Short- and long-term treatment targets in inflammatory bowel diseases (IBDs) evolved during the last decade, shifting from symptom control to endoscopic healing and patient-centered parameters. The ...STRIDE-II consensus placed these targets on a timeline from initiating treatment and introduced additional targets, normalization of serum and fecal biomarkers, restoration of quality of life, prevention of disability, and, in children, restoration of growth. Transmural healing in Crohn’s disease and histologic healing in ulcerative colitis currently serve as adjunct measures to gauge remission depth. However, whether early treatment according to a treat-to-target paradigm affects the natural course of IBD remains unclear, leading to the need for prospective disease-modification trials. The SPIRIT consensus defined the targets for these trials to assess the long-term impact of early treatment on quality of life, disability, disease complications, risk of neoplastic lesions, and mortality. As further data emerge about the risk-benefit balance of aiming toward deeper healing, the targets in treating IBDs may continue to shift.
Background & Aims Infliximab, a tumor necrosis factor antagonist, is effective for treating patients with Crohn’s disease (CD) and ulcerative colitis (UC). We aimed to determine whether dosing based ...on therapeutic drug monitoring increases rate of remission and whether continued concentration-based dosing is superior to clinically based dosing of infliximab for maintaining remission in patients with CD and UC. Methods We performed a 1-year randomized controlled trial at a tertiary referral center, including 263 adults (178 with CD and 85 with UC) with stable responses to maintenance infliximab therapy. Doses were escalated or reduced using an algorithm to reach a target trough concentration (TC) of 3–7 μg/mL in all patients (optimization phase). Patients were randomly assigned (1:1) to groups that received infliximab dosing based on their clinical features (n = 123) or continued dosing based on TCs (n = 128) (maintenance phase). The primary end point was clinical and biochemical remission at 1 year after the optimization phase. Results At screening, 115 of 263 patients had a TC of infliximab of 3–7 μg/mL (43.7%). Of 76 patients with TCs <3 μg/mL, 69 patients (91%) achieved TCs of 3–7 μg/mL after dose escalation. This resulted in a higher proportion of CD patients in remission than before dose escalation (88% vs 65%; P = .020) and a decrease in the median concentration of C-reactive protein, compared with before the dose increase (3.2 vs 4.3 mg/L; P < .001); these changes were not observed in patients with UC. Of 72 patients with TCs >7 μg/mL, 67 patients (93%) achieved TCs of 3–7 μg/mL after dose reduction. This resulted in a 28% reduction in drug cost from before dose reduction ( P < .001). Sixty-six percent of patients whose dosing was based on clinical features and 69% whose dosing was based on TC achieved remission, the primary end point ( P = .686). Disease relapsed in 21 patients who received clinically based dosing (17%) and 9 patients who received concentration-based dosing (7%) ( P = .018). Conclusions Targeting patients’ infliximab TCs to 3–7 μg/mL results in a more efficient use of the drug. After dose optimization, continued concentration-based dosing was not superior to clinically based dosing for achieving remission after 1 year, but was associated with fewer flares during the course of treatment. ClinicalTrialsRegister.eu number: 2011-002061-38.
Ulcerative colitis (UC) is an inflammatory disease that mainly affects the colon and rectum. It is believed that genetic factors, host immune system disorders, intestinal microbiota dysbiosis, and ...environmental factors contribute to the pathogenesis of UC. However, studies on the role of intestinal microbiota in the pathogenesis of UC have been inconclusive. Studies have shown that probiotics improve intestinal mucosa barrier function and immune system function and promote secretion of anti-inflammatory factors, thereby inhibiting the growth of harmful bacteria in the intestine. Fecal microbiota transplantation (FMT) can reduce bowel permeability and thus the severity of disease by increasing the production of short-chain fatty acids, especially butyrate, which help maintain the integrity of the epithelial barrier. FMT can also restore immune dysbiosis by inhibiting Th1 differentiation, activity of T cells, leukocyte adhesion, and production of inflammatory factors. Probiotics and FMT are being increasingly used to treat UC, but their use is controversial because of uncertain efficacy. Here, we briefly review the role of intestinal microbiota in the pathogenesis and treatment of UC.
Highlights • Chronic colonic inflammation may lead to colitis associated cancer (CAC). • CAC does not display the adenoma-carcinoma sequence typical for sporadic CRC. • Early mutations in p53 and ...K-ras are found frequently, mutations in APC occur late. • Reactive oxygen species (ROS) are thought to contribute to dysplastic lesions. • The intestinal microbiome may play an important role in CAC development.
The intestinal mucosal barrier controlling the resident microbiome is dependent on a protective mucus layer generated by goblet cells, impairment of which is a hallmark of the inflammatory bowel ...disease, ulcerative colitis. Here, we show that IL-18 is critical in driving the pathologic breakdown of barrier integrity in a model of colitis. Deletion of Il18 or its receptor Il18r1 in intestinal epithelial cells (Δ/EC) conferred protection from colitis and mucosal damage in mice. In contrast, deletion of the IL-18 negative regulator Il18bp resulted in severe colitis associated with loss of mature goblet cells. Colitis and goblet cell loss were rescued in Il18bp−/−;Il18rΔ/EC mice, demonstrating that colitis severity is controlled at the level of IL-18 signaling in intestinal epithelial cells. IL-18 inhibited goblet cell maturation by regulating the transcriptional program instructing goblet cell development. These results inform on the mechanism of goblet cell dysfunction that underlies the pathology of ulcerative colitis.
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•IL-18/IL-18R signaling in intestinal epithelial cells promotes DSS-induced colitis•Hyperactive epithelial IL-18 signaling drives goblet cell depletion during colitis•Epithelial IL-18 signaling prevents goblet cell maturation prior to colitis•IL-18 intercepts the transcriptional program controlling goblet cell development
Production of the cytokine IL-18 by epithelial cells, previously thought to protect the mucosal barrier from the effect of inflammation, is critical to drive the pathologic breakdown of intestinal barrier integrity, directly inhibiting goblet cell maturation prior to the onset of colitis.
A comprehensive review and update on ulcerative colitis Gajendran, Mahesh; Loganathan, Priyadarshini; Jimenez, Guillermo ...
Disease-a-month,
December 2019, 2019-Dec, 2019-12-00, 20191201, Letnik:
65, Številka:
12
Journal Article
Recenzirano
Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disorder of the colon that causes continuous mucosal inflammation extending from the rectum to the more proximal colon, with ...variable extents. UC is characterized by a relapsing and remitting course. UC was first described by Samuel Wilks in 1859 and it is more common than Crohn's disease worldwide. The overall incidence and prevalence of UC is reported to be 1.2–20.3 and 7.6–245 cases per 100,000 persons/year respectively. UC has a bimodal age distribution with an incidence peak in the 2nd or 3rd decades and followed by second peak between 50 and 80 years of age. The key risk factors for UC include genetics, environmental factors, autoimmunity and gut microbiota. The classic presentation of UC include bloody diarrhea with or without mucus, rectal urgency, tenesmus, and variable degrees of abdominal pain that is often relieved by defecation. UC is diagnosed based on the combination of clinical presentation, endoscopic findings, histology, and the absence of alternative diagnoses. In addition to confirming the diagnosis of UC, it is also important to define the extent and severity of inflammation, which aids in the selection of appropriate treatment and for predicting the patient's prognosis. Ileocolonoscopy with biopsy is the only way to make a definitive diagnosis of UC. A pathognomonic finding of UC is the presence of continuous colonic inflammation characterized by erythema, loss of normal vascular pattern, granularity, erosions, friability, bleeding, and ulcerations, with distinct demarcation between inflamed and non-inflamed bowel. Histopathology is the definitive tool in diagnosing UC, assessing the disease severity and identifying intraepithelial neoplasia (dysplasia) or cancer. The classical histological changes in UC include decreased crypt density, crypt architectural distortion, irregular mucosal surface and heavy diffuse transmucosal inflammation, in the absence of genuine granulomas. Abdominal computed tomographic (CT) scanning is the preferred initial radiographic imaging study in UC patients with acute abdominal symptoms. The hallmark CT finding of UC is mural thickening with a mean wall thickness of 8 mm, as opposed to a 2–3 mm mean wall thickness of the normal colon. The Mayo scoring system is a commonly used index to assess disease severity and monitor patients during therapy. The goals of treatment in UC are three fold—improve quality of life, achieve steroid free remission and minimize the risk of cancer. The choice of treatment depends on disease extent, severity and the course of the disease. For proctitis, topical 5-aminosalicylic acid (5-ASA) drugs are used as the first line agents. UC patients with more extensive or severe disease should be treated with a combination of oral and topical 5-ASA drugs +/− corticosteroids to induce remission. Patients with severe UC need to be hospitalized for treatment. The options in these patients include intravenous steroids and if refractory, calcineurin inhibitors (cyclosporine, tacrolimus) or tumor necrosis factor-α antibodies (infliximab) are utilized. Once remission is induced, patients are then continued on appropriate medications to maintain remission. Indications for emergency surgery include refractory toxic megacolon, colonic perforation, or severe colorectal bleeding.
Administration of tryptophan and some of its metabolites reduces the severity of colitis in mice, whereas removing tryptophan from the diet increases susceptibility to colitis. Transfer of the ...intestinal microbiome transfers the colitogenic phenotype from tryptophan starved animals to normally nourished mice. We aimed to systematically evaluate serum levels of tryptophan and its metabolites in patients with inflammatory bowel diseases (IBD), and study their association with clinical and serologic features.
We studied 535 consecutive patients with IBD (211 with ulcerative colitis UC, 234 with Crohn’s disease CD; 236 male), enrolled in Germany from August 2013 through April 2014 and followed until July 2016. Serum samples were collected from patients and 291 matched individuals without IBD (controls); levels of tryptophan were measured using high-performance liquid chromatography. Metabolites of tryptophan were measured in serum from 148 patients and 100 controls by mass spectrometry. We measured levels of interleukin 22 in serum from 28 patients by enzyme-linked immunosorbent assay. Paired stool and serum samples were collected from a subset of patients with active UC (n = 10) or CD (n = 8) to investigate associations between serum levels of tryptophan and composition of the fecal microbiota, analyzed by 16S ribosomal DNA amplicon sequencing. We used real-time polymerase chain reaction to measure levels of messenger RNAs in colonic biopsies from 60 patients with UC, 50 with CD, and 30 controls. We collected information on patients’ disease activity scores, medications, laboratory assessments, and clinical examinations during recruitment and follow-up visits.
Serum levels of tryptophan were significantly lower in patients with IBD than in controls (P = 5.3 × 10−6) with a stronger reduction in patients with CD (vs control; P = 1.1 × 10−10) than UC (vs control; P = 2.8 × 10−3). We found a negative correlation between serum levels of tryptophan and disease activity or levels of C-reactive protein. Levels of messenger RNAs encoding tryptophan 2,3-dioxygenase-2 and solute carrier family 6 member 19 (also called B0AT1) were significantly decreased in colonic biopsies from patients with IBD compared with controls, whereas level of messenger RNA encoding indoleamine 2,3-dioxygenase-1 was significantly increased. The composition of the fecal microbiota associated with serum levels of tryptophan. Analysis of tryptophan metabolites revealed activation of the kynurenine pathway, based on high levels of quinolinic acid, in patients with IBD compared with controls. Serum concentration of interleukin 22 associated with disease activity in patients with IBD; there was an inverse association between levels of interleukin 22 and serum levels of tryptophan.
In an analysis of serum samples from more than 500 patients with IBD, we observed a negative correlation between serum levels of tryptophan and disease activity. Increased levels of tryptophan metabolites—especially of quinolinic acid—indicated a high activity of tryptophan degradation in patients with active IBD. Tryptophan deficiency could contribute to development of IBD or aggravate disease activity. Interventional clinical studies are needed to determine whether modification of intestinal tryptophan pathways affects the severity of IBD.
Decreases in the diversity of enteric bacterial populations are observed in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Less is known about the virome in these diseases. We show ...that the enteric virome is abnormal in CD and UC patients. In-depth analysis of preparations enriched for free virions in the intestine revealed that CD and UC were associated with a significant expansion of Caudovirales bacteriophages. The viromes of CD and UC patients were disease and cohort specific. Importantly, it did not appear that expansion and diversification of the enteric virome was secondary to changes in bacterial populations. These data support a model in which changes in the virome may contribute to intestinal inflammation and bacterial dysbiosis. We conclude that the virome is a candidate for contributing to, or being a biomarker for, human inflammatory bowel disease and speculate that the enteric virome may play a role in other diseases.
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•The enteric virome is abnormal in multiple inflammatory bowel disease patient cohorts•The enteric virome richness increases in Crohn’s disease and ulcerative colitis•Decreases in bacterial diversity and richness in IBD do not explain virome changes•Virome changes in Crohn’s disease and ulcerative colitis are disease specific
The enteric virome is abnormal in multiple cohorts of inflammatory bowel disease patients, exhibiting disease-specific features that are not explained by changes in bacterial diversity and richness.
SERENE UC (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Ulcerative Colitis) evaluated the efficacy of higher adalimumab induction ...and maintenance dose regimens in patients with ulcerative colitis.
This phase 3, double-blind, randomized trial included induction and maintenance studies, with a main study (ex-Japan) and Japan substudy. Eligible patients (18–75 years, full Mayo score 6–12, centrally read endoscopy subscore 2–3) were randomized 3:2 to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3) or standard induction regimen (160 mg at week 0 and 80 mg at week 2); all received 40 mg at weeks 4 and 6. At week 8, all patients were rerandomized 2:2:1 (main study) to 40 mg every week (ew), 40 mg every other week (eow), or exploratory therapeutic drug monitoring; or 1:1 (Japan substudy) to 40 mg ew or 40 mg eow maintenance regimens.
In the main study, 13.3% vs 10.9% of patients receiving the higher induction regimen vs standard induction regimen achieved clinical remission (full Mayo score ≤2 with no subscore >1) at week 8 (induction primary end point; P = .265); among week-8 responders, 39.5% vs 29.0% receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (maintenance primary end point; P = .069). In the integrated (main + Japan) population, 41.1% vs 30.1% of week-8 responders receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (nominal P = .045). Safety profiles were comparable between dosing regimens.
Although primary end points were not met, a >10% absolute difference in clinical remission was demonstrated with higher adalimumab maintenance dosing. Higher dosing regimens were generally well tolerated and consistent with the known safety profile of adalimumab in ulcerative colitis. ClinicalTrials.gov, Number: NCT002209456.
SERENE UC confirms adalimumab is safe and effective in ulcerative colitis. Higher and standard induction dosing were similar and clinical remission was more frequently achieved with higher vs standard maintenance dosing.
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