Clinical, serological and genetic predictors of inflammatory bowel disease course

Patients with extensive or complicated Crohn's disease (CD) at diagnosis should be treated straightaway with immunosuppressive therapy according to the most recent guidelines. In patients with localized and uncomplicated CD at diagnosis, early use of immunosuppressive therapy is debated for preventing disease progression and limiting the disabling clinical impact. In this context, there is a need for predictors of benign or unfavourable subsequent clinical course, in order to avoid over-treating with risky drugs those patients who would have experienced spontaneous mid-term asymptomatic disease without progression towards irreversible intestinal lesions. At diagnosis, an age below 40 years, the presence of perianal lesions and the need for treating the first flare with steroids have been consistently associated with an unfavourable subsequent 5-year or 10-year clinical course. The positive predictive value of unfavourable course in patients with 2 or 3 predictors ranges between 0.75 and 0.95 in population-based and referral centre cohorts. Consequently, the use of these predictors can be integrated into the elements that influence individual decisions. In the CD postoperative context, keeping smoking and history of prior resection are the strongest predictors of disease symptomatic recurrence. However, these clinical predictors alone are not as reliable as severity of early postoperative endoscopic recurrence in clinical practice. In ulcerative colitis (UC), extensive colitis at diagnosis is associated with unfavourable clinical course in the first 5 to 10 years of the disease, and also with long-term colectomy and colorectal inflammation-associated colorectal cancer. In patients with extensive UC at diagnosis, a rapid step-up strategy aiming to achieve sustained deep remission should therefore be considered. At the moment, no reliable serological or genetic predictor of inflammatory bowel disease clinical course has been identified.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Use of thiopurines in inflammatory bowel disease

The use of thiopurines as immunosuppression for the treatment of refractory or chronic active inflammatory bowel disease is established for both Crohn’s disease and ulcerative colitis.Nevertheless,many questions remain concerning the optimal treatment regimens of azathioprine,6-mercaptopurine and thioguanine.We will briefly summarize dose recommendations,indications for thiopurine therapy and side effects which are relevant in clinical practice.We discuss some currently debated topics,including the combination of azathioprine and allopurinol,switching of thiopurine therapy in case of side effects,the use of azathioprine in pregnancy,the infection risk using thiopurines and the evidence when to stop thiopurines.Excellent reviews have been published on the thiopurine metabolic pathway which will not be discussed here in detail.     

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.     

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.     

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.     

Immunosuppressive therapies for inflammatory bowel disease

Inflammatory bowel disease(IBD)is comprised of Crohn’s disease and ulcerative colitis,both chronic inflammatory intestinal disorders of unknown etiology characterized by a waxing and waning clinical course.For many years,the drug therapy was limited to sulfasalazine and related aminosalicylates,corticosteroids and antibiotics.Studies suggesting that the pathophysiology of these disorders relates to a disregulated,overactive immune response to indigenous bacteria have led to the increasing importance of immunosuppressive drugs for the therapy of IBD.This review details the mechanisms of action,clinical efficacy,and adverse effects of these agents.     

Quality of care delivered to hospitalized inflammatory bowel disease patients

Hospitalized patients with inflammatory bowel disease(IBD)are at high risk for morbidity,mortality,and health care utilization costs.While the literature on trends in hospitalization rates for this disease is conflicting,there does appear to be significant variation in the delivery of care to this complex group,which may be a marker of suboptimal quality of care.There is a need for improvement in identifying patients at risk for hospitalization in an effort to reduce admissions.Moreover,appropriate screening for a number of hospital acquired complications such as venous thromboembolism and Clostridium difficile infection is suboptimal.This review discusses areas of inpatient care for IBD patients that are in need of improvement and outlines a number of potential quality improvement initiatives such as payfor-performance models,quality improvement frameworks,and healthcare information technology.     

Case-control study of factors that trigger inflammatory bowel disease flares

AIM:To explore the association between inflammatory bowel diseases(IBD)flares and potential triggers.METHODS:Patients evaluated for an acute flare of IBD by a gastroenterologist at the Dallas VA Medical Center were invited to participate,as were a control group of patients with IBD in remission.Patients were systematically queried about nonsteroidal anti-inflammatory drug use,antibiotic use,stressful life events,cigarette smoking,medication adherence,infections,and travel in the preceding 3 mo.Disease activity scores were calculated for each patient at the time of enrollment and each patient’s chart was reviewed.Multivariate regression analysis was performed.RESULTS:A total of 134 patients with IBD(63 with Crohn’s disease,70 with ulcerative colitis,and 1 with indeterminate colitis)were enrolled;66 patients had flares of their IBD and 68 were controls with IBD in remission(for Crohn’s patients,average Crohn’s disease activity index was 350 for flares vs 69 in the controls;for UC patients,Mayo score was 7.6 for flares vs 1 for controls in those with full Mayo available and 5.4p for flares vs 0.1p for controls in those with partial Mayo score).Only medication non-adherence was significantly more frequent in the flare group than in the control group(48.5%vs 29.4%,P=0.03)and remained significant on multivariate analysis(OR=2.86,95%CI:1.33-6.18).On multivariate regression analysis,immunomodulator use was found to be associated with significantly lower rates of flare(OR=0.40,95%CI:0.19-0.86).CONCLUSION:In a study of potential triggers for IBD flares,medication non-adherence was significantly associated with flares.These findings are incentive to improve medication adherence.     

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.     

Histological healing in inflammatory bowel disease:A still unfulfilled promise

Treatment of inflammatory bowel disease(IBD) is traditionally based on several drugs,including salicylates,corticosteroids,and antibiotics;in addition,the therapeutic armamentarium has considerably evolved with the advent of newer,effective therapeutic measures(such as the biological agents) that are able to improve in a considerable manner both the clinical and endoscopic variables.Thus,mucosal healing,at least considered from an endoscopic point of view,is today regarded as the ultimate endpoint for treatment of these conditions.However,it is also increasingly clear that endoscopic healing is not necessarily paralleled by histological healing;There are few doubts that the latter should be considered as a true,objective healing and the ultimate goal to reach when treating patients with IBD.Unfortunately,and surprisingly,only a few,incomplete,and somewhat conflicting data exist on this topic,especially because there is still the need to standardize both histological assessment and the severity grading of these disorders;Issues that have not been yet been resolved for clinical practice and therapeutic trials.Hopefully,with the help of an increased awareness on the clinical researchers’ side,and the availability of dedicated pathologists on the other side,this matter will be effectively faced and resolved in the near future.     

Crucial steps in the natural history of inflammatory bowel disease

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic, progressive and disabling disorders. Over the last few decades, new therapeutic approaches have been introduced which have led not only to a reduction in the mortality rate but also offered the possibility of a favorable modification in the natural history of IBD. The identification of clinical, genetic and serological prognostic factors has permitted a better stratification of the disease, thus allowing the opportunity to indicate the most appropriate therapy. Early treatment with immunosuppressive drugs and biologics has offered the opportunity to change, at least in the short term, the course of the disease by reducing, in a subset of patients with IBD, hospitalization and the need for surgery. In this review, the crucial steps in the natural history of both UC and CD will be discussed, as well as the factors that may change their clinical course. The methodological requirements for high quality studies on the course and prognosis of IBD, the true impact of environmental and dietary factors on the clinical course of IBD, the clinical, serological and genetic predictors of the IBD course (in particular, which of these are relevant and appropriate for use in clinical practice), the impact of the various forms of medical treatment on the IBD complication rate, the role of surgery for IBD in the biologic era, the true magnitude of risk of colorectal cancer associated with IBD, as well as the mortality rate related to IBD will be stressed; all topics that are extensively discussed in separate reviews included in this issue of World Journal of Gastroenterology.     

Utility of faecal calprotectin analysis in adult inflammatory bowel disease

The inflammatory bowel diseases (IBD), Crohn’s disease and ulcerative colitis, are chronic relapsing, remitting disorders. Diagnosis, along with assessment of disease activity and prognosis present challenges to managing clinicians. Faecal biomarkers, such as faecal calprotectin, are a non-invasive method which can be used to aid these decisions. Calprotectin is a calcium and zinc binding protein found in the cytosol of human neutrophils and macrophages. It is released extracellularly in times of cell stress or damage and can be detected within faeces and thus can be used as a sensitive marker of intestinal inflammation. Faecal calprotectin has been shown to be useful in the diagnosis of IBD, correlates with mucosal disease activity and can help to predict response to treatment or relapse. With growing evidence supporting its use, over the last decade this faecal biomarker has significantly changed the way IBD is managed.     

Epidemiological and clinical characteristics of inflammatory bowel diseases in Cairo,Egypt

AIM:To study the natural history,patterns and clinical characteristics of inflammatory bowel diseases(IBD)in Egypt.METHODS:We designed a case-series study in the gastroenterology centre of the Internal Medicine department of Cairo University,which is a tertiary care referral centre in Egypt.We included all patients in whom the diagnosis of ulcerative colitis(UC)or Crohn’s disease(CD)was confirmed by clinical,laboratory,endoscopic,histological and/or radiological criteria over the 15 year period from 1995 to 2009,and we studied their sociodemographic and clinical characteristics.Endoscopic examinations were performed by 2 senior experts.This hospital centre serves patients from Cairo,as well as patients referred from all other parts of Egypt.Our centre received 24156 patients over the described time period for gastro-intestinal consultations and/or interventions.RESULTS:A total of 157 patients with established IBD were included in this study.Of these,135 patients were diagnosed with UC(86%of the total),and 22patients,with CD(14%of the total).The mean ages at diagnosis were 27.3 and 29.7,respectively.Strikingly,we noticed a marked increase in the frequency of both UC and CD diagnoses during the most recent 10 years of the 15 year period studied.Regarding the gender distribution,the male:female ratio was 1:1.15 for UC and 2.6:1 for CD.The mean duration of follow up for patients with UC was 6.2±5.18 years,while the mean duration of follow up for patients with CD was 5.52±2.83 years.For patients with UC we found no correlation between the severity of the disease and the presence of extraintestinal manifestations.Eleven patients had surgical interventions during the studied years:4cases of total colectomy and 7 cases of anal surgery.CONCLUSION:We observed a ratio of 6:1 for UC to CD in our series.The incidence of IBD seems to be rising in Egypt.