白细胞介素在溃疡性结肠炎中的作用

溃疡性结肠炎(ulcerative colitis,UC)是一种以慢性肠道炎症为特征的炎症性肠病。UC的发病机制还未完全明确,其发生与免疫、遗传、环境及感染因素有关,细胞因子在UC等炎症性肠病中起到重要作用。白细胞介素(interleukin,IL)是细胞因子中最主要的具有多种生物活性的一组淋巴因子,并在免疫细胞的发育、分化、免疫应答等过程中有重要调节作用。目前研究发现很多IL在UC的发病中起重要作用。本文对在UC中起重要作用的IL作一概述。     

The role of biologics in ulcerative colitis

Since the introduction of anti-TNF agents for the treatment of Crohn's disease there has been interest in the potential for treating ulcerative colitis with biological therapies. Early observational series suggested a benefit in the setting of severe, hospitalized patients. However, the recent completion of two large multi-center, double-blind placebo-controlled trials confirmed a role for infliximab for outpatients with refractory, moderate-severe disease with evidence for clinical remissions, mucosal healing, and a reduction in colectomies. Despite this evidence, there are numerous questions remaining regarding the optimal positioning in the setting of moderate-severe disease, potential benefits of concomitant immune suppression and the need for maintenance treatment after induction therapy. Additional clinical trials have demonstrated a less profound benefit for adalimumab at similar doses that are used in Crohn's disease. Other biological agents that have targeted T cells such as visiluzimab and abatacept were not demonstrated to be effective in controlled trials.     

Protective effect of appendectomy on the development of ulcerative colitis

PURPOSE: Appendectomy and cigarette smoking have been suggested to reduce the chance of developing ulcerative colitis. A case-control study was undertaken to determine the relative incidence of appendectomy in patients with ulcerative colitis. METHODS: This case-control study examined the incidence of appendectomy in patients with ulcerative colitis and patients attending an orthopedic outpatient clinic. RESULTS: Of 100 patients with ulcerative colitis, 75 pairs were matched for age, gender, and cigarette smoking. The ulcerative colitis group had an appendectomy rate of 8 percent (6/75), compared with 21 percent in the control group (P=0.018). The odds ratio was 3.5 (95 percent confidence interval, 1.15–10.6). CONCLUSIONS: No previous study has examined the effect of appendectomy, controlling for cigarette smoking. This study confirms that appendectomy protects against or reduces the chance of development of ulcerative colitis. A possible immunological explanation for this effect is advanced.     

A patient with improvement of ulcerative colitis after appendectomy

Recently, several retrospective studies have shown an inverse association between appendectomy and development of ulcerative colitis. We describe a 21-year-old man with distal ulcerative colitis and appendiceal involvement. The patient passed bloody stools continually during the 3 years before admission. Macroscopic and microscopic findings showed chronic moderate inflammation of the appendix and rectum. The ratio of CD4 to CD8 lymphocytes isolated from rectal and appendiceal mucosa was increased (4.3 and 3.8, respectively) compared with controls (n = 11; 1.0 in the rectum and 1.4 in the appendix). Clinical symptoms and colonoscopic and microscopic findings improved significantly after appendectomy. In addition, the amount of interferon gamma secreted from rectal lymphocytes was reduced to 89 pg/mL after surgery (before appendectomy, 254 pg/mL). However, interleukin 4 production was below detectable levels both before and after appendectomy. These findings suggest that appendectomy resulted in altered T-helper (Th)1/Th2 balance in this patient. In the 3 years since surgery, the patient has been in good condition without recurrence of symptoms. This is the first report demonstrating therapeutic benefit of appendectomy in a patient with ulcerative colitis and potential mechanistic relationship.     

The role of Budesonide-MMX in active ulcerative colitis

Traditional corticosteroids represent a well-established and effective treatment for active ulcerative colitis (UC). However, the severity of their systemic side effects, led in recent years to look for new steroid molecules that could reduce them, maximizing the anti-inflammatory activity. Budesonide has been one of the most studied steroid compounds and it has been approved for the treatment of mild to moderate active Crohn's disease (CD). In order to extend the release until the distally located inflammation, budesonide has been coupled with a controlled delivery system, called Multi-Matrix system (MMX^®), already successfully tested with oral mesalazine for the treatment of distal UC. After in vitro and in vivo models, the efficacy of Budesonide-MMX has been investigated in active UC with a first small phase II study, and partially encouraging results. This article will review the evidences on the use of budesonide in inflammatory bowel diseases and will discuss the role of Budesonide-MMX in active UC nowadays.     

The role of aminosalicylates in the treatment of ulcerative colitis

Aminosalicylates (5-ASA, sulfasalazine and mesalazine) play a central role in the treatment of ulcerative colitis (UC). For acute treatment of mild to moderate flares and in maintenance treatment, their efficacy has been established. Since ulcerative colitis is limited to the distal colon in two thirds of the patients, topical therapy also plays an important role. In mild/moderate active disease 5-ASA 4 g/d is as effective as oral corticosteroids. Ulcerative proctitis is treated with 2 x 500 mg or 1 x 1 g suppositories and proctosigmoiditis with 1 to 4 g enemas. Oral 5-ASA is also safe in maintenance treatment and is generally well tolerated. The risk of colorectal tumours is increased in patients with longstanding ulcerative colitis and epidemiological evidence indicates that chronic 5-ASA treatment reduces this risk. However, at present there is insufficient evidence to maintain patients on life-long 5-ASA maintenance treatment for this indication.     

The role of azathioprine in the management of ulcerative colitis

The use of azathioprine in ulcerative colitis is unclear. The authors present the details and outcome of 47 patients who received azathioprine for either a) severe, resistant disease otherwise requiring surgery (28 patients) or b) patients with steroid dependence who have been followed up for at least 12 months (19 patients). Duration of treatment ranged from one week to 66 months (median, 12 months). Of the patients in Group I, 13 (46 percent) achieved remission, 11 of whom had not relapsed during a median follow-up of 22 months (range, 12 to 58 months), and 15 underwent surgery one week to 12 months (median, five weeks) after commencing azathioprine. In Group II, steroids were withdrawn or reduced in 12 (63 percent) patients and three patients required colectomy. Side effects necessitating withdrawal of azathioprine occurred in 12 patients (hematologic effects, 6 patients; gastrointestinal effects, 4 patients; other effects, 2 patients). Two patients required a reduced dose of azathioprine because of leukopenia. The authors conclude that azathioprine is a valuable therapeutic option in selected patients with ulcerative colitis.     

Prevalence of appendectomy among ulcerative colitis patients and their relatives.

BACKGROUND: It has been suggested that appendectomy may protect against ulcerative colitis (UC). However, the incidences of appendectomy and UC in developed countries have diverged over the last 50 years, possibly as a consequence of environmental factors. AIM: To determine whether the incidence of appendectomy is lower in patients with UC than in the general population. METHODS: Patients with UC (153), their relatives (116) and members of the general population (306) that had been matched for age, sex and educational status were studied. RESULTS: Six per cent of UC patients had undergone appendectomy. The corresponding figure for non-family controls was 20% (P < 0.0001; OR = 0.27; 95% CI = 0.15-0.45). The rate of appendectomy within families (cases plus siblings) was 17/269 (6.3%) and was similar to that for UC patients alone(P < 0.001). CONCLUSIONS: A negative association between appendectomy and UC exists in our patients with UC. In addition, the appendectomy rate in families of UC patients was lower than that in the general population, possibly implying that common environmental and genetic factors could play an important role in the divergent incidences of appendicitis and UC over the last 50 years.     

Role of appendicitis and appendectomy in the pathogenesis of ulcerative colitis: a critical review

Besides a genetic predisposition, a causal role of various environmental factors has been considered in the etiology of ulcerative colitis (UC). The association between appendectomy and UC has recently been the subject of intense scrutiny in the hope that it may lead to the identification of important pathogenetic mechanisms. Published data from animal models of colitis demonstrated reduction in experimental colitis after appendectomy, especially if performed at an early age. Several epidemiological case control and cohort studies have shown a strong and consistent relationship. The metaanalysis of 17 case-controlled studies showed an overall odds ratio 0.312 (95% confidence intervals = 0.261-0.373) in favor of appendectomy (p < 0.0001). One of the two recent large cohort studies is in agreement with these results, but the other failed to confirm them. All these studies have suggested that alterations in mucosal immune responses leading to appendicitis or resulting from appendectomy may negatively affect the pathogenetic mechanisms of UC. Further investigation of the role of appendectomy in UC is expected to open new fields for basic scientific research and may lead to the improvement of our understanding for the disease pathogenesis.     

Protective effect of appendectomy on the development of ulcerative colitis. A case-control study

AIMS: To examine by a case-control study the relationship between appendectomy and subsequent ulcerative colitis development in a French population.METHODS: A total of 150 patients with ulcerative colitis were matched for age (+/- 5 years) and sex, with 150 controls recruited in a preventive medicine center. The following data were collected from medical records and by standardised questionnaire in consultation or by phone: appendectomy and tonsillectomy before the onset of ulcerative colitis, smoking habits and area of residence.RESULTS: The rate of previous appendectomy in patients with ulcerative colitis was 8% (12/150) compared with 30.6% (46/150) in the control group (P=0.001). There was no significant association between ulcerative colitis and tonsillectomy (25.3 and 27.3% in the control and the ulcerative colitis groups, respectively). Smoking was more frequent in the control group (36%) than in the ulcerative colitis group (25.3%) but the difference was not significant (P=0.07). In multivariate analysis, the risk of developing ulcerative colitis was significantly lower after previous appendectomy (odds ratio=0.26; 95% confidence interval: 0.13-0.55; P=7 x 10(-4)).CONCLUSION: Our study confirms the inverse association between appendectomy and subsequent ulcerative colitis, in a French population, after adjusting on smoking.     

Cigarette smoking and appendectomy are risk factors for extraintestinal manifestations in ulcerative colitis

OBJECTIVE: Two common factors, cigarette smoking and appendectomy, have been found to play a role in ulcerative colitis (UC). Data on their role in the development of extraintestinal manifestations (EIM) are scarce. METHODS: The relationship between cigarette smoking, appendectomy, and EIM was examined in a prospective study involving 535 (M/F = 319/216) consecutive UC patients followed up for 18 yr. We considered the major EIM: seronegative spondyloarthropathy, pyoderma gangrenosum/erythema nodosum, acute anterior uveitis, and primary sclerosing cholangitis. We excluded patients with a history of EIM or those colectomized before study entry, ex-smokers, and those who started to smoke during the course of UC. RESULTS: In UC patients, seronegative spondyloarthropathy and dermatologic complications were found increased in smokers (p < 0.0001; p = 0.001) or in subjects with appendectomy (p = 0.0003; p = 0.02), while acute anterior uveitis and primary sclerosing cholangitis did not differ. The Kaplan-Meier analysis showed 18-yr rates for EIM of 71% in smokers and 45% in nonsmokers (log-rank test, p = 0.0001), and of 85% in patients with appendectomy and 48% in those without (p = 0.0001). Cox proportional-hazard model showed that cigarette smoking and appendectomy are independent factors promoting EIM. In smokers with appendectomy the adjusted hazard ratio (3.197, 95% CI 1.529-6.684) was higher than in patients with appendectomy alone (2.617, 95% CI 1.542-4.442) or smoking alone (1.947, 95% CI 1.317-2.879). CONCLUSIONS: In UC patients, appendectomy and cigarette smoking are prognostic factors for the development of EIM. The unfavorable effect of cigarette smoking on EIM is additive to that of appendectomy.     

The role of bile salts in diarrhoea of patients with ulcerative colitis

Faecal bile salt elimination, which was determined in patients with ulcerative colitis, was mostly within normal limits, suggesting that in this disease water and electrolyte diarrhoea was hardly contributed to by excessive amounts of bile salts in the large bowel. In a therapeutic trial cholestyramine had no beneficial effect on the general condition, diarrhoea, or faecal composition, findings which further strengthen the view that bile salts play no role in the diarrhoea of ulcerative colitis, provided that the disease is limited to the large bowel. Faecal elimination of cholesterol as bile salts and neutral steroids tended initially to be higher than normal, but increased less than in controls during treatment with cholestyramine, particularly in the heavier patients. Serum cholesterol was low in the patients with ulcerative colitis and decreased by cholestyramine less (27%) than in controls (39%).     

溃疡性结肠炎中Fas/FasL介导的结肠上皮

目的探讨Fas/FasL介导的结肠上皮细胞凋亡在溃疡性结肠炎(UC)发病机制中的作用.方法按Powell-Tuck评分系统对UC患者疾病活动性进行评分.免疫组化法检测35例UC和15例对照标本Fas、FasL表达,M30Cytodeath特异性检测结肠上皮细胞凋亡,图像分析仪定量分析.结果UC组表达Fas、FasL的水平平均为(27.1±2.9)%、(16.5±3.2)%,凋亡指数平均为(3.5±1.0)%,均比对照组明显增高[分别为(11.6±3.1)%、(5.3±2.4)%及(0.3±0.1)%,P＜0.01];UC表达Fas、FasL的水平与疾病活动性评分有正相关性(r=0.42和r=0.38,P＜0.05),而与组织学分级没有相关性(P＞0.05);组织学分级与疾病活动性评分呈显著正相关(r=0.848,P＜0.01).Fas与M30可共同表达且具有相关性.结论Fas/FasL介导的结肠上皮细胞大量凋亡可能是UC上皮层破坏的机制之一.     

The role of CMV in steroid-resistant ulcerative colitis: A systematic review

Background and aimsSteroid-resistance presents a management challenge in ulcerative colitis. How steroid-resistance occurs is unknown, but cytomegalovirus infection, often unrecognised, may be the cause in some patients. Current evidence and therapeutic recommendations are examined.MethodsA systematic review of PubMed and EMBASE databases was performed. Search and exclusion criteria are defined in the text.ResultsHeterogeneity of experimental design and definitions of key terms were notable. Criteria for cytomegalovirus disease, infection or detection varied, as did definitions of steroid-resistance. CMV infection defined by antigenaemia or serology was common in patients on steroids and associated with a higher rate of steroid-resistance (41.66–61% versus 0–68% in steroid-responsive patients). Colonic mucosal cytomegalovirus disease detected by histopathology was associated with intravenous steroid-resistance in 5–36%, compared to 0–10% of steroid-responsive patients. CMV colitis has rarely been reported in association with ulcerative colitis without steroids or other immunomodulators. CMV colitis in healthy individuals is so exceptional as to be the topic of case reports.ConclusionUlcerative colitis and its treatment put patients at risk of CMV infection or reactivation. A distinction is necessary between CMV disease (colitis) and CMV infection. Only colonic mucosal CMV infection detected by histopathology appears clinically relevant and appropriate for antiviral therapy. CMV antigenaemia may be associated with steroid-resistance, but may also be a self-limiting marker of viral reactivation. The impact of CMV on steroid-resistance is complicated by inconsistencies in the literature. Coherent definitions of clinically relevant CMV infection and steroid-resistance are needed.     

5-羟色胺与焦虑、抑郁的关系及其在溃疡性结肠炎发病中的作用

目的研究溃疡性结肠炎患者5-羟色胺与焦虑、抑郁评分的关系,进一步探讨神经肽及焦虑、抑郁因素在溃疡性结肠炎中的作用。方法收集UC病例（42例）、IBS病例（20例）及正常对照（10例）的结肠镜活检标本。采用汉密顿抑郁量表（HAMD）和汉密顿焦虑量表（HAMA）对所有受试者进行焦虑抑郁评分;应用高效液相色谱法检测肠黏膜中5-羟色胺的含量。结果 UC患者存在明显的焦虑、抑郁症状,中重度UC患者结肠黏膜中5-HT的含量均较正常对照组增高,尤其重度UC增高明显,UC患者焦虑、抑郁评分与肠黏膜5-HT含量呈正相关,并在一定程度上反映临床轻重程度分级。结论 UC存在神经内分泌的改变,且神经激素的改变可能参与UC疾病进展。