Sharyle Fowler

The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy

BACKGROUND & AIMS The management of inflammatory bowel disease (IBD) poses a particular challenge during pregnancy because the health of both the mother and the fetus must be considered. METHODS A systematic literature search identified studies on the management of IBD during pregnancy. The quality of evidence and strength of recommendations were rated using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. RESULTS Consensus was reached on 29 of the 30 recommendations considered. Preconception counseling and access to specialist care are paramount in optimizing disease management. In general, women on 5-ASA, thiopurine, or anti-tumor necrosis factor (TNF) monotherapy for maintenance should continue therapy throughout pregnancy. Discontinuation of anti-TNF therapy or switching from combination therapy to monotherapy may be considered in very select low-risk patients. Women who have a mild to moderate disease flare while on optimized 5-ASA or thiopurine therapy should be managed with systemic corticosteroid or anti-TNF therapy, and those with a corticosteroid-resistant flare should start anti-TNF therapy. Endoscopy or urgent surgery should not be delayed during pregnancy if indicated. Decisions regarding cesarean delivery should be based on obstetric considerations and not the diagnosis of IBD alone, with the exception of women with active perianal Crohns disease. With the exception of methotrexate, the use of medications for IBD should not influence the decision to breast-feed and vice versa. Live vaccinations are not recommended within the first 6 months of life in the offspring of women who were on anti-TNF therapy during pregnancy. CONCLUSIONS Optimal management of IBD before and during pregnancy is essential to achieving favorable maternal and neonatal outcomes.

SMAD3 gene variant is a risk factor for recurrent surgery in patients with Crohn's disease

BACKGROUND AND AIMS More than 80% of Crohns disease (CD) patients will require surgery. Surgery is not curative and rates of re-operation are high. Identification of genetic variants associated with repeat surgery would allow risk stratification of patients who may benefit from early aggressive therapy and/or post-operative prophylactic treatment. METHODS CD patients who had at least one CD-related bowel resection were identified from the Prospective Registry in IBD Study at Massachusetts General Hospital (PRISM). The primary outcome was surgical recurrence. Covariates and potential interactions were assessed using the Cox proportional hazard model. Kaplan-Meier curves for time to surgical recurrence were developed for each genetic variant and analyzed with the log-rank test. RESULTS 194 patients were identified who had at least 1 resection. Of these, 69 had two or more resections. Clinical predictors for repeat surgery were stricturing (HR 4.18, p=0.022) and penetrating behavior (HR 3.97, p=0.024). Smoking cessation was protective for repeat surgery (HR 0.45, p=0.018). SMAD3 homozygosity for the risk allele was also independently associated with increased risk of repeat surgery (HR 4.04, p=0.001). NOD2 was not associated with increased risk of surgical recurrence. CONCLUSION Stricturing and penetrating behavior were associated with increased risk of surgical recurrence, while smoking cessation was associated with a decreased risk. A novel association between SMAD3 and increased risk of repeat operation and shorter time to repeat surgery was observed. This finding is of particular interest as SMAD3 may represent a new therapeutic target specifically for prevention of post-surgical disease recurrence.

Efficacy and safety of natalizumab in Crohn's disease patients treated at 6 Boston academic hospitals.

Background:Despite trials demonstrating its efficacy, many physicians harbor concerns regarding the use of natalizumab in the treatment of patients with refractory Crohn’s disease (CD). The purpose of this study was to perform a descriptive analysis of a series of CD patients not currently enrolled in a clinical trial. Methods:A retrospective case review of patients treated with natalizumab at 6 sites in Massachusetts: Boston Medical Center, Beth Israel Deaconess Medical Center, Brigham & Women’s Hospital, Lahey Clinic, Massachusetts General Hospital, and UMass Medical Center. Results:Data on 69 CD patients on natalizumab were collected. At the start of treatment, patients’ disease duration was 12 years. A high proportion of patients were women (68%), presented with perianal disease (65%) and upper gastrointestinal tract involvement (14%). Prior nonbiologic therapies were steroids (96%), thiopurines (94%), antibiotics (74%), methotrexate (58%), and at least two anti-tumor necrosis factor agent failures (81%). Sixty-nine percent (44 of 64 patients) with available medical evaluation had a partial or complete clinical response. Loss of response was 13% after an average of 1 year of treatment. Adverse events were infusion reactions, headaches, fever, and infections. No case of progressive multifocal leukoencephalopathy was observed. Conclusions:In our clinical experience outside the context of a clinical trial, natalizumab is largely reserved for CD patients with extensive ileocolonic disease who have failed conventional immunosuppressants and of at least 2 anti-tumor necrosis factor agents. This drug is, however, well tolerated and offers significant clinical improvement for more than a year in one-third of these difficult-to-treat CD patients.

Effects of cancer treatment on inflammatory bowel disease remission and reactivation.

BACKGROUND & AIMS Little is known about the effects of cancer therapy for extraintestinal malignancy in patients with inflammatory bowel diseases (IBDs). METHODS We analyzed data from the Massachusetts General Hospital and the Brigham and Womens Hospital on 84 patients diagnosed with Crohns disease, ulcerative colitis, or indeterminate colitis found to have a solid malignant extraintestinal neoplasm between January 15, 1993, and December 15, 2011. We investigated the incidence of remission with cancer treatment (cytotoxic chemotherapy, hormone therapy, or both) among patients with active IBD (n = 15) and time to disease activation after cancer treatment of those with inactive disease (n = 69). Cox proportional hazards models and survival curves were constructed to identify independent predictors of these outcomes. RESULTS Among patients with active IBD at cancer diagnosis, 66.7% (n = 10/15) achieved remission during cancer treatment; the median duration of remission was 27 months. Ninety percent of these patients had received cytotoxic chemotherapy. For patients with IBD in remission at cancer diagnosis, 17.4% (n = 12/69) developed active IBD; the type of treatment was the strongest predictor of IBD reactivation. The risk of IBD reactivation was greatest among patients who received a combination of cytotoxic chemotherapy and adjuvant hormone therapy (hazard ratio, 12.25; 95% confidence interval, 1.51-99.06) or only hormone therapy (hazard ratio, 11.56; 95% confidence interval, 1.39-96.43). Ninety percent of patients who received cytotoxic chemotherapy remained in remission at 5 years compared with 64% of those who received only hormone therapy or the combination of cytotoxic chemotherapy and adjuvant hormone therapy (log rank, P = .02). CONCLUSIONS IBD is more likely to remit among patients who receive cytotoxic chemotherapy for solid malignancies than those who receive only hormone therapy or the combination of cytotoxic chemotherapy and adjuvant hormone therapy. Among patients with inactive IBD at the time of cancer diagnosis, hormonal therapy, alone or in combination with cytotoxic chemotherapy, increases the risk of IBD reactivation.

Protocol for a 24-Week Randomized Controlled Study of Once-Daily Oral Dose of Flax Lignan to Healthy Older Adults.

Background Increased oxidative stress and inflammation are associated with aging, and contribute to an increased risk of chronic disease in older adults. Flaxseed lignans demonstrate antioxidant and anti-inflammatory activity, but their ability to reduce oxidative stress and inflammation markers in older adult populations has received limited investigation. Objective This is a chronic intervention trial of community-dwelling healthy older adults to examine the effects of a flaxseed lignan (secoisolariciresinol diglucoside; SDG) enriched supplement (BeneFlax) compared to a placebo. The primary aim was to demonstrate the safety of BeneFlax and confirm its anti-inflammatory efficacy on markers of oxidative stress and inflammation, and subsequent functional outcomes, including those associated with its anti-inflammatory efficacy. A secondary aim was to determine flaxseed lignan metabolite concentrations in blood. Methods A double-blind randomized clinical trial was conducted. Subjects were healthy community-dwelling adults aged 60-80 years. Testing was performed at baseline, 8, 16, and 24 weeks. The 24-week intervention consisted of 600 milligrams (mg) of SDG daily or an equivalent amount (volume) of placebo. All participants received 1000 international units of vitamin D to ensure adequate vitamin D status. Measurements consisted of blood pressure, hematology, and tolerability for safety assessments; blood oxidative stress and inflammatory biomarkers for efficacy; and cognition, muscle strength, and pain as functional outcomes. Secondary endpoints of plasma levels of lignan metabolites were analyzed by mass spectrometry. Other tests, such as bone turnover markers and fecal levels of flax cyclolinopeptides, will be performed at a later date. Results Thirty-two participants were recruited (19 intervention and 13 control) and all completed the trial. Numerous Health Canada-imposed exclusion criteria limited recruitment success. Analyses are ongoing, but the baseline data available for a number of parameters indicate no differences between treatment groups. Safety measures (vital signs) did not change from baseline and were not significantly different between treatment and placebo groups at 24 weeks. Conclusions Preliminary results indicate that no safety concerns are associated with administering 600 mg SDG for 24 weeks to adults between the ages of 60 and 80 years. Trial Registration Clinicaltrials.gov NCT01846117; https://clinicaltrials.gov/ct2/show/NCT01846117 (Archived by WebCite at http://www.webcitation.org/6nlDZNjmA)

Metagenomic Characterization of Microbial Communities In Situ Within the Deeper Layers of the Ileum in Crohn’s Disease

Background & Aims Microbial dysbiosis and aberrant host–microbe interactions in the gut are believed to contribute to the development and progression of Crohn’s disease (CD). Microbiome studies in CD typically have focused on microbiota in feces or superficial mucosal layers of the colon because accessing DNA from deeper layers of the bowel is challenging. In this study, we analyzed the deep tissue microbiome in patients who underwent surgical resection of the small intestine. Methods Paraffin blocks were obtained from 12 CD patients undergoing ileocecal resection, and healthy ileum samples (inflammatory bowel disease–free controls) were obtained from 12 patients undergoing surgery for right-sided colon cancer. Diseased and healthy-appearing ileum was identified using microscopy, and paraffin blocks were macrodissected using a core needle to specifically isolate DNA. Illumina Whole Genome Sequencing was used for microbial sequence identification and subsequent taxonomic classification using the PathSeq tool. Results We observed significant differences between the microbiome of CD samples vs inflammatory bowel disease–free controls, including depletion of Bacteroidetes and Clostridia. Notably, microbial composition at the phyla level did not differ markedly between healthy and diseased areas of CD patients. However, we observed enrichment of potentially pathogenic organisms at the species level. Conclusions Our study showed dysbiosis within deeper layers of the ileum of CD patients, specifically enrichment of enterotoxigenic Staphylococcus aureus and an environmental Mycobacterium species not described previously. Future studies with larger cohort sizes are warranted to confirm these findings. Studies would benefit from effective microbial DNA extraction methods from paraffin sections and host nucleic acid depletion approaches to increase microbial read coverage.

Non-pharmacological therapies for inflammatory bowel disease: Recommendations for self-care and physician guidance

We performed a scoping review on sought-after complementary therapies for patients with inflammatory bowel disease (IBD), specifically diet, physical activity and exercise (PA/E), and psychotherapy. We aim to update patients with IBD on therapies for self-care and provide physicians with guidance on how to direct their patients for the management of IBD. A search of MEDLINE, EMBASE, and PUBMED was completed in Sept 2016. Studies on diet, PA/E, or psychotherapy in patients with IBD were included. Medical Subject Heading terms and Boolean operators were used. The search was limited to full-text English articles describing an adult population. This review included 67 studies: Diet (n = 19); PA/E (n = 19); and psychotherapy (n = 29). We have made the following recommendations: (1) Diet: Consumption of diets rich in vegetables, fruit and soluble fiber may be beneficial in IBD. A trial of a low FODMAP diet can be considered in those patients with functional gastrointestinal symptoms. Restrictive diets are lacking in evidence and should be avoided; (2) PA/E: Regular low-moderate intensity activity, including cardiovascular and resistance exercise, has been shown to improve quality of life (QOL) and may improve inflammation; and (3) psychotherapy: Therapies such as cognitive-behavioural interventions, mindfulness, hypnosis, and stress management have been shown to improve QOL, but evidence is limited on their impact on anxiety, depression, and disease activity. Overall, these complementary therapies are promising and should be used to treat patients with IBD from a more holistic perspective.

P297 Efficacy and safety of natalizumab in Crohn's disease patients treated at six academic Boston hospitals

immune cell populations was evaluated by flow cytometry. The impact of Ovasave on the proliferative response of patients’ PBMC to ovalbumin in vitro was also evaluated. Results: Mean age was 34.5 and disease duration 12.9 years. CD was predominantly ileo-colic (65%) with a baseline CDAI of 364±81 (n = 20) and IBDQ of 114±21 (n = 19); 19/20 had previous failure to immuno supressors and anti-TNF and 16 had previous CD related surgery. Ovasave injections were well tolerated with 54 adverse events (15 possibly and 2 definitely related) and 11 serious adverse events (3 possibly related), all recovered. Response was observed in 40% (8/20) patients at weeks 5 and 8. In the best dose group (10e6 cells), response was 75% (6/8) at both time points; remission was 38% (3/8) and 25% (2/8) and the mean CDAI reduction 143.4±105 (p = 0.0062) and 131.6.3±65.4 (p = 0.002) at weeks 5 and 8 respectively. CRP (mg/l) dropped significantly (p = 0.04) in responder ( 11.4±6.3) patients versus non-responders (5.2±4.2). Immunomonitoring studies revealed that blood CD16+ proinflammatory monocytes, one of the contributors of mucosal inflammation, were selectively decreased 3 weeks after Ovasave administration in the group of responder patients. In this group, the proliferative response of PBMC to ovalbumin in vitro was abolished 3 weeks after treatment, suggesting a direct suppression of ovalbumin-specific immune response. Conclusions: Treg cell therapy is well tolerated and shows a positive dose related efficacy in severe CD patients consistent across multiple assessment methods including mechanistic immunological measurements in patient’s blood.