Medical Therapy For Inflammatory Bowel Disease Research Articles

Systematic review: the association between the gut microbiota and medical therapies in inflammatory bowel disease.

The gut microbiota has been implicated in the pathogenesis of inflammatory bowel disease (IBD), with Faecalibacterium prausnitizii associated with protection, and certain genera (including Shigella and Escherichia) associated with adverse features. The variability of patient response to medical therapies in IBD is incompletely understood. Given the recognised contribution of the microbiota to treatment efficacy in other conditions, there may be interplay between the gut microbiota, IBD medical therapy and IBD phenotype. To evaluate the bidirectional relationship between IBD medical therapies and the gut microbiota. We conducted a systematic search of MEDLINE and EMBASE. All original studies analysing interactions between the gut microbiota and established IBD medical therapies were included. We screened 1296 records; 19 studies were eligible. There was heterogeneity in terms of sample analysis, treatment protocols, and outcome reporting. Increased baseline α-diversity was observed in responders versus non-responders treated with exclusive enteral nutrition (EEN), infliximab, ustekinumab or vedolizumab. Higher baseline Faecalibacterium predicted response to infliximab and ustekinumab. A post-treatment increase in Faecalibacterium prausnitzii was noted in responders to aminosalicylates, anti-TNF medications and ustekinumab; conversely, this species decreased in responders to EEN. Escherichia was a consistent marker of unfavourable drug response, and its presence in the gut mucosa correlated with inflammation in aminosalicylate-treated patients. Both gut microbiota diversity and specific taxonomic features (including high abundance of Faecalibacterium) are associated with the efficacy of a range of IBD therapies. These findings hold promise for a potential role for the gut microbiota in explaining the heterogeneity of patient response to IBD treatments.

Shining a Light on Skin Cancer in Inflammatory Bowel Disease: A Role for Prevention.

Risks of nonmelanoma skin cancer in patients with inflammatory bowel disease (IBD) have been well described. Newer data have classified risks of subsequent squamous cell carcinoma or basal cell carcinoma in patients with IBD after an initial skin cancer excision. In this editorial, risks of continuing medical therapy for IBD after a skin cancer diagnosis are discussed in the context of a holistic preventive care approach for patients with IBD.

P070 TRENDS AND CHARACTERISTICS OF CLINICAL TRIALS PARTICIPATION IN THE IBD PARTNERS COHORT

Abstract Background and Aims There are currently several recruitment challenges in randomized controlled trials (RCT) for inflammatory bowel disease (IBD) which prolong the drug approval process and affect the generalizability of study results. The purpose of this study is to characterize individuals who participate in IBD RCTs and identify factors which could influence future recruitment strategies. Methods We performed a cross-sectional study within the IBD Partners cohort comparing patients with current or prior participation in an interventional randomized controlled trial (RCT) of a medical therapy for IBD to those without any RCT participation. Bivariate statistics were used to compare RCT participation by IBD subtype and by other demographic and disease characteristics, and predictive modeling was used to identify factors predictive of RCT participation. We calculated the percent of the cohort that participated an in RCT during each calendar year from 2011–2018 and Clinicaltrials.gov was accessed to determine the number of active RCTs for IBD therapies per year during that same period. Results A total of 14,747 patients with IBD were included in the analysis and 1,116 (7.6%) reported RCT participation at any time. Demographic factors predictive of RCT participation (Table 1) included following at an academic institution (OR=1.8; 95%CI: 1.51–2.04) and age 36–75 (OR=1.6; 95%CI: 1.43–1.87). Patients with Crohn’s disease (CD) were more likely to participate than those with ulcerative colitis (UC) (OR=1.5; 95%CI: 1.35–1.77). Patients with more severe disease were more likely to participate, including those with prior IBD-related hospitalization (OR=2.6; 95%CI: 2.19–2.99), IBD-related surgery (OR=2.5; 95%CI: 2.24–2.87), biologic exposure (OR=3.2; 95%CI: 2.76–3.65), and “Poor” or worse quality of life (OR=1.7; 95%CI: 1.45–1.93). Steroid-free remission was associated with lower likelihood of RCT participation (OR=0.6; 95%CI: 0.53–0.70). While the number of active RCTs for IBD more than doubled between 2011 and 2018, RCT participation rates during that same time period decreased from 1.1% to 0.7% of the cohort (Figure 1). Conclusions RCT participation rates declined within this cohort between 2011–2018. Groups underrepresented in RCTs for IBD included younger patients, patients followed in community settings, and patients with more mild disease. The non-RCT group had mean sCDAI and SCCAI scores that did not meet remission thresholds, demonstrating populations in need of alternate therapies for whom clinical trials could be an option. Given anti-TNF exposure rates in this national cohort, studies should focus on anti-TNF failure populations. Investigators should make every effort to offer RCTs to all patients and network with community providers to increase awareness of RCTs.

P060 COMBINATION THERAPY WITH TNF-INHIBITORS AND IMMUNOMODULATORS ARE ASSOCIATED WITH SHORTER DURATION TO FIRST SERIOUS INFECTION – THE DEVELOP EXPERIENCE

DEVELOP is a multicenter, international, prospective, observational registry of the long-term safety and clinical status of 6070 pediatric patients (pts) with inflammatory bowel disease (IBD) diagnosed prior to 18 years of age who were treated with anti-tumor necrosis factor biologics (aTNF) and/or other medical therapies for IBD. Our aim was to assess the risk factors that lead to first serious infection (SI): an infection requiring hospitalization and/or IV therapy. Physicians participating in the registry prescribe IBD treatments based on their usual clinical practice and standards of care. Pts are categorized into cohorts according to their IBD medication exposure representing prevalent or incident exposure. The registry started enrollment in 2007 and completed enrollment in 2017. After the initial enrollment visit, data are obtained by the registry physician or designee every 6 months. SI data includes infections that occurred within 91 days of exposure to aTNF relative to non-biologics. The most recent available data cut (June 30 2018) includes 33586 patient years (PY) of follow up in the registry. The analysis of the stepwise Cox regression model for time to first SI among aTNF only pts relative to the non-biologics cohort included 3,566 Crohn’s disease (CD) pts who had at least 1 post-baseline follow-up visit, complete baseline covariate data, and complete disease severity data at event. Covariates that were significantly associated with a shorter duration of time to first SI within 91 days of aTNF exposure (Table 1) included: PCDAI Score (Moderate to Severe vs. Inactive) monotherapy with corticosteroids (CS) combination therapy with aTNF and immunomodulators (IMM), Hospitalization in the year prior to enrollment monotherapy with aTNF, PCDAI Score (Mild vs. Inactive) Female gender Time since IBD was diagnosed The analysis of the stepwise Cox regression model included 1063 ulcerative colitis (UC) pts who also had at least 1 post-baseline follow-up visit, complete baseline covariate data, and complete disease severity data at event. The covariates that were significantly associated with shorter duration of time to first SI (Table 2) included: Monotherapy with CS Monotherapy with aTNF Hospitalization in the year prior to enrollment Partial Mayo Score (Mild vs. Inactive) Combination therapy with aTNF and IMM In CD pts, combination therapy with aTNF/IMM, monotherapy with aTNF or CS, disease severity, recent hospitalization, gender, length of diagnosis and geographic region were all significantly associated with shorter duration of time to first SI. In UC pts, only monotherapy with aTNF or CS, combination therapy with aTNF and IMM, disease severity and recent hospitalization were significantly associated with shorter duration of time to first SI.

Ernährung und chronisch entzündliche Darmerkrankungen – ein Konsensus der Arbeitsgruppe chronisch entzündliche Darmerkrankungen der Österreichischen Gesellschaft für Gastroenterologie und Hepatologie (Austrian Guidelines for nutrition in IBD)

This is a consensus of the Austrian working group of IBD (inflammatory bowel diseases) of the ÖGGH on nutrition in IBD. Malnutrition should be assessed in case of IBD (in 20 - 70 % of Crohn's patients) and weight loss(> 5 % within 3 months) or nutritional deficiencies or after extensive bowel resection and afterwards also treated. Malnutrition should be treated with medical therapy of IBD and also adequate - as far as possible - with oral nutritional therapy particularly because of reduced life quality, risk of opportunistic infections, osteopenia/osteoporosis, longer hospitalisations and higher mortality. Iron homeostasis, serum levels of Vitamin B12- and folic acid, 25-hydroxyvitamin D and zinc should be checked. Therapy with enteral liquid diets is only indicated as therapy of first choice in children and adolescents, but only in rare situations in adults with IBD. There is - up to now - no proven oral diet for maintenance of remission in IBD. Probiotics as E. coli Nissle could be used as alternative to mesalazine for maintenance of remission in patients with ulcerative colitis. A specific dietary counselling is mandatory in patients with ileostoma or short bowel syndrome. Malnutrition of short bowel patients is particularly dependent on the function and length of the remaining bowel, therefore the most effective medical therapy should be administered.

The Effects of Race and Socioeconomic Status on Immunomodulator and Anti-Tumor Necrosis Factor Use among Ambulatory Patients With Inflammatory Bowel Disease in the United States

Health-care disparities exist for patients of minority race and low socioeconomic status (SES) in many chronic disease states, but little is known regarding health-care disparities for patients with inflammatory bowel disease (IBD). Using nationally representative data, we sought to determine whether use of immunomodulators and anti-tumor necrosis factor (TNF) agents differed by race/ethnicity and SES among ambulatory patients with IBD. We used data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey from 1998 to 2010. We identified visits associated with IBD and the medications associated with those visits. Race/ethnicity and SES were characterized. The frequency of immunomodulator and anti-TNF use over time was assessed. We performed analyses accounting for the survey's complex multistage probability sampling design. Associations between race/ethnicity, SES and IBD medication use were identified. A total of 26,400,000 visits for patients with IBD occurred in the United States from 1998 to 2010. Seventy-six per cent of visits were for whites, 9% were for blacks, 7% were for Hispanics, and 2% were for Asians. Sixty-one per cent of visits were privately insured, whereas 7% had Medicaid coverage. From 1998 to 2010, the proportion of visits associated with immunomodulators increased from 6 to 13%, whereas the proportion associated with anti-TNF agents increased from <1 to 14%. In adjusted analyses, visits with Medicaid were three times more likely to be associated with immunomodulators than visits with private insurance, but there were no race/ethnicity-based differences in immunomodulator use. There were no race/ethnicity- or SES-based differences in anti-TNF therapy. Using nationally representative data over a 13-year time period, we found no evidence of disparities in medical therapy for IBD among visits with minority race/ethnicity or low SES.

Limited Risks of Major Congenital Anomalies in Children of Mothers With IBD and Effects of Medications

Concerns persist about the risk of major congenital anomalies in children of women with inflammatory bowel disease (IBD), and whether medication use affects risk. We assessed these risks, and variations in use of medications by women with IBD before, during, and after pregnancy. We accessed data on children born to women 15-45 y old from 1990 through 2010, using a mother-child linked dataset from an electronic database of primary care records containing medical diagnoses, events, and drug prescriptions from across the United Kingdom. We identified pregnant women with IBD, and all prescriptions for 5-aminosalicylates azathioprine/6-mercaptopurine, and corticosteroids were extracted from their primary care records. We calculated risks of major congenital anomaly in children of mothers with and without IBD, and in children exposed or not exposed to 5-aminosalicylates, azathioprine/6-mercaptopurine, or corticosteroids during their first trimester of fetal development. Logistic regression with a generalized estimating equation was used to provide risk estimates adjusted for confounders. We calculated proportions of women taking medications before, during, and after pregnancy and assessed whether cessation was associated with subsequent disease flares. Risks of a major congenital anomaly in 1703 children of mothers with IBD and 384,811 children of mothers without IBD were 2.7% and 2.8%, respectively. This corresponded to an adjusted odds ratio of 0.98 (95% confidence interval [CI], 0.73-1.31). In children of women with IBD, the adjusted odds ratios of a major congenital anomaly associated with drug use were 0.82 (95% CI, 0.42-1.61) for 5-aminosalicylates 0.48 (95% CI, 0.15-1.50) for corticosteroids, and 1.27 (95% CI, 0.48-3.39) for azathioprine/6-mercaptopurine. No increases in heart, limb, or genital anomalies were found in children of women with IBD; 31.2% of women discontinued 5-aminosalicylates and 24.6% discontinued azathioprine/6-mercaptopurine in early pregnancy. The risk of flares later in pregnancy was not related to cessation of medication. We found no evidence that IBD during pregnancy or medical therapy for IBD during pregnancy increases the risk of a major congenital anomaly in children. Patients should receive appropriate guidance on use of medication before and during pregnancy.

1127 Infliximab in Steroid-Dependent Ulcerative Colitis: Efficacy and Predictors of Clinical and Endoscopic Remission

P247 Uptake in the UK of vaccination recommendations in inflammatory bowel disease (IBD) D. Burger1 *, W. Blad1, L. White1, A. Walsh2, S. Travis1. 1John Radcliffe Hospital, Gastroenterology Unit, Oxford, United Kingdom, 2St Vincent’s Hospital, Sydney, Australia Background: Vaccine preventable illness provides an opportunity for reducing infective complications associated with medical therapy for IBD. We examined patient uptake of vaccination recommendations based on ECCO guidelines. Methods: An A4-size vaccination checklist was introduced for routine clinic consultations at the IBD clinic, John Radcliffe Hospital, Oxford, with one copy each to the patient, GP, notes and research file. A covering letter explaining the initiative was given to patients and accompanied the recommendations to the GP. Patients were contacted by telephone 3 months after clinic review to audit the uptake of these recommendations. Results: 182 patients were screened with the vaccination checklist over a 3-month period (September November, 2010), with 146/182 (80%) follow up at 3 months. Median age was 39 (range 17 75), 64% female; 56% had Crohn’s disease, 35% ulcerative colitis and 9% IBD-U. 60/146 (41%) were taking immunomodulators and 39/146 (27%) anti-TNFa therapy. Of 146 respondents, vaccine uptake was 119 (82%) against influenza (including H1N1), 69 (47%) against Pneumococcus spp., and 50 (35%) against hepatitis B. No patients had serological evidence of past or current hepatitis B or Hepatitis C. Only 2 (1%) of patients did not have immunity to varicella. Qualitative feedback from primary care, identified barriers to hepatitis B and pneumococcal vaccination for this patient group, which are not currently endorsed by the UK Department of Health. Hepatitis B seroconversion data are in progress. Conclusions: Apart from influenza, there is low uptake of vaccination recommendations, with only a third of patients receiving hepatitis B vaccination. This may be due to the vaccination system in the UK, where patients with IBD are not explicitly included among those considered at risk.

Hepatobiliary disorders and complications of inflammatory bowel disease

One of typical examples of liver-gut cross talk is the interaction and impact of inflammatory bowel disease (IBD) and hepatobiliary (HB) abnormalities on each other's disease course. There are several layers of association between IBD and HB diseases: (i) HB diseases and IBD share pathogenetic mechanisms; (ii) HB diseases parallel structural and pathophysiological changes seen with IBD; and (iii) hepatic toxicity is associated with medical therapy for IBD. Interdisciplinary approach, involving gastroenterologists, hepatologists and, in advanced cases, general, colorectal, and liver transplant surgeons, is advocated.

Medical Therapy of IBD in the First Year After Diagnosis: Preliminary Results from the Ocean State Crohnʼs and Colitis Area Registry (OSCCAR)

Purpose: The Ocean State Crohn's and Colitis Area Registry (OSCCAR) is a novel population-based, prospective inception cohort of patients with inflammatory bowel disease (IBD) in Rhode Island. The frequency of medications used to treat IBD during the first year after diagnosis was analyzed with a focus on steroids, immunomodulators and biologics. Methods: Residents of Rhode Island with newly diagnosed Crohn's disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC) were eligible for enrollment beginning January 1, 2008. Diagnosis of IBD was confirmed using criteria from the NIDDK IBD Genetics Consortium. Individuals diagnosed before January 2008, unwilling to provide consent, and those imprisoned or pregnant at diagnosis were excluded. Research assistants collected demographic data, medical history and disease related information, quality of life and disease activity questionnaires, blood, urine and stool samples, with quarterly follow-up in the first year, then every 6 months. 97 of 98 gastroenterologists/colorectal surgeons in RI and 11 in MA agreed to refer patients. Practice billing data were queried and chart reviews were conducted to capture missed referrals. IRB approval was obtained. Results: For enrolled patients, medical therapy during the first year is summarized in tables 1 & 2. 5-ASA was the mainstay of therapy for UC, and a high rate of 5-ASA use was observed in CD. The rate of immunomodulator use was much higher in pediatric compared to adult patients (both CD and UC). CD patients were more likely to be on an immunomodulator or anti-TNF agent compared with UC patients. A substantial percentage of patients were started on anti-TNF therapy early after diagnosis. Conclusion: Among patients captured in this prospective, inception cohort from RI, different patterns of medication usage are seen in adult and pediatric patients, as well as in UC and CD. More than half of patients were exposed to steroids in the first year after diagnosis. A large portion of CD patients were on 5-ASA despite the lack of evidence supporting its use for this indication. Long term follow-up of these patients will yield insight into prescribing patterns and clinical effectiveness of various IBD therapies. Funding:CCFA/CDC 5U01DP000340-03 and NIH 1R21DK078555-02.Table: OSCCAR: medication use in patients with Crohn's diseaseTable: OSCCAR: medication use in patients with ulcerative colitis and indeterminant colitis

Drug therapy for inflammatory bowel disease in pregnancy and the puerperium

Inflammatory bowel disease (IBD) has a peak age of onset in the 3rd decade and a peak prevalent age in the fourth decade in most studies. As a result many patients affected by Crohn's disease and ulcerative colitis are females of reproductive age interested in bearing children. It has been shown that the most important factor in the success of a pregnancy in patients with IBD is the state of disease activity. Therefore, the goal prior to and during pregnancy is to best optimise control of the disease through medical therapy. Unfortunately, many medications utilised to treat IBD are potentially toxic and/or teratogenic, leaving many physicians and patients without a clear answer as to the safest methods of therapy. This review attempts to summarise the medical literature to date, as it pertains to the safety of medical therapy for IBD during pregnancy and the puerperium.

Levels of Peptidoleukotriene E4 Are Elevated in Active Crohn's Disease

Summary: Proinflammatory mediators, including leukotriene (LT) B4, are elevated in the intestinal mucosa in active chronic inflammatory bowel diseases (IBD). LTE4 is the major peptidoleukotriene metabolite and it is stable in urine. The aim of this study was to measure LTE4 levels in the urine of 27 children with Crohn's disease and 27 control subjects including 12 children with functional recurrent abdominal pain and 15 unaffected siblings of IBD patients. LTE4 levels were measured in urine using high‐performance liquid chromatography separation and radioimmunoassay with specific antibody. The Pediatric Crohn's Disease Activity Index and physician global assessment were used to categorize patient groups. C‐reactive protein, orosomucoid, and erythrocyte sedimentation rate were employed as laboratory markers of mucosal inflammation. Urinary LTE4 levels were elevated in the 13 children with active Crohn's disease (160.5 ± 59.4 pg/ml; mean ± SEM) compared with both levels in the 14 patients with inactive disease (67.1 ± 18.1 pg/ml; p &lt; 0.05) and controls (45.0 ± 10.9 pg/ml; p &lt; 0.05). We conclude that measurement of urinary LTE4 is a useful test for monitoring the activation of peptidoleukotrienes in patients with Crohn's disease. It provides a noninva‐sive, objective adjunct for assessment of disease activity and could be employed in future trials examining the role of the leukotriene inhibitors in the medical therapy of IBD.

Levels of peptidoleukotriene E4 are elevated in active Crohn's disease.

Proinflammatory mediators, including leukotriene (LT) B4, are elevated in the intestinal mucosa in active chronic inflammatory bowel diseases (IBD). LTE4 is the major peptidoleukotriene metabolite and it is stable in urine. The aim of this study was to measure LTE4 levels in the urine of 27 children with Crohn's disease and 27 control subjects including 12 children with functional recurrent abdominal pain and 15 unaffected siblings of IBD patients. LTE4 levels were measured in urine using high-performance liquid chromatography separation and radioimmunoassay with specific antibody. The Pediatric Crohn's Disease Activity Index and physician global assessment were used to categorize patient groups. C-reactive protein, orosomucoid, and erythrocyte sedimentation rate were employed as laboratory markers of mucosal inflammation. Urinary LTE4 levels were elevated in the 13 children with active Crohn's disease (160.5 +/- 59.4 pg/ml; mean +/- SEM) compared with both levels in the 14 patients with inactive disease (67.1 +/- 18.1 pg/ml; p < 0.05) and controls (45.0 +/- 10.9 pg/ml; p < 0.05). We conclude that measurement of urinary LTE4 is a useful test for monitoring the activation of peptidoleukotrienes in patients with Crohn's disease. It provides a noninvasive, objective adjunct for assessment of disease activity and could be employed in future trials examining the role of the leukotriene inhibitors in the medical therapy of IBD.

Chronic Inflammatory Bowel Disease.

Chronic inflammatory bowel disease (IBD) encompasses the disease entities, ulcerative colitis (UC) and Crohn's disease (CD). An aetiologic agent has not yet been defined and the diagnosis is based, therefore, on the sum of clinical, paraclinical, radiologic, endoscopic and histopathologic features. In recent years pathogenetic studies have focused on immune mechanisms, transmissible infectious agents, the potential role of the normal intestinal flora, dietary factors, enzymatic alterations and genetic features, in addition to vascular, neuromotor, allergic and psychologic factors. The corner stones in medical therapy of IBD are still corticosteroids and sulphasalazine (SAZ). The new oral salicylates, which are analogues of SAZ or "slow release" preparations of 5-aminosalicylic acid (mesalazine), have provided a therapeutic progress, because they are tolerated better than SAZ. Immunosuppressive agents, such as azathioprine and 6-mercaptopurine, reduce the requirement for corticosteroids and are effective in refractory CD, but the effect is delayed up to several months. The therapeutic action of cyclosporine A is not sustained, but often associated with side effects. Metronidazole has a beneficial effect on perineal disease. The efficacy of antimycobacterial drugs, sodium-cromoglycate, lidocaine, clonidine and sucralfate has been reported only in optimistic case stories and small open trials. A diet, rich in omega-3-fatty acids, modifies leukotriene (LT) production, but its clinical efficacy is insufficient. The first anti-leukotriene-drug, zileuton, has recently been evaluated and a significant, although insufficient, clinical response was obtained by a 70 per cent inhibition of rectal LTB4 synthesis. Dietary therapy may be useful as an adjunct to treatment of local complications in CD.(ABSTRACT TRUNCATED AT 250 WORDS)