Extraintestinal manifestations in inflammatory bowel disease

Inflammatory bowel diseases (IBD) can be really considered to be systemic diseases since they are often associated with extraintestinal manifestations, complications, and other autoimmune disorders. Indeed, physicians who care for patients with ulcerative colitis and Crohn's disease, the two major forms of IBD, face a new clinical challenge every day, worsened by the very frequent rate of extraintestinal complications. The goal of this review is to provide an overview and an update on the extraintestinal complications occurring in IBD. Indeed, this paper highlights how virtually almost every organ system can be involved, principally eyes, skin, joints, kidneys, liver and biliary tracts, and vasculature (or vascular system) are the most common sites of systemic IBD and their involvement is dependent on different mechanisms.     

Pharmacogenetics in inflammatory bowel disease

Pharmacogenetics is the study of the association between variability in drug response and (or) drug toxicity and polymorphisms in genes. The goal of this field of science is to adapt drugs to a patient's specific genetic background and therefore make them more efficacious and safe. In this article we describe the variants in genes that influence either the efficacy or toxicity of common drugs used in the treatment of inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn's disease (CD) including sulfasalazine and mesalazine, azathioprine (AZA) and 6-mercaptopurine (6-MP), methotrexate (MIX), glucocorticosteroids (CSs) and infliximab. Furthermore, difficulties with pharmacogenetic studies in general and more specifically in IBD are described. Although pharmacogenetics is a promising field that already contributed to a better understanding of some of the underlying mechanisms of action of drugs used in IBD, the only discovery translated until now into daily practice is the relation between thiopurine S-methyltransferase (TPMT) gene polymorphisms and hematological toxicity of thiopurine treatment. In the future it is necessary to organize studies in well characterized patient cohorts who have been uniformly treated and systematically evaluated in order to quantitate drug response more objectively. An effort should be made to collect genomic DNA from all patients enrolled in clinical drug trials after appropriate informed consent for pharmacogenetic studies.     

益生菌对炎症性肠病诱导缓解、维持治疗和贮袋炎作用系统评价

目的 评价益生菌对炎症性肠病缓解、维持治疗和贮袋炎的作用。方法 检索MEDLINE，EMBASE，the Cochrane Con—trolled Trials Register，OVID，BIOSIS和中国生物科技数据库，两位作者独立选取和炎症性肠病缓解率、复发率以及副作用相关的，对比益生菌治疗和非益生菌治疗的随机对照试验，使用Rev Man4．2．10软件统计分析，同时做亚组分析和敏感性分析。结果21项随机对照试验中共有1515例患者符合入选标准：4项研究评估了缓解率，14项研究评估了复发率，3项研究同时评估了缓解率和复发率。通过荟萃分析，炎症性肠病的总体缓解率相对危险度（relativerisk，RR）为1．05（95％CI=0．84—1．31），克罗恩病的缓解率RR0．85（95％CI=0．64—1．13），溃疡性结肠炎的缓解率RR1．18（95％CI=0．87—1．58）；贮袋炎临床复发率RR0．24（95％CI=0．12—0．48），克罗恩病临床复发率RR1．11（95％CI=0．69—1．80）；内镜复发率的RR1．08（95％CI=0．67—1．74）；益生菌与安慰剂比较，炎症性肠病的复发率RR0．51（95％CI=0．29—0．92）；益生菌与5-氨基水杨酸比较，溃疡性结肠炎的复发率RR0．96（95％CI=0．76—1．19）。结论 溃疡性结肠炎患者使用益生菌作为缓解治疗具有和5-氨基水杨酸相同的效果并优于安慰剂，但在炎症性肠病的诱导缓解中无额外益处。     

Venous thromboembolism with inflammatory bowel disease

Venous thrombosis and thromboembolism appear to be increased in patients with inflammatory bowel disease. Although several acquired and genetic risk factors are known, about half that develop a thromboembolic event have no identifiable risk factor. Control of the inflammatory process is thought to be the key factor in risk reduction for thrombotic events. Prophylactic use of anticoagulants is not universally recommended, but possible use should be reviewed in an individual patient after evaluation of the risks, such as hemorrhage, compared to potential benefits. Particular consideration should be given if there has been a prior thrombotic event, if hospitalization will require surgery, or if an underlying coagulation disorder is present.     

Update on inflammatory bowel disease in patients with primary sclerosing cholangitis

Patients with primary sclerosing cholangitis(PSC) complicated by inflammatory bowel disease(IBD) represent a distinct subset of patients with unique characteristics,which have serious clinical implications.The aim of this literature review was to shed light to the obscure clinical and molecular aspects of the two diseases combined utilizing current data available and putting issues of diagnosis and treatment into perspective.The prevalence of IBD,mainly ulcerative colitis in PSC patients is estimated to be 21%-80%,dependent on screening programs and nationality.PSC-associated colitis is likely to be extensive,characterized by rectal sparing,backwash ileitis,and generally mild symptoms.It is also more likely to progress to colorectal malignancy,making it imperative for clinicians to maintain a high level of suspicion when tackling PSC patients.There is no optimal surveillance strategy but current guidelines advocate that colonoscopy is necessary at the time of PSC diagnosis with annual endoscopic follow-up.Random biopsies have been criticized and a shift towards targeted biopsies using chromoendoscopy,laser endomicroscopy and narrow-band imaging has been noted.Techniques directed towards genetic mutations instead of histological abnormalities hold promise for easier,more accurate diagnosis of dysplastic lesions.Chemopreventive measures against colorectal cancer have been sought in these patients.Ursodeoxycholic acid seemed promising at first but subsequent studies yielded conflicting results showing anticarcinogenic effects in low doses(8-15 mg/kg per day) and carcinogenic properties in high doses(15-30 mg/kg per day).     

Risk of cardiovascular disease in inflammatory bowel disease

Abundant scientific evidence supporting an association between inflammatory bowel disease(IBD) and venous thromboembolic events, caused by an IBD related hypercoagulability, is acknowledged and thromboprophylactic treatment strategies are now implemented in the management of IBD patients. In contrary, the risk of arterial thromboembolic disease, as ischemic heart disease, cerebrovascular events, and mesenteric ischemia in patients with IBD remains uncertain and the magnitude of a potentially increased risk is continuously debated, with ambiguous risk estimates among studies. The evident role of inflammation in the pathogenesis of atherosclerosis forms the basis of a biological plausible link; the chronic systemic inflammation in IBD patients increases the risk of atherosclerosis and thereby the risk of thrombotic events. Further, studies have shown that the burden of traditional risk factors for atherosclerosis, such as obesity, diabetes mellitus, and dyslipidemia is lower in IBD populations, thus further strengthen the role of non-traditional risk factors, as chronic inflammation in the linking of the two disease entities. Likewise, mortality from cardiovascular disease in IBD remains questioned. The aim of the current review is to give an up-date on the existing evidence of the possible association between IBD and cardiovascular disease and to discuss traditional and non-traditional risk factors.     

Role of cytokines in inflammatory bowel disease

Inflammatory bowel disease （IBD）, which includes Crohn’s disease （CD） and ulcerative colitis （UC）, rep- resents a group of chronic disorders characterized by inflammation of the gastrointestinal tract, typically with a relapsing and remitting clinical course. Mucosal mac- rophages play an important role in the mucosal im- mune system, and an increase in the number of newly recruited monocytes and activated macrophages has been noted in the inflamed gut of patients with IBD. Activated macrophages are thought to be major con- tributors to the production of inflammatory cytokines in the gut, and imbalance of cytokines is contributing to the pathogenesis of IBD. The intestinal inflammation in IBD is controlled by a complex interplay of innate and adaptive immune mechanisms. Cytokines play a key role in IBD that determine T cell differentiation of Th1, Th2, T regulatory and newly described Th17 cells. Cytokines levels in time and space orchestrate the development, recurrence and exacerbation of the inflammatory process in IBD. Therefore, several cyto- kine therapies have been developed and tested for the treatment of IBD patients.     

Treatment of inflammatory bowel disease： A review of medical therapy

Crohn＇s disease （CD） and ulcerative colitis （UC） are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor （TNF） alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; non- systemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease. 6-mercaptopurine （6-MP） and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn＇s disease, and infliximab is also approved for the treatment of UC.     

379例炎症性肠病临床特征分析

目的探讨炎症性肠病(IBD)患者的临床特征。方法收集1994年至2003年浙江省邵逸夫医院确诊的IBD患者相关资料共379例，分析其临床特点。结果379例患者中，有317例为溃疡性结肠炎(UC)，62例为克罗恩病(CD)，男女之比分别为1．1：1和1．7：1，平均诊断年龄分别是44与33岁。1994年IBD入院患者构成比为31／10^6，而2003年为152／10^6。在UC患者中，11．4％为直肠炎，25．2％为直乙状结肠炎，18．6％为左半结肠炎，全结肠炎为44．8％。22．4％的患者入院治疗，其中仅39．4％患者诊断为重症UC，9例UC患者伴有关节炎，3例出现葡萄膜炎及巩膜炎。CD患者中有25．8％病变局限于末端回肠，24．2％为结肠，32．3％为回结肠，而17．7％病变累及回肠以上部位。33例患者(53．2％)入院治疗，16例有手术史。结论本院近9年来IBD发病数明显增多，以UC患者为主，但症状的严重程度低，肠外表现少。     

Antineutrophil cytoplasmic antibodies in inflammatory bowel disease

PURPOSE: Perinuclear antineutrophil cytoplasmic antibodies have been found consistently in patients with ulcerative colitis; however, their pathogenetic and clinical role is still uncertain. In this study we tested the prevalence of perinuclear antineutrophil cytoplasmic antibodies in a large population of patients with ulcerative colitis and Crohn's disease, with particular attention to the possible correlation with clinical features. METHODS: Perinuclear antineutrophil cytoplasmic antibody reactivity was investigated with indirect immunofluorescence in 279 patients with ulcerative colitis, 110 patients with Crohn's disease, and 252 unrelated healthy subjects. RESULTS: Perinuclear antineutrophil cytoplasmic antibodies were found in 84 of 279 patients with ulcerative colitis (30 percent), 10 of 110 patients with Crohn's disease (9 percent), and 2 of 252 healthy subjects (<1 percent;P<0.001), respectively. Perinuclear antineutrophil cytoplasmic antibodies were significantly more frequent in patients with ulcerative colitis with higher relapse rate (43vs. 27 percent;P<0.002), and patients with Crohn's disease with colitis (27vs. 2.5 percent;P<0.0003). Perinuclear antineutrophil cytoplasmic antibodies were also significantly less frequent in patients with ulcerative colitis in remission (18vs. 34 percent;P<0.0025). CONCLUSIONS: In this study we confirm the relative specific of perinuclear antineutrophil cytoplasmic antibodies, either for ulcerative colitis or for Crohn's disease involving the colon. Perinuclear antineutrophil cytoplasmic antibodies were more frequently found in patients with ulcerative colitis with a more aggressive clinical behavior; however, their presence had a limited value in identifying homogeneous subgroups of patients in our population.Presented in part at the Digestive Disease Week Meeting, San Francisco, California, May 19 to 22, 1996.     

High incidence of inflammatory bowel disease in The Netherlands

PURPOSE: To gain recent epidemiologic information about inflammatory bowel disease in The Netherlands, a prospective study over four years (1991–1995) was performed. METHODS: The incidence of inflammatory bowel disease and its subgroups was examined using standardized reports of newly diagnosed patients. A separate study compared the Inflammatory Bowel Disease Registration and computerized diagnostic files of a subgroup of general practitioners with the aim of estimating completeness of case ascertainment. RESULTS: The following mean incidence rates (per 100,000 inhabitants and year) were found: 6.9 (95 percent confidence interval, 5.9–7.9) for Crohn's disease, 10 (95 percent confidence interval, 8.7–11.2) for ulcerative colitis (23 percent of these with ulcerative proctitis), and 1.1 (95 percent confidence interval, 0.7–1.5) for indeterminate colitis. In the age category 20 to 29 years, the incidence rate of Crohn's disease with small-bowel involvement was higher in females than in males. In extended ulcerative colitis, a male preponderance was observed in the older age groups. Estimated case ascertainment was 78 percent. CONCLUSIONS: Compared with recent studies in neighboring countries, the observed age and gender standardized incidence rates are high in the south of The Netherlands. Completeness of case ascertainment might have contributed to this observation; however, case ascertainment was low in ulcerative proctitis. In the study area, differences in age and gender standardized incidence rates and in disease localizations could be compatible with an influence of environmental risk factors.Supported by The Development Fund, University Hospital Maastricht, Byk BV, Zwanenburg, and Pharmacia BV, Woerden, The Netherlands. The European Collaborative Study of Inflammatory Bowel Disease has been assisted by a grant of the European Communities Brussels (DG XII-F-6).     

炎症性肠病与肠道细菌研究进展

炎症性肠病(inflammatory bowel disease,IBD)包括溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn's disease,CD).其发病机制至今仍不清楚,可能的病因包括由基因决定的宿主易感性、黏膜免疫和肠道微生态环境三者的相互作用.近年来随着微生态学的发展,肠道菌群与IBD发病的关系日益受到关注.关于肠道病原微生物在IBD发病机制及其引起的一系列免疫学、微生态学、病理生理等方面的变化出现了研究和报道,同时微生态制剂在肠道免疫调节、控制炎症反应等方面的优点已有许多动物实验及临床应用证明,其中微生态制剂之一益生菌在IBD应用较普遍,本文就IBD与肠道菌群研究进展及益生菌制剂治疗IBD作一综述.     

Genetic factors associated with the development of inflammatory bowel disease

Crohn＇s disease （CD） and ulcerative colitis （UC） are complex polygenic disorders, characterized by several genes together with environmental factors contributing to the development of inflammatory bowel disease （IBD）. Recent advances in research on genetic susceptibility have allowed the identification of diverse genes at different levels： （1） Innate immunity; （2） Antigen presentation molecules; （3） Epithelial integrity; （4） Drug transporter; （5） Cell adhesion. The application of genetic testing into clinical practice is close and all genetic markers may have several clinical implications： prediction of disease phenotype, molecular classification, prevention of complications, and prognosis.     

ST2在炎症性肠病中的表达及其作用探讨

目的探讨血清中人基质裂解素（ST2）水平的变化在炎症性肠病（IBD）活动性评估中的意义。方法ELISA法（酶联免疫吸附测定）检测IBD患者45例，其中UC患者29例，CD患者16例，已排除IBD的其他胃肠疾病（包括主诉不明原因腹痛、腹泻、胃肠炎）的患者24例和15例健康人血清中ST2水平，20例IBD患者检测治疗前后ST2水平的改变。结果IBD活动期血清中ST2水平为（1884．72±338．38）pg／mL，显著高于缓解期（1292．27±347．73）pg／mL和健康对照组（1026．85±382．35）pg／mL，血清ST2水平在治疗前和治疗后（t=4．067，P〈0．01）、UC患者和CD患者（t=2．202，P=0．035）之间差异具有统计学意义。结论血清中ST2水平可作为炎症性肠病活动性评估和临床治疗效果的评价指标。     

白细胞介素-25在炎症性肠病患者中的表达及临床意义

目的 通过检测白细胞介素(IL)-25在炎症性肠病(IBD)患者肠黏膜及血清中的表达水平,探讨其在IBD发病过程中的作用及意义.方法 收集12例溃疡性结肠炎(UC)患者、16例克罗恩病(CD)患者及13例对照者的内镜肠黏膜活检标本,采用荧光定量PCR技术检测肠黏膜内IL-25 mRNA的表达情况,免疫组化技术分析IL-25在肠黏膜中的原位表达;同期收集20例UC、24例CD患者及20名健康对照者血清标本,采用酶联免疫吸附测定(ELISA)检测血清中IL-25水平.结果 与健康对照组相比,UC及CD患者肠黏膜组织内IL-25 mRNA表达显著降低(P＜0.05),UC及CD组间的表达量差异无统计学意义(P＞0.05).免疫组化分析显示IL-25阳性细胞在正常肠黏膜固有层内有较多表达,同时黏膜内的肠上皮细胞也存在IL-25低表达,UC及CD患者肠黏膜IL-25蛋白表达量显著降低(P＜0.05),UC及CD组间的表达量差异无统计学意义(P＞0.05).ELISA显示UC及CD患者血清中IL-25表达量显著低于健康对照组(P＜0.05).结论 IL-25在IBD患者肠黏膜及血清中表达显著降低,提示IL-25表达缺陷与IBD的发生发展密切相关,IL-25有可能成为IBD治疗的新靶点.     

炎症性肠病患者的肠外表现(附201例临床分析)

目的了解炎症性肠病(IBD)患者肠外表现的发生情况。方法对1978-01~2003-12期间北京大学第一医院收治的201例IBD患者的临床资料进行回顾性分析。结果25年间共收治IBD患者201例,其中溃疡性结肠炎(UC)患者182例,克罗恩病(CD)患者19例。IBD伴肠外表现发生率为20·9%(42/201),UC患者为21·43%(39/182),CD患者为15·79%(3/19)。女性显著多于男性(P<0·05)。UC患者年龄小于20岁者肠外表现发生率高(P<0·01),年龄大于50岁者肠外表现发生率低(P<0·01)。发生于UC活动期者占89·74%(35/39),而发生在缓解期者仅占10·26%(4/39);CD患者肠外表现均发生在活动期。肠外表现中关节、肌肉损害最为多见,其次为皮肤损害。侵犯泌尿系统、甲状腺及肝胆系统者罕见。伴有结节性红斑、坏疽性脓皮病及外周关节炎的患者多易合并其他种肠外表现。结论IBD患者伴有肠外表现者并非少见,女性年轻患者肠外表现发生率高,关节、肌肉及皮肤损害是IBD患者最多见的肠外表现,肠外表现的发生随IBD疾病活动性、疾病严重程度、病变范围的增加有增多的趋势。     

Osteoporosis in adult Sri Lankan inflammatory bowel disease patients

AIM： To determine if inflammatory bowel disease （IBD） is a risk factor for osteoporosis in adult Sri Lankans. METHODS： We identified eligible subjects from among consecutive patients diagnosed with IBD who attended our outpatient clinic. We included only patients aged between 20 and 70 years. Patients who were pregnant, had significant comorbidity, or were on calcium supplements or treatment for osteoporosis within the past 6 mo, were excluded. Healthy, ageand sex-matched controls were also recruited, in a control to patient ratio of 3：1. Both groups were screened for osteoporosis using peripheral dual energy X-ray absorptiometry scanning. RESULTS： The study population consisted of 111 IBD patients （male：female = 43：68; mean age 42.5 years） and 333 controls （male：female = 129：204; mean age 43.8 years）. The occurrence of osteoporosis among IBD patients （13.5%） was significantly higher than among controls （4.5%） （P = 0.001）. The frequency of osteoporosis was not significantly different between ulcerative colitis （14.45%） and Crohn＇s disease （10.7%）. However, on multivariate analysis, only age （P = 0.001）, menopause （P = 0.024） and use of systemic steroids （P 〈 0.001） were found to be associated independently with the occurrence of osteoporosis, while IBD, severity of disease, number of relapses, duration of illness or treatment other than systemic steroids were not. CONCLUSION： IBD does not appear to be an independent risk factor for the occurrence of osteoporosis in this population. However, the use of systemic steroids was a risk factor.     

Role of bacteria in the etiopathogenesis of inflammatory bowel disease

Increased numbers of mucosa-associated Escherichia coli are observed in both of the major inflammatory bowel diseases, Crohn＇s disease （CD） and ulcerative colitis （UC）. A potential pathophysiological link between the presence of pathogenic invasive bacteria and genetic host susceptibility of patients with ileal CD is suspected. In CD patients, with increased ileal expression of the CEACAM6 molecule acting as a receptor recognized by type 1 pilus bacterial adhesin, and with the identification of mutations in the NOD2-encoding gene, the presence of pathogenic invasive bacteria could be the link between abnormal ileal bacterial colonization and innate immune responses to invasive bacteria. In a susceptible host, the sequential etiological steps of the disease induced by adherent-invasive E. coli （AIEC） are： （1） abnormal colonization via binding to the CEACAM6 receptor, which is overexpressed in the ileal mucosa of CD patients; （2） ability to adhere to and to invade intestinal epithelial cells, which allows bacteria to cross the mucosal barrier; （3） survival and replication within infected macrophages in the lamina propria; and （4） induction of tumor necrosis factor-α secretion and granuloma formation.     

Use of mycophenolate mofetil in inflammatory bowel disease

AIM： To assess the efficacy and safety of mycophenolate mofetil （MMF） prospectively in inflammatory bowel disease （IBD） patients intolerant or refractory to conventional medical therapy.
METHODS： Crohn＇s disease （CD） or ulcerative colitis/ IBD unclassified （UC/IBDU） patients intolerant or refractory to conventional medical therapy received MMF （500-2000 mg bid）. Clinical response was assessed by the Harvey Bradshaw index （HBI） or colitis activity index （CAI） after 2, 6 and 12 mo of therapy, as were steroid usage and adverse effects.
RESULTS： Fourteen patients （9 CD/5 UC/IBDU; 8M/6F; mean age 50.4 years, range 28-67 years） were treated and prospectively assessed for their response to oral MMF. Of the 11 patients who were not in remission on commencing MMF, 7/11 （63.6%） achieved remission by 8 wk. All 3 patients in remission on commencing MMF maintained their remission. Ten patients were still on MMF at 6 mo with 9/14 （64.3%） in remission, while of 12 patients followed for 12 mo, 8 were in remission without dose escalation （66.7%）. Three patients were withdrawn from the MMF due to drug intolerance. There were no serious adverse events attributed due to the medication.
CONCLUSION： MMF demonstrated efficacy in the management of difficult IBD. MMF appeared safe, well tolerated and efficacious for both short and long-term therapy, without the need for dose escalation. Further evaluation of MMF comparing it to conventional immunosuppressants is required.     

Importance of nutrition in inflammatory bowel disease

Inflammatory bowel disease （IBD） results from the interaction between an individual＇s immune response and precipitant environmental factors, which generatean anomalous chronic inflammatory response in thosewho are genetically predisposed. Various feeding practices have been implicated in the origin of IBD based on epidemiological observations in developed countries, but we do not have solid evidence for the etiological role played by specific food types. IBD is associated with frequent nutritional deficiencies, thepattern and severity of which depends on the extent,duration and activity of the inflammation. Nutritional support allows these deficiencies in calories, macro and micronutrients to be rectified. Enteral nutrition is also aprimary therapy for IBD, especially for Crohn＇s disease,as it allows the inflammatory activity to be controlled,kept in remission, and Drevents or delays the need forsurgery. Nutritional support is especially important in childhood IBD as an alternative to pharmacological treatment. This report discusses the complex relationship between diet and IBD.