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.     

Diet therapy for inflammatory bowel diseases: The established and the new

Although patients with inflammatory bowel diseases(IBD) have a strong interest in dietary modifications as part of their therapeutic management, dietary advice plays only a minor part in published guidelines. The scientific literature shows that dietary factors might influence the risk of developing IBD, that dysbiosis induced by nutrition contributes to the pathogenesis of IBD, and that diet may serve as a symptomatic treatment for irritable bowel syndrome-like symptoms in IBD. The role of nutrition in IBD is underscored by the effect of various dietary therapies. In paediatric patients with Crohn’s disease(CD) enteral nutrition(EN) reaches remission rates similar to steroids. In adult patients, however, EN is inferior to corticosteroids. EN is not effective in ulcerative colitis(UC). Total parenteral nutrition in IBD is not superior to steroids or EN. The use of specific probiotics in patients with IBD can be recommended only in special clinical situations. There is no evidence for efficacy of probiotics in CD. By contrast, studies in UC have shown a beneficial effect in selected patients. For patients with pouchitis, antibiotic treatment followed by probiotics, like VSL#3 or Lactobacillus GG, is effective. When probiotics are used, the risk of bacterial translocation and subsequent bacteremia has to be considered. More understanding of the normal intestinal microflora, and better characterization of probiotic strains at the phenotypic and genomic levels is needed as well as clarification of the mechanisms of action in different clinical settings. A FODMAP reduced diet may improve symptoms in IBD.     

Cardiovascular involvement in inflammatory bowel disease: dangerous liaisons

Increasing evidence of a link between inflammatory bowel disease(IBD) and adverse cardiovascular events has emerged during the last decade.In 2014,an important number of meta-analyses and cohort studies clarified the subtle dangerous liaisons between gut inflammation and cardiovascular pathology.The evidence suggests that patients with IBD have a significantly increased risk of myocardial infarction,stroke,and cardiovascular mortality,especially during periods of IBD activity.Some populations(e.g.,women,young patients) may have an even greater risk.Current effective treatment of IBD is aimed at disease remission and seems to reduce cardiovascular risk in these patients.A beneficial effect was demonstrated for salicylates,but not for steroids or azathioprine.tumor necrosis factor-α antagonists,which are highly effective in the reduction of inflammation and in the restoration of the digestive mucosa,lead to conflicting cardiovascular effects,as they seem to reduce the risk for ischemic heart disease but increase the rate of cerebrovascular events.Future supplemental treatment strategies that may reduce the atherothrombotic risk during periods of IBD activity should be explored.     

Hyperhomocysteinemia as a potential contributor of colorectal cancer development in inflammatory bowel diseases: A review

Homocysteine is an amino acid generated metabolically by the S-adenosylmethionine-dependent transmethylation pathway. In addition to being a well-known independent risk factor for coronary heart disease, is also a risk factor for cancer. Patients suffering from inflammatory bowel diseases(IBD) including ulcerative colitis and Crohn’s disease are at increased risk of developing colorectal cancer in comparison to healthy individuals. Furthermore, the risk of hyperhomocysteinaemia is significantly higher in IBD patients when compared with controls. In the present article, we review the mechanisms in which hyperhomocysteinemia may contribute to increased risk of colorectal cancer in IBD patients.     

Prevalence,predictors, and clinical consequences of medical adherence in IBD： How to improve it？

Inflammatory bowel diseases （IBD） are chronic diseases with a relapsing-remitting disease course necessitating lifelong treatment. However, non-adherence has been reported in over 40% of patients, especially those in remission taking maintenance therapies for IBD. The economical impact of non-adherence to medical therapy including absenteeism, hospitalization risk, and the health care costs in chronic conditions, is enormous. The causes of medication non-adherence are complex, where the patient-doctor relationship, treatment regimen, and other disease-related factors play key roles. Moreover, subjective assessment might underestimate adherence. Poor adherence may result in more frequent relapses, a disabling disease course, in ulcerative colitis, and an increased risk for colorectal cancer. Improving medication adherence in patients is an important challenge for physicians. Understanding the different patient types, the reasons given by patients for non-adherence, simpler and more convenient dosage regimens, dynamic communication within the health care team, a self-management package incorporating enhanced patient education and physician-patient interaction, and identifying the predictors of non-adherence will help devise suitable plans to optimize patient adherence. This editorial summarizes the available literature on frequency, predictors, clinical consequences, and strategies for improving medical adherence in patients with IBD.     

Predicting(side) effects for patients with inflammatory bowel disease: The promise of pharmacogenetics

Inflammatory bowel disease (IBD) is a chronic and heterogeneous intestinal inflammatory disorder. The medical management of IBD aims for long-lasting disease remission to prevent complications and disease progression. Early introduction of immunosuppression forms the mainstay of medical IBD management. Large inter-individual variability in drug responses, in terms of both efficacy and toxicity, leads to high rates of therapeutic failure in the management of IBD. Better patient stratification is needed to maximize patient benefit and minimize the harm caused by adverse events. Pre-treatment pharmacogenetic testing has the potential to optimize drug selection and dose, and to minimize harm caused by adverse drug reactions. In addition, optimizing the use of cheap conventional drugs, and avoiding expensive ineffective drugs, will lead to a significant reduction in costs. Genetic variation in both TPMT and NUDT15, genes involved in thiopurine metabolism, is associated to an increased risk of thiopurine-induced myelosuppression. Moreover, specific HLA haplotypes confer risk to thiopurine-induced pancreatitis and to immunogenicity to tumor necrosis factor-antagonists, respectively. Falling costs and increased availability of genetic tests allow for the incorporation of pre-treatment genetic tests into clinical IBD management guidelines. In this paper, we review clinically useful pharmacogenetic associations for individualized treatment of patients with IBD and discuss the path from identification of a predictive pharmacogenetic marker to implementation into IBD clinical care.     

Pharmacological- and non-pharmacological therapeutic approaches in inflammatory bowel disease in adults

Inflammatory bowel diseases(IBDs) are a group of chronic inflammatory conditions mainly of the colon and small intestine. Crohn's disease(CD) and ulcerative colitis(UC) are the most frequent types of IBD. IBD is a complex disease which arises as a result of the interaction of environmental, genetic and immunological factors. It is increasingly thought that alterations of immunological reactions of the patients to their own enterable bacteria(microfilm) may contribute to inflammation. It is characterized by mucosal and sub mucosal inflammation, perpetuated by infiltration of activated leukocytes. CD may affect the whole gastrointestinal tract while UC only attacks the large intestine. The therapeutic goal is to achieve a steroidfree long lasting remission in both entities. UC has the possibility to be cured by a total colectomy, while CD never can be cured by any operation. A lifelong intake of drugs is mostly necessary and essential. Medical treatment of IBD has to be individualized to each patient and usually starts with anti-inflammatory drugs. The choice what kind of drugs and what route administered(oral, rectal, intravenous) depends on factors including the type, the localization, and severity of the patient's disease. IBD may require immune-suppression to control symptoms such as prednisolone, thiopurines, calcineurin or sometimes folic acid inhibitors or biologics like TNF-α inhibitors or anti-integrin antibodies. For both types of disease(CD, UC) the same drugs are available but they differ in their preference in efficacy between CD and UC as 5-aminosalicylic acid for UC or budesonide for ileocecal CD. As therapeutic alternative the main mediators of the disease, namely the activated pro-inflammatory cytokine producing leukocytes can be selectively removed via two apheresis systems(Adacolumn and Cellsorba) in steroid-refractory or dependent cases. Extracorporeal photopheresis results in an increase of regulatory B cells, regulatory CD8~+ T cells and T-regs Type 1. Both types of apheresis were able to induce clinical remission and mucosal healing accompanied by tapering of steroids.     

Why interleukin-10 supplementation does not work in Crohn’s disease patients

Inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) or ulcerative colitis are chronic intestina disorders, which are on the increase in "Westernised" countries. IBD can be caused by both genetic and environmental factors. Interleukin-10 (IL-10) is an immunoregulatory cytokine that has been identified as being involved in several diseases including IBD. Studies have shown that polymorphisms in the promoter region reduce serum levels of IL-10 and this reduction has been associated with some forms of IBD. Mouse models have shown promising results with IL-10 supplementation, as such IL-10 supplementation has been touted as being a possible alternative treatment for CD in humans. Clinical trials have shown that recombinant human IL-10 is safe and well tolerated up to a dose o 8 μg/kg. However, to date, the results of the clinica trials have been disappointing. Although CD activity was reduced as measured by the CD activity index IL-10 supplementation did not result in significantly reduced remission rates or clinical improvements when compared to placebo. This review discusses why IL-10supplementation is not effective in CD patients currently and what can be addressed to potentially make IL-10 supplementation a more viable treatment option in the future. Based on the current research we conclude that IL-10 supplementation is not a one size fits all treatment and if the correct population of patients is chosen then IL-10 supplementation could be of benefit.     

Advances in refractory ulcerative colitis treatment: A new therapeutic target,Annexin A2

Medical treatment has progressed significantly over the past decade towards achieving and maintaining clinical remission in patients with refractory ulcerative colitis(UC). Proposed mediators of inflammation in UC include pro-inflammatory cytokines such as tumor necrosis factor-α(TNF-α) and interleukin-2, and the cellsurface adhesive molecule integrin α4β7. Conventional therapeutics for active UC include 5-aminosalicylic acid, corticosteroids and purine analogues(azathioprine and 6-mercaptopurine). Patients who fail to respond to conventional therapy are treated with agents such as the calicineurin inhibitors cyclosporine and tacrolimus, the TNF-α inhibitors infliximab or adalimumab, or a neutralizing antibody(vedolizumab) directed against integrin α4β7. These therapeutic agents are of benefit for patients with refractory UC, but are not universally effective. Our recent research on TNF-α shedding demonstrated that inhibition of annexin(ANX) A2 may be a new therapeutic strategy for the prevention of TNF-α shedding during inflammatory bowel disease(IBD) inflammation. In this review, we provide an overview of therapeutic treatments that are effective and currently available for UC patients, as well as some that are likely to be available in the near future. We also propose the potential of ANX A2 as a new molecular target for IBD treatment.     

Preventing infective complications in inflammatory bowel disease

Over the past decade there has been a dramatic change in the treatment of patients with Crohn’s disease and ulcerative colitis,which comprise the inflammatory bowel diseases(IBD).This is due to the increasing use of immunosuppressives and in particular the biological agents,which are being used earlier in the course of disease,and for longer durations,as these therapies result in better clinical outcomes for patients.This,however,has the potential to increase the risk of opportunistic and serious infections in these patients,most of which are preventable.Much like the risk for potential malignancy resulting from the use of these therapies long-term,a balance needs to be struck between medication use to control the disease with minimization of the risk of an opportunistic infection.This outcome is achieved by the physician’s tailored use of justified therapies,and the patients’education and actions to minimize infection risk.The purpose of this review is to explore the evidence and guidelines available to all physicians managing patients with IBD using immunomodulating agents and to aid in the prevention of opportunistic infections.     

New serological markers in pediatric patients with inflammatory bowel disease

The spectrum of serological markers associated with inflammatory bowel disease(IBD)is rapidly growing.Due to frequently delayed or missed diagnoses,the application of non-invasive diagnostic tests for IBD,as well as differentiation between ulcerative colitis(UC)and Crohn’s disease(CD),would be useful in the pediatric population.In addition,the combination of pancreatic autoantibodies and antibodies against Saccharomyces cerevisiae antibodies/perinuclear cytoplasmic antibody(pANCA)improved the sensitivity of serological markers in pediatric patients with CD and UC.Some studies suggested that age-associated differences in the patterns of antibodies may be present,particularly in the youngest children.In CD,most patients develop stricturing or perforating complications,and a significant numberof patients undergo surgery during the disease course.Based on recent knowledge,serum antibodies are qualitatively and quantitatively associated with complicated CD behavior and CD-related surgery.Pediatric UC is characterized by extensive colitis and a high rate of colectomy.In patients with UC,high levels of antiCBir1 and pANCA are associated with the development of pouchitis after ileal pouch-anal anastomosis.Thus,serologic markers for IBD can be applied to stratify IBD patients into more homogeneous subgroups with respect to disease progression.In conclusion,identification of patients at an increased risk of rapid disease progression is of great interest,as the application of early and more aggressive pharmaceutical intervention could have the potential to alter the natural history of IBD,and reduce complications and hospitalizations.     

Mucosal biomarkers in inflammatory bowel disease: Key pathogenic players or disease predictors?

Inflammatory bowel diseases(IBDs) are chronic inflammatory disorders of the bowel,including ulcerative colitis and Crohn's disease.A single etiology has not been identified,but rather the pathogenesis of IBD is very complex and involves several major and minor contributors,employing different inflammatory pathways which have different roles in different patients.Although new and powerful medical treatments are available,many are biological drugs or immunosuppressants,which are associated with significant si...     

Are we giving biologics too much time？ When should we stop treatment？

The optimal duration of biological treatment, particularly anti-TNF, in inflammatory bowel disease （IBD） is a very important question both for patients and physicians. There is no published evidence to clearly and definitely answer this question. However data on natural history of IBD, long term safety of biologics, immunosuppressors （IS） cessation and some preliminary studies on biologics cessation may help us to discuss this topic. The decision to stop a biological treatment is currently based on a compromise between the benefits and risks associated with the prolongation of this treatment. IBD, more particularly CD, are characterized by the development of complications and the need for recurrent hospitalizations and surgeries in approximately 2/3 of cases. In these patients potentially in need of biological treatments, it is probable that, as it has been demonstrated for IS, the longer a stable remission has be achieved under treatment, the lower the risk of relapse is alter treatment cessation. Further prospective studies should now aim at disclosing patient characteristics associated with a low risk of relapse to imple- ment this strategy.     

Anti-TNF alpha in the treatment of ulcerative colitis:A valid approach for organ-sparing or an expensive option to delay surgery?

Ulcerative colitis(UC)is an inflammatory bowel disease affecting large bowel with variable clinical course.The history of disease has been modified by the introduction of biologic therapy,in particular Infliximab(IFX),that has demonstrated efficacy in inducing fast symptoms remission,promoting mucosal healing and maintaining long-term remission.However,surgery is still needed for UC patients:in case of failure of medical therapy and if acute complications or a malignancy occurred.Surgical treatment is associated with a short-term postoperative mortality and morbidity respectively of 0%-4%and 30%.In this study we systematically analyzed:the role of IFX in reducing the colectomy rate,the risk of post-operative morbidity in pre-operatively IFX-treated patients and the cost-effectiveness of IFX therapy.Four of 5 analyzed randomized controlled trials demonstrated that therapy with IFX significantly reduces the colectomy rate.Moreover,pre-operative treatment with IFX doesn’t seem to increase post-operative infectious complications.By an economic point of view,the cost-effectiveness of IFX-therapy was demonstrated for UC patients suffering from moderate to severe UC in a study based on a cost estimation of the National Health Service of England and Wales.However,the argument is debated.     

Optimization of the treatment with immunosuppressants and biologics in inflammatory bowel disease

Many placebo controlled trials and meta-analyses evaluated the efficacy of different drugs for the treatment of inflammatory bowel disease(IBD),including immunosuppressants and biologics.Their use is indicated in moderate to severe disease in non responders to corticosteroids and in steroid-dependent patients,as induction and maintainance treatment.Infliximab,as well as cyclosporine,is considered a second line therapy in the case of severe ulcerative colitis,or non-responders to intravenous corticosteroids.An adequate dosage and duration of therapy with thiopurines should be reached before evaluating their efficacy.Methotrexate is a valid option in patients with Crohn’s disease but its use is confined to patients who are intolerant or non-responders to thiopurines.Evidence for the use of methotrexate in ulcerative colitis is insufficient.The use of thalidomide and mycophenolate mofetil is not recommended in patients with inflammatory bowel disease,these treatments could be considered in case of failure of all other therapeutic options.In patients with moderately active ulcerative colitis,refractory to thiopurines,the use of tacrolimus is considered an alternative to biologics.An increase of the dose or a decrease in the interval of administration of biologic treatment could be useful in the presence of an incomplete clinical response.In the case of primary failure of an anti-tumor necrosis factor alpha a switch to another one should be considered.Data on the efficacy of combination therapy are up to now insufficient to consider this strategy in all IBD patients.The final outcome of the treatment should be considered the clinical remission,with mucosa healing,and not the clinical response.The evaluation of serum concentration of thiopurine methyl transferase activity,thiopurine metabolites,biologic serum levels and antibiologic antibodies could be useful for the management of the treatment but it has not been routinely applied in clinical practice.The evidence of high risk development of lymphoma and cutaneous malignancies should be considered in patients treated with immunosuppressants and biologics for a long period.     

Inflammatory bowel disease:Epidemiology,pathology and risk factors for hypercoagulability

Hypercoagulability observed in patients with inflammatory bowel diseases(IBD)may lead to thromboembolic events(TE),which affect the venous and arterial systems alike and are an important factor in patients’morbidity and mortality.The risk of TE in IBD patients has been demonstrated to be approximately threefold higher as compared to the general population.The pathogenesis of thrombosis in IBD patients is multifactorial and not fully explained.The most commonly listed factors include genetic and immune abnormalities,disequilibrium between procoagulant and anticoagulant factors,although recently,the role of endothelial damage as an IBD-triggering factor is underlined.Several studies report that the levels of some coagulation enzymes,including fibrinogen,factorsⅤ,Ⅶ,Ⅷ,active factorⅪ,tissue factor,prothrombin fragment 1+2and the thrombin-antithrombin complex,are altered in IBD patients.It has been demonstrated that there is a significant decrease of tissue plasminogen activator level,a marked increase of plasminogen activator inhibitor type 1 and thrombin-activable fibrinolysis inhibitor,a significantly lower level of antithrombinⅢand tissue factor pathway inhibitor.IBD patients have been also observed to produce an increased amount of various anticoagulant antibodies.Hyperhomocysteinemia,which is a potential risk factor for TE was also observed in some IBD patients.Further studies are necessary to assess the role of coagulation abnormalities in IBD etiology and to determine indications for thromboprophylactic treatment in patients at high risk of developing TE.     

Has the risk of colorectal cancer in inflammatory bowel disease decreased?

The association between inflammatory bowel disease(IBD)and colorectal cancer(CRC)has been acknowledged for almost a century and is assumedly promoted by a chronic inflammation-driven carcinogenic process in the intestine in combination with a genetic predisposition.The magnitude of the risk of CRC in IBD remains a continuing subject of debate.The early,high risk estimates for CRC in IBD were most likely overestimated due to selected patient populations originating from tertiary referral centers with a disproportional high percentage of patients with severe disease.Later population-based studies calculating risk estimates from a broad spectrum of IBD patients have found the risk to be significantly lower.At present,there is evidence that IBD patients with longstanding and extensive disease with uncontrolled inflammation are those at increased risk.Additional,other recognized risk factors include early age at onset,family history of CRC,and concomitant primary sclerosing cholangitis.A significant amount of effort is put into identifying potential preventive factors of CRC in IBD,including surveillance programs and chemopreventive agents but the individual effect of these remains uncertain.Interestingly,recent studies have reported a decline in risk of CRC over time.Surveillance programs and the new treatment strategies,particular biological treatment might be part of the reason for the observed decline in risk of CRC in IBD over time but future studies will have investigate this assumption.     

Venous thrombosis and prothrombotic factors in inflammatory bowel disease

Patients with inflammatory bowel disease(IBD)may have an increased risk of venous thrombosis(VTE).PubMed,ISI Web of Knowledge and Scopus were searched to identify studies investigating the risk of VTE and the prevalence of acquired and genetic VTE risk factors and prothrombotic abnormalities in IBD.Overall,IBD patients have a two-to fourfold increased risk of VTE compared with healthy controls,with an overall incidence rate of 1%-8%.The majority of studies did not show significant differences in the risk of VTE between Crohn’s disease and ulcerative colitis.Several acquired factors are responsible for the increased risk of VTEin IBD:inflammatory activity,hospitalisation,surgery,pregnancy,disease phenotype(e.g.,fistulising disease,colonic involvement and extensive involvement)and drug therapy(mainly steroids).There is also convincing evidence from basic science and from clinical and epidemiological studies that IBD is associated with several prothrombotic abnormalities,including initiation of the coagulation system,downregulation of natural anticoagulant mechanisms,impairment of fibrinolysis,increased platelet count and reactivity and dysfunction of the endothelium.Classical genetic alterations are not generally found more often in IBD patients than in nonIBD patients,suggesting that genetics does not explain the greater risk of VTE in these patients.IBD VTE may have clinical specificities,namely an earlier first episode of VTE in life,high recurrence rate,decreased efficacy of some drugs in preventing further episodes and poor prognosis.Clinicians should be aware of these risks,and adequate prophylactic actions should be taken in patients who have disease activity,are hospitalised,are submitted to surgery or are undergoing treatment.     

Positioning of old and new biologicals and small molecules in the treatment of inflammatory bowel diseases

The past decade has brought substantial advances in the management of inflammatory bowel diseases(IBD). The introduction of tumor necrosis factor(TNF) antagonists, evidence for the value of combination therapy, the recog-nition of targeting lymphocyte trafficking and activation as a viable treatment, and the need for early treatment of high-risk patients are all fundamental concepts for current modern IBD treatment algorithms. In this article, authors review the existing data on approved biologicals and small molecules as well as provide insight on the current positioning of approved therapies. Patient stratification for the selection of specific therapies, therapeutic targets and patient monitoring will be discussed as well. The thera-peutic armamentarium for IBD is expanding as novel and more targeted therapies become available. In the absence of comparative trials, positioning these agents is becoming difficult. Emerging concepts for the future will include an emphasis on the development of algorithms which will facilitate a greater understanding of the positioning of novel biological drugs and small molecules in order to best tailor therapy to the patient. In the interim, anti-TNF therapy remains an important component of IBD therapy with the most real-life evidence and should be considered as first-line therapy in patients with complicated Crohn's disease and in acute-severe ulcerative colitis. The safety and efficacy of these ‘older' anti-TNF therapies can be optimized by adhering to therapeutic algorithms which combine clinical and objective markers of disease severityand response to therapy.