Deep Remission in Inflammatory Bowel Disease: Looking Beyond Symptoms

Inflammatory bowel diseases (IBD) are chronic and disabling conditions. Accumulating evidence indicates that we need to look beyond clinical symptoms as current therapeutic strategies have not modified the course of IBD. Therapeutic goals for IBD have evolved from a mere control of symptoms to mucosal healing (MH). Achieving deep remission (clinical remission, biomarker remission and MH) might be the only way to alter disease course in IBD patients. In Crohn’s disease (CD), deep remission has been recently defined as Crohn’s Disease Activity Index <150 and complete MH. In ulcerative colitis (UC), there is no proposed definition of deep remission. It could be defined as clinical and endoscopic remission in UC. These definitions remain to be validated in large prospective studies. In the near future, the concept of deep remission might include transmural healing in CD and histologic healing in UC. Advances in drug development have provided highly effective treatments for IBD, making deep remission a realistic goal. Whether IBD patients may benefit by experiencing a ‘deep’ remission beyond the control of clinical symptoms, which might ultimately impact on important outcomes such as the need for surgery and the development of disability, needs to be evaluated in future disease modification trials.     

黏膜愈合在炎症性肠病中的临床应用

至上世纪90年代末,症状缓解仍是炎症性肠病（IBD）疗效评估的重要指标.近年,黏膜愈合（MH）逐渐被纳入IBD的疗效评估,并作为临床试验的重要终点和治疗目标.MH可改变IBD的自然病程,以达持续临床缓解,由此降低患者的住院率和手术风险.本文就MH在IBD临床应用中的价值作一综述.     

Inflammatory Bowel Disease During Pregnancy

Opinion statement The management of both male and female patients with inflammatory bowel disease (IBD) who wish to have a baby is challenging. For women, the most important factor to bear in mind is that the outcome of pregnancy is largely influenced by disease activity at the time of conception. Women with quiescent disease are likely to have an uncomplicated pregnancy with the delivery of a healthy baby, whereas women with active disease are more likely to have complications such as spontaneous abortions, miscarriages, stillbirths, and exacerbation of the disease. This is more true of patients with Crohn’s disease than of patients with ulcerative colitis. Although the safety of medications used during pregnancy is an important issue, the impact of the medications used to treat IBD is less important in comparison to disease activity itself. 5-Aminosalicylic acid (5-ASA) products appear to be safe during pregnancy; corticosteroids are probably safe; 6-mercaptopurine and azathioprine should be used with caution; and methotrexate is contraindicated. There are inadequate data on the use of infliximab during pregnancy. In regard to men with IBD, the disease itself does not seem to have any negative impact on fertility. However, there is controversy about the effects of using 6-mercaptopurine and azathioprine prior to and during fertilization. In view of possible adverse pregnancy outcomes, it would be prudent to withhold 6-mercaptopurine and azathioprine therapy in men with IBD for 3 months prior to conception, when feasible. Most IBD medications should be continued before, during, and after pregnancy, with careful attention to the known cautions and exceptions. If IBD in a pregnant patient is in remission, the prognosis for pregnancy is the same as if she did not have IBD. Active disease should therefore be treated aggressively and remission accomplished before pregnancy is attempted. Similarly, a woman who unexpectedly becomes pregnant while her IBD is active should be treated aggressively, as remission remains the greatest investment for a favorable pregnancy outcome.     

Nutritional status and nutritional therapy in inflammatory bowel diseases

Underweight and specific nutrient deficiencies are frequent in adult patients with inflammatory bowel disease （IBD）. In addition, a significant number of children with IBD, especially Crohn＇s disease （CD） have impaired linear growth. Nutrition has an important role in the management of IBD. In adults with CD, enteral nutrition （EN） is effective in inducing clinical remission of IBD, although it is less efficient than corticosteroids. Exclusive EN is an established primary therapy for pediatric CD. Limited data suggests that EN is as efficient as corticosteroids for induction of remission. Additional advantages of nutritional therapy are control of inflammation, mucosal healing, positive benefits to growth and overall nutritional status with minimal adverse effects. The available evidence suggests that supplementary EN may be effective also for maintenance of remission in CD. More studies are needed to confirm these findings. However, EN supplementation could be considered as an alternative or as an adjunct to maintenance drug therapy in CD. EN does not have a primary therapeutic role in ulcerative colitis. Specific compositions of enteral diets-elemental diets or diets containing specific components-were not shown to have any advantage over standard polymeric diets and their place in the treatment of CD or UC need further evaluation. Recent theories suggest that diet may be implicated in the etiology of IBD, however there are no proven dietary approaches to reduce the risk of developing IBD.     

Disease monitoring in inflammatory bowel disease

The optimal method for monitoring quiescent disease in patients with Crohn's disease(CD) and ulcerative colitis is yet to be determined. Endoscopic evaluation with ileocolonoscopy is the gold standard but is invasive,costly,and time-consuming. There are many commercially available biomarkers that may be used in clinical practice to evaluate disease status in patients with inflammatory bowel disease(IBD),but the most widely adopted biomarkers are C-reactive protein(CRP) and fecal calprotectin(FC). This review summarizes the evidence for utilizing CRP and FC for monitoring IBD during clinical remission and after surgical resection. Endoscopic correlation with CRP and FC is evaluated in each disease state. Advantages and drawbacks of each biomarker are discussed with special consideration of isolated ileal CD. Fecal immunochemical testing,traditionally used for colorectal cancer screening,is mentioned as a potential new alternative assay in the evaluation of IBD. Based on a mixture of information gleaned from biomarkers,clinical status,and endoscopic evaluation,the best treatment decisions can be made for the patient with IBD.     

Current evidence supporting mucosal healing and deep remission as important treatment goals for inflammatory bowel disease

Mucosal healing (MH) is now considered as a major treatment goal in clinical trials and clinical practice for patients with inflammatory bowel disease (IBD). MH is associated with sustained clinical remission, steroid-free remission, and reduced rates of hospitalization and surgery. There is a well-known disconnect between clinical symptoms and mucosal lesions that is more pronounced in CD. More stringent therapeutic goals have been discussed recently such as deep remission defined as clinical remission associated with MH. Recent international guidelines from the IOIBD recommended deep remission as a treatment goal in clinical practice. However there is no validated definition of deep remission in IBD. Also, the efficacy of available drugs to induce and maintain deep remission in IBD is poorly known. Finally, whether deep remission is the best way to modify the course of IBD and whether it should be achieved before considering drug de-escalation have to be formally evaluated in upcoming disease-modification trials.     

Serum Ghrelin Levels in Inflammatory Bowel Disease with Relation to Disease Activity and Nutritional Status

Ghrelin possesses various biological activities -- it stimulates growth hormone (GH) release, plays a major role in energy metabolism, and is one of the hormones that affects body composition. It also plays a role in modulating immune response and inflammatory processes. In this study we aimed to determine whether serum ghrelin levels had correlation with markers associated with disease activation. We also investigated any probable relationship between serum ghrelin level and nutritional status. Serum levels of ghrelin and its relationship with disease activity and nutritional status were evaluated in 34 patients with ulcerative colitis (UC), 25 patients with Crohn's disease (CD), and 30 healthy controls. Serum ghrelin levels, serum IGF-1 and GH levels, and markers of disease activity (sedimentation, C-reactive protein, and fibrinogen) were measured in all subjects. Body composition and nutritional status was assessed by both direct (by anthropometry) and indirect (by bioimpedance) methods. Serum ghrelin levels were significantly higher in patients with active UC and CD than in those in remission (108 +/- 11 pg/ml vs. 71 +/- 13 pg/ml for UC patients, P < 0.001; 110 +/- 10 pg/ml vs. 75 +/- 15 pg/ml for CD patients, P < 0.001). Circulating ghrelin levels in UC and CD patients were positively correlated with sedimentation, fibrinogen and CRP and was negatively correlated with IGF-1, BMI, TSFT, MAC, fat mass (%), and fat free mass (%). This study demonstrates that patients with active IBD have higher serum ghrelin levels than patients in remission and high levels of circulating ghrelin correlate with the severity of disease and the activity markers. Ghrelin levels in inflammatory bowel disease (IBD) patients show an appositive correlation with IGF-1 and bioelectrical impedance analysis, body composition, and anthropometric assessments. Finally, we arrived at the conclusion that ghrelin level may be important in determination of the activity in IBD patients and evaluation of nutritional status.     

糖皮质激素治疗炎症性肠病的相关问题

目前炎症性肠病（IBD）的发病机制尚未完全明确,各种治疗方法虽各有利弊,但均未能达到彻底治愈的理想效果。糖皮质激素（GC）是治疗中-重度和暴发性IBD的有效药物,但不能长期维持炎症缓解,且耐药和毒副作用使GC在临床上的应用受到限制。本文就GC治疗IBD的作用机制、GC耐药、GC制剂布地奈德的应用等作-综述。     

Risk of impaired nutritional status and flare occurrence in IBD outpatients

BackgroundInflammatory bowel disease (IBD) patients are at risk of an impaired nutritional status. The impact thereof on the IBD relapse risk is clinically relevant, though sparsely investigated.AimThe aim was to explore the association between an impaired nutritional status risk and the occurrence of disease flares in IBD outpatients participating in a longitudinal telemedicine study.MethodsIBD outpatients were recruited from the myIBDcoach study cohort, with one year clinical follow-up. Through myIBDcoach, a telemedicine tool, patients reported on disease activity and risk of impaired nutritional status (i.e. Short Nutritional Assessment Questionnaire >1 and/or BMI < 18.5 kg/m²) every one to three months. Data was analysed by generalized estimating equation modelling.ResultsIn total, 417 patients were included. During follow-up, 49 patients (11.8%) flared after initial clinical remission and 53 patients (12.7%) showed an increased risk of impaired nutritional status. The risk of impaired nutritional status was associated with flare occurrence (OR 2.61 (95% CI 1.02–6.69)).ConclusionsThe risk of an impaired nutritional status was associated with subsequent flares in IBD outpatients. This emphasizes the importance of monitoring disease activity in IBD patients at risk of impaired nutritional status.     

炎症性肠病治疗目标的演变

炎症性肠病(IBD)目前发病机制未明,可能与环境、遗传、感染、免疫等多种因素有关。IBD的治疗目标最初为临床缓解,随着基础研究进展及新型生物制剂的临床广泛实践,推荐黏膜愈合作为炎症性肠病的重要治疗目标,最近深度缓解作为一个新的治疗目标被提出,在国外已被广泛接受并应用于疾病评估,本文主要介绍炎症性肠病治疗目标的演变及黏膜愈合、深度缓解作为IBD治疗目标的重要意义。     

Nutritional Treatments in Inflammatory Bowel Disease

Opinion statement  

Nutritional Therapy in Very Early-Onset Inflammatory Bowel Disease: A Case Report

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract caused by a dysregulated immune response to the fecal microbiota. Very early-onset inflammatory bowel disease (VEO-IBD) refers to a subgroup of pediatric patients with IBD diagnosed before 6 years of age. This subgroup is often characterized by increased severity, aggressive progression, strong family history of IBD, and often poor response to conventional treatments. Nutritional therapies have been utilized to treat IBD, but their role in VEO-IBD is unclear. Disease behavior in VEO-IBD is often different from disease in adolescents and adults, as it is often restricted to the colon and refractory to standard medical therapies. Up to 25% of VEO-IBD patients have an identified underlying immunodeficiency, which may impact response to therapy. While specific mutations in interleukin 10 (IL-10), the IL-10 receptor (IL-10R), and mutations in NCF2, XIAP, LRBA, and TTC7 have been identified in VEO-IBD, polymorphisms in these genes are also associated with increased risk of developing IBD in adolescence or adulthood. We describe two cases in which infants presenting with VEO-IBD achieved clinical remission using exclusive enteral nutrition, a formula-based diet which has been shown to induce remission in older children with active Crohn’s disease.

     

Histological scores in inflammatory bowel disease

The role of histology in inflammatory bowel disease (IBD) has not yet been well defined. Endoscopic mucosal healing has been proposed as a predictor of the clinical course of IBD and it is indeed considered one of the main therapeutic targets. However, it does not necessarily imply histological healing. Histological remission has been reported to be associated with a better clinical outcome than endoscopic remission only in IBD patients. These observations support the view that histology plays a role as a potential therapeutic target in Crohn's disease and ulcerative colitis. Histological scores being able to quantify the degree of microscopic activity are needed for this purpose. In the era of biologics, indication for proper treatment may benefit from the assessment of clinical and endoscopic activity, as well as histological scores. Such scores may allow us to quantify the microscopic mucosal response to treatment and to define complete healing in IBD. A validated histological score in IBD may lead to the definition of microscopic activity in clinical practice, trials and investigational settings. Several attempts to develop such scores have been reported, but few are currently used and none is applied worldwide in clinical practice. The present review summarizes the main histological scores currently used for assessing IBD activity.     

Advances in nutritional therapy in inflammatory bowel diseases: Review

Inflammatory bowel diseases(IBD), including ulcerative colitis and Crohn's disease are chronic, life-long, and relapsing diseases of the gastrointestinal tract. Currently, there are no complete cure possibilities, but combined pharmacological and nutritional therapy may induce remission of the disease. Malnutrition and specific nutritional deficiencies are frequent among IBD patients, so the majority of them need nutritional treatment, which not only improves the state of nutrition of the patients but has strong anti-inflammatory activity as well. Moreover, some nutrients, from early stages of life are suspected as triggering factors in the etiopathogenesis of IBD. Both parenteral and enteral nutrition is used in IBD therapy, but their practical utility in different populations and in different countries is not clearly established, and there are sometimes conflicting theories concerning the role of nutrition in IBD. This review presents the actual data from research studies on the influence of nutrition on the etiopathogenesis of IBD and the latest findings regarding its mechanisms of action. The use of both parenteral and enteral nutrition as therapeutic methods in induction and maintenance therapy in IBD treatment is also extensively discussed. Comparison of the latest research data, scientific theories concerning the role of nutrition in IBD, and different opinions about them are also presented and discussed. Additionally, some potential future perspectives for nutritional therapy are highlighted.     

Drug Therapy of Inflammatory Bowel Disease in Fertile Women

Inflammatory bowel disease (IBD) is a disease that affects women of childbearing age. Active disease at conception increases the risk for adverse outcomes and thus postponement of pregnancy until the disease is in remission is the best advice that physicians can give their IBD patients. The majority of medications used to treat IBD are safe in pregnancy and breastfeeding; active, untreated, or undertreated disease is more deleterious than active therapy.     

Hyperhomocysteinaemia,Coagulation Pathway Activation and Thrombophilia in Patients with Inflammatory Bowel Disease

Background : The 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C → T polymorphism encoding the thermolabile variant is, when present as homozygote type (TT variant), a known genetic cause of mild hyperhomocysteinaemia (HHCY). This polymorphism has been observed in increased numbers in patients with inflammatory bowel disease (IBD). Coagulation and fibrinolysis are activated in patients with active IBD, but it is not known whether raised plasma homocysteine (HCY) found in patients with IBD significantly contributes to this activation. The aim of this study was to investigate if HHCY or presence of the TT variant significantly induces a hypercoagulable state in IBD patients receiving anti-inflammatory therapy during active disease, and to study if genetic determinants for thromboembolic disease are more frequent in these patients. Methods : The study was designed as a cross-sectional study in an outpatient clinic comprising 106 IBD patients receiving anti-inflammatory therapy. Markers of coagulation were measured in order to elucidate whether patients with HHCY or the MTHFR TT variant were hypercoagulant compared with patients with no impairment of HCY metabolism. In addition, markers of inflammation and acute-phase reactants were measured in order to compare activity during active disease and during remission. Genetic determinants of thromboembolic disease in patients with IBD and in relevant controls were investigated in the expectation of a more frequent occurrence of these markers of thrombophilia if hypercoagulability could be a primary or contributory factor in IBD. Results : No significant difference could be found in coagulation activity, acute-phase reactants or inflammatory markers in IBD patients with the TT variant of the 677C → T polymorphism or high (>15 μmol/L) plasma HCY levels, compared with IBD patients with no impairment of HCY metabolism. In patients with IBD, the coagulation activity was significantly increased during active disease compared with a state of remission. As expected, a significant difference regarding interleukin 6, C-reactive protein and erythrocyte sedimentation rate was present in IBD, comparing active disease with a state of remission. No significant complement activation was present in either of the groups or during active disease. Neither of the allele frequencies of genetic determinants for thrombophilia (coagulation factor V 1691G → A (factor V Leiden) and factor II 20210G → A polymorphisms) in the background population differed significantly from that in IBD patients. Conclusions : This study found no correlation between the MTHFR TT variant or HHCY and a hypercoagulable state in IBD patients receiving anti-inflammatory treatment. This coagulation activity is high during exacerbations of disease, but a considerable reduction is seen in patients on anti-inflammatory therapy compared with non-treated patients. Coagulation activation in IBD is probably a consequence of the inflammatory nature of the disease. That thrombophilia could be a contributory or primary factor in the development of IBD is not supported by the present study, as the frequencies for the genetic determinants for thrombophilia are similar in IBD patients and controls.     

炎症性肠病患者硫嘌呤甲基转移酶与嘌呤类药物毒副反应的关系

背景：嘌呤类药物广泛用于炎症性肠病（IBD）患者的诱导缓解和维持治疗,然而毒副反应的频繁发生使其临床应用受到限制。有研究显示检测硫嘌呤甲基转移酶（TPMT）活性和基因型能预测硫唑嘌呤（AZA）相关的毒副反应。目的：评价TPMT活性和基因型与AZA治疗IBD的毒副反应的关系。方法：收集2008年10月～2010年12月于上海仁济医院确诊并接受AZA治疗（每日1（？）kg）的78例IBD患者。采用高效液相色谱法（HPLC）检测TPMT活性,以直接测序和PCR法检测TPMT基因型。分析TPMT活性和基因型与AZA毒副反应的关系。结果：共19例患者发生毒副反应,包括4例血液学毒副反应。78例IBD患者的平均TPMT活性为（36.10±10.11）nmol 6-MTG·gHb~（-1）·h~（-1）。低TPMT活性组与高TPMT活性组发生总毒副反应和血液学毒副反应的OR值分别为6.82（95%CI：0.58～79.91）和12.00（95%CI：0.84～172.22）,但差异均无统计学意义。仅1例患者发生TPMT＊3C杂合子突变,突变率为1.3%,且该例患者发生了血液学毒副反应。结论：IBD患者的TPMT活性降低和基因突变与嘌呤类药物的总毒副反应和血液学毒副反应可能相关,但其临床实际应用价值有待进一步研究。     

Histopathological assessment of the microscopic activity in inflammatory bowel diseases: What are we looking for?

Advances in diagnostics of inflammatory bowel diseases (IBD) and improved treatment strategies allowed the establishment of new therapeutic endpoints. Currently, it is desirable not only to cease clinical symptoms, but mainly to achieve endoscopic remission, a macroscopic normalization of the bowel mucosa. However, up to one-third of IBD patients in remission exhibit persisting microscopic activity of the disease. The evidence suggests a better predictive value of histology for the development of clinical complications such as clinical relapse, surgical intervention, need for therapy escalation, or development of colorectal cancer. The proper assessment of microscopic inflammatory activity thus became an important part of the overall histopathological evaluation of colonic biopsies and many histopathological scoring indices have been established. Nonetheless, a majority of them have not been validated and no scoring index became a part of the routine bioptic practice. This review summarizes a predictive value of microscopic disease activity assessment for the subsequent clinical course of IBD, describes the most commonly used scoring indices for Crohn's disease and ulcerative colitis, and comments on current limitations and unresolved issues.     

Enteral diet in Crohn's disease. Nutritional and therapeutic implications in patient's management

Inflammatory bowel diseases (IBD) are often characterized by impairment of nutritional status. Crohn's disease (CD) patients, especially in the active phase of disease, show a reduced body weight, due to the reduction of lipid stores, in spite of lean mass depletion. Fat mass reduction has been correlated to an increased utilization of lipids as fuel substrate. The alterations of nutritional status are able, in turn, to influence, as independent factors, the disease course and patient prognosis. A disease's treatment based only on pharmacologic therapy, especially on corticosteroid use in the active phases, often does not take into account the relevant need for preserving a normal nutritional status. In this connection, enteral nutrition has been shown to be able to improve nutritional status and induce and maintain remission. We present some of the possible mechanisms of efficacy of enteral feeding and some rules to attempt to treat patients with IBD, especially those with Crohn's disease.     

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.