炎症性肠病内镜活检标本的诊断及鉴别诊断

目的探讨炎症性肠病(inflammatory bowel disease,IBD)内镜活检标本的病理诊断及鉴别诊断。方法对209例内镜下活检诊断为IBD的HE切片重新阅片,按照系统性诊断步骤,即组织结构、上皮及固有层的改变综合评估,进行病理形态分析。结果溃疡性结肠炎(ulcerative colitis,UC)108例,克罗恩病(Crohn disease,CD)19例,不能排除CD 20例,不能确定为UC或CD 27例,按系统性诊断方法,其中35例不能诊断为IBD。结论按照系统性诊断步骤,IBD不易漏诊,也不会过诊断。内镜活检标本诊断UC较容易,诊断CD较难,除非看到非干酪样上皮样肉芽肿,CD内镜活检的主要目的是排除淋巴瘤和肠结核。     

Genetic dissection of inflammatory bowel disease: unravelling etiology and improving diagnostics

Over the past 10 years, remarkable advances in the mapping and identification of genes involved in susceptibility to inflammatory bowel disease have been witnessed. Most notable among these advances has been the discovery of variants in the CARD15, DLG5, SLC22A4 and SLC22A5 genes, which are associated with increased risk of inflammatory bowel disease or specifically Crohn’s disease. These discoveries have provided critical new insights into the molecular pathophysiology of inflammatory bowel disease and the pathways wherein genetic and environmental factors such as enteric bacterial flora may interact to trigger immune dysregulation and intestinal inflammation. This review will outline the discovery of these inflammatory bowel disease-related genes, describe future prospects for further inflammatory bowel disease gene identification, and consider the impact of a genetic understanding of inflammatory bowel disease on future clinical practice.     

Characterization of genotype-phenotype relationships and stratification by the CARD15 variant genotype for inflammatory bowel disease susceptibility loci using multiple short tandem repeat genetic markers

The classification of ulcerative colitis (UC), Crohn disease (CD), and indeterminate colitis (IC) as forms of inflammatory bowel disease (IBD) is based on clinical, radiological, and histological criteria. The genetic basis of IBD is well founded, and susceptibility loci have been identified on several different chromosomes. We aimed to define genotype-phenotype relationships and interactions with the IBD susceptibility gene CARD15for various IBD susceptibility loci (IBD1, IBD2, IBD5, IBD6, IBD7, and chromosome 4) by characterizing previously described peak LOD score short tandem repeat (STR) markers. The study population consisted of 484 severely affected Caucasian patients with IBD, 144 healthy controls, and 348 nonaffected first-degree relatives of IBD patients. Associations were defined with the use of population- and family-based methodology. Correction for multiple testing was performed with a method based on an experimental false discovery rate. We provide novel evidence to show that IBD2 is involved in susceptibility to IC and terminal ileal CD in this population, with overrepresentation of IBD2 STR D12S83 (GenBank Z16592.1) allele 7 (g.49_60del[CA](6)) in IC (q = 0.038, P = 0.014) and underrepresentation of allele 8 (g.51_60del[CA](5)) in terminal ileal CD (q = 0.038, P = 0.016). The association of IBD2 with IC was confirmed by family-based testing. We also provide novel evidence to show that IBD5 is involved in susceptibility to IC and colonic/ileocolonic CD in this population, with overrepresentation of IBD5 STR D5S1984 (GenBank Z52623.1) allele 5 (g.183_186del[CA](2)) in both IC (q = 0.040, P = 0.005) and colonic/ileocolonic CD (q = 0.040, P = 0.004). Evidence is also given for potential interactions between CARD15and IBD2/IBD5. Other findings include an association of IBD2 with UC, and an association of IBD1 with terminal ileal and colonic/ileocolonic CD.     

Budesonide in the treatment of inflammatory bowel disease

Inflammatory bowel disease, including Crohn’s disease and ulcerative colitis, features recurrent episodes of inflammation of the GI tract. The treatment of inflammatory bowel disease is aimed at breaking the cycle of relapsing and remitting inflammation by inducing and maintaining remission. Systemically active conventional corticosteroids have long played a role in the induction of remission in both Crohn’s disease and ulcerative colitis, however, their long-term use can lead to adverse systemic effects. Budesonide, a synthetic steroid, has potent local anti-inflammatory effects and limited systemic bioavailability making it an appealing therapeutic option. Ulcerative colitis with predominantly distal disease may be treated with topical budesonide, however, novel oral controlled-release formulations have also been developed to allow for treatment of the entire colon. This article summarizes the use of budesonide in the management of inflammatory bowel disease.     

炎症性肠病发病机制及间充质干细胞治疗的作用与问题

文题释义： 炎症性肠病：是一类肠道慢性、特异性及复发性炎性疾病,其发病机制复杂,受到遗传、环境等多种因素的影响,尤其与自身免疫失调密切相关。 间充质干细胞的治疗作用：间充质干细胞是一群具有潜在自我更新能力和多元分化能力的异质基质细胞群,具有组织修复和免疫调节等功能,在多种疾病中,间充质干细胞的治疗作用已得到充分验证。 背景：近年来,炎症性肠病的发病率逐年增加,尚无良好治疗方案。间充质干细胞在治疗系统性红斑狼疮、心肌梗死、移植物抗宿主病等多项免疫相关疾病的研究中展现出良好的效果;同时,多项研究表明,间充质干细胞在炎症性肠病的治疗中拥有独特优势,因此关于间充质干细胞治疗炎症性肠病的研究逐渐成为目前的热点。 目的：总结间充质干细胞治疗炎症性肠病的现有研究,并对其应用前景和安全性进行展望。 方法：以“间充质干细胞,炎症性肠病,发病机制,治疗”及“mesenchymal stem cells,inflammatory bowel disease,mechanisms,treatment”分别作为中、英文关键词,在中国知网数据库、万方数据库及PubMed数据库对近20年间的相关文献进行检索,最终纳入符合要求的62篇文献进行综述。 结果与结论：间充质干细胞具有自我更新、组织迁移和多能性的能力以及强大的免疫调节作用,不仅在系统性红斑狼疮、心肌梗死、移植物抗宿主病等多种免疫相关疾病中表现出良好的治疗效果,同时在炎症性肠病中也拥有良好治疗表现,但目前用于临床的研究仍为少数,间充质干细胞治疗炎症性肠病仍面临安全性等多方面的问题。 ORCID: 0000-0001-5595-8257(黄文文) 中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程     

Optimising use of thiopurines in inflammatory bowel disease

Introduction: Thiopurines are central to inflammatory bowel disease (IBD) therapeutics, either as monotherapy or in combination with newer biologic therapies, however it is only recently that focus has increased on improving effectiveness and tolerability through optimisation.

Areas covered: We review the role of thiopurines in IBD and the importance of the timing of initiation of therapy. Drug metabolism and pharmacogenetics have increasingly played a role in determining dosing and dose optimisation and we review the rationale for this in both thiopurine monotherapy and in combination with biologic agents. We also discuss allopurinol co-therapy as a strategy for enhancing both efficacy and tolerability of thiopurine therapy. Although immunomodulators carry safety considerations, we discuss methods of optimisation to minimise side-effects and maximise safety to ensure the broadest number of patients can benefit.

Expert commentary: We provide a practical guide to drug initiation and dose optimisation in a clinical setting, and address potential treatment duration. The forward view considers the place for thiopurines in the treatment of IBD, and how the application of the plethora of genetic data may help inform thopurine therapy in the future.     

The clinical implications of thalidomide in inflammatory bowel diseases

Thalidomide has anti-inflammatory and anti-angiogenetic activity that makes it suitable for treating inflammatory bowel diseases (IBD). The recent guidelines from the European Crohn’s and Colitis Organization/European Society for Pediatric Gastroenterology Hepatology and Nutrition conclude that thalidomide cannot be recommended in refractory pediatric Crohn’s disease but that it may be considered in selected cohorts of patients who are not anti-TNFα agent responders. The main adverse effect is the potential teratogenicity that renders the long-term use of thalidomide problematic in young adults due to the strict need for contraceptive use. In short-term use it is relatively safe; the most likely adverse effect is the neuropathy, which is highly reversible in children. So far the use of thalidomide is reported in 223 adult and pediatric IBD patients (206 with Crohn’s disease). In the following sections, the authors will discuss efficacy and safety of thalidomide, in the short-term treatment of IBD.     

Genetic association between CARD9 variants and inflammatory bowel disease was not replicated in a Chinese Han population

Objective: In order to investigate whether CARD9 gene is associated with IBD in Chinese Han population, we replicated 2 SNPs of CARD9 which have been reported to be significantly associated with IBD. Methods: Two SNPs were genotyped using polymerase chain reaction with sequence-specific primers in 288 patients (232 CD patients, 56 UC patients) and 274 controls. Results: The frequencies and distributions of alleles and genotypes of the tested SNPs were analyzed, and no significant differences were found between patients and controls. Conclusions: We observed no significant association between the investigated CARD9 SNPs and the susceptibility of either CD or UC. Further studies with larger sample size focusing on different ethnicities are required to elucidate the correlation between CARD9 and IBD.     

Evidence for genetic heterogeneity in inflammatory bowel disease (IBD); HLA genes in the predisposition to suffer from ulcerative colitis (UC) and Crohn's disease (CD)

Family and epidemiological studies support a genetic susceptibility to UC and CD. Conflicting reports regarding associations between UC and HLA-DR2 and between CD and various HLA alleles have been published. The aim of this study was to determine whether molecularly defined HLA-DR genes are associated with these diseases in a Dutch group of patients. Fifty-nine unrelated Dutch UC patients and 89 CD patients were typed using DNA-based methods. A total of 2400 healthy local blood donors served as controls. The phenotype frequency of the HLA-DRB1*15 allele was increased in UC patients compared with controls (42% versus 26% in controls; P = 0.006; odds ratio (OR) = 2.1), and was predominantly found in female patients (53% versus 24%; P = 0.001; OR = 3.5). The DRB1*15 allele was increased in UC patients having a positive family history (P = 0.01; OR = 5.8). Among the 16 patients who showed an increase in extent of disease during follow up, 10 were DRB1*15⁺ (P = 0.002; OR = 4.8). The frequency of the DRB1*13 allele was decreased in patients with UC (15% versus 28% in controls; P = 0.04; OR = 0.5). In CD, no association was observed between disease or particular clinical subgroups and any allele tested. The present study provides additional evidence for the genetic association between UC and HLA-DRB1*15, and supports recent findings that the susceptibility gene(s) for CD is not located in the HLA class II region.     

Complementary and alternative medicine in inflammatory bowel disease: keeping an open mind

Complementary and alternative medicine use is increasing in both the general population and in individuals with chronic illness. A significant proportion of adult and pediatric patients with inflammatory bowel disease use or have used complementary and alternative medicine as determined by multiple surveys conducted in North America, Europe and Australia. There was a heterogenous selection of complementary and alternative medicine therapies chosen by patients, with variations due to geography and age. However, in general, their use is sought due to frustration with conventional therapies and the perceived safety of complementary and alternative medicine therapies. One of the dilemmas that arises when assessing the topic of complementary and alternative medicine use is rapidly changing definitions of what is and what is not considered conventional medicine. With our increasing understanding of the intricacies of the gastrointestinal immune system and host–microflora interactions, determining a scientific basis behind many complementary and alternative medicine therapies in vitro or in vivo is leading to evaluation of these therapies in humans. This will require well-designed and rigourously conducted clinical trials with sufficient sample size.     

JAK inhibition in inflammatory bowel disease

Introduction: Current available treatments for inflammatory bowel disease (IBD) have some limitations and new options are needed. Several new molecules are being tested for the treatment of IBD and other immune-mediated inflammatory diseases. Among them, Janus kinase (JAK) inhibitors seem to have the lead, since tofacitinib has received regulatory approval in 2012 for the treatment of rheumatoid arthritis, and also it has shown a favorable risk-benefit ratio in phase 3 studies for ulcerative colitis, both in anti-TNF naïve and anti-TNF experienced patients. Other compounds with JAK inhibitory activity are also being tested with promising results.

Areas covered: This review discusses the molecular aspects of the JAK-STAT pathway, which gives rationale for the use of JAK inhibitors in immune-mediated inflammatory diseases, especially in IBD. Different compounds with JAK inhibitory activity are presented, and relevant efficacy and safety data in IBD and other conditions are discussed.

Expert commentary: It would not be surprising that in a foreseeable future many new orally administrated drugs will be available. This enhanced armamentarium will probably pose new dilemmas, in terms of drug positioning, escalation and de-escalation strategies, and combination therapy.     

Inflammatory bowel disease and pregnancy: an update

Women with inflammatory bowel disease have similar rates of conception to the general population unless they have had pelvic surgery. Once pregnant, regardless of disease activity, they have an increased risk of adverse pregnancy outcome and should be followed as high-risk obstetric patients. Most medications are compatible with pregnancy and lactation, as described in this article. Ideally, women should discuss their plans for pregnancy with their physician prior to conception so that risks and benefits can be reviewed, medications adjusted and healthcare maintenance updated. Once pregnant, a multidisciplinary team of gastroenterologists, obstetricians and pediatricians should help to ensure the best care for the mother and child.     

Nutrigenetics,nutrigenomics and inflammatory bowel diseases

Inflammatory bowel disease includes ulcerative colitis and Crohn’s disease, which are both inflammatory disorders of the gastrointestinal tract. Both types of inflammatory bowel disease have a complex etiology, resulting from a genetically determined susceptibility interacting with environmental factors, including the diet and gut microbiota. Genome Wide Association Studies have implicated more than 160 single-nucleotide polymorphisms in disease susceptibility. Consideration of the different pathways suggested to be involved implies that specific dietary interventions are likely to be appropriate, dependent upon the nature of the genes involved. Epigenetics and the gut microbiota are also responsive to dietary interventions. Nutrigenetics may lead to personalized nutrition for disease prevention and treatment, while nutrigenomics may help to understand the nature of the disease and individual response to nutrients.     

Association of ulcerative colitis with the inflammatory bowel disease susceptibility locus IBD2 in non‐Jewish Caucasians and evidence of genetic heterogeneity among racial and ethnic populations with Crohn disease

Genomewide scanning has been used to identify chromosomal regions encoding susceptibility loci to inflammatory bowel disease (IBD). The greatest evidence for linkage to IBD has been reported for a region of chromosome 12q14 surrounding the microsatellite marker D12S83, with a logarithm of odds score of 5.47 and a positive transmission disequilibrium test, and which was subsequently named IBD2. We wished to confirm this locus by genotyping the highly polymorphic microsatellites D12S1022, D12S1056, and D12S83, spanning a continuous region on chromosome 12 of 342 kb, in a cohort of nonrelated individuals with ulcerative colitis (89 patients), Crohn disease (121 patients), and population‐based control subjects (100 patients). In non‐Jewish Caucasians, one D12S1022 allele, one D12S1056 genotype, and three D12S83 alleles were found to have statistically significant differences in distribution between the two disease groups and the control population. These data support a significant association of IBD with the IBD2 locus in close vicinity to the three markers studied. The replication of genetic risk loci in a case control association study may indicate susceptibility genes in this region and may facilitate identification of candidate genes for IBD. Subgroup analysis revealed a notable difference in genotype distribution among Jewish Caucasian and African American patients affected with Crohn disease when compared with similarly affected non‐Jewish Caucasians. Using Fisher exact test, statistically significant distribution differences were observed for D12S1022 and D12S83. These data indicate that there may be significant genetic heterogeneity between different ethnic and racial IBD populations or may simply reflect differences in marker allele frequencies among populations. © 2002 Wiley‐Liss, Inc.     

Immune-mediated inflammatory reactions and tumors as skin side effects of inflammatory bowel disease therapy

Abstract

All drugs currently used for treating patients with inflammatory bowel disease (IBD – including Crohn’s disease and ulcerative colitis) have the potential to induce skin lesions ranging from mild eruptions to more serious and widespread clinical presentations. The number of cutaneous adverse reactions due to IBD therapies is progressively increasing and the most frequently involved drugs are thiopurines and biologics like tumor necrosis factor (TNF)-α antagonists. The main drug-induced cutaneous manifestations are non-melanoma skin cancer (NMSC), notably basal cell and squamous cell carcinomas, and viral skin infections for thiopurines and psoriasiform, eczematoid and lichenoid eruptions as well as skin infections and cutaneous lupus erythematosus for biologics. Cutaneous manifestations should be promptly recognized and correctly diagnosed in order to quickly establish an adequate therapy. The main treatment for NMSC is surgical excision whereas the management of immune-mediated inflammatory skin reactions varies from topical therapy for mild presentations to the shift to another drug alone or in combination with corticosteroids for extensive eruptions.     

High resolution MIC genotyping: design and application to the investigation of inflammatory bowel disease susceptibility

The highly polymorphic nonclassical MHC class I chain-related (MIC) genes MICA and MICB encode stress inducible glycoproteins expressed on a variety of epithelial cells including intestinal cells. Interaction with the receptor NKG2D is likely to provide an important costimulatory signal for activation and proliferation of NK cells, activated macrophages and CD8 alphabeta and gammadelta T cells. Fifty-four MICA and 17 MICB alleles have been described to date. Although the functional significance of this polymorphism is not known, the high degree of nonconservative substitution, concentration to the putative ligand-binding site and recent observation that different MICA alleles bind to NKG2D with varying affinity has generated much interest. The MIC genes are attractive functional and positional candidate genes for inflammatory bowel disease susceptibility as a consequence of their position in the HLA region and expression on the gastrointestinal epithelium. We developed a robust, high-resolution PCR-SSP genotyping method that can be incorporated into the standard 'Phototyping' system and which effectively identifies 46 of 54 MICA alleles, and all 17 MICB alleles. We applied this system in combination with microsatellite genotyping of the exon 5 variable number of tandem repeats (VNTR) to the investigation of genetic susceptibility to the inflammatory bowel diseases, ulcerative colitis and Crohn's disease. We studied 248 patients with Crohn's disease, 329 with ulcerative colitis and 354 ethnically matched controls. Linkage disequilibrium patterns between HLA-B, MICA and MICB are presented. Analysis by individual allele or by multilocus haplotype failed to identify any significant disease associations.     

Current,experimental, and future treatments in inflammatory bowel disease: a clinical review

Abstract

Inflammatory bowel diseases (IBDs) may result from dysregulated mucosal immune responses directed toward the resident intestinal microbiota. This review describes the hallmark immunobiology of Crohn’s disease and ulcerative colitis as well as therapeutic targets and mechanisms of action for current, experimental, and future treatments in IBD. Conventional therapies include 5-aminosalicylic acid, glucocorticosteroids, thiopurines, and methotrexate. Since 1997, monoclonal antibodies have gained widespread use. These consist of antibodies directed against pro-inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-12, and IL-23, or anti-homing antibodies directed against α4β7 integrin. Emerging oral therapies include modulators of intracellular signal transduction such as Janus kinase inhibitors. Vitamin D may help to regulate innate and adaptive immune responses. Modulation of the intestinal microbiota, using live microorganisms (probiotics), substrates for the colonic microbiota (prebiotics), or fecal microbiota transplantation (FMT), is in development. Dietary supplements are in widespread use, but providing evidence for their benefit is challenging. Stem cell treatment and nervous stimulation are promising future treatments.     

Th17 cells: interactions with predisposing factors in the immunopathogenesis of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic inflammatory state of the GI tract of unknown etiology. Classically, tissue injury in IBD is thought to be primarily mediated by Th1 cells in Crohn’s disease or Th2 cells in ulcerative colitis. The discoveries of new subsets of T-helper cells, especially Th17 cells, have revolutionized our understanding of the disease immunopathology. Th17 cells seem to affect both innate and adaptive immune responses by the release of regulatory cytokines. Understanding the role of Th17 cells in IBD pathogenesis and targeting their regulatory cytokines may provide potential therapeutic approaches for the treatment of IBD in the future.     

The relationship between coagulation state and inflammatory bowel disease: current understanding and clinical implications

Inflammatory bowel disease (IBD) is associated with a hypercoagulable state and subsequently with an increased risk for venous thromboembolism (VTE). VTE in IBD is characterized by a high recurrence rate and is associated with the disease activity. Acquired endothelial dysfunction, abnormalities of platelets, activation of coagulation system and impaired fibrinolysis are the main changes in the coagulation state in IBD. The development of VTE in IBD has been considered to be the result of multiple interactions between acquired and inherited risk factors. The treatment of VTE in IBD patients is recommended to be similar and to follow the same protocols as for non-IBD patients. In the clinical practice, the management of IBD patients and especially the hospitalized patients should include thromboprophylaxis.