Evaluation of inflammatory activity in Crohn's disease and ulcerative colitis

Crohn's disease and ulcerative colitis evolve with a relapsing and remitting course. Determination of inflammatory state is crucial for the assessment of disease activity and for tailoring therapy. However, no simple diagnostic test for monitoring intestinal inflammation is available. Noninvasive markers give only indirect assessments of disease activity. Histopathological or endoscopical examinations accurately assess inflammatory activity, but they are invasive, time consuming and expensive and therefore are unsuitable for routine use. Imaging procedures are not applicable for ulcerative colitis. The usefulness of ultrasound and Doppler imaging in assessing disease activity is still a matter of discussion for Crohn's disease, and an increased interest in computed tomography enterograph (CTE) has been seen, mainly because it can delineate the extent and severity of bowel wall inflammation, besides detecting extraluminal findings. Until now, the available data concerning the accuracy of magnetic resonance enterography in detecting disease activity is less than CTE. Due to this, clinical activity indices are still commonly used for both diseases.     

Laboratory markers in ulcerative colitis: Current insights and future advances

Ulcerative colitis(UC)and Crohn’s disease(CD)are the major forms of inflammatory bowel diseases(IBD)in man.Despite some common features,these forms can be distinguished by different genetic predisposition,risk factors and clinical,endoscopic and histological characteristics.The aetiology of both CD and UC remains unknown,but several evidences suggest that CD and perhaps UC are due to an excessive immuneresponse directed against normal constituents of the intestinal bacterial flora.Tests sometimes invasive are routine for the diagnosis and care of patients with IBD.Diagnosis of UC is based on clinical symptoms combined with radiological and endoscopic investigations.The employment of non-invasive biomarkers is needed.These biomarkers have the potential to avoid invasive diagnostic tests that may result in discomfort and potential complications.The ability to determine the type,severity,prognosis and response to therapy of UC,using biomarkers has long been a goal of clinical researchers.We describe the biomarkers assessed in UC,with special reference to acute-phase proteins and serologic markers and thereafter,we describe the new biological markers and the biological markers could be developed in the future:(1)serum markers of acute phase response:The laboratory tests most used to measure the acute-phase proteins in clinical practice are the serum concentration of C-reactive protein and the erythrocyte sedimentation rate.Other biomarkers of inflammation in UC include platelet count,leukocyte count,and serum albumin and serum orosomucoid concentrations;(2)serologic markers/antibodies:In the last decades serological and immunologic biomarkers have been studied extensively in immunology and have been used in clinical practice to detect specific pathologies.In UC,the presence of these antibodies can aid as surrogate markers for the aberrant host immune response;and(3)future biomarkers:The development of biomarkers in UC will be very important in the future.The progress of molecular biology tools(microarrays,proteomics and nanotechnology)have revolutionised the field of the biomarker discovery.The advances in bioinformatics coupled with cross-disciplinary collaborations have greatly enhanced our ability to retrieve,characterize and analyse large amounts of data generated by the technological advances.The techniques available for biomarkers development are genomics(single nucleotide polymorphism genotyping,pharmacogenetics and gene expression analyses)and proteomics.In the future,the additionof new serological markers will add significant benefit.Correlating serologic markers with genotypes and clinical phenotypes should enhance our understanding of pathophysiology of UC.     

Emerging role of novel biomarkers in the diagnosis of inflammatory bowel disease

There is currently no gold standard test for the diagnosis of inflammatory bowel disease(IBD). Physicians must rely on a number of diagnostic tools including clinical and endoscopic evaluation as well as histologic, serologic and radiologic assessment. The real difficulty for physicians in both primary and secondary care is differentiating between patients suffering from functional symptoms and those with true underlying IBD. Alongside this, there is always concern regarding the possibility of a missed, or delayed diagnosis of ulcerative colitis(UC) or Crohn's disease. Even once the diagnosis of IBD has been made, there is often uncertainty in distinguishing between cases of UC or Crohn's. As a consequence, in cases of incorrect diagnosis, optimal treatment and management may be adversely affected. Endoscopic evaluation can be uncomfortable and inconvenient for patients. It carries significant risks including perforation and in terms of monetary cost, is expensive. The use of biomarkers to help in the diagnosis and differentiation of IBD has been increasing over time. However, there is not yet one biomarker, which is sensitive of specific enough to be used alone in diagnosing IBD. Current serum testing includes C-reactive protein and erythrocyte sedimentation rate, which are cheap, reliable but non-specific and thus not ideal. Stool based testing such as faecal calprotectin is a much more specific tool and is currently in widespread clinical use. Noninvasive sampling is of the greatest clinical value and with the recent advances in metabolomics, genetics and proteomics, there are now more tools available to develop sensitive and specific biomarkers to diagnose and differentiate between IBD. Many of these new advances are only in early stages of development but show great promise for future clinical use.     

Crohn’s and colitis in children and adolescents

Crohn’s disease and ulcerative colitis can be grouped as the inflammatory bowel diseases (IBD). These conditions have become increasingly common in recent years, including in children and young people. Although much is known about aspects of the pathogenesis of these diseases, the precise aetiology is not yet understood, and there remains no cure. Recent data has illustrated the importance of a number of genes-several of these are important in the onset of IBD in early life, including in infancy. Pain, diarrhoea and weight loss are typical symptoms of paediatric Crohn’s disease whereas bloody diarrhoea is more typical of colitis in children. However, atypical symptoms may occur in both conditions: these include isolated impairment of linear growth or presentation with extra-intestinal manifestations such as erythema nodosum. Growth and nutrition are commonly compromised at diagnosis in both Crohn’s disease and colitis. Consideration of possible IBD and completion of appropriate investigations are essential to ensure prompt diagnosis, thereby avoiding the consequences of diagnostic delay. Patterns of disease including location and progression of IBD in childhood differ substantially from adult-onset disease. Various treatment options are available for children and adolescents with IBD. Exclusive enteral nutrition plays a central role in the induction of remission of active Crohn’s disease. Medical and surgical therapies need to considered within the context of a growing and developing child. The overall management of these chronic conditions in children should include multi-disciplinary expertise, with focus upon maintaining control of gut inflammation, optimising nutrition, growth and quality of life, whilst preventing disease or treatment-related complications.     

Frequency and associated factors of hair loss among patients with inflammatory bowel disease

AIM: To identify the frequency of hair loss among patients with inflammatory bowel disease(IBD) and associated clinical and disease related factors.METHODS: We performed a cross sectional study in a tertiary referral adult IBD clinic.Self-reported history and characteristics of hair loss as well as clinical and demographic information were collected.Data were analyzed using univariate and multivariate analyses.RESULTS: Two hundred and ten consecutive IBD patients were recruited; one hundred and fifty patients met predefined inclusion and exclusion criteria.Thirtythree percent of patients reported a history of hair loss.Age,gender,IBD type and disease duration were not associated with hair loss.Hair loss was reported less frequently among patients with use of mesalamine(54% vs 73%,P = 0.03) and antitumor necrosis factor medications(anti-TNF)(14% vs 40%,P = 0.001).In multivariate analyses adjusting for gender,IBD type and duration of disease,these associations with mesalamine and anti-TNF remained significant [(adjusted values for mesalamine(OR = 0.43,95%CI: 0.19-0.86) and anti-TNFs(OR = 0.28,95%CI: 0.08-0.98)].CONCLUSION: Hair loss is common among patients with IBD.Mesalamine and anti-TNF medications were associated with lower odds of hair loss.Further studies are required to assess the mechanism of hair loss among patients with IBD.     

Contribution of the IL-17/IL-23 axis to the pathogenesis of inflammatory bowel disease

Inflammatory bowel diseases(IBDs) are chronic disorders of modern society, requiring management strategies aimed at prolonging an active life and establishing the exact etiology and pathogenesis.These idiopathic diseases have environmental, genetic,immunologic, inflammatory, and oxidative stress components. On the one hand, recent advances have shown that abnormal immune reactions against the microorganisms of the intestinal flora are responsible for the inflammation in genetically susceptible individuals. On the other hand, in addition to T helper cell-type(Th) 1 and Th2 immune responses,other subsets of T cells, namely regulatory T cells and Th17 maintained by IL-23 are likely to develop IBD. IL-23 acts on innate immune system members and also facilitates the expansion and maintenance of Th17 cells. The IL-17/IL-23 axis is relevant in IBD pathogenesis both in human and experimental studies. Novel biomarkers of IBD could be calprotectin,microRNAs, and serum proinflammatory cytokines.An efficient strategy for IBD therapy is represented by the combination of IL-17 A and IL-17 F in acute IL-17 A knockout TNBS-induced colitis, and also definite decrease of the inflammatory process in IL-17 F knockout, DSS-induced colitis have been observed.Studying the correlation between innate and adaptive immune systems, we hope to obtain a focused reviewin order to facilitate future approaches aimed at elucidating the immunological mechanisms that control gut inflammation.     

Relationship between pouch microbiota and pouchitis following restorative proctocolectomy for ulcerative colitis

Restorative proctocolectomy with ileal pouch-anal anastomosis(IPAA)has become the surgical treatment of choice for many patients with medically refractory ulcerative colitis(UC)and familial adenomatous polyposis(FAP).UC patients with IPAA(UC-IPAA)are,nevertheless,susceptible to inflammatory and noninflammatory sequelae such as pouchitis,which is only rarely noted in FAP patients with IPAA.Pouchitis is the most frequent long-term complication of UC-IPAA patients,with a cumulative prevalence of up to 50%.Although the aetiology of pouchitis remains unclear,accumulating evidence suggests that a dysbiosis of the pouch microbiota and an abnormal mucosal immune response are implicated in its pathogenesis.Studies using culture and molecular techniques have detected a dysbiosis of the pouch microbiota in patients with pouchitis.Risk factors,genetic associations,and serological markers suggest that interactions between the host immune response and the pouch microbiota underlie the aetiology of this idiopathic inflammatory condition.This systematic review focuses on the dysbiosis of the microbiota that inhabit the pouch in UC and FAP patients and its interaction with the mucosal immune system.A metaanalysis was not attempted due to the highly heterogeneous microbiota composition and the different detection methods used by the various studies.Although no specific bacterial species,genus,or family has as yet been identified as pathogenic,there is evidence that a dysbiosis characterized by decreased gut microbiota diversity in UC-IPAA patients may,in genetically predisposed subjects,lead to aberrant mucosal immune regulation triggering an inflammatory process.     

Vaccines and recommendations for their use in inflammatory bowel disease

The patient with inflammatory bowel disease will be predisposed to numerous infections due their immune status. It is therefore important to understand the immune and serologic status at diagnosis and to put the patient into an adapted vaccination program. This program would be applied differently according to two patient groups: the immunocompromised and the non-immunocom-promised. In general, the first group would avoid the use of live-virus vaccines, and in all cases, inflammatory bowel disease treatment would take precedence over vaccine risk. It is important to individualize vaccination schedules according to the type of patient, the treatment used and the disease pattern.In addition, patient with inflammatory bowel disease should be considered for the following vaccines: varicella vaccine, human papilloma virus, influenza, pneumococcal polysaccharide vaccine and hepatitis B vaccine.     

Biomarkers in inflammatory bowel diseases:Current status and proteomics identification strategies

Unambiguous diagnosis of the two main forms of inflammatory bowel diseases(IBD):Ulcerative colitis(UC)and Crohn’s disease(CD),represents a challenge in the early stages of the diseases.The diagnosis may be established several years after the debut of symptoms.Hence,protein biomarkers for early and accurate diagnostic could help clinicians improve treatment of the individual patients.Moreover,the biomarkers could aid physicians to predict disease courses and in this way,identify patients in need of intensive treatment.Patients with low risk of disease flares may avoid treatment with medications with the concomitant risk of adverse events.In addition,identification of disease and course specific biomarker profiles can be used to identify biological pathways involved in the disease development and treatment.Knowledge of disease mechanisms in general can lead to improved future development of preventive and treatment strategies.Thus,the clinical use of a panel of biomarkers represents a diagnostic and prognostic tool of potentially great value.The technological development in recent years within proteomic research(determination and quantification of the complete protein content)has made the discovery of novel biomarkers feasible.Several IBD-associated protein biomarkers are known,but none have been successfully implemented in daily use to distinguish CD and UC patients.The intestinal tissue remains an obvious place to search for novel biomarkers,which blood,urine or stool later can be screened for.When considering the protein complexity encountered in intestinal biopsysamples and the recent development within the field of mass spectrometry driven quantitative proteomics,a more thorough and accurate biomarker discovery endeavor could today be performed than ever before.In this review,we report the current status of the proteomics IBD biomarkers and discuss various emerging proteomic strategies for identifying and characterizing novel biomarkers,as well as suggesting future targets for analysis.     

Increasing thirty-day readmissions of Crohn’s disease and ulcerative colitis in the United States: A national dilemma

BACKGROUNDThe prevalence of Crohn’s disease (CD) and ulcerative colitis (UC) is on the rise worldwide. This rising prevalence is concerning as patients with CD and UC may frequently relapse leading to recurrent hospitalizations and increased healthcare utilization.AIMTo identify trends and adverse outcomes for 30 d readmissions for CD and UC. METHODSThis was a retrospective, interrupted trends study involving all adult (≥ 18 years) 30 d readmissions of CD and UC from the National Readmission Database (NRD) between 2008 and 2018. Patients < 18 years, elective, and traumatic hospitalizations were excluded from this study. We identified hospitalization characteristics and readmission rates for each calendar year. Trends of inpatient mortality, mean length of hospital stay (LOS) and mean total hospital cost (THC) were calculated using a multivariate logistic trend analysis adjusting for age, gender, insurance status, comorbidity burden and hospital factors. Furthermore, trends between CD and UC readmissions were compared using regression of the interaction coefficient after adjusting for age and gender to determine relative trends between the two populations. Stata^® Version 16 software (StataCorp, TX, United States) was used for statistical analysis and P value ≤ 0.05 were considered statistically significant. RESULTSTotal number of 30 d readmissions increased from 6202 in 2010 to 7672 in 2018 for CD and from 3272 in 2010 to 4234 in 2018 for UC. We noted increasing trends for 30-day all-cause readmission rate of CD from 14.9% in 2010 to 17.6% in 2018 (P-trend < 0.001), CD specific readmission rate from 7.1% in 2010 to 8.2% in 2018 (P-trend < 0.001), 30-day all-cause readmission rate of UC from 14.1% in 2010 to 15.7% in 2018 (P-trend = 0.003), and UC specific readmission rate from 5.2% in 2010 to 5.6% in 2018 (P-trend = 0.029). There was no change in the risk adjusted trends of inpatient mortality and mean LOS for CD and UC readmissions. However, we found an increasing trend of mean THC for UC readmissions. After comparison, there was no statistical difference in the trends for 30 d all-cause readmission rate, inpatient mortality, and mean LOS between CD and UC readmissions.CONCLUSIONThere was an increase in total number of 30 d readmissions for CD and UC with a trend towards increasing 30 d all-cause readmission rates.     

Canadian Digestive Health Foundation Public Impact Series. Inflammatory bowel disease in Canada: Incidence, prevalence, and direct and indirect economic impact

The Canadian Digestive Health Foundation initiated a scientific program to assess the incidence, prevalence, mortality and economic impact of digestive disorders across Canada in 2009. The current article presents the updated findings from the study concerning inflammatory bowel diseases - specifically, Crohn's disease and ulcerative colitis.     

Minimally invasive approaches for the treatment of inflammatory bowel disease

Despite significant improvements in medical management of inflammatory bowel disease, many of these patients still require surgery at some point in the course of their disease. Their young age and poor general conditions, worsened by the aggressive medical treatments, make minimally invasive approaches particularly enticing to this patient population. However, the typical inflammatory changes that characterize these diseases have hindered wide diffusion of laparoscopy in this setting, currently mostly pursued in high-volume referral centers, despite accumulating evidences in the literature supporting the benefits of minimally invasive surgery. The largest body of evidence currently available for terminal ileal Crohn’s disease shows improved short term outcomes after laparoscopic surgery, with prolonged operative times. For Crohn’s colitis, high quality evidence supporting laparoscopic surgery is lacking. Encouraging preliminary results have been obtained with the adoption of laparoscopic restorative total proctocolectomy for the treatment of ulcerative colitis. A consensus about patients’ selection and the need for staging has not been reached yet. Despite the lack of conclusive evidence, a wave of enthusiasm is pushing towards less invasive strategies, to further minimize surgical trauma, with single incision laparoscopic surgery being the most realistic future development.     

Role of wireless capsule endoscopy in inflammatory bowel disease

Capsule endoscopy (CE) offers state-of-the-art imaging of the small bowel. In Crohn's disease its clinical role is still uncertain. This report analyses the usefulness of CE in patients with suspected Cronh's disease, in patients with established Crohn's disease (when assessing severity, occult gastrointestinal bleeding and/or as a guide to therapy), in patients with inflammatory bowel disease unclassified (IBDU), and in individuals with ulcerative colitis. The first item in this group is the most important although there is no strong evidence to establish the position of CE in the diagnostic workup. In patients with established Crohn's disease, recently developed activity scores are promising tools for an accurate assessment of severity. As a guide to therapy, CE should be focused on patients with unexplained symptoms when other investigations are inconclusive. In postoperative Crohn's Disease, international consensus recommended considering CE only if ileocolonoscopy is contraindicated or unsuccessful. In the case of IBDU, studies have shown a significant proportion of patients reclassified with Crohn's disease. In this setting, CE could have a role determining small bowel involvement. The role of CE in ulcerative colitis is limited. Some authors advocate CE before colectomy for refractory cases in order to exclude Crohn's disease. In summary, CE offers a new horizon in inflammatory bowel disease, and a better knowledge of mucosal abnormalities that could offer a paradigm shift: changing from symptom-based disease activity estimation to direct mucosal healing monitoring. Nevertheless, randomized controlled studies are still needed to provide stronger evidence in this setting.     

Trefoil factors in inflammatory bowel disease

Inflammatory bowel disease(IBD),which comprises ulcerative colitis and Crohn’s disease,is characterized by inflammation of the gastrointestinal tract.The trefoil factors 1,2,and 3(TFF1-3)are a family of peptides that play important roles in the protection and repair of epithelial surfaces,including the gastrointestinal tract.TFFs may be involved in IBD pathogenesis and are a potential treatment option.In the present review,we describe the TFF family and their potential role in IBD by summarizing the current knowledge of their expression,possible function and pharmacological role in IBD.     

Diagnosis and management of functional symptoms in inflammatory bowel disease in remission

Inflammatory bowel disease(IBD) patients in remission may suffer from gastrointestinal symptoms that resemble irritable bowel syndrome(IBS). Knowledge on this issue has increased considerably in the last decade, and it is our intention to review and summarize it in the present work. We describe a problematic that comprises physiopathological uncertainties, diagnostic difficulties, as IBS-like symptoms are very similar to those produced by an inflammatory flare, and the necessity of appropriate management of these patients, who, although in remission, have impaired quality of life. Ultimately, from almost a philosophical point of view, the presence of IBS-like symptoms in IBD patients in remission supposes a challenge to the traditional functional-organic dichotomy, suggesting the need for a change of paradigm.     

Pulmonary manifestations of inflammatory bowel disease

Extraintestinal manifestations of inflammatory bowel disease(IBD) are a systemic illness that may affect up to half of all patients. Among the extraintestinal manifestations of IBD, those involving the lungs are relatively rare and often overlooked. However, there is a wide array of such manifestations, spanning from airway disease to lung parenchymal disease, thromboembolic disease, pleural disease, enteric-pulmonary fistulas, pulmonary function test abnormalities, and adverse drug reactions. The spectrum of IBD manifestations in the chest is broad, and the manifestations may mimic other diseases. Although infrequent, physicians dealing with IBD must be aware of these conditions, which are sometimes life-threatening, to avoid further health impairment of the patients and to alleviate their symptoms by prompt recognition and treatment. Knowledge of these manifestations in conjunction with pertinent clinical data is essential for establishing the correct diagnosis and treatment. The treatment of IBD-related respiratory disorders depends on the specific pattern of involvement, and in most patients, steroids are required in the initial management. Corticosteroids, both systemic and aerosolized, are the mainstay therapeutic approach, while antibiotics must also be administered inthe case of infectious and suppurative processes, whose sequelae sometimes require surgical intervention.     

Cytomegalovirus in inflammatory bowel disease: A systematic review

AIM: To identify definitions of cytomegalovirus(CMV) infection and intestinal disease, in inflammatory bowel disease(IBD), to determine the prevalence associated with these definitions.METHODS: We conducted a systematic review and interrogated Pub Med, EMBASE and Cochrane for literature on prevalence and diagnostics of CMV infection and intestinal disease in IBD patients. As medical headings we used "cytomegalovirus" OR "CMV" OR "cytomegalo virus" AND "inflammatory bowel disease" OR "IBD" OR "ulcerative colitis" OR "colitis ulcerosa" OR "Crohn's disease". Both Me SH-terms and free searches were performed. We included all types of English-language(clinical) trials concerning diagnostics and prevalence of CMV in IBD.RESULTS: The search strategy identified 924 citations, and 52 articles were eligible for inclusion. We identified 21 different definitions for CMV infection, 8 definitions for CMV intestinal disease and 3 definitions for CMV reactivation. Prevalence numbers depend on used definition, studied population and region. The highest prevalence for CMV infection was found when using positive serum PCR as a definition, whereas for CMV intestinal disease this applies to the use of tissue PCR 10 copies/mg tissue. Most patients with CMV infection and intestinal disease had steroid refractory disease and came from East Asia.CONCLUSION: We detected multiple different definitions used for CMV infection and intestinal disease in IBD patients, which has an effect on prevalence numbers and eventually on outcome in different trials.     

Pregnancy related issues in inflammatory bowel disease: evidence base and patients' perspective

Inflammatory bowel disease (IBD) affects women of childbearing age and can influence fertility, pregnancy and decisions regarding breastfeeding. Women with IBD need to consider the possible course of disease during pregnancy, the benefits and risks associated with medications required for disease management during pregnancy and breastfeeding and the effects of mode of delivery on their disease. When indicated, aminosalicylates and thiopurines can be safely used during pregnancy. Infliximab and Adalimumab are considered probably safe during the first two trimesters. During the third trimester the placenta can be crossed and caution should be applied. Methotrexate is associated with severe teratogenicity due to its folate antagonism and is strictly contraindicated. Women with IBD tend to deliver earlier than healthy women, but can have a vaginal delivery in most cases. Caesarean sections are generally recommended for women with active perianal disease or after ileo-anal pouch surgery.While the impact of disease activity and medication has been addressed in several studies, there are minimal studies evaluating patients' perspective on these issues. Women's attitudes may influence their decision to have children and can positively or negatively influence the chance of conceiving, and their beliefs regarding therapies may impact on the course of their disease during pregnancy and/or breastfeeding. This review article outlines the impact of IBD and its treatment on pregnancy, and examines the available data on patients' views on this subject.