Garret Cullen

3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and Medical Management

This paper is the first in a series of two publications relating to the European Crohn’s and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohn’s disease and concerns the methodology of the consensus process, and the classification, diagnosis and medical management of active and quiescent Crohn’s disease. Surgical management as well as special situations including management of perianal Crohn’s disease of this ECCO Consensus are covered in a subsequent second paper [Gionchetti et al JCC 2016].

Long-term clinical results of ileocecal resection for Crohn's disease.

Background: The efficacy of biologic agents in Crohns disease (CD) has led to proposals that they be introduced early in the disease (top‐down treatment) with the aim of reducing corticosteroid dependency and surgical resection. However, the long‐term use of biologic agents in limited CD may be difficult to justify. The aims were to assess outcomes for ileocecal resection in CD and evaluate its role in the current era. Methods: The study included 139 CD patients who underwent ileocecal resection between 1980 and 2000. Data were retrieved from a prospectively maintained database. Disease recurrence was defined as symptoms in addition to endoscopic or radiological evidence of disease activity. Severe disease recurrence was defined as a need for repeat resection surgery. Results: Seventy‐two (52%) patients developed disease recurrence. Median (interquartile range) time to recurrence was 7.1 (5–10.6) years. Forty‐nine (35%) patients required repeat resection surgery. Median (IQ range) time to repeat surgery was 7.2 (4.9–10.8) years. The presence of granulomas was associated with disease recurrence (P = 0.03) and repeat resection surgery (P = 0.01). Conclusions: Long‐term outcomes for ileocecal resection in CD are excellent with 48% of patients remaining symptom‐free and only 35% requiring repeat resection surgery at 10 years. This should be borne in mind when considering biologic therapy.

DNA methylation profiling in inflammatory bowel disease provides new insights into disease pathogenesis

BACKGROUND AND AIMS Inflammatory bowel diseases (IBDs) are heterogeneous disorders with complex aetiology. Quantitative genetic studies suggest that only a small proportion of the disease variance observed in IBD is accounted for by genetic variation, indicating a potential role for differential epigenetic regulation in disease aetiology. The aim of this study was to assess genome-wide DNA methylation changes specifically associated with ulcerative colitis (UC), Crohns disease (CD) and IBD activity. METHODS DNA methylation was quantified in peripheral blood mononuclear cells (PBMCs) from 149 IBD cases (61 UC, 88 CD) and 39 controls using the Infinium HumanMethylation450 BeadChip. Technical and functional validation was performed using pyrosequencing and the real-time polymerase chain reaction. Cross-tissue replication of the top differentially methylated positions (DMPs) was tested in colonic mucosa tissue samples obtained from paediatric IBD cases and controls. RESULTS A total of 3196 probes were differentially methylated between CD cases and controls, while 1481 probes were differentially methylated between UC cases and controls. There was considerable (45%) overlap between UC and CD DMPs. The top-ranked IBD-associated PBMC differentially methylated region (promoter region of TRIM39-RPP2) was also significantly hypomethylated in colonic mucosa from paediatric UC patients. In addition, we confirmed TRAF6 hypermethylation using pyrosequencing and found reduced TRAF6 gene expression in PBMCs of IBD patients. CONCLUSIONS Our data provide new insights into differential epigenetic regulation of genes and molecular pathways, which may contribute to the pathogenesis and activity of IBD.

Systematic review: the quality of the scientific evidence and conflicts of interest in international inflammatory bowel disease practice guidelines.

Guidelines published by the international gastroenterology societies establish standards of care and seek to improve patient outcomes.

Community-acquired pneumonia in older patients: does age influence systemic cytokine levels in community-acquired pneumonia?

Background and objective:  Community‐acquired pneumonia (CAP) is a major cause of death in the elderly. The age‐related increase in comorbid illnesses plays a part but the effect of aging on the immune response may be equally important. We aimed to evaluate patients with CAP for evidence of a muted response to infection in elderly patients admitted to hospital compared with a younger patient group.

Body image dissatisfaction: clinical features, and psychosocial disability in inflammatory bowel disease.

Background:Body image refers to a persons sense of their physical appearance and body function. A negative body image self-evaluation may result in psychosocial dysfunction. Crohns disease and ulcerative colitis are associated with disabling features, and body image dissatisfaction is a concern for many patients with inflammatory bowel disease (IBD). However, no study has assessed body image and its comorbidities in patients with IBD using validated instruments. Our aim was to explore body image dissatisfaction in patients with IBD and assess its relationship with biological and psychosocial variables. Methods:We studied 330 patients (median age, 36 yr; range, 18–83; 169 men) using quantitative and qualitative methods. Patients completed a self-administered questionnaire that included a modified Hopwood Body Image Scale, the Cash Body Image Disturbance Questionnaire, and other validated instruments. Clinical and disease activity data were also collected. Results:Body image dissatisfaction was associated with disease activity (P < 0.001) and steroid treatment (P = 0.03) but not with immunotherapy (P = 0.57) or biological (P = 0.55) therapy. Body image dissatisfaction was also associated with low levels of general (P < 0.001) and IBD-specific (P < 0.001) quality of life, self-esteem (P < 0.001), and sexual satisfaction (P < 0.001), and with high levels of anxiety (P < 0.001) and depression (P < 0.001). Qualitative analysis indicated that patients were concerned about both physical and psychosocial consequences of body image dissatisfaction, including steroid side effects and impaired work and social activities. Conclusions:Body image dissatisfaction is common in patients with IBD, relates to specific clinical variables and is associated with significant psychological dysfunction. Its measurement is warranted as part of a comprehensive patient-centered IBD assessment.

Multimodal treatment of perianal fistulas in Crohn’s disease: seton versus anti-TNF versus advancement plasty (PISA): study protocol for a randomized controlled trial

BackgroundCurrently there is no guideline for the treatment of patients with Crohn’s disease and high perianal fistulas. Most patients receive anti-TNF medication, but no long-term results of this expensive medication have been described, nor has its efficiency been compared to surgical strategies. With this study, we hope to provide treatment consensus for daily clinical practice with reduction in costs.Methods/DesignThis is a multicentre, randomized controlled trial. Patients with Crohn’s disease who are over 18 years of age, with newly diagnosed or recurrent active high perianal fistulas, with one internal opening and no anti-TNF usage in the past three months will be considered. Patients with proctitis, recto-vaginal fistulas or anal stenosis will be excluded. Prior to randomisation, an MRI and ileocolonoscopy are required. All treatment will start with seton placement and a course of antibiotics. Patients will then be randomised to: (1) chronic seton drainage (with oral 6-mercaptopurine (6MP)) for one year, (2) anti-TNF medication (with 6MP) for one year (seton removal after six weeks) or (3) advancement plasty after eight weeks of seton drainage (under four months anti-TNF and 6MP for one year). The primary outcome parameter is the number of patients needing fistula-related re-intervention(s). Secondary outcomes are the number of patients with closed fistulas (based on an evaluated MRI score) after 18 months, disease activity, quality of life and costs.DiscussionThe PISA trial is a multicentre, randomised controlled trial of patients with Crohn’s disease and high perianal fistulas. With the comparison of three generally accepted treatment strategies, we will be able to comment on the efficiency of the various treatment strategies, with respect to several long-term outcome parameters.Trial registrationNederlands Trial Register identifier: NTR4137 (registered on 23 August 2013).

Intravenous proton pump inhibitor use in hospital practice.

Aim North American studies suggest that intravenous proton pump inhibitors are used inappropriately in hospital practice, but little is known of prescribing patterns in Europe. Our aim was to examine intravenous proton pump inhibitors prescribing in a single university teaching hospital. Methods Observational study of 101 consecutive hospital patients administered intravenous proton pump inhibitors over a 3-month period in a single hospital in Dublin, Ireland. Demographic, clinical, biochemical, haematological, endoscopic and follow-up data were collected and analysed. Results Sixty-five percent (65 of 101) of the patients had no objective evidence of gastrointestinal blood loss and 85 were haemodynamically stable before treatment. Two patients underwent endoscopic haemostasis before IV administration. The remaining 99 were treated for ulcer prophylaxis, presumed gastrointestinal haemorrhage, unrelated gastrointestinal conditions or for unknown reasons. Relatively senior nonconsultant staff prescribed intravenous therapy in most cases. Only six patients in the study were deemed to have received intravenous therapy for an appropriate indication. Conclusions Intravenous proton pump inhibitors use in hospital practice is usually inappropriate. It may be that other valid indications exist within hospital practice, but these might reasonably be evaluated in randomized trials that would assess the risks and costs of intravenous treatments as well as their benefits.

Heightened Expression of CD39 by Regulatory T Lymphocytes Is Associated with Therapeutic Remission in Inflammatory Bowel Disease

Background:To evaluate whether changes in expression of CD39 by regulatory T lymphocytes (Treg) impact treatment response in inflammatory bowel disease. To then define the biological role of expression of CD39 on Treg in an animal model of colitis. Methods:A prospective study of consecutive patients commencing anti-tumor necrosis factor therapy with infliximab (IFX) or adalimumab (ADA), who were then followed for 12 months. Treatment responses were defined both symptomatically and by endoscopy showing mucosal healing. Peripheral blood Tregs were quantified by flow cytometry. Functional importance of CD39 expression by Treg was determined in an adoptive T-cell transfer model of colitis. Results:Forty-seven patients (ulcerative colitis, n = 22; Crohns disease, n = 25) were recruited; 16 patients were complete responders and 13 nonresponders to anti-tumor necrosis factor. CD39 expression by Treg was lower in active inflammatory bowel disease and increased significantly after treatment in responders (CD39+Treg/total Treg; 8% at baseline to 22.5% at late time point, P < 0.001). Responders were more likely to have therapeutic drug levels and in multivariate analysis therapeutic drug levels were associated with higher expression of CD39 by FoxP3+ Treg and lower frequencies of interleukin 17A expressing cells. Tregs with genetic deletion of CD39 exhibit decrements in potential to suppress intestinal inflammation in a murine (CD45RBhi) T-cell transfer model of colitis in vivo, when compared with wild-type Treg. Conclusions:Increased expression of CD39 by peripheral blood Treg is observed in the setting of clinical and endoscopic remission in inflammatory bowel disease. Deficiency of CD39 expression by Treg can be linked to inability to suppress experimental colitis.

A 5-year prospective observational study of the outcomes of international treatment guidelines for Crohn's disease.

BACKGROUND & AIMS Therapeutic strategies for patients with Crohns disease are based on American and European guidelines. High rates of corticosteroid dependency and low remission rates are identified as weaknesses of this therapy and as justification for early introduction of biologic agents (top-down treatment) in moderate/severe Crohns disease. We reviewed outcomes and corticosteroid-dependency rates of patients with moderate-to-severe disease who were treated according to the international guidelines. METHODS Consecutive patients (102) newly diagnosed with Crohns disease in 2000-2002 were identified from a prospectively maintained database. Severity of disease was scored using the Harvey-Bradshaw Index (HBI). Disease was classified by Montreal classification. Five-year follow-up data were recorded. RESULTS Seventy-two patients had moderate/severe disease at diagnosis (HBI >8). Fifty-four (75%) had nonstricturing, nonpenetrating disease (B1). Sixty-four (89%) received corticosteroids, and 44 (61%) received immunomodulators. Twenty-one patients (29%) received infliximab. Thirty-nine patients (54%) required resection surgery. At a median of 5 years, 66 of 72 (92%) patients with moderate/severe disease were in remission (median HBI, 1). Twenty-five patients (35%) required neither surgery nor biologic therapy. CONCLUSIONS When international treatment guidelines are strictly followed, Crohns disease patients can achieve high rates of remission and low rates of morbidity at 5 years. Indiscriminate use of biologic agents therefore is not appropriate for all patients with moderate-to-severe disease.