Improving Precision in Crohn's Disease: Insights From the VCE Trial.

Does Consuming the Recommend Daily Level of Fiber Prevent Crohn's Disease?

Background Crohn disease and coeliac disease are two inflammatory conditions known to cause small intestine inflammation. Using high throughput transcriptomics, microbial, and bioinformatics approaches we aimed to capture differences and similarities linked to the pathogenesis and to future potential interventions for those chronic manifestations. Methods We performed high throughput transcriptomics and 16S microbial characterisation of 55 paediatric new-onset coeliac patients and controls using clinical pathology specimens, and compared those signatures to our previously reported 248 RISK Crohn’s disease newly diagnosed cohort. ToppGene/ToppCluster and ClueGO platforms were used for functional annotation enrichment analyses, and MaAsLin for microbial differential abundance. Results A substantial number (>90%) of genes passed the expression filtering criteria in both studies enabling the comparison. Of the 354 coeliac down-regulated genes, 59% (209/354) overlapped with the reduced Crohn signature. Shared reduced signatures and functions included a decrease in epithelial lipid metabolism, oxidoreductase activity, and brush border transport signatures. In contrast, a significantly smaller proportion [19% (97/427, Chi-squares p < 0.001] of the coeliac disease 524 up-regulated genes overlapped with the induced Crohn disease signature. We noted shared enriched signatures for adaptive immune-related pathways and interferon-γ in both coeliac and Crohn diseases. However, the Crohn disease signature exhibited more specific enrichments for signatures associated with innate immune pathways and with a strong signal for granulocytes, an extracellular matrix signature, and CXCR chemokines signalling, while the coeliac up-regulated signature showed unique enrichment for cell cycle and mitosis. As opposed to the robust dysbiosis previously characterised in Crohn disease, we were only able to identify significant enrichment for Bacteroidetes taxa in coeliac patients in comparison to controls. Conclusion We highlight important biologic differences between Crohn and coeliac diseases emphasising an intensified innate granulocytes activation signature in Crohn disease and a specific epithelial proliferative signal in coeliac disease. Unlike the robust dysbiosis linked to Crohn disease, the coeliac patient showed only modest enrichment for several Bacteroidetes taxa in comparison to controls. It is possible that microbial alteration in Crohn disease triggers granulocytes activation, and that this signal inhibits epithelial proliferation/renewal, eventually leading the epithelial damage seen in Crohn but not coeliac disease. Inhibiting innate immune activation or reverting Crohn dysbiosis may be a beneficial future therapy for Crohn disease.

A cure for Crohn's disease by 2032

The role of mycobacteria, specifically Mycobacterium paratuberculosis, in Crohn's disease has aroused considerable controversy for many years. Using the ultra sensitive polymerase chain reaction some studies have reported detection of M paratuberculosis DNA in as many as 65% of Crohn's disease patients but also in patients without disease. Other studies have been negative for both groups. We therefore designed a double blind control trial to investigate the presence of mycobacterial DNA in age, sex, and tissue matched paraffin wax embedded tissues from 31 Crohn's disease tissues, 20 diseased gut control tissues, and 10 ulcerative colitis tissues. The specimens were coded and analysed blind with three separate polymerase chain reactions (PCR) based on DNA sequences specific for M paratuberculosis (IS900), M avium (RFLP type A/1) (IS901), and the Mycobacterium genus (65 kDa gene, TB600). The number of granulomata and presence of acid fast bacilli in each Crohn's disease tissue was also investigated. The sensitivity of the system was determined using similarly prepared gut tissue from an animal infected with M paratuberculosis. Four of 31 Crohn's disease tissues and none of the 30 control and ulcerative colitis derived tissues amplified M paratuberculosis DNA. Crohn's disease tissues containing granulomata were significantly more likely to amplify M paratuberculosis specific DNA on PCR than the non-Crohn's disease tissues (p = 0.02). All the positive Crohn's disease tissues contained granulomata, and none contained acid fast bacilli. Equivalent numbers of Crohn's and non-Crohn's disease tissues amplified the region of the 65 kD gene on PCR for non-specific mycobacterial DNA (11/31 and 9/30 respectively). No sections produced an amplified product with the IS901 PCR. These results suggest that few Crohn's disease gut biopsy sections contain M paratuberculosis DNA in association with granulomata. The absence of such DNA in any control and ulcerative colitic tissue strengthens the case for it having a specific association, which may be pathogenic, with Crohn's disease in this minority of patients.

Crohn's disease (CD) affects the small bowel in most patients and between 20% and 40% of CD patients have isolated small bowel CD. Given that mucosal healing is widely accepted as a target of therapy in CD, assessing the mucosa of the small bowel is important. In clinical practice, however, assessment of small bowel mucosa is frequently sub-optimal. This may be because it is difficult to inspect endoscopically; cross–sectional imaging does not give sufficient detail of mucosal disease or because video capsule endoscopy (VCE) is not available or is felt to be associated with unacceptable risks. Several options are available for small bowel mucosal inspection; VCE, single or double balloon enteroscopy via anal or oral approaches, or push enteroscopy are widely available in the Asia-Pacific region. Multiple studies have demonstrated efficacy of VCE in identifying CD-associated changes including ulcers, erosions, erythema, aphthae, and strictures and in evaluating response to therapy.1, 2 There are however, some impediments to the universal use of VCE in evaluating small bowel mucosa in CD. First amongst these is the cost of the procedure, which needs to be considered in the specific health economic setting of each country. The caecum is reached less often than with VCE for other indications.3 Small bowel preparation and therefore image quality are slightly poorer than seen for other indications.4 An additional procedure to obtain biopsies for histology (typically a device-assisted enteroscopy) is often required, which adds to cost and invasiveness for health systems and patients, respectively. Capsule retention is a much feared complication of VCE. For VCE used to investigate suspected CD, rates of capsule retention are low and comparable with VCE for other indications. For VCE in the context of established CD, the risk of capsule retention is higher and testing with a patency capsule prior to VCE is recommended.3, 4 The Lewis score (LS) is a composite score reflecting CD activity identified at VCE5 and is built into some VCE reporting software. Patients with a LS confirming moderate–severe activity have been shown to be more likely to have features associated with poor prognosis in CD (smoking and immunomodulator use) and have greater risk for corticosteroid use and admission in follow-up (relative risk 5.0; P = 0.011, relative risk 13.7; P = 0.028 respectively).6 VCE also has demonstrated efficacy in assessing disease progression or response and can demonstrate substantial response in LS, where less objective markers (Crohn's Disease Activity Index and Inflammatory Bowel Disease Questionnaire) are unpredictable and correlate poorly with endoscopic disease activity. Video capsule endoscopy is effective in diagnosing CD and is safe for diagnosing CD. VCE performs at least as well as magnetic resonance enterography in identifying small bowel CD and colonoscopy for evaluating terminal ileal CD. Scoring systems of disease activity exist that correlate with short-term and long-term outcomes and can demonstrate response. Chromoendoscopy in IBD colonoscopy has found an important role in recent years. It is important to remember that chromoendoscopy can only be of optimal use if other factors, patient attendance, bowel preparation, performing surveillance in remission, endoscopist training and technique, and high-definition endoscopes, are attended to and optimized. The recent SCENIC guidelines have summarized and systematically reviewed the literature on chromoendoscopy in IBD dysplasia surveillance. There is a demonstrated incremental yield of chromoendoscopy over white-light endoscopy (6%, 95% confidence interval 3–9%). Narrow band imaging (NBI) has not demonstrated the same benefit over white-light endoscopy. Curiously, comparative studies of NBI and chromoendoscopy have not shown a significant benefit of chromoendoscopy over NBI (6% incremental yield, 95% confidence interval 1–14%). More data is needed comparing these two modalities. There is good evidence to suggest that targeted biopsies of abnormal appearing areas have a far greater diagnostic yield than random biopsies and that not performing random biopsies does not carry a high risk of missing dysplasia. The uptake of NBI and chromoendoscopy is increasing in Australia although only 3% of gastroenterologists in Australia performing surveillance colonoscopy in IBD do not take random biopsies.7

Interleukin-21 enhances T-helper cell type I signaling and interferon-γ production in Crohn’s disease

Infliximab treatment of postoperative ulcers in Crohn's disease: to inject or not to inject—that is the question

Ustekinumab is a human monoclonal antibody targeting the p40 subunit of both interleukin-12 and interleukin-23 with reported efficacy to treat Crohn's disease. However, few studies have reported the use of ustekinumab for pediatric inflammatory bowel disease. This study aimed to assess the clinical efficacy and safety of ustekinumab in children and adolescents with inflammatory bowel disease. Medical records of patients aged under 20years with Crohn's disease or Crohn's disease-like inflammatory bowel disease who had received ustekinumab at a Japanese pediatric inflammatory bowel disease center were retrospectively reviewed for efficacy and safety. The primary outcome was the steroid-free clinical remission rate at weeks 26 and 52. The steroid-free remission rate beyond week 52 was also evaluated. Weighted pediatric Crohn's disease activity index and simple endoscopic score for Crohn's disease were used to assess disease activity. Seventeen patients were included (male:female=8:9, A1a [diagnosed<10years old]:A1b [diagnosed≥10years old]=8:9). All patients were on ustekinumab at week 26, and 9/10 continued treatment over 1year. The steroid-free clinical remission rates were 59% at week 26, 50% at week 52, and 70% over 1year. Three of eight children who underwent endoscopy after ustekinumab introduction achieved endoscopic remission. No serious adverse events were recorded during the study period. Ustekinumab may be an effective and safe treatment option for pediatric and adolescent Crohn's disease and Crohn's disease-like inflammatory bowel disease patients having nonresponse or adverse reactions to anti-tumor necrosis factor agents.

Interventions for the management of abdominal pain in Crohn's disease and inflammatory bowel disease.

This Month in Gastroenterology

There is evidence that, in Crohn's disease (CD), lamina propria T lymphocytes (LPLs) are resistant to FAS-mediated apoptosis and that this defect contributes to the mucosal T-cell accumulation. In this study we examined the functional role of Flip, a Flice inhibitor protein, in the resistance of CD LPL to FAS-mediated apoptosis. Biopsy specimens and LPLs were taken from CD and ulcerative colitis (UC) patients and normal controls and analyzed for Flip by Western blotting. We also examined whether inhibition of Flip by antisense oligonucleotide restored the susceptibility of CD LPLs to FAS-induced apoptosis. LPL apoptosis was assessed by flow cytometry. After FAS stimulation, the rate of apoptosis of CD3+ LPLs was higher in normal controls and patients with UC than in patients with CD. Enhanced expression of both long and short Flip isoforms was seen in biopsy specimens and purified CD3+ and CD45RO+ LPLs of CD patients in comparison with UC patients and normal controls. No increase in Flip was documented in untreated celiac disease mucosa, thus suggesting the possibility that induction of Flip in the gut does not simply rely on the ongoing inflammation. Finally, we showed that inhibition of Flip by antisense oligonucleotide reverted the resistance of CD LPLs to FAS-induced apoptosis. Data suggest a role for Flip in the resistance of CD LPLs to FAS-mediated apoptosis.

Perianal Crohn's disease in infancy.

The Value of Myenteric Plexitis to Predict Early Postoperative Crohn’s Disease Recurrence

Crohn's disease is a systemic illness with a plethora of extraintestinal manifestations affecting various organs, of which the lungs are relatively rare. Pulmonary involvement may include airway diseases, lung parenchymal diseases, pleural diseases, or drug-related diseases. Tracheobronchial involvement is the most common respiratory presentation, whereas Crohn's disease-related interstitial lung disease is seen less frequently.A 41-year-old woman with a past medical history of Crohn's disease (status-post subtotal colectomy) presented to the hospital for an enlarging ground-glass opacity in her right middle lobe detected on routine computed tomography of the abdomen six months earlier. The opacity had increased in size from 21 x 18 mm to 28 x 18 mm and another ground-glass opacity in the right lower lobe increased in size from 5 mm to 12.4 mm. A robotic right middle lobectomy with lymph node dissection was done and bronchoscopy showed benign nodular lymphoid hyperplasia and a single perivascular epithelioid granuloma. A year later, her relapsing episodes of cough and shortness of breath were managed with prednisone, 20 mg, for a probable pulmonary manifestation of Crohn's disease. A non-contrast computed tomography of the chest showed interval resolution of the right lower lobe ground-glass opacity. A year after that, she presented to the hospital with increasing cough, shortness of breath, and a new right lower lobe ground-glass opacity (14 x 14 mm) on non-contrast computed tomography of the chest and has been managed with steroids with consideration of immunosuppression.In conclusion, pulmonary manifestations of Crohn's disease present in a myriad of varieties and often present confounding diagnostic problems necessitating an extensive work-up. Thus, Crohn's disease should be kept in the differential list in case of unusual clinical symptoms and radiological signs of idiopathic pulmonary presentations. These infrequent, and sometimes life-threatening, extraintestinal manifestations need to be considered when dealing with Crohn's disease to avoid further impairment of health status and alleviate patient symptoms by prompt recognition and treatment.

Long-term disease course, cost and prognosis of inflammatory bowel disease: epidemiological studies of a European and a Danish inception cohort.