Ulcerative Colitis Feuerstein, Joseph D; Moss, Alan C; Farraye, Francis A
Mayo Clinic proceedings,
07/2019, Volume:
94, Issue:
7
Journal Article
Peer reviewed
Open access
Ulcerative colitis (UC) is a chronic inflammatory bowel disease that can involve any aspect of the colon starting with mucosal inflammation in the rectum and extending proximally in a continuous ...fashion. Typical symptoms on presentation are bloody diarrhea, abdominal pain, fecal urgency, and tenesmus. In some patients, extraintestinal manifestations may predate the onset of gastrointestinal symptoms. A diagnosis of UC is made on the basis of presenting symptoms consistent with UC as well as endoscopic evidence showing continuous and diffuse colonic inflammation that starts in the rectum. Biopsies of the colon documenting chronic inflammation confirm the diagnosis of UC. Most cases are treated with pharmacological therapy to first induce remission and then to maintain a corticosteroid-free remission. There are multiple classes of drugs used to treat the disease. For mild to moderate UC, oral and rectal 5-aminosalycilates are typically used. In moderate to severe colitis, medication classes include thiopurines, biological agents targeting tumor necrosis factor and integrins, and the small-molecule Janus kinase inhibitors. However, in up to 15% of cases, patients in whom medical therapy fails or who have development of dysplasia secondary to their long-standing colitis will require surgical treatment. Finally, to minimize the complications of UC and adverse events from medications, a working collaboration between primary care physicians and gastroenterologists is necessary to make sure that vaccinations are optimized and that patients are screened for colon cancer, skin cancer, bone loss, depression, and other treatable and preventable complications.
The microbiota in the lumen of patients with Crohn's disease (CD) is characterized by reduced diversity, particularly Firmicutes and Bacteroidetes. It is unknown whether the introduction of the ...intestinal microbiota from healthy individuals could correct this dysbiosis and reverse mucosal inflammation. We investigated the response to fecal microbial transplantation (FMT) from healthy individuals to subjects with active CD.
We performed a prospective open-label study (uncontrolled) of FMT from healthy donors to subjects with active CD. A single FMT was performed by colonoscopy. Recipients' microbial diversity, mucosal T-cell phenotypes, and clinical and inflammatory parameters were measured over 12 weeks, and safety over 26 weeks.
Nineteen subjects were treated with FMT and completed the study follow-up. Fifty-eight percent (11/19) demonstrated a clinical response (Harvey-Bradshaw Index decrease >3) following FMT. Fifteen subjects had sufficient pre/postfecal samples for analysis. A significant increase in microbial diversity occurred after FMT (P = 0.02). This was greater in clinical responders than nonresponders. Patients who experienced a clinical response demonstrated a significant shift in fecal microbial composition toward their donor's profile as assessed by the Bray-Curtis index at 4 weeks (P = 0.003). An increase in regulatory T cells (CD4CD25CD127lo) was also noted in recipients' lamina propria following FMT. No serious adverse events were noted over the 26-week study period.
In this open-label study, FMT led to an expansion in microbial bacterial diversity in patients with active CD. FMT was overall safe, although the clinical response was variable. Determining donor microbial factors that influence clinical response is needed before randomized clinical trials of FMT in CD.
The role of cytomegalovirus (CMV) in exacerbations of inflammatory bowel disease (IBD) remains a topic of ongoing debate. Current data are conflicting as to whether CMV worsens inflammation in those ...with severe colitis, or is merely a surrogate marker for severe disease. The interpretation of existing results is limited by mostly small, retrospective studies, with varying definitions of disease severity and CMV disease. CMV colitis is rare in patients with Crohn's disease or mild-moderate ulcerative colitis. In patients with severe and/or steroid-refractory ulcerative colitis, local reactivation of CMV can be detected in actively inflamed colonic tissue in about 30% of cases. Where comparisons between CMV+ and CMV- steroid-refractory patients can be made, most, but not all, studies show no difference in outcomes according to CMV status. Treatment with antiviral therapy has allowed some patients with severe colitis to avoid colectomy despite poor response to conventional IBD therapies. This article reviews the immunobiology of CMV disease, the evidence for CMV's role in disease severity, and discusses the outcomes with antiviral therapy.
Exosomes are 30–150 nm sized vesicles released by a variety of cells, and are found in most physiological compartments (feces, blood, urine, saliva, breast milk). They can contain different cargo, ...including nucleic acids, proteins and lipids. In Inflammatory Bowel Disease (IBD), a distinct exosome profile can be detected in blood and fecal samples. In addition, circulating exosomes can carry targets on their surface for monoclonal antibodies used as IBD therapy. This review aims to understand the exosome profile in humans and other mammals, the cargo contained in them, the effect of exosomes on the gut, and the application of exosomes in IBD therapy.
Antibodies to infliximab (ATIs) have been associated with loss of clinical response and lower serum infliximab (IFX) levels in some studies of patients with inflammatory bowel disease (IBD). This has ...important implications for patient management and development of novel biologic therapies. The objective of this study was to perform a systematic review and meta-analysis of studies that reported clinical outcomes and IFX levels according to patients' ATI status.
MEDLINE, Web of Science, CINAHL, Scopus, and EMBASE were searched for eligible studies. Quality assessment was undertaken using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. Raw data from studies meeting inclusion criteria was pooled for meta-analysis of effect estimates. Sensitivity analysis was performed for all outcomes. Funnel plot was performed to assess for publication bias.
Thirteen studies met the inclusion criteria, and reported results in 1,378 patients with IBD. All included studies had a high risk of bias in at least one quality domain. The pooled risk ratio (RR) of loss of clinical response to IFX in patients with IBD who had ATIs was 3.2 (95% confidence interval (CI): 2.0-4.9, P<0.0001), when compared with patients without ATIs. This effect estimate was predominantly based on data from patients (N=494) with Crohn's disease (RR: 3.2, 95% CI: 1.9-5.5, P<0.0001). Data only from patients with ulcerative colitis (n=86) exhibited a non-significant RR of loss of response of 2.2 (95% CI: 0.5-9.0, P=0.3) in those with ATIs. Heterogeneity existed between studies, in both methods of ATI detection, and clinical outcomes reported. Three studies (n=243) reported trough serum IFX levels according to ATI status; the standardized mean difference in trough serum IFX levels between groups was -0.8 (95% CI -1.2, -0.4, P<0.0001). A funnel plot suggested the presence of publication bias.
The presence of ATIs is associated with a significantly higher risk of loss of clinical response to IFX and lower serum IFX levels in patients with IBD. Published studies on this topic lack uniform reporting of outcomes. High risk of bias was present in all the included studies.
Summary
Background
Vitamin D deficiency is highly prevalent among patients with IBD, however, data on its association with clinical outcomes are conflicting.
Aim
To perform a systematic review and ...meta‐analysis to explore the association of low vitamin D status with clinical outcomes in patients with IBD.
Methods
We searched PubMed, Embase, Scopus and Web of Science from inception to February 2018 for observational studies evaluating the association of low 25(OH)D status on IBD disease activity, mucosal inflammation, clinical relapse and quality of life. Odds ratios (ORs) were pooled and analysed using a random effects model.
Results
Twenty‐seven studies were eligible for inclusion comprising 8316 IBD patients (3115 ulcerative colitis, 5201 Crohn's disease). Among IBD patients, low 25(OH)D status was associated with increased odds of disease activity (OR 1.53, 95% CI 1.32‐1.77, I2 = 0%), mucosal inflammation (OR 1.25, 95% CI 1.06‐1.47, I2 = 0%), low quality of life (QOL) scores (OR 1.30, 95% CI 1.06‐1.60, I2 = 0%) and future clinical relapse (OR 1.23, 95% CI 1.03‐1.47, I2 = 0%). In subgroup analysis, low vitamin D status was associated with Crohn's disease activity (OR 1.66, 95% CI 1.36‐2.03, I2 = 0%), mucosal inflammation (OR 1.39, 95% CI 1.03‐1.85, I2 = 0%), clinical relapse (OR 1.35, 95% CI 1.14‐1.59, I2 = 0%), and low QOL scores (OR 1.25, 95% CI 1.04‐1.50, I2 = 0%) and ulcerative colitis disease activity (OR 1.47, 95% CI 1.03‐2.09, I2 = 0%) and clinical relapse (OR 1.20, 95% 1.01‐1.43, I2 = 0%).
Conclusions
Low 25(OH)D status is a biomarker for disease activity and predictor of poor clinical outcomes in IBD patients.
Background and Aims:
A number of observational studies have reported an association between serum levels of infliximab IFX at various thresholds, and clinical outcomes in inflammatory bowel disease ...IBD. This association has not previously been systematically analysed.
Methods:
Systematic review of studies that reported serum infliximab levels according to outcomes in IBD. Primary outcome was clinical remission, and secondary outcomes included endoscopic remission, C-reactive protein CRP levels, and colectomy. Meta-analysis of raw data was performed where appropriate. A quality assessment was also undertaken.
Results:
A total of 22 studies met the inclusion criteria, including 3483 patients; 12 studies reported IFX levels in a manner suitable for determining effect estimates. During maintenance therapy, patients in clinical remission had significantly higher mean trough IFX levels than patients not in remission: 3.1 µg/ml versus 0.9 µg/ml. The standardised mean difference in serum IFX levels between groups was 0.6 µg/ml (95% confidence interval CI 0.4-0.9, p = 0.0002. Patients with an IFX level > 2 µg/ml were more likely to be in clinical remission (risk ratio RR 2.9, 95% CI 1.8-4.7, p < 0.001, or achieve endoscopic remission RR 3, 95% CI 1.4-6.5, p = 0.004 than patients with levels < 2 µg/ml.
Conclusions:
There is a significant difference between serum infliximab levels in patients with IBD in remission, compared with those who relapse. A trough threshold during maintenance > 2 µg/ml is associated with a greater probability of clinical remission and mucosal healing.
Long-standing ulcerative colitis is an established risk factor for colorectal neoplasia. A number of observational studies have suggested that evidence of mucosal inflammation (endoscopic or ...histologic) is associated with a greater risk for colorectal neoplasia than is mucosal healing. Our goal was to systematically analyze the risk of colorectal neoplasia in patients with ulcerative colitis who have ongoing mucosal inflammation to better inform surveillance strategies.
We performed a systematic review and meta-analysis of the effect of endoscopic and/or histologic inflammation on the risk of colorectal neoplasia in cohort and case-control studies. Sensitivity analyses for study setting and case definition were performed.
Six studies met the inclusion criteria, incorporating outcomes in 1443 patients. No study used a single validated measure for mucosal inflammation. The pooled odds ratio for colorectal neoplasia was 3.5 (95% confidence interval CI, 2.6-4.8; P < .001) in those with any mucosal inflammation and 2.6 (95% CI, 1.5-4.5; P = .01) in those with histologic inflammation, when compared with those with mucosal healing. The overall quality of the studies was good.
The presence of objective evidence of mucosal inflammation during follow-up in patients with ulcerative colitis is associated with a greater risk of subsequent colorectal neoplasia than in those with mucosal healing. This risk factor should be considered in guidelines on surveillance intervals for these patients.
Extracellular vesicles (EVs) are membrane-enclosed particles released by cells as a means of intercellular communication. They are potential novel biomarkers, as they are readily isolated from body ...fluids, and their composition reflects disease pathways. Whether these particles are released from sites of intestinal inflammation in inflammatory bowel disease (IBD) has not previously been determined.
EVs were isolated by ultracentrifugation of colonic luminal fluid aspirates and characterized according to surface proteins, and constituent mRNA and proteins. The effects of EVs on colonic epithelial cells and macrophages in culture were assessed at the transcriptional, translational, and functional levels.
Intestinal luminal aspirates contained abundant EVs, at a mean concentration of 4.3 × 10 particles/mL and with a mean diameter of 146 nm. EVs from patients with IBD with a high endoscopic score (≥1) contained significantly higher mRNA and protein levels of interleukin 6 (IL-6), IL-8, IL-10, and tumor necrosis factor α than EVs from healthy controls. EVs were absorbed by cultured colonic epithelial cells, leading to an increased translation of IL-8 protein by recipient cells when treated with EVs from patients with IBD. EVs and EV-treated epithelial cells induced migration of a significantly greater number of macrophages than epithelial cells alone.
EVs shed from sites of intestinal inflammation in patients with IBD have a distinct mRNA and protein profile from those of healthy individuals. These EVs have proinflammatory effects on the colonic epithelium, in vitro. Their stability in luminal samples and their mRNA and protein content identify them as a potential fecal biomarker that reflects mucosal inflammatory pathways.
Antibodies to infliximab (ATIs) have been associated with a risk of infusion reactions in some studies of patients with inflammatory bowel disease. However, many factors, such as immunomodulators and ...dosing schedule, may influence this association. The aim of this article was to provide a pooled estimate of the risk of infusion reactions according to patients' ATI status and analyze the relationship of immunomodulators to this risk.
Public databases were searched for eligible studies. Quality assessment was undertaken for all studies using Grading of Recommendations Assessment, Development and Evaluation criteria. Raw data from studies meeting inclusion criteria were pooled for meta-analysis of effect estimates. Sensitivity analysis was performed for all outcomes. Funnel plot was performed to assess for publication bias.
Eight studies met the inclusion criteria, with a pooled total of 1351 subjects. Seven of the 8 studies had a high risk of bias in at least 1 quality domain. The cumulative data indicated that there was a higher risk ratio (RR) of any acute infusion reaction (RR 2.4; 95% confidence interval CI 1.5-3.8, P < 0.001) and severe infusion reactions (RR 5.8, 95% CI 1.7-19, P = 0.004) in patients with ATIs when compared with patients without ATIs. The RR of delayed hypersensitivity reactions was not significantly different between ATI+ and ATI- patients (RR 2.8, 95% CI 0.2-33, P = 0.4). Patients prescribed immunomodulators during maintenance infliximab therapy had a reduction in their risk for ATI development (RR 0.6, 95% CI 0.4-0.9, P = 0.02) and infusion reactions (RR 0.6, 95% CI 0.4-0.8, P < 0.001).
The presence of ATIs is associated with a significantly higher risk of acute infusion reactions, but not delayed hypersensitivity reactions, in patients with inflammatory bowel disease. Concomitant immunomodulators reduce this risk.
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