Mortality and causes of death in Crohn's disease: results from 20 years of follow-up in the IBSEN study.

OBJECTIVE: Population-based studies have shown a slightly decreased life expectancy in patients with Crohn's disease (CD). The primary aim of the present study was to evaluate mortality and causes of death 20 years after the diagnosis in a well defined population-based cohort of CD patients in Norway. DESIGN: The Inflammatory Bowel South-Eastern Norway study has prospectively followed all patients diagnosed with CD in the period between 1 January 1990 and 31 December 1993 in four geographically well-defined areas. All patients (n=237) were age and sex matched with 25 persons from the same county selected at random from the general population. Data on death and causes of deaths were collected from the Norwegian Causes of Death Register. All causes and cause-specific mortality (gastrointestinal cancer, cancer and heart disease) were modelled with Cox regression model stratified by matched sets. Results are expressed as HRs with 95% CIs. RESULTS: There was no significant difference between CD patients and controls in overall mortality (HR=1.35, 95% CI 0.94 to 1.94, p=0.10). Furthermore, there were no marked differences in deaths from gastrointestinal cancer, other cancers or cardiovascular diseases in the CD group compared with the controls. In the CD group, 13.9% had died compared with 12.7% in the control group (p=0.578). CONCLUSIONS: In our population-based inception cohort followed for 20 years, there was no increased mortality or more deaths from cancer compared with the general population.

Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α.

OBJECTIVE: Cryptogenic multifocal ulcerating stenosing enteritis (CMUSE) is an extremely rare, but devastating, disease of unknown aetiology. We investigated the genetic basis of this autosomal recessive condition in a pair of affected siblings who have 40-year histories of catastrophic gastrointestinal and extraintestinal disease. DESIGN: Genome-wide single-nucleotide polymorphism homozygosity mapping in the two affected family members combined with whole-exome sequencing of one affected sibling. This was followed by confirmatory Sanger sequencing of the likely disease-causing sequence variant and functional studies in affected and unaffected family members. RESULTS: Insertion/deletion variation analysis revealed the presence of a homozygous 4 bp deletion (g.155574_77delGTAA) in the PLA2G4A gene, located in the splice donor site directly after exon 17 (the penultimate exon) of the gene in both affected siblings. This introduces a frameshift of 10 amino acids before a premature stop codon (p.V707fsX10), which is predicted to result in the loss of 43 amino acids (residues 707-749) at the C-terminus of cytosolic phospholipase A2-α (cPLA(2)α). cPLA(2)α protein expression was undetectable in the gut of both siblings, with platelet aggregation and thromboxane A(2) production, as functional assays for cPLA(2)α activity, grossly impaired. CONCLUSIONS: We have identified mutations in PLA2G4A as a cause of CMUSE in two affected siblings. Further studies are needed to determine if mutations in this gene are also responsible for disease of a similar phenotype in other cases.

Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease.

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, has multifactorial aetiology with complex interactions between genetic and environmental factors. Over 150 genetic loci are associated with IBD. The genetic contribution of the majority of those loci towards explained heritability is low. Recent studies have reported an increasing spectrum of human monogenic diseases that can present with IBD-like intestinal inflammation. A substantial proportion of patients with those genetic defects present with very early onset of intestinal inflammation. The 40 monogenic defects with IBD-like pathology selected in this review can be grouped into defects in intestinal epithelial barrier and stress response, immunodeficiencies affecting granulocyte and phagocyte activity, hyper- and autoinflammatory disorders as well as defects with disturbed T and B lymphocyte selection and activation. In addition, there are defects in immune regulation affecting regulatory T cell activity and interleukin (IL)-10 signalling. Related to the variable penetrance of the IBD-like phenotype, there is a likely role for modifier genes and gene-environment interactions. Treatment options in this heterogeneous group of disorders range from anti-inflammatory and immunosuppressive therapy to blockade of tumour necrosis factor α and IL-1ß, surgery, haematopoietic stem cell transplantation or gene therapy. Understanding of prototypic monogenic 'orphan' diseases cannot only provide treatment options for the affected patients but also inform on immunological mechanisms and complement the functional understanding of the pathogenesis of IBD.

A randomised phase I study of etrolizumab (rhuMAb ß7) in moderate to severe ulcerative colitis.

OBJECTIVE: Etrolizumab (rhuMAb ß7, anti-ß7, PRO145223) is a humanised monoclonal antibody targeting the ß7 subunit of the heterodimeric integrins α4ß7 and αEß7, which are implicated in leucocyte migration and retention in ulcerative colitis (UC). This randomised phase I study evaluated the safety and pharmacology of etrolizumab in patients with moderate to severe UC. DESIGN: In the single ascending dose (SAD) stage, etrolizumab (0.3, 1.0, 3.0, 10 mg/kg intravenous, 3.0 mg/kg subcutaneous (SC) or placebo) was administered 4:1 (n=25) in each cohort. In the multiple dose (MD) stage, new patients received monthly etrolizumab (0.5 mg/kg SC (n=4), 1.5 mg/kg SC (n=5), 3.0 mg/kg SC (n=4), 4.0 mg/kg intravenous (n=5)) or placebo (n=5). The pharmacokinetics was studied and Mayo Clinic Score evaluated at baseline, day 29 (SAD), and days 43 and 71 (MD). RESULTS: In the SAD stage, there were no dose limiting toxicities, infusion or injection site reactions. Two impaired wound healing serious adverse events occurred in two patients receiving etrolizumab. In the MD stage, there were no dose limiting toxicities, and no infusion or injection site reactions. Headache was the most common adverse event, occurring more often in etrolizumab patients. Antietrolizumab antibodies were detected in two subjects. The duration of ß7 receptor full occupancy was dose related. A clinical response was observed in 12/18 patients, and clinical remission in 3/18 patients treated with etrolizumab in the MD stage, compared with 4/5 and 1/5 placebo patients, respectively. CONCLUSION: Etrolizumab is well tolerated in moderate to severe UC. Further investigation is warranted.

Tofacitinib and faecal microbiota transplantation in treating checkpoint inhibitor-induced enterocolitis: case report.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can induce a wide range of immune-related adverse events (irAEs), potentially affecting any organ. ICI-induced colitis is a frequently reported irAE, whereas enteritis is rare and not well documented. CASE PRESENTATION: We are presenting a patient with metastatic melanoma who developed severe ICI-induced enterocolitis multirefractory for glucocorticoids, infliximab and vedolizumab, partially responding to faecal microbiota transplantation and final complete response to tofacitinib. CONCLUSION: This case supports that tofacitinib may be an(other) effective agent in managing multirefractory ICI-induced diarrhoea caused by colitis and/or enteritis.

Identification and Management of Eating Disorders (including ARFID) in GI Patients.

Eating disorders are characterized by cognitions (eg, fear of gastrointestinal symptoms around eating, overvaluation of body shape/weight) and behaviors (eg, dietary restriction, binge eating) associated with medical (eg, weight loss), and/or psychosocial impairments (eg, high distress around eating). With growing evidence for bidirectional relationships between eating disorders and gastrointestinal disorders, gastroenterology providers' awareness of historical, concurrent, and potential risk for eating disorders is imperative. In this conceptual review, we highlight risk and maintenance pathways in the eating disorder-gastrointestinal disorder intersection, delineate different types of eating disorders, and provide recommendations for the gastroenterology provider in assessing and preventing eating disorder symptoms..

Successful use of TNFα blockade in a severe case of idiopathic non-granulomatous ulcerative jejunoileitis associated with thrombotic thrombocytopenic purpura.

We describe the case of 50-year-old female patient who presented with severe gastrointestinal symptoms and progressive weight loss of unknown origin. Shortly after admission, she developed an acute flare of thrombotic thrombocytopaenic purpura (TTP) that had to be treated by plasma exchange therapy and rituximab administration. While the signs of TTP subsided, the gastrointestinal symptoms worsened with abdominal cramps, massive gastric retention, malnourishment and a stenosis due to extensive inflammation and wall thickening of the small bowel. Extensive diagnostic efforts yielded no specific cause, so the patient-based on the histopathological findings-was diagnosed with idiopathic non-granulomatous ulcerative jejunoileitis. Following a highly complicated clinical course over several months, successful remission of the inflammatory activity and recovery of the patient could be obtained by TNF-alpha blockade.

Long-term follow-up of the use of maintenance antibiotic therapy for chronic antibiotic-dependent pouchitis.

OBJECTIVE: Restorative proctolectomy is considered the procedure of choice in patients with ulcerative colitis who have failed medical therapy. Chronic pouchitis occurs in 10%-15% of patients, which often require long-term antibiotics to alleviate symptoms. Safety and efficacy of long-term maintenance antibiotics for chronic pouchitis has yet to be established. We aimed to assess the long-term safety and efficacy of maintenance antibiotic therapy for chronic pouchitis. DESIGN: This was an observational study. We followed up patients who were diagnosed with chronic antibiotic-dependent pouchitis. SETTING: Data were collected from our single specialist pouch centre. PATIENTS: Patients with chronic antibiotic-dependent pouchitis who had been maintained on antibiotics continuously for at least 1 year with a least one follow-up visit. MAIN OUTCOME MEASURE: Development of pouch failure defined by the need for an ileostomy, patient-reported side effects of antibiotics and development of antibiotic resistance found on stool coliform testing. RESULTS: Long-term use of antibiotics achieve remission in 21% of patients over a median follow-up of 102 (range 9-125). Pouch failure in association with chronic pouchitis after a median follow-up of 8.5 years occurred in 18%. Side effects of long-term antibiotic use occurred in 28% of patients, with resistance to antibiotics from at least one stool sample occurring in 78% patients. CONCLUSIONS: Although the use of antibiotics in chronic pouchitis may be justified, the use of long-term antibiotics must be weighed against potential complications associated with pouchitis and antibiotics.

Neuronal regulation of intestinal immune functions in health and disease.

BACKGROUND: Nerve-mucosa interactions control various elements of gastrointestinal functions, including mucosal host defense, gut barrier function, and epithelial cell growth and differentiation. In both intestinal and extra-intestinal diseases, alterations of autonomic nerve activity have been observed to be concurrent with the disease course, such as in inflammatory and functional bowel diseases, and neurodegenerative diseases. This is relevant as the extrinsic autonomic nervous system is increasingly recognized to modulate gut inflammatory responses. The molecular and cellular mechanisms through which the extrinsic and intrinsic nerve pathways may regulate digestive mucosal functions have been investigated in several pre-clinical and clinical studies. PURPOSE: The present review focuses on the involvement of neural pathways in gastrointestinal disease, and addresses the current strategies to intervene with neuronal pathway as a means of treatment.

Efficacy and safety of a herbal medicinal product containing myrrh, chamomile and coffee charcoal for the treatment of gastrointestinal disorders: a non-interventional study.

OBJECTIVE: This prospective observational postmarketing multicentre study was performed to collect data on the clinical efficacy, safety and tolerability of a licensed herbal combination of myrrh, coffee charcoal and chamomile extracts in patients with symptoms of acute diarrhoea. MATERIAL AND METHODS: Patients aged 12 years and above with symptoms of acute diarrhoea due to acute inflammatory disorders (AID) of the gastrointestinal tract, inflammatory bowel diseases (IBD) or irritable bowel syndrome (IBS) were treated with the herbal preparation either as monotherapy, add-on therapy or with other therapies. The primary outcome parameter was the pre-post change of total mean symptom score. Secondary outcome parameters were changes of score of single symptoms, physician's assessment of the clinical course and efficacy, and patient's satisfaction. RESULTS: 1062 patients (mean age 43.2±17.8 years, range 12-89, 42.3% men) were included. A decrease of the overall mean total symptom score was observed in all treatment groups (monotreatment: 1.33±0.51 to 0.15±0.34, add-on treatment: 1.39±0.41 to 0.30±0.37, other therapy: 1.31±0.43 to 0.24±0.33). No significant differences between three treatment options were observed within AID and IBD groups. However, in the IBS group, monotreatment with the herbal preparation resulted in a significantly better outcome when compared to either add-on treatment (mean difference 0.140; 95% CI 0.036 to 0.245; p=0.009) or other therapy (mean difference 0.217; 95% CI 0.085 to 0.349; p=0.001). Secondary efficacy criteria showed comparable results between different treatment options in the respective disorder groups. Patient satisfaction was generally higher with monotreatment in the AID and IBS groups, while add-on treatment was preferred in the IBD group. CONCLUSIONS: The combination of myrrh, coffee charcoal and chamomile flower extract is effective, well tolerated and safe for use in patients with symptoms of acute diarrhoea. The effects are comparable to conventional therapies used in routine care.