Th17细胞及IL-23在炎症性肠病中的研究进展

炎症性肠病(IBD)是一种病因和发病机制尚不清楚的发生在胃肠道的慢性非特异性炎症性疾病。大量证据表明先天性和获得性免疫系统的异常均对该疾病起着关键性作用。传统观点认为炎症性肠病与Th1细胞和Th2细胞所介导的免疫应答有关;但最新研究指出,体内Th17细胞以及白细胞介素IL-23的存在,与炎症性肠病的发生息息相关。本文对炎症性肠病中Th17细胞及IL-23的研究进展作一综述。     

The impacts of an inflammatory bowel disease nurse specialist on the quality of care and costs in Finland

Abstract:

Introduction: A specialized inflammatory bowel disease (IBD) nurse is considered a valuable and cost-effective member of a multidisciplinary team, not all clinics responsible for IBD care employ such nurses. We evaluated IBD nurse resources, quality of care and cost effects on IBD patients care in a nationwide study in Finland.

Methods: A healthcare professional electronic survey was conducted in order to assess the impact of an IBD nurse on the quality of care. To study the cost effects, we obtained nationwide comprehensive data covering years between 2008 and 2016 from major administrative healthcare districts of Finland. Patients with a diagnosis of IBD (ICD-code K50 or K51) were identified from the data and their personal contacts and hospitalization were analyzed. The results were compared between healthcare districts with an IBD nurse and healthcare districts without an IBD nurse.

Results: Forty-nine physicians and 88 nurses responded to the survey. Of the physicians, 92% reported that an established IBD nurse had released physician’s resources. The most important IBD nurse contributions listed were patient support and follow-up (79–81% of the respondents).

Healthcare district, which had an established IBD nurse, produced more patient contacts. A larger proportion of the contacts was managed by the IBD nurse. Clinics with an IBD nurse reported less patient hospitalization (4–9% vs 11–19%, p?Conclusion: The introduction of an IBD nurse led to better quality of care and potentially significant cost savings by reducing hospitalization rates and reallocating physician’s time resources.     

Chromogranin A as a biomarker of disease activity and biologic therapy in inflammatory bowel disease: a prospective observational study

Abstract

Objective. To access the correlation of Chromogranin A (CgA) with inflammatory bowel disease (IBD) activity and responsiveness to medical therapy. Material and methods. A prospective observational study was conducted in 56 patients with moderate ulcerative colitis (UC) or Crohn’s disease (CD) (UC, n = 29, CD, n = 27), 17 patients with irritable bowel syndrome and predominant diarrhea (IBS-D) and 40 healthy volunteers. IBD patients were treated by biologics (infliximab or adalimumab) or conventional agents (aminosalicylates, thiopurines or methotrexate and steroids) and were classified according to their treatment in two groups. Serum CgA was measured at baseline and 4-week posttreatment period. Results. Serum CgA was significantly higher in IBD patients than in those with IBS-D or healthy volunteers (p < 0.01). Furthermore, serum CgA was markedly increased in CD patients than in UC patients (p < 0.01). CgA value was significantly reduced in ‘biologic’ group (24 IBD patients, UC, n = 15, CD, n = 9) at 4-week posttreatment period (p < 0.01), while 18/24 (72%) patients were already in remission during that time. In contrast, CgA value was significantly increased in the ‘conventional’ treatment group (32 IBD patients, UC, n = 14, CD, n = 18) between the two visits (p < 0.01), although 22/32 (69%) patients were in remission during the 4-week posttreatment period. Conclusion. CgA appears to be a reliable marker of disease activity in IBD patients and especially in those who received biologic therapy. IBS-D patients presented normal CgA values.     

Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract with a multifactorial pathophysiology. Full comprehension of IBD pathology is still out of reach and, therefore, treatment is far from ideal. Nevertheless, components involved in IBD pathogenesis including environmental, genetic, microbial, and immunological factors are continuously being investigated and the improved knowledge contributes to the development of new therapies. In this article we review the aspects of the immunopathogenesis of IBD, with focus on mucosal immunity, and discuss mechanisms of action for current and emerging biological therapies.     

IL-17基因多态性与中国汉族人群炎症性肠病的关系

目的:研究IL-17A和IL-17F的5个多态性位点与中国汉族人炎症性肠病之间的关系.方法:采用病例-对照研究方法,收集确诊的溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn’s disease,CD)患者共350例(UC270例;CD80例),健康对照组268例,收集外周血标本2mL,提取DNA,运用LDR(ligasedetection reaction allelic)技术进行多态性检测.采用SPSS17.0软件进行数据分析.结果:CD患者中IL-17F(rs763780,7488T/C)突变等位基因C的频率明显高于对照组(13.8%vs8.4%,P=0.044,OR=1.74,95%CI1.01-2.99).在亚型分析中,rs763780基因多态性与CD病变范围有关,突变等位基因C在CD回结肠型患者中的频率明显高于对照组(P=0.02).IL-17A(rs2275913,G-197A)与UC患者疾病的严重程度有弱相关性,含有突变基因A的患者倾向于临床轻型.IL-17F(rs763780,7488T/C)多态性与U C患者发病年龄之间有弱相关性,T/C基因型患者趋向于年轻型(P=0.046).结论:IL-17F rs763780基因多态性与CD易感性之间有弱相关性,在亚组分析中发现rs763780与CD的病变范围和UC的发病年龄有关.IL-17A rs2275913基因多态性与UC疾病严重程度呈负相关.     

Scoring systems in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic, relapsing condition affecting the GI tract that can affect individuals of any age and results in lifelong treatment, frequently including the need for surgery. Historically, the lack of a single effective and sensitive test for IBD has posed a great challenge in assessing disease severity, effectiveness of medication and predicting outcomes for this complex condition. Several IBD scoring and classification systems have been developed over many years to classify and characterize IBD patients, with the goal of helping to better define the disease status and effectiveness of therapy. Recent genetic investigations have revealed the complexity of IBD at the pathophysiologic level, revealing numerous genetic mutations associated with the disease. Thus, these clinically based IBD classification systems can provide the basis for the eventual correlation between the underlying genotype with clinical expression of disease and lead to better characterization of disease subtypes and, hopefully, customized treatment regimens.     

Gender-related issues in the female inflammatory bowel disease patient

Inflammatory bowel diseases (IBDs) commonly affect women in their childbearing years. Women identify unique psychologic issues compared with men related to body image and their ability to bear children. The menstrual cycle can be disrupted because of disease activity, medications and/or malnutrition. Oral contraceptives can be used; however, monitoring for thromboembolic events should be performed. Women with IBD are potentially at risk of higher rates of cervical dysplasia and should be screened as are other immunocompromised women. Fertility rates are comparable to those of women without IBD. The risk of disease activity during pregnancy depends on the disease activity at the time of conception. Pregnancy for the majority of women is uncomplicated, although women with Crohn’s disease do tend to deliver children of lower birthweights than do healthy women. The majority of medications used in the treatment of IBD are not harmful to the fetus and should be continued throughout pregnancy in order to maintain maternal health. Breastfeeding should not be discouraged and the majority of medications are safe for nursing. Menopause tends to occur earlier in women with IBD; the cause of this is unclear.     

Antibiotics exposure and risk of inflammatory bowel disease: a systematic review

Aim: The aim of this study was to critically assess all available evidence suggesting an association between antibiotic exposure and new onset of inflammatory bowel disease (IBD).

Materials and methods: This systematic review was conducted according to the PRISMA statement and eligible studies were identified through search of PubMed, Embase and the Cochrane Library. Data on patient demographics, antibiotic exposure and confounding factors were analyzed. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of eligible studies.

Results: A total of 15 observational studies (10 case control and five cohort) including 8748 patients diagnosed with IBD were systematically reviewed. Antibiotic exposure was mostly associated with Crohn’s disease but not with ulcerative colitis. In particular, penicillin’s, cephalosporins, metronidazole and fluoroquinolones were most commonly associated with the onset of Crohn’s disease. The impact of tetracycline-family antibiotics on the pathogenesis of IBD was not clear.

Conclusion: There may be an association between antibiotic exposure and the development of IBD; especially Crohn’s disease. Even though, clinicians should be cautious when prescribing certain antibiotic regimens to patients with a strong family history of IBD, it should be emphasized that available data are not granular enough to reach any definitive conclusions.     

Specific considerations in the treatment of pediatric inflammatory bowel disease

Inflammatory bowel disease is one of the most prevalent chronic inflammatory disorders and commonly presents during childhood or adolescence. Occurring during a critical period of growth and development, pediatric Crohn’s disease and ulcerative colitis require special consideration. Children often experience growth failure, malnutrition, pubertal delay and bone demineralization. Medical treatment must be optimized to promote clinical improvement and reverse growth failure with minimal toxicity. In addition to pharmacologic and surgical interventions, nutritional therapies play a vital role in the management of pediatric inflammatory bowel disease. This review will outline the epidemiology and clinical complications that are unique to pediatric inflammatory bowel disease, current trends, and recent advances in nutritional and pharmacologic treatment, and projected future therapeutic direction.     

Fatigue in a population-based cohort of patients with inflammatory bowel disease 20 years after diagnosis: The IBSEN study

Objective: Fatigue is a major concern for patients with ulcerative colitis (UC) and Crohn’s disease (CD), but evidence from population-based studies regarding fatigue in long-standing inflammatory bowel disease (IBD) patients is scarce. Our aims were to assess fatigue scores and the prevalence of chronic fatigue in IBD patients 20 years after diagnosis and to identify variables associated with fatigue in this cohort.

Methods: Twenty years after diagnosis, patients from a cohort with incident IBD were invited to a follow-up visit that included a structured interview, a clinical examination, laboratory tests and the Fatigue Questionnaire (FQ). Fatigue scores were obtained, and factors associated with fatigue were assessed via linear and logistic regression analyses.

Results: Of the 599 invited patients, 440 (73.5%) completed the FQ. Among those with active disease, we found significantly higher fatigue scores than among those with quiescent disease (fatigue scores: UC 17.1 versus 12.4, p?<?.001, and CD 17.5 versus 13.3, p?<?.001). The fatigue scores of those with quiescent disease were comparable with those of the reference population. Chronic fatigue was more frequent among IBD patients than in the reference population. Factors associated with fatigue included self-perceived disease activity, poor sleep quality, anxiety and depression.

Conclusion: At 20 years after IBD diagnosis, fatigue scores were higher and chronic fatigue was more frequent among IBD patients with active disease than in the reference population and among those with quiescent IBD. Subjectively perceived disease activity, sleep quality, anxiety and depression were associated with fatigue in IBD patients.     

The adherence to the therapy in inflammatory bowel disease: beyond the number of the tablets

Objectives: The therapy of the inflammatory bowel diseases is quite complex. A partial compliance increases the relapse probability and the health expenditure. The aim of the study is to correctly study the adherence to the therapy in a single centre eliminating the bias of a different relationship of trust with different doctors.

Materials and methods: We conducted a blind prospective study on the adherence evaluated for mesalazine.

Results: Three hundred and seventy-six patients were included in the final analysis. Of the patients, 57.4% never missed a single dose of mesalazine, 29.3% missed one or two doses, 7.4% missed three to four doses, 5.9% missed more than five doses. A greater adherence among males (p?=?.015) and, in ulcerative colitis, among the group with a disease duration of <2 years compared to the one with a disease duration between 2 and 5 years (p?=?.04) were found. In Crohn’s diseases, among the patients who had never undergone to surgical interventions, the adherence was 49.6%, compared to 51.9% among patients who underwent to one surgical resection and 78.6% among patients underwent to multiple surgical resections (p?=?.001).

Conclusions: The factors influencing the adherence to the therapy are only partly related to the prescribed therapy, but also to factors affecting the patient life: to increase the adherence rate it would be necessary not only interventions on the posology but also the psychological support to the patient at the time of the visit.     

TWEAK is not elevated in patients with newly diagnosed inflammatory bowel disease

Objective: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) may be involved in the pathogenesis of inflammatory bowel disease. The aim was to investigate if TWEAK may reflect disease activity in inflammatory bowel disease.

Materials and methods: In this cohort study, 139 consecutive patients with newly diagnosed and previously untreated inflammatory bowel disease – 95 with ulcerative colitis (UC) and 44 with Crohn’s disease (CD) – underwent colonoscopy. Disease activity was assessed by the Mayo score and the Mayo endoscopic score (MES) for UC, or the Simple Endoscopic Score (SES) for CD. Serum C-reactive protein (CRP) and fecal calprotectin were measured in IBD patients, as were plasma TWEAK levels in patients and 85 healthy subjects. Associations between TWEAK levels and disease activity markers were explored.

Results: In the total IBD group, the median (interquartile range) TWEAK level was 430?pg/ml (109–6570), in UC 502?pg/ml (109–4547) and in CD patients 352?pg/ml (101–9179), respectively. Healthy subjects had a median (IQR) TWEAK of 307?pg/ml (63–3492). There were no significant differences in TWEAK levels between the total IBD group and healthy control subjects, nor between UC and CD, or between UC/CD and healthy subjects. Furthermore, we found no significant associations between Mayo scores, MES-UC, SES-CD, CRP, and fecal calprotectin with plasma TWEAK levels.

Conclusions: Plasma TWEAK levels do not reflect disease activity or the grade of inflammation in patients with newly diagnosed inflammatory bowel disease. NCT01551563.     

Psychological factors and stress in inflammatory bowel disease

The role of psychological distress and personality as predisposing factors for the development of inflammatory bowel disease (IBD) remains controversial. Attempts to investigate the role of psychological factors in IBD exhibited rather conflicting results. Among the studies concerning the effects of stress or depression on the course of IBD, the majority suggest that stress worsened IBD, the rest giving either negative or inconclusive results. However, application of strategies, including avoidance of coping and training patients in problem solving or emotion-oriented, could influence the course of IBD. Large controlled clinical trials are needed in order to clarify the impact of psychological interventions on the quality of life and the course of disease.     

The Interleukin-23 / Interleukin-17 axis in intestinal inflammation

Although the precise aetiology of inflammatory bowel disease (IBD) remains unclear, recent discoveries have led to an improved understanding of disease pathogenesis. Whilst these findings have underscored the central role of innate and adaptive immune responses in intestinal inflammation, they have also precipitated a paradigm shift in the key cytokine pathways that drive disease. The prevailing dogma that IBD was mediated by interleukin (IL)-12-driven T-helper (Th)1 CD4 T cell responses towards the bacterial flora has been largely dispelled by findings that the closely related cytokine IL-23 appears to be the key mediator of intestinal inflammation. IL-23 is associated with a novel subset of IL-17-secreting CD4 T cells termed Th17 cells and rodent studies have implicated the IL-23/IL-17 axis in autoimmune inflammation. Genome-wide association studies in IBD patients have confirmed the predominant role of the IL-23 pathway, indicating that this could represent an important future therapeutic target.     

Advances in understanding the role of cytokines in inflammatory bowel disease

Introduction: Cytokines represent the key pathophysiologic elements that govern the initiation, progression, and, in some circumstances, the resolution of the inflammation occurring in inflammatory bowel disease (IBD).

Areas covered: In this review, we will focus on the main effector and anti-inflammatory cytokines produced in IBD and discuss the results of recent trials in which cytokine-based therapy has been used for treating IBD patients.

Expert commentary: The possibility to sample mucosal biopsies from IBD patients and analyze which molecular pathways are prominent during the active phases of the disease and the easy access to various models of experimental colitis has largely advanced our understanding about the role of cytokines in IBD. These progresses have facilitated the development of several therapeutic compounds, which either target inflammatory cytokines or enhance the regulatory function of immunosuppressive cytokines. While some of such drugs are effective in the induction and maintenance of remission of the disease, other compounds are not useful for attenuating the ongoing mucosal inflammation, thus establishing a hierarchical scale of the relevance of cytokines in IBD. Further work is needed to identify biomarkers, which could help personalize cytokine-targeted therapy and minimize potential side effects.     

Infliximab-induced skin manifestations in patients with inflammatory bowel disease

Objective The use of infliximab in rheumatoid and inflammatory bowel diseases (IBD) has been associated with a variety of adverse skin reactions, including paradoxical psoriatic lesions. The prevalence and possible predictors for these lesions were under observation in our cross-sectional prospective study. Material and methods Nurses screened the skin of 118 adult patients with IBD during infliximab infusions between 4 September 2013 and 30 September 2014 based on the structured questionnaire. Data on skin manifestations, concomitant medications, extraintestinal manifestations and inflammatory markers were collected for analysis. Results Non-infectious skin manifestations were observed in 27 (22.9%) patients during the study period, of which eight (29.6%) were new-onset, eight (29.6%) were exacerbations of existing lesions and 11 (40.7%) were baseline lesions that did not worsen during the study. Scaling eczema was the most commonly described skin manifestation (n?=?8; 29.6%), followed by exacerbated atopic eczema (n?=?5; 18.5%) and plausible infliximab-induced psoriasiform lesions (n?=?5; 18.5%). The strongest associating factor for skin manifestations was Crohn’s disease, in nearly 80% of afflicted patients. Conclusions Anti-TNF-α therapy is frequently associated with newly onset skin reactions, most commonly in patients with Crohn’s disease. Non-infectious skin manifestations can be treated topically and do not require cessation of anti-TNF-α therapy.     

Potential role of Th17 cells in the pathogenesis of inflammatory bowel disease

The etiopathology of inflammatory bowel disease (IBD) remains elusive. Accumulating evidence suggests that the abnormality of innate and adaptive immunity responses plays an important role in intestinal inflammation. IBD including Crohn's disease (CD) and ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract, which is implicated in an inappropriate and overactive mucosal immune response to luminal flora. Traditionally, CD is regarded as a Th1mediated inflammatory disorder while UC is regarded as a Th2like disease. Recently, Th17 cells were identified as a new subset of T helper cells unrelated to Th1 or Th2 cells, and several cytokines [e.g. interleukin (IL)-21, IL-23] are involved in regulating their activation and differentiation. They not only play an important role in host defense against extracellular pathogens, but are also associated with the development of autoimmunity and inflammatory response such as IBD. The identification of Th17 cells helps us to explain some of the anomalies seen in the Th1/Th2 axis and has broadened our understanding of the immunopathological effects of Th17 cells in the development of IBD.     

Selecting appropriate anti-TNF agents in inflammatory bowel disease

Infliximab was the first anti-TNF agent to be approved by the US FDA for the treatment of Crohn’s disease (CD) in 1998. In the past 10 years, two other agents, adalimumab and certolizumab pegol, have also been approved for the treatment of CD. In the absence of head-to-head comparisons, the efficacy of these agents appear to be similar for the treatment of luminal CD. There are also prospective, randomized, controlled data to support the use of infliximab for the treatment of fistulizing CD and ulcerative colitis, and supportive post hoc data for the use of adalimumab and certolizumab pegol for the treatment of fistulizing CD. Practical matters, such as patient preference regarding the mode of administration, approval by third-party payers and residual patient cost, may actually play a larger role in choosing a particular anti-TNF agent, as efficacy and safety issues are similar for all three. Unfortunately, many patients do not respond, lose response or develop intolerance to anti-TNF treatment. Thus, new therapies are needed. Natalizumab, the first biologic that is not an anti-TNF agent, was FDA-approved in January 2008 for the treatment of CD patients who have failed conventional treatment, including anti-TNF therapy. As we continue to learn more about the pathogenesis of inflammatory bowel disease, novel targets for drug therapy are being developed.