Robert Hirten

Vedolizumab and Infliximab Combination Therapy in the Treatment of Crohn’s Disease

To the Editor: A 43-year-old man diagnosed with ileocolic Crohn’s disease (CD) at 19 years of age was evaluated in our offi ce. His course was complicated by an ileocolic resection in 2009 and treatment failures with 6-mercaptopurine, methotrexate, adalimumab, and certolizumab. He received infl iximab for 4 years, currently at a dose of 5 mg/kg every 4 weeks, and delayed release mesalamine. At the time of his infl iximab infusion he reported increasing diarrheal episodes with associated blood. Sigmoidoscopy revealed moderateto severe-ulcerated mucosa and exudates ( Figure 1a ). Given ongoing symptoms vedolizumab was initiated and infl iximab was discontinued ~5 weeks aft er his last infusion. Repeat sigmoidoscopy, 4 days aft er receiving vedolizumab, revealed minimal colonic ulcerations and an improved vascular pattern ( Figure 1b ). He reported 2–3 formed bowel movements daily with less urgency. Approximately 7 weeks aft er his last infl iximab infusion, and 10 days aft er starting vedolizumab, he developed erythema nodosum (EN). He received his ferent MSA patterns was observed, probably owing to small sample size. Neither a signifi cant association was detected with no extra hepatic autoimmune disease. We studied aft erwards an independent control group with hypertransaminasemia (>2s.d.) by IIF ( n =123). We observed that 8% ( n =10) showed anti-MSA autoAb vs. the 1.43% described overall. Not previously described, anti-MSA autoAb were associated with a high prevalence of hypertransaminasemia in two independent cohorts. Th ese preliminary fi ndings point to the possibility to identify a subgroup of hepatopathy patients with up to 75% with a cholestatic profi le, with autoimmune alterations. Further studies with wider samples’ number and followup design should be performed to warrant the clinical relevance of our preliminary results.

Adherent-invasive Escherichia coli in inflammatory bowel disease

Intestinal microbiome dysbiosis has been consistently described in patients with IBD. In the last decades, Escherichia coli, and the adherent-invasive E coli (AIEC) pathotype in particular, has been implicated in the pathogenesis of IBD. Since the discovery of AIEC, two decades ago, progress has been made in unravelling these bacteria characteristics and its interaction with the gut immune system. The mechanisms of adhesion of AIEC to intestinal epithelial cells (via FimH and cell adhesion molecule 6) and its ability to escape autophagy when inside macrophages are reviewed here. We also explore the existing data on the prevalence of AIEC in patients with Crohn’s disease and UC, and the association between the presence of AIEC and disease location, activity and postoperative recurrence. Finally, we highlight potential therapeutic strategies targeting AIEC colonisation of gut mucosa, including the use of phage therapy, bacteriocins and antiadhesive molecules. These strategies may open new avenues for the prevention and treatment of IBD in the future.

Combining Biologics in Inflammatory Bowel Disease and Other Immune Mediated Inflammatory Disorders

&NA; Current therapies used in the treatment of inflammatory bowel disease (IBD) are not effective in all patients. Biologic agents result in approximately 40% remission rates at 1 year in selected populations, prompting a growing interest in combining biologic therapy to improve outcomes. There are limited published data regarding the efficacy and safety of combination targeted therapy in IBD specifically, which include only 1 exploratory randomized control trial and 3 case reports or series. This review evaluates the published literature regarding this therapeutic paradigm in IBD and its extensive utilization in the treatment of other immune‐mediated inflammatory disorders. The combination of biologic therapies demonstrates variable degrees of efficacy and highlights some safety concerns, depending upon the agents used and the disease state treated. A trial (ClinicalTrials.gov Identifier: NCT02764762) combining vedolizumab and adalimumab is currently underway evaluating the effectiveness and safety of this approach in patients with Crohn’s disease, which should provide further insight into this treatment concept. While combination biologic therapy is an attractive strategy, the lack of consistent superior efficacy as well as safety concerns militates the need for further trials prior to its general application in IBD.

Endoscopic ultrasound-guided fine-needle aspiration of solid lesions on clopidogrel may not be a high-risk procedure for bleeding: A case series.

The major gastrointestinal endoscopy society guidelines list endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) as a high‐risk procedure for bleeding. However, there are no studies evaluating the risk of bleeding for EUS‐FNA of solid organs while patients continue to take clopidogrel. The aim of the present case series was to evaluate the rate of bleeding in a cohort of patients who underwent EUS‐FNA for solid lesions while on clopidogrel. Bleeding was measured at the time of the procedure by bleeding seen on EUS, endoscopic visualization of blood, or drop in hemoglobin after the procedure. From 2013 to 2015, 10 patients were identified for this case series. Lesions that underwent EUS‐FNA included gastric and rectal subepithelial lesions, pancreas masses, and liver masses. No immediate or delayed bleeding was observed in any of the patients. EUS‐FNA of solid lesions on clopidogrel may not be a high‐risk procedure for bleeding. Larger studies are needed to confirm this finding.

Hepatic manifestations of non-steroidal inflammatory bowel disease therapy.

Inflammatory bowel disease (IBD) is composed of Crohns disease and ulcerative colitis and is manifested by both bowel-related and extraintestinal manifestations. Recently the number of therapeutic options available to treat IBD has dramatically increased, with each new medication having its own mechanism of action and side effect profile. A complete understanding of the hepatotoxicity of these medications is important in order to distinguish these complications from the hepatic manifestations of IBD. This review seeks to evaluate the hepatobiliary complications of non-steroid based IBD medications and aide providers in the recognition and management of these side-effects.

Vedolizumab for Ulcerative Colitis: Treatment Outcomes from the VICTORY Consortium

OBJECTIVES: We aimed to quantify the safety and effectiveness of vedolizumab (VDZ) when used for UC, and to identify predictors of response to treatment. METHODS: Retrospective review (May 2014‐December 2016) of VICTORY Consortium data. Adults with follow‐up after starting VDZ for clinically active UC were included. Primary effectiveness outcomes were cumulative rates of clinical remission (resolution of all UC‐related symptoms) and endoscopic remission (Mayo endoscopic sub‐score 0). Key secondary effectiveness outcomes included cumulative rates of corticosteroid‐free remission and deep remission (clinical remission and endoscopic remission). Cox proportional hazard analyses were used to identify independent predictors of treatment effectiveness. Non‐response imputation (NRI) sensitivity analyses were performed for effectiveness outcomes. Key safety outcomes were rates of serious infection, serious adverse events, and colectomy. RESULTS: We included 321 UC patients (71% prior TNF&agr; antagonist exposure, median follow‐up 10 months). The 12‐month cumulative rates of clinical remission and endoscopic remission were 51% and 41%, respectively. Corresponding rates for corticosteroid‐free remission and deep remission were 37% and 30%, respectively. Using NRI, 12‐month rates were 20% (n = 64/321) for clinical remission, 17% (n=35/203) for endoscopic remission, 15% (n=30/195) for corticosteroid‐free remission, and 14% (n = 28/203) for deep remission. A majority of the patients without adequate follow‐up at 12 months who were deemed non‐responders using NRI had already achieved clinical remission (n = 70) or a significant clinical response (n=36) prior to 12 months. VDZ discontinuation prior to 12 months was observed in 91 patients, for lack of response (n =56), need for surgery (n=29), or adverse event (n=6). On multivariable analyses, prior exposure to a TNF&agr; antagonist was associated with a reduced probability of achieving clinical remission (HR 0.53, 95% CI 0.38–0.75) and endoscopic remission (HR 0.51, 95% CI 0.29–0.88). Serious adverse events and serious infections were reported in 6% and 4% of patients, respectively. Overall cumulative rates of colectomy over 12 months were 13%, with lower rates observed in patients naive to TNF&agr; antagonist therapy (2%) than those who had been exposed to TNF&agr; antagonists (19%). CONCLUSION: In this large real‐world cohort we observed that VDZ was well tolerated and effective in achieving key clinical outcomes.

Gut microbiota density influences host physiology and is shaped by host and microbial factors

To identify factors that regulate gut microbiota density and the impact of varied microbiota density on health, we assayed this fundamental ecosystem property in fecal samples across mammals, human disease, and therapeutic interventions. Physiologic features of the host (carrying capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohn’s disease, ulcerative colitis, and ileal pouch-anal anastomosis. The gut microbiota in recurrent Clostridium difficile infection had lower density and reduced fitness that were restored by fecal microbiota transplantation. Understanding the interplay between microbiota and disease in terms of microbiota density, host carrying capacity, and microbiota fitness provide new insights into microbiome structure and microbiome targeted therapeutics.

The Management of Intestinal Penetrating Crohn’s Disease

Crohns disease (CD) leads to the development of complications through progressive uncontrolled inflammation and the transmural involvement of the bowel wall. Most of the available literature on penetrating CD focuses on the perianal phenotype. The management of nonperianal penetrating complications poses its own set of challenges and can result in significant morbidity and an increased risk of mortality. Few controlled trials have been published evaluating this subgroup of patients for clinicians to use for guidance. Utilizing the available evidence, we review the epidemiology, presentation, and modalities used to diagnosis and assess intestinal fistulas, phlegmons, and abscesses. The literature regarding the medical, endoscopic, and surgical management options are reviewed providing physicians with a therapeutic framework to comprehensively treat these nonperianal penetrating complications. Through a multidisciplinary evidence-based approach to the complex sequela of CD outcomes can be improved and patients quality of life enhanced.10.1093/ibd/izx108_video1izx108_Video5754037501001.

EUS-guided botulinum toxin injection of the internal anal sphincter in anorectal outlet obstruction.

EUS-Guided Botulinum Toxin Injection of the Internal Anal Sphincter in Anorectal Outlet Obstruction

Overall Incidence of Hepatosplenic T Cell Lymphoma in Patients With Inflammatory Bowel Disease on Thiopurines: A Meta-Analysis of Three Population Based Studies

Background: Hepatosplenic T-cell lymphoma is a feared complication of thiopurine treatment for Inflammatory Bowel Disease. While estimates of the risk of Hepatosplenic T-cell lymphoma have been stated in the past, it has not been possible to calculate an estimated incidence as no population based studies of patients with IBD on thiopurines has yet reported a case of HSTCL. Aims: Here we aim to calculate the incidence of HSTCL via a meta-analysis of three population based studies of IBD patients taking thiopurine therapy. We also aim to calculate the relative risk of HSTCL. Methods: We included three population based studies in our analysis, a study from the UK, (Armstrong 2010 Am J of Gastro), one from France (CESAME; Beaugerie 2009 Lancet), and one from Spain (Gisbert Gastro 2010). In our study data were extracted from the Spanish collaborative registry ENEIDA (of which the Gisbert study was published). We examined overall incidence, the incidence in men, those less than 36 years old, and men under 36 years old. 95% confidence intervals (CIs) were estimated by summing observed and expected cases of lymphoma. CIs assumed a Poisson distribution. To examine for heterogeneity, the deviance statistic from Poisson regression models was examined. All patient studies were in compliance with the Helsinki Protocol. Results: One case of HSTCL was present among the three studies, (in ENEIDA). The overall incidence was 1.32 cases per 100,000 person-years with a number needed to harm (NNH) of 1:75,488 patients per year. For men, the incidence was 2.69 cases per 100,000 person-years with an NNH of 1:37,208 per year, and in those under 36 years of age the incidence was 3.63 cases per 100,000 person years with an NNH of 1:27,528. In men under 36, the incidence was 7.93 cases per 100,000 person years with an NNH of 1:12,616 patients per year. Confidence intervals were very large secondary to only one patient being described and there was no significant heterogeneity (see Table 1). Conclusion: In a recent systematic review of HSTCL in IBD (Kotlyar 2010, Clin Gastroenterol Hepatol), while incidence could not be estimated, the absolute risk was estimated at being 1:44,444 overall and 1:7404 in men under 35. These estimates accord with calculated numbers needed to harm of 1:75,488 per year overall and 1:12,616 per year in men under 36. Confidence Interval for Incidence and Tests for Heterogeneity