Recent studies reported a role for more than 70 genes or loci in the susceptibility to Crohn's disease (CD). However, the impact of these associations in clinical practice remains to be defined. The ...aim of the study was to analyse the relationship between genotypes and phenotypes for the main 53 CD-associated polymorphisms.
A cohort of 798 CD patients with a median follow up of 7 years was recruited by tertiary adult and paediatric gastroenterological centres. A detailed phenotypic description of the disease was recorded, including clinical presentation, response to treatments and complications. The participants were genotyped for 53 CD-associated variants previously reported in the literature and correlations with clinical sub-phenotypes were searched for. A replication cohort consisting of 722 CD patients was used to further explore the putative associations.
The NOD2 rare variants were associated with an earlier age at diagnosis (p = 0.0001) and an ileal involvement (OR = 2.251.49-3.41 and 2.77 1.71-4.50 for rs2066844 and rs2066847, respectively). Colonic lesions were positively associated with the risk alleles of IL23R rs11209026 (OR = 2.25 1.13-4.51) and 6q21 rs7746082 (OR = 1.60 1.10-2.34 and negatively associated with the risk alleles of IRGM rs13361189 (OR = 0.29 0.11-0.74) and DEFB1 rs11362 (OR = 0.50 0.30-0.80). The ATG16L1 and IRGM variants were associated with a non-inflammatory behaviour (OR = 1.75 1.22-2.53 and OR = 1.50 1.04-2.16 respectively). However, these associations lost significance after multiple testing corrections. The protective effect of the IRGM risk allele on colonic lesions was the only association replicated in the second cohort (p = 0.03).
It is not recommended to genotype the studied polymorphisms in routine practice.
5-aminosalicylic acid (5-ASA) is an antiinflammatory drug widely used in the treatment of inflammatory bowel diseases. It is known to inhibit the production of cytokines and inflammatory mediators, ...but the mechanism underlying the intestinal effects of 5-ASA remains unknown. Based on the common activities of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands and 5-ASA, we hypothesized that this nuclear receptor mediates 5-ASA therapeutic action. To test this possibility, colitis was induced in heterozygous PPAR-gamma(+/-) mice and their wild-type littermates, which were then treated with 5-ASA. 5-ASA treatment had a beneficial effect on colitis only in wild-type and not in heterozygous mice. In epithelial cells, 5-ASA increased PPAR-gamma expression, promoted its translocation from the cytoplasm to the nucleus, and induced a modification of its conformation permitting the recruitment of coactivators and the activation of a peroxisome-proliferator response element-driven gene. Validation of these results was obtained with organ cultures of human colonic biopsies. These data identify PPAR-gamma as a target of 5-ASA underlying antiinflammatory effects in the colon.
Research into Crohn's disease has recently been focused on the genetics of the patient, the gastrointestinal flora, the gut epithelium and mucosal immune responses. For over 60 years pathologists ...have reported that the fundamental alteration in Crohn's disease occurs in regional lymphatics of the intestine--the disease is a lymphocytic and granulomatous lymphangitis. At an earlier time, experimental sclerosis of regional intestinal lymphatics of the pig produced a chronic segmental enteritis with many features of Crohn's disease, including lymphocytic and granulomatous lymphangitis of the bowel wall and enteroenteric and enterocutaneous fistulas. In Crohn's disease, differences in the anatomic distribution of vasa recta appear to explain long-segment disease of the ileum and short-segment disease of the more proximal intestine. A variety of bacteria and viruses cause lymphangitis, suggesting that microorganisms may be at the centre of the basic changes in Crohn's disease. Dietary antigens and lipids are worthy of consideration as well. Now that antibodies to label lymphatics are available, attention should be directed at defining the initial damage to lymphatic endothelium and agents that might be responsible.
There are a number of gaps in our current quality of care for patients with inflammatory bowel diseases. This review proposes changes that could be made now to improve inflammatory bowel disease ...care.
Evidence from the literature and clinical experience are presented that illustrate best practice for improving current quality of care of patients with inflammatory bowel diseases.
Best care for inflammatory bowel disease patients will involve services provided by a multidisciplinary team, ideally delivered at a centre of excellence and founded on current guidelines. Dedicated telephone support lines, virtual clinics and networking may also provide models through which to deliver high-quality, expert integrated patient care. Improved physician–patient collaboration may improve treatment adherence, producing tangible improvements in disease outcomes, and may also allow patients to better understand the benefits and risks of a disease management plan. Coaching programmes and tools that improve patient self-management and empowerment are likely to be supported by payers if these can be shown to reduce long-term disability.
Halting disease progression before there is widespread bowel damage and disability are ideal goals of inflammatory bowel disease management. Improving patient–physician communication and supporting patients in their understanding of the evidence base are vital for ensuring patient commitment and involvement in the long-term management of their condition. Furthermore, there is a need to create more centres of excellence and to develop inflammatory bowel disease networks to ensure a consistent level of care across different settings.
Summary
Background
Little is known about the role of the microbiome in primary sclerosing cholangitis.
Aim
To explore the mucosa‐associated microbiota in primary sclerosing cholangitis (PSC) patients ...across different locations in the gut, and to compare it with inflammatory bowel disease (IBD)‐only patients and healthy controls.
Methods
Biopsies from the terminal ileum, right colon, and left colon were collected from patients and healthy controls undergoing colonoscopy. Microbiota profiling using bacterial 16S rRNA sequencing was performed on all biopsies.
Results
Forty‐four patients were recruited: 20 with PSC (19 with PSC‐IBD and one with PSC‐only), 15 with IBD‐only and nine healthy controls. The overall microbiome profile was similar throughout different locations in the gut. No differences in the global microbiome profile were found. However, we observed significant PSC‐associated enrichment in Barnesiellaceae at the family level, and in Blautia and an unidentified Barnesiellaceae at the genus level. At the operational taxa unit level, most shifts in PSC were observed in Clostridiales and Bacteroidales orders, with approximately 86% of shifts occurring within the former order.
Conclusions
The overall microbiota profile was similar across multiple locations in the gut from the same individual regardless of disease status. In this study, the mucosa associated‐microbiota of patients with primary sclerosing cholangitis was characterised by enrichment of Blautia and Barnesiellaceae and by major shifts in operational taxa units within Clostridiales order.
Background
Over the last decade, biologics have gained an important place for the treatment of moderate to severe inflammatory bowel disease (IBD), and many randomized control trials have evaluated ...their efficacy.
Aim
The goal of this review is to analyze the results of these trials and to highlight the evidence and indications emerging from these studies for their implementation in the management of IBD patients.
Methods
A PubMed search was realized to screen high-quality clinical trials studying biologic agents currently available in clinics for the treatment of IBD. Words used were: “infliximab,” “adalimumab,” “certolizumab,” “golimumab,” “natalizumab,” “vedolizumab,” “ustekinumab,” “azathioprine,” “methotrexate,” “Crohn's disease,” and “ulcerative colitis.”
Results
In Crohn's disease, studies supporting induction and maintenance therapies were documented for infliximab, adalimumab, certolizumab, natalizumab, vedolizumab, and ustekinumab. Infliximab, adalimumab, and certolizumab have evidences for fistulizing Crohn's disease and only infliximab and adalimumab have evidences for mucosal healing. In ulcerative colitis, studies supporting induction, maintenance, and mucosal healing were found with infliximab, adalimumab, golimumab, and vedolizumab. Only infliximab was associated with evidences for combination therapy with thiopurine and acute severe colitis in ulcerative colitis.
Conclusion
Management with biologics in IBD patients is well validated by high-quality clinical trials.
Nodular regenerative hyperplasia (NRH) of the liver is associated with several diseases and drugs. Clinical symptoms of NRH may vary from absence of symptoms to full-blown (non-cirrhotic) portal ...hypertension. However, diagnosing NRH is challenging. The objective of this study was to determine inter- and intraobserver agreement on the histopathologic diagnosis of NRH.
Liver specimens (n=48) previously diagnosed as NRH, were reviewed for the presence of NRH by seven pathologists without prior knowledge of the original diagnosis or clinical background. The majority of the liver specimens were from thiopurine using inflammatory bowel disease patients. Histopathologic features contributing to NRH were also assessed. Criteria for NRH were modified by consensus and subsequently validated. Interobserver agreement was evaluated by using the standard kappa index.
After review, definite NRH, inconclusive NRH and no NRH were found in 35% (23-40%), 21% (13-27%) and 44% (38-56%), respectively (median, IQR). The median interobserver agreement for NRH was poor (κ = 0.20, IQR 0.14-0.28). The intraobserver variability on NRH ranged between 14% and 71%. After modification of the criteria and exclusion of biopsies with technical shortcomings, the interobserver agreement on the diagnosis NRH was fair (κ = 0.45).
The interobserver agreement on the histopathologic diagnosis of NRH was poor, even when assessed by well-experienced liver pathologists. Modification of the criteria of NRH based on consensus effort and exclusion of biopsies of poor quality led to a fairly increased interobserver agreement. The main conclusion of this study is that NRH is a clinicopathologic diagnosis that cannot reliably be based on histopathology alone.
Epidemiology studies have consistently found an increased risk of oral malignancies in organ transplant recipients, patients with graft-versus-host disease, and people with human immunodeficiency ...virus infection. We assessed the risk of oral cancer in patients with inflammatory bowel diseases (IBD).
We collected data on 7294 patients with IBD (3785 women) seen at Mount Sinai Medical Center, New York, from 2000 through 2011. The expected incidence of oral cancer was calculated for each sex-specific and 5-year age-specific stratum by specific incidence rates using the Surveillance, Epidemiology and End Results 18 registry data (2000-2011), adjusted for age to the 2000 United States population (census P25-1130).
Eleven patients (7 men) were found to have biopsy-proven oral cancer. Six patients had cancer of the tongue; 2 patients had cancer of the hard palate; and the remaining 3 had tonsillar, buccal, or mandibular sarcoma. Before the cancer diagnosis, IBD had been treated in 4 patients with azathioprine or mercaptopurine, in 1 patient with infliximab, and 3 in patients with combination of biologic agents and azathioprine; 4 of the patients had not been treated for IBD. The age- and sex-adjusted standardized incidence ratio (SIR) for oral cancer in patients with IBD was 9.77 (95% confidence interval CI, 5.14-16.98). In women, the SIR was 12.07 (95% CI, 3.84-29.11), and in men the SIR was 8.49 (95% CI, 3.71-16.78). The age-adjusted SIR for tongue cancer was 18.91 (95% CI, 7.66-39.33): 17.06 for men (95% CI, 5.42-41.15) and 22.10 for women (95% CI, 3.70-73.01).
We found patients with IBD to be at increased risk for oral cancers, especially tongue cancer. Women are at higher risk than men.
Little is known about the efficacy and safety of thalidomide therapy for patients with refractory Crohn's disease (CD), particularly in respect to long-term outcomes of patients.
We conducted a ...retrospective multicenter observational study to evaluate thalidomide efficacy and the probability of its withdrawal because of either toxicity or lack/loss of efficacy. We analyzed data from 77 patients with active intestinal and/or perineal CD, refractory to conventional immunosuppressive therapies, treated with thalidomide at 5 tertiary referral inflammatory bowel disease centers in France. We also analyzed the long-term efficacy of thalidomide.
Fifty-four percent of the patients were in clinical remission after thalidomide treatment within the first year. The proportions of patients from whom thalidomide was withdrawn because of lack/loss of efficacy and/or toxicity were 35% at 3 months of treatment, 69% at 12 months, and 88% at 24 months. The proportions of patients from whom thalidomide was withdrawn because of toxicity alone were 22% at 3 months, 34% at 12 months, and 46% at 24 months. Overall, neuropathy occurred in 30 patients and was the main reason for thalidomide withdrawal.
On the basis of a retrospective multicenter observational study, thalidomide therapy is effective in most patients with refractory active intestinal and/or perineal CD. However, its toxicity limits its use as a maintenance therapy.
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