Crohn's disease associated strictures Chan, Webber Pak Wo; Mourad, Fadi; Leong, Rupert WL
Journal of gastroenterology and hepatology,
20/May , Volume:
33, Issue:
5
Journal Article
Peer reviewed
Open access
Crohn's disease (CD) is a chronic relapsing and remitting disease that can affect any segments of the gastrointestinal tract. More than 50% of patients with CD develop stricturing or penetrating ...complications within the first 10 years after diagnosis. Strictures can lead to intestinal obstruction, which is a common indication for surgery. Despite significant advances in the understanding of the pathogenesis of intestinal fibrostenosis, imaging and therapeutic armamentarium of CD, the risk of intestinal surgery remained significantly high. Endoscopic balloon dilation is a promising first‐line alternative to surgery as it is less invasive and could preserve intestinal length. In this review, we will evaluate the literature on the mechanism of intestinal fibrosis, emerging imaging techniques, and management strategies for CD associated strictures.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Summary Background The intestinal microbiota is implicated in the pathogenesis of ulcerative colitis. Faecal microbiota transplantation is a novel form of therapeutic microbial manipulation, but its ...efficacy in ulcerative colitis is uncertain. We aimed to establish the efficacy of intensive-dosing, multidonor, faecal microbiota transplantation in active ulcerative colitis. Methods We conducted a multicentre, double-blind, randomised, placebo-controlled trial at three hospitals in Australia. We randomly allocated patients with active ulcerative colitis (Mayo score 4–10) in a 1:1 ratio, using a pre-established randomisation list, to either faecal microbiota transplantation or placebo colonoscopic infusion, followed by enemas 5 days per week for 8 weeks. Patients, treating clinicians, and other study staff were unaware of the assigned treatment. Faecal microbiota transplantation enemas were each derived from between three and seven unrelated donors. The primary outcome was steroid-free clinical remission with endoscopic remission or response (Mayo score ≤2, all subscores ≤1, and ≥1 point reduction in endoscopy subscore) at week 8. Analysis was by modified intention-to-treat and included all patients receiving one study dose. We performed 16S rRNA stool analysis to assess associated microbial changes. This trial is registered with ClinicalTrials.gov , number NCT01896635 . The trial has ended; this report presents the final analysis. Findings From November, 2013, to May, 2015, 85 patients were enrolled to our trial, of whom 42 were randomly assigned faecal microbiota transplantation and 43 were allocated placebo. One patient assigned faecal microbiota transplantation and three allocated placebo did not receive study treatment and were excluded from the analysis. The primary outcome was achieved in 11 (27%) of 41 patients allocated faecal microbiota transplantation versus three (8%) of 40 who were assigned placebo (risk ratio 3·6, 95% CI 1·1–11·9; p=0·021). Adverse events were reported by 32 (78%) of 41 patients allocated faecal microbiota transplantation and 33 (83%) of 40 who were assigned placebo; most were self-limiting gastrointestinal complaints, with no significant difference in number or type of adverse events between treatment groups. Serious adverse events occurred in two patients assigned faecal microbiota transplantation and in one allocated placebo. Microbial diversity increased with and persisted after faecal microbiota transplantation. Several bacterial taxa were associated with clinical outcome; in particular, the presence of Fusobacterium spp was associated with lack of remission. Interpretation Intensive-dosing, multidonor, faecal microbiota transplantation induces clinical remission and endoscopic improvement in active ulcerative colitis and is associated with distinct microbial changes that relate to outcome. Faecal microbiota transplantation is, thus, a promising new therapeutic option for ulcerative colitis. Future work should focus on precisely defining the optimum treatment intensity and the role of donor–recipient matching based on microbial profiles. Funding Broad Medical Research Program, Gastroenterological Society of Australia, Mount Sinai (New York) SUCCESS fund, University of New South Wales.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
LINKED CONTENT
This article is linked to Aliu et al papers. To view these articles, visit https://doi.org/10.1111/apt.17988 and https://doi.org/10.1111/apt.18031.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract Background & Aims Many patients with inflammatory bowel diseases (IBD) have ongoing bowel symptoms of diarrhea or abdominal pain despite mucosal healing. We investigated whether impaired ...intestinal permeability contributes to these symptoms. Methods We performed a prospective study of intestinal permeability, measured by endoscopic confocal laser endomicroscopy in 110 consecutive subjects (31 with ulcerative colitis UC, 57 with Crohn’s disease CD, and 22 healthy individuals controls) in Sydney Australia from May 2009 and September 2015. Symptomatic CD was defined by a CD Activity Index score of 150 or more and symptomatic UC by a partial Mayo score of 2 or more. Mucosal healing was defined as CD Endoscopic Index of Severity of 0 in CD or Mayo endoscopic sub-score of 0–1 for patients with UC. Intestinal permeability was quantified by the Confocal Leak Score (CLS, range: 0=no impaired permeability to 100=complete loss of barrier function). The primary endpoint was intestinal permeability in patients with symptomatic IBD in mucosal healing vs patients with asymptomatic IBD in mucosal healing. We determined the sensitivity and specificity of CLS in determining symptoms based on receiver operating characteristic (ROC) analysis. Results Ongoing bowel symptoms were present in 16.3% of patients with IBD and mucosal healing (15.4% of patients with CD and 17.4% with UC). Patients with symptomatic IBD had a significantly higher median CLS (19.0) than patients with asymptomatic IBD (7.3, P <.001) or controls (5.9, P <.001). There were no significant differences between patients with IBD in remission vs controls ( P =.261). The median CLS was significantly higher in patients with symptomatic than asymptomatic CD (17.7 vs 8.1, P =.009) and patients with symptomatic than asymptomatic UC (22.2 vs 6.9, P =.021). A CLS of 13.1 or more identified ongoing bowel symptoms in patients with IBD and mucosal healing with 95.2% sensitivity and 97.6% specificity; the ROC area under curve value was 0.88. Based on this cutoff, 36.2% of patients with IBD in mucosal healing have increased intestinal permeability. On regression analysis, every increase in CLS of 1.9 correlated with an additional diarrheal motion per day ( P =.008). Conclusions In a prospective study of intestinal permeability in patients with IBD and mucosal healing, we associated impaired intestinal permeability with ongoing bowel symptoms ; increases in permeability correlated with increased severity of diarrhea. Resolution of mucosal permeability beyond mucosal healing might improve outcomes of patients with IDB. ANZCTR.org.au: ACTRN12613001248752
Summary
Background
Medication persistence contributes real‐world evidence about treatment effectiveness, tolerability and prescriber and patient acceptability.
Aims
To evaluate persistence of ...biological agents in Crohn's disease (CD) and ulcerative colitis (UC) and the effects of immunomodulator use and treatment lines.
Methods
Retrospective national population‐based data on treatment persistence for adalimumab, infliximab vedolizumab and ustekinumab for CD and UC were analysed from the Australian Pharmaceutical Benefits Scheme using Kaplan‐Meier analysis and Cox proportional hazards models.
Results
There were 2499 patients included with 8219 person‐years of follow‐up. In CD patients ustekinumab had increased persistence compared to anti‐TNF agents (HR: 1.79, 95%CI: 1.32‐2.38, P < 0.01). Twelve‐month CD persistence rates were ustekinumab 80.0%, vedolizumab 73.5%, infliximab 68.1% and adalimumab 64.2% (P = 0.01). In moderate‐severe UC vedolizumab had increased persistence compared to anti‐TNF agents (HR: 1.67, 95% CI: 1.27‐2.18 P < 0.001). Twelve‐month UC persistence rates were vedolizumab 73.4%, infliximab 61.1% and adalimumab 45.5% (P < 0.001). Immunomodulator co‐therapy did not significantly increase persistence in non‐anti‐TNF therapy (P > 0.05). Thiopurines increased persistence of anti‐TNF agents in CD (P < 0.001) and UC (P = 0.03). Methotrexate co‐therapy increased persistence of anti‐TNF agents in CD (P = 0.001) only. First‐line therapy was superior to non‐first line in persistence (P < 0.001). In fistulising CD, the persistence of infliximab and adalimumab was not significantly different (P = 0.11).
Conclusion
Persistence was highest in ustekinumab in CD and vedolizumab in UC. Factors which increased the persistence of biological agents are first‐line therapy, and immunomodulator co‐therapy in anti‐TNF agent use.
Treatment persistence in Crohn's disease and ulcerative colitis ‐ data from the PANIC registry. Superior persistence with ustekinumab in Crohn's disease and vedolizumab in ulcerative colitis. Thiopurine co‐therapy increases persistence with anti‐TNF agents.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Faecal microbiota transplantation (FMT) has emerged as a potent form of therapeutic microbial manipulation. There is much interest in exploring its potential in conditions such as inflammatory bowel ...disease (IBD) where disturbances in the gastrointestinal microbiota play a crucial role in disease pathogenesis.
There are 4 randomized controlled trials of FMT as induction therapy in ulcerative colitis, with meta-analyses suggesting significant benefit over placebo. Allied microbial studies have identified potential microbial and metabolic predictors of therapeutic efficacy and highlighted the importance of optimizing future donor and patient selection. Recent literature has evaluated the use of complementary microbial manipulation through pre-antibiotics to improve treatment efficacy. Studies have also assessed the durability of FMT response and its use in maintenance therapy of UC. While data on FMT are more limited in Crohn’s disease and pouchitis, cohort and pilot randomized controlled data a now also emerging in these areas.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Sex significantly influences the clinical and pathological characteristics of colorectal cancer (CRC). These include differences in incidence and mortality rates, clinical presentations including ...age, emergency surgery for complications from CRC, screening participation rates, site, stage and treatment utilization, histopathology and survival. Environmental, behavioral and biological factors contribute to the differential risk. Recent advances in the molecular biology of CRC, specifically in microsatellite status, estrogen hormone and estrogen receptor β, have led to greater understanding of the effect of estrogen in colorectal carcinogenesis. Estrogen may preferentially protect against microsatellite unstable cancers through its effect on selected molecular targets; however, the exact pathways have not been elucidated. Recognition of important sex disparities in these areas may lead to the implementation of specific measures to diminish these differences and facilitate equitable distribution of health resources. Identifying specific molecular targets on CRC that interact with estrogen may stimulate research to improve the overall outcomes of all patients with CRC.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background & Aims Transplantation of peripheral blood stem cells has been successful therapy for small numbers of patients with Crohn's disease (CD), but requires prior myeloconditioning. Mesenchymal ...stromal cells (MSCs) escape immune recognition, so myeloconditioning is not required before their administration. We investigated the efficacy of allogeneic MSCs in patients with luminal CD. Methods Our phase 2, open-label, multicenter study included 16 patients (21-55 y old; 6 men) with infliximab- or adalimumab-refractory, endoscopically confirmed, active luminal CD (CD activity index CDAI, >250). Subjects were given intravenous infusions of allogeneic MSCs (2 × 106 cells/kg body weight) weekly for 4 weeks. The primary end point was clinical response (decrease in CDAI >100 points) 42 days after the first MSC administration; secondary end points were clinical remission (CDAI, <150), endoscopic improvement (a CD endoscopic index of severity CDEIS value, <3 or a decrease by >5), quality of life, level of C-reactive protein, and safety. Results Among the 15 patients who completed the study, the mean CDAI score was reduced from 370 (median, 327; range, 256-603) to 203 (median, 129) at day 42 ( P < .0001). The mean CDAI scores decreased after each MSC infusion (370 before administration, 269 on day 7, 240 on day 14, 209 on day 21, 182 on day 28, and 203 on day 42). Twelve patients had a clinical response (80%; 95% confidence interval, 72%-88%; mean reduction in CDAI, 211; range 102-367), 8 had clinical remission (53%; range, 43%-64%; mean CDAI at day 42, 94; range, 44-130). Seven patients had endoscopic improvement (47%), for whom the mean CDEIS scores decreased from 21.5 (range, 3.3-33) to 11.0 (range, 0.3-18.5). One patient had a serious adverse event (2 dysplasia-associated lesions), but this probably was not caused by MSCs. Conclusions In a phase 2 study, administration of allogeneic MSCs reduced CDAI and CDEIS scores in patients with luminal CD refractory to biologic therapy. ClinicalTrials.gov number, NCT01090817.
Fecal microbiota transplantation (FMT) can induce remission in patients with ulcerative colitis (UC). In a randomized controlled trial of FMT in patients with active UC, we aimed to identify ...bacterial taxonomic and functional factors associated with response to therapy.
We performed a double-blind trial of 81 patients with active UC randomly assigned to groups that received an initial colonoscopic infusion and then intensive multidonor FMT or placebo enemas, 5 d/wk for 8 weeks. Patients in the FMT group received blended homogenized stool from 3–7 unrelated donors. Patients in the placebo group were eligible to receive open-label FMT after the double-blind study period. We collected 314 fecal samples from the patients at screening, every 4 weeks during treatment, and 8 weeks after the blinded or open-label FMT therapy. We also collected 160 large-bowel biopsy samples from the patients at study entry, at completion of 8 weeks of blinded therapy, and at the end of open-label FMT, if applicable. We analyzed 105 fecal samples from the 14 individual donors (n = 55), who in turn contributed to 21 multidonor batches (n = 50). Bacteria in colonic and fecal samples were analyzed by both 16S ribosomal RNA gene and transcript amplicon sequencing; 285 fecal samples were analyzed by shotgun metagenomics, and 60 fecal samples were analyzed for metabolome features.
FMT increased microbial diversity and altered composition, based on analyses of colon and fecal samples collected before vs after FMT. Diversity was greater in fecal and colon samples collected before and after FMT treatment from patients who achieved remission compared with patients who did not. Patients in remission after FMT had enrichment of Eubacterium hallii and Roseburia inulivorans compared with patients who did not achieve remission after FMT and had increased levels of short-chain fatty acid biosynthesis and secondary bile acids. Patients who did not achieve remission had enrichment of Fusobacterium gonidiaformans, Sutterella wadsworthensis, and Escherichia species and increased levels of heme and lipopolysaccharide biosynthesis. Bacteroides in donor stool were associated with remission in patients receiving FMT, and Streptococcus species in donor stool was associated with no response to FMT.
In an analysis of fecal and colonic mucosa samples from patients receiving FMT for active UC and stool samples from donors, we associated specific bacteria and metabolic pathways with induction of remission. These findings may be of value in the design of microbe-based therapies for UC. ClinicalTrials.gov, Number NCT01896635
Display omitted
PDF
