprine and 59% (20/34) for those taking placebo (hazard rate ratio 0.5, 95% confidence interval 0.25 to 1.0). For the subgroup of 54 patients in long term remission (greater than six months before entry to trial) benefit was still evident, with a 31% (8/26) rate of relapse with azathioprine and 61% (17/28) with placebo (p less than 0.01). For the small group of patients with chronic stable colitis (six were corticosteroid dependent and six had low grade symptoms) no benefit was found from continued azathioprine therapy. Adverse events were minimal. CONCLUSIONS--Azathioprine maintenance treatment in ulcerative colitis is beneficial for at least two years if patients have achieved remission while taking the drug. Demonstration of the relapse preventing properties of azathioprine has implications for a large number of patients with troublesome ulcerative colitis, who may benefit from treatment with azathioprine.     

Controlled trial of azathioprine in chronic ulcerative colitis.

A double-blind controlled trial of azathioprine in a dose of 2-2.5 mg/kg body weight over six months was conducted among 44 patients with active chronic ulcerative colitis. Three patients treated with placebo did not complete the trial because their disease became so severe that colectomy was performed. Among patients who completed the trial the mean dose of prednisolone necessary to control the disease decreased in those treated with azathioprine and those treated with placebo; the reduction was greater among those who took azathioprine (p less than 0.001). Activity of the disease apparently improved in both treatment groups but a significant (p less than 0.001) trend was observed only in those patients treated with azathioprine. No serious side effects from azathioprine occurred during the trial but seven of 24 patients had to stop the drug because of nausea. Azathioprine may have a role in the treatment of a few patients wih troublesome chronic colitis for whom conventional drug treatment is ineffectual, or for whom continuous systemic corticosteroid treatment is needed to control symptoms, and for whom surgical treatment is inappropriate.     

Inflammatory Bowel Disease Among College Students

Of 52 student patients with chronic inflammatory bowel disease who were observed at Stanford University over a three-year period, 16 had Crohn disease, 17 had ulcerative colitis and 19 had ulcerative proctitis. Patients with ulcerative colitis had relatively few complications. During the study period, only two students from the entire group of 52 were obliged to interrupt college attendance because of bowel disease or complications. Of the patients, 33 were first observed on remission or attained remission during the three-year observation period. Incidence and prevalence rates for Crohn disease and ulcerative colitis were comparable with age-specific rates from other published studies. At Stanford, the high reported frequency of proctitis, which exceeded that of proximal ulcerative colitis, was possibly a reflection of the diagnostic zeal with which patients with rectal bleeding were evaluated at the student health service.     

Acute colitis in a district general hospital.

A review of all patients who had been admitted to hospital with acute ulcerative colitis in one health district between 1975 and 1984 showed that 96 had required 114 admissions with acute colitis: 42% (40) were admitted during their first attack, and 20% (19) required urgent surgery. A further nine patients underwent surgery after responding initially to intensive medical treatment that did not check the attack. There were no deaths from acute colitis. Thirteen patients underwent elective surgery for ulcerative colitis, and there were no deaths. The prognosis for acute colitis in district general hospitals has improved.     

Fatal myelotoxicity after azathioprine treatment

Azathioprine and 6-mercaptopurine have been used for many years in the treatment of inflammatory bowel disease. Approximately 0.3% of the population are homozygous for variant alleles associated with extremely low thiopurine S-methyltransferase enzyme activity. We describe the case of a young patient with ulcerative colitis, homozygous for TPMT*3A alleles, who suffered fatal azathioprine-induced myelotoxicity after standard dosing with azathioprine. Screening for decreased activity of TPMT in patients prior to azathioprine treatment is advised to minimize the risk of drug-induced toxicity.     

Inducible nitric oxide synthase activity in colon biopsies from inflammatory areas: correlation with inflammation intensity in patients with ulcerative colitis but not with Crohn's disease

Summary. Nitric oxide synthase (NOS) activities are responsible for the enzymatic conversion of L-arginine into NO and L-citrulline. Relatively low amounts of NO are produced in intestinal epithelial cells or are released from nerve endings. The effects of NO production are related to the maintenance of epithelial integrity and permeability. A pathological role of an increased NO production has been suggested to play a role in models of experimental colitis. In humans, NOS activity in colon mucosa from patients with ulcerative colitis is clearly increased when compared with the activity of the control group. In contrast, an increase of NOS activity in the colon mucosa from patients with Crohn's disease remains controversial. In the present work, we have measured NOS activity in colon biopsies originating from the control group (n = 16), from patients with ulcerative colitis (n = 23) and Crohn's disease (n = 17) using the radiochemical method of the conversion of L-[guanido-¹⁴C] arginine into radioactive L-citrulline. In the control group, NOS activity was mainly of the inducible type (88% of total NOS activity) since it was characterised by its insensibility to the absence of calcium in the assay medium. In colon biopsies originating from patients with ulcerative colitis, inducible NOS activity was increased 3 fold (p < 0.005) and in patients with Crohn's disease, inducible NOS activity was increased 5 fold (p < 0.005). Correlations between NOS activity in colon biopsies and the intensity parameters of the disease i.e. Truelove index, endoscopic score and histo-logical parameters were evidenced in patients with ulcerative colitis. In contrast, in patients with Crohn's disease, the high inducible NOS activity was not correlated with any intensity parameters of the disease. From these data, we concluded that although inducible NOS activity was increased several fold in colon biopsies originating from patients with both ulcerative colitis and Crohn's disease, a correlation between this activity and the severity of bowel inflammation was not found in either cases. Received August 7, 1999     

Fatal Myelotoxicity After Azathioprine Treatment

Azathioprine and 6-mercaptopurine have been used for many years in the treatment of inflammatory bowel disease. Approximately 0.3% of the population are homozygous for variant alleles associated with extremely low thiopurine S-methyltransferase enzyme activity. We describe the case of a young patient with ulcerative colitis, homozygous for TPMT?3A alleles, who suffered fatal azathioprine-induced myelotoxicity after standard dosing with azathioprine. Screening for decreased activity of TPMT in patients prior to azathioprine treatment is advised to minimize the risk of drug-induced toxicity.     

Tumor Necrosis Factor Alpha Blocking Agents as Treatment for Ulcerative Colitis Intolerant or Refractory to Conventional Medical Therapy: A Meta-Analysis

Background

Efficacy of tumor necrosis factor alpha (TNF-α) blockers for treatment of ulcerative colitis that is unresponsive to conventional therapy is unclear due to recent studies yielding conflicting results.

Aim

To assess the efficacy and safety of anti-TNF-α agents for treatment of ulcerative colitis patients who were intolerant or refractory to conventional medical therapy.

Methods

Pubmed, Embase, and the Cochrane database were searched. Analysis was performed on randomized controlled trials that assessed anti-TNF-α therapy on ulcerative colitis patients that had previously failed therapy with corticosteroids and/or immunosuppressants. The primary outcome focused on was the frequency of patients that achieved clinical remission. Further trial outcomes of interest included rates of remission without patient use of corticosteroids during the trial, extent of mucosal healing, and the number of cases that resulted in colectomy and serious side effects.

Results

Eight trials from seven studies (n = 2122) met the inclusion criteria and were thus included during analysis. TNF-α blockers demonstrated clinical benefit as compared to placebo control as evidenced by an increased frequency of clinical remission (p<0.00001), steroid-free remission (p = 0.01), endoscopic remission (p<0.00001) and a decrease in frequency of colectomy (p = 0.03). No difference was found concerning serious side effects (p = 0.05). Three small trials (n = 57) comparing infliximab to corticosteroid treatment, showed no difference in frequency of clinical remission (p = 0.93), mucosal healing (p = 0.80), and requirement for a colectomy (p = 0.49). One trial compared infliximab to cyclosporine (n = 115), wherein no difference was found in terms of mucosal healing (p = 0.85), colectomy frequency (p = 0.60) and serious side effects (p = 0.23).

Conclusion

TNF-α blockers are effective and safe therapies for the induction and maintenance of long-term remission and prevention of treatment by colectomy for patients with refractory ulcerative colitis where conventional treatment was previously ineffective. Furthermore, infliximab and cyclosporine were found to be comparable for treating acute severe steroid-refractory ulcerative colitis.     

复方苦参汤联合美沙拉嗪对溃疡性结肠炎治疗效果及炎性因子水平的影响

目的:探讨复方苦参汤联合美沙拉嗪对溃疡性结肠炎治疗效果及炎性因子水平的影响。方法:以我院2017年1月至2019年12月中西医结合科和消化内科收治的206例溃疡性结肠炎患者为研究对象,根据随机抽样法将受试者分为对照组和研究组,每组各103例,对照组接受美沙拉嗪治疗,研究组在对照组的基础上口服复方苦参汤治疗,比较两组的治疗总有效率,治疗前后黏膜病变、疾病活动指数与各炎性因子水平变化以及用药安全性。结果:研究组治疗总有效率较对照组高(P<0.05);治疗后两组肠镜下黏膜病变与疾病活动指数较治疗前均明显改善,且研究组显著优于对照组(P<0.05);治疗后两组白细胞介素(interleukine,IL)-6、IL-8、肿瘤坏死因子(tumor necrosis factor, TNF)-α、C反应蛋白(C-reactive protein,CRP)及降钙素原(procallcitonin,PCT)等炎性因子水平较治疗前均显著下降,且研究组低于对照组(P<0.05);两组药物所致不良反应发生率比较无统计学差异(P>0.05)。结论:复方苦参汤联合美沙拉嗪可有效缓解临床症状,改善肠道黏膜病变,降低肠道炎性反应,控制病情进展,疗效安全显著,对促进溃疡性结肠炎患者病情康复具有积极意义。     

TNF-alpha、IL-6及IL-8在不同程度溃疡性结肠炎患者血清中的表达及意义

目的：探讨不同严重程度溃疡性结肠炎患者血清TNF-alpha、IL-6 及IL-8 的表达及意义。方法：选择2011 年1 月~2014 年7 月 我院收治的溃疡性结肠炎患者47 例,根据严重程度将患者分为轻度组、中度组和重度组。另选取同期在我院接受健康体检的志 愿者80 例作为对照组。采用酶联免疫吸附试验（ELISA）检测各组患者血清TNF-alpha、IL-6 及IL-8 的水平。结果：溃疡性结肠炎患者 血清TNF-琢、IL-6 及IL-8 水平高于对照组,差异有统计学意义（P<0.05）;不同严重程度溃疡性结肠炎患者的TNF-alpha、IL-6 及IL-8 水平呈显著差异（P<0.05）。结论：检测溃疡性结肠炎患者血清TNF-alpha、IL-6 及IL-8的水平变化有利于预测病情进展。     

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。     

参苓白术散与美沙拉嗪对溃疡性结肠炎患者血清IL-17、IL-23 及TNF-alpha水平的影响

目的:探讨参苓白术散联合美沙拉嗪治疗脾胃气虚型溃疡性结肠炎的疗效及对血清细胞因子水平的影响。方法:按照随机数字表法将2013年1月至2014年1月我院收治的脾胃气虚型溃疡性结肠炎患者分为两组,对照组给予美沙拉嗪口服治疗,观察组在对照组基础上予参苓白术散口服治疗,比较两组患者的临床疗效及血清细胞因子的水平变化。结果:观察组患者治疗的总有效率优于对照组,差异有统计学意义(P<0.05);治疗后,两组患者Sutherland DAI评分均获得改善,且观察组优于对照组,差异具有统计学意义(P<0.05);两组患者的IL-17、IL-23及TNF-α水平均显著降低,且观察组低于对照组,差异具有统计学意义(P<0.05)。结论:参苓白术散联合美沙拉嗪对脾胃气虚型溃疡性结肠炎具有良好的临床疗效,能够改善患者血清细胞因子的水平。     

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。     

South Asians with ulcerative colitis exhibit altered lectin binding compared with matched European cases

Ulcerative colitis is associated with abnormalities of mucin synthesis and secretion, features that may also be associated with malignant change. It has been shown that South Asians in Britain have a high incidence of ulcerative colitis but a low incidence of colorectal carcinoma compared with their European counterparts. Previous studies have demonstrated changes in colonic mucin sialylation and sulphation in both South Asian and European cases with ulcerative colitis. This was related to disease severity, but changes were also found in quiescent disease. The aim of the present study was to determine glycoconjugate expression in the colon from South Asian cases and to compare results with those from a group of affected Europeans. Glycans were identified in formalin-fixed, paraffin-embedded tissue from 17 South Asian patients with ulcerative colitis and from 11 European patients with a similar degree of colitis, by the application of 10 biotinylated lectins. These were directed against a range of sialyl, fucosyl and 2-deoxy, 2-acetamido-galactosyl sequences, using an avidin--peroxidase revealing system and semiquantitative assessment. The South Asian group showed a reduction in the binding of agglutinins from Sambucus nigra in the apical-membranous region of enterocytes, and a decrease in apical Maackia amurensis agglutinin binding. These results suggest that South Asians with ulcerative colitis show a different distribution of terminal N-acetyl neuraminyl residues, either in their α-2,6 or α-2,3 linkage, compared with their European counterparts. The changes in sialylation observed in European cases compared with normal disease-free control subjects were present in quiescent disease, but were also related to disease activity. Their absence in Asians with ulcerative colitis may imply an inherent, genetically determined variation in this group, which may also play a part in their reduced risk of subsequent malignancy     

Immunoresponsiveness in Ulcerative Colitis and Crohn's Disease—Effect of Colectomy and Suppression of Disease Activity

We evaluated the effect of medically induced symptomatic disease improvement on in vitro tests of cell-mediated immune responses in 33 patients with Crohn''s disease. When results obtained in 17 patients with ulcerative colitis were compared with those of 10 patients with ulcerative colitis who had undergone a colectomy, no significant correlation was detected between individual clinical and laboratory variables or the Crohn''s disease activity index and in vitro tests of cell-mediated immunity. A different pattern emerged from the longitudinal tests of cell-mediated immunity: when these test results were initially abnormal in patients with Crohn''s disease, clinical improvement as assessed by the Crohn''s disease activity index was associated with normalizing cell-mediated immunity. In contrast, when the test results were initially normal, clinical improvement was not associated with any change in the immune response. Following colectomy in patients with ulcerative colitis, some abnormalities of suppressed immune responses remained, although patients were cured of their disease. Factors other than clinical disease activity may be responsible for the suppressed immunoresponsiveness in some patients with inflammatory bowel disease, and variable changes in cell-mediated immunity occur after both surgical and medical treatment.     

FSTL1在溃疡性结肠炎患者外周血中的表达及意义

目的:探讨溃疡性结肠炎患者外周血和肠组织中卵泡抑素样蛋白1(FSTL1)的表达及其临床意义。方法:选取2013年3月-2014年3月我院收治的溃疡性结肠炎患者为研究组(n=60),另选取病理和肠镜均正常者为对照组(n=60)。采用酶联免疫吸附试验(ELISA)法检测两组患者外周血中FSTL1水平,采用免疫组织化学染色法检测两组肠粘膜组织中的FSTL1水平,应用Pearson相关性分析来分析溃疡性结肠炎活动指数(DAI)评分和FSTI1水平的相关性。结果:研究组血浆FSTL1高于对照组,差异具有统计学意义(t=11.063,P=0.025);研究组肠粘膜组织中FSTL1阳性表达率高于对照组,差异具有统计学意义(x2=12.987,P=0.019);研究组DAI评分和FSTI1水平呈正相关关系(r=0.719,P=0.023)。结论:溃疡性结肠炎患者FSTL1表达水平升高,并且和疾病的活动性呈正相关关系。     

Olsalazine in active ulcerative colitis.

Olsalazine (azodisalicylate) is a new drug in which two molecules of 5-aminosalicylic acid are linked by an azo bond. Its role in the treatment of mildly active, distal ulcerative colitis was investigated. Sixty patients were randomly allocated to receive olsalazine 1 g or a placebo as a retention enema nightly for two weeks. Clinical improvement was seen in 19 (66%) and sigmoidoscopic improvement in 17 (59%) of the 29 patients receiving olsalazine compared with 12 (43%) and 11 (39%), respectively, of the 28 in the control group. These differences were not significant. In a second trial 40 patients were randomised to receive oral olsalazine 2 g daily or a placebo capsule for two weeks. Significant clinical and sigmoidoscopic improvement was seen in the patients receiving oral olsalazine compared with the patients receiving placebo capsules. Oral olsalazine may be valuable in the treatment of mildly active ulcerative colitis. Its role in maintaining remission is yet to be determined.     

思连康治疗溃疡性结肠炎的疗效及机制研究

目的研究微生态制剂思连康辅助治疗溃疡性结肠炎的疗效及其可能的机制。方法将溃疡性结肠炎患者79例随机分成治疗组及对照组,治疗组40例,对照组39例。对照组采用常规治疗,治疗组在常规治疗的基础上加用双歧四联活菌制剂——思连康。比较2组治疗前及治疗2个月后患者的临床症状评分、结肠黏膜炎症表现、细胞因子IL-10、IL-18的变化。结果治疗2个月后2组临床症状评分、结肠黏膜炎症评分均较治疗前有明显改善（P〈0.01）,且治疗组临床症状、结肠黏膜炎症改善程度优于对照组（P〈0.01）,IL-10、IL-18的含量治疗前后有明显的变化,IL-10增加,IL-18降低。结论思连康可辅助治疗溃疡性结肠炎,其机制可能是通过调节细胞因子的变化,进一步影响结肠黏膜的免疫功能。     

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。