We evaluated the efficacy and safety of upadacitinib, an oral selective inhibitor of Janus kinase 1, as induction therapy for ulcerative colitis (UC).
We performed a multicenter, double-blind, phase ...2b study of 250 adults with moderately to severely active UC and an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressive agents, and/or biologic therapies. Patients were randomly assigned to groups that received placebo or induction therapy with upadacitinib (7.5 mg, 15 mg, 30 mg, or 45 mg, extended release), once daily for 8 weeks. The primary endpoint was the proportion of participants who achieve clinical remission according to the adapted Mayo score at week 8. No multiplicity adjustments were applied.
At week 8, 8.5%, 14.3%, 13.5%, and 19.6% of patients receiving 7.5 mg, 15 mg, 30 mg, or 45 mg upadacitinib, respectively, achieved clinical remission compared with none of the patients receiving placebo (P = .052, P = .013, P = .011, and P = .002 compared with placebo, respectively). Endoscopic improvement at week 8, defined as endoscopic subscore of ≤ 1, was achieved in 14.9%, 30.6%, 26.9%, and 35.7% of patients receiving upadacitinib 7.5 mg, 15 mg, 30 mg, or 45 mg, respectively, compared with 2.2% receiving placebo (P = .033, P < .001, P < .001, and P < .001 compared with placebo, respectively). One event of herpes zoster and 1 participant with pulmonary embolism and deep venous thrombosis (diagnosed 26 days after treatment discontinuation) were reported in the group that received upadacitinib 45 mg once daily. Increases in serum lipid levels and creatine phosphokinase with upadacitinib were observed.
In a phase 2b trial, 8 weeks of treatment with upadacitinib was more effective than placebo for inducing remission in patients with moderately to severely active UC. (ClinicalTrials.gov, Number: NCT02819635)
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Inflammatory bowel disease (IBD) is an inflammatory disorder caused by hyperactivation of effector immune cells that produce high levels of proinflammatory cytokines. The aims of our study were to ...determine whether orally administered blueberry extract (BE) could attenuate or prevent the development of experimental colitis in mice and to elucidate the mechanism of action. Female Balb/C mice (n=7) were randomized into groups differing in treatment conditions (prevention and treatment) and dose of BE (50 mg/kg body weight). Acute ulcerative colitis was induced by oral administration of 3% dextran sodium sulfate for 7 days in drinking water. Colonic mucosal injury was assessed by clinical, macroscopic, biochemical and histopathological examinations. BE significantly decreased disease activity index and improved the macroscopic and histological score of colons when compared to the colitis group (P<.05). BE markedly attenuated myeloperoxidase accumulation (colitis group 54.97±2.78 nmol/mg, treatment group 30.78±1.33 nmol/mg) and malondialdehyde in colon and prostaglandin E2 level in serum while increasing the levels of superoxide dismutase and catalase (colitis group 11.94±1.16 U/ml, BE treatment group 16.49±0.39 U/ml) compared with the colitis group (P<.05). mRNA levels of the cyclooxygenase (COX)-2, interferon-γ, interleukin (IL)-1β and inducible nitric oxide synthase cytokines were determined by reverse transcriptase polymerase chain reaction. Immunohistochemical analysis showed that BE attenuates the expression of COX-2 and IL-1β in colonic tissue. Moreover, BE reduced the nuclear translocation of nuclear transcription factor kappa B (NF-κB) by immunofluorescence analysis. Thus, the anti-inflammatory effect of BE at colorectal sites is a result of a number of mechanisms: antioxidation, down-regulation of the expression of inflammatory mediators and inhibition of the nuclear translocation of NF-κB.
Background & Aims Levels of microRNAs are altered in intestinal tissues of patients with Crohn's disease (CD). The adherent-invasive Escherichia coli (AIEC), which colonize the ileal mucosa of ...patients with CD, adhere to and invade intestinal epithelial cells. We investigated the mechanism by which AIEC infection alters the expression of microRNAs and the host immune response. Methods Levels of microRNAs in human intestinal epithelial T84 cells and in mouse enterocytes were measured using quantitative reverse-transcription polymerase chain reaction. Luciferase assays were used to measure binding of microRNAs to the 3′-untranslated region of messenger RNA targets. Binding of nuclear factor-κB to promoters of genes encoding microRNAs was assessed by chromatin immunoprecipitation assays. Autophagy was measured by immunoblot analyses and immunofluorescent labeling of LC3. Anti-microRNAs were transferred to mice using ileal loops. Biopsy specimens from the terminal ileum of patients with ulcerative colitis (n = 20), CD (n = 20), or individuals without inflammatory bowel disease undergoing surveillance colonoscopies (controls, n = 13) were collected during endoscopic examination. Results AIEC infection up-regulated levels of microRNA (MIR) 30C and MIR130A in T84 cells and in mouse enterocytes by activating nuclear factor-κB. Up-regulation of these microRNAs reduced the levels of ATG5 and ATG16L1 and inhibited autophagy, leading to increased numbers of intracellular AIEC and an increased inflammatory response. In ileal biopsy samples of patients with CD, there was an inverse correlation between levels of MIR30C and MIR130A and those of ATG5 and ATG16L1, supporting in vitro findings. Inhibition of MIR30C and MIR130A in cultured intestinal epithelial cells and in mouse enterocytes blocked AIEC-induced inhibition of ATG5 and ATG16L1 expression and restored functional autophagy. This resulted in more effective clearance of intracellular AIEC and reduced AIEC-induced inflammation. Conclusions Infection with AIEC up-regulates microRNAs to reduce expression of proteins required for autophagy and autophagy response in intestinal epithelial cells. Ileal samples from patients with CD have increased levels of these same microRNAs and reduced levels of ATG5 and ATG16L1.
No specific biomarker for immune checkpoint inhibitor (ICI)-induced colitis has been established. Previously, we identified anti-integrin αvβ6 autoantibodies in >90% of patients with ulcerative ...colitis (UC). Given that a subset of ICI-induced colitis is similar to UC, we aimed to clarify the relationship between such autoantibodies and ICI-induced colitis.
Serum anti-integrin αvβ6 autoantibody levels were compared between 26 patients with ICI-induced colitis and 157 controls. Endoscopic images of ICI-induced colitis were centrally reviewed. Characteristics of anti-integrin αvβ6 autoantibodies in the ICI-induced colitis patients were compared with those of UC patients.
Anti-integrin αvβ6 autoantibodies were found in 8/26 (30.8%) patients with ICI-induced colitis and 3/157 (1.9%) controls (P < 0.001). Patients with anti-integrin αvβ6 autoantibodies had significantly more typical UC endoscopic features than those without the autoantibodies (P < 0.001). Anti-integrin αvβ6 autoantibodies in ICI-induced colitis patients were associated with grade ≥3 colitis (P = 0.001) and steroid resistance (P = 0.005). Anti-integrin αvβ6 autoantibody titers correlated with ICI-induced colitis disease activity. Anti-integrin αvβ6 autoantibodies of ICI-induced colitis exhibited similar characteristics to those of UC.
Anti-integrin αvβ6 autoantibodies may serve as potential biomarkers for the diagnosis, classification, risk management, and monitoring the disease activity, of ICI-induced colitis.
The optimal method for monitoring quiescent disease in patients with Crohn’s disease(CD) and ulcerative colitis is yet to be determined. Endoscopic evaluation with ileocolonoscopy is the gold ...standard but is invasive,costly,and time-consuming. There are many commercially available biomarkers that may be used in clinical practice to evaluate disease status in patients with inflammatory bowel disease(IBD),but the most widely adopted biomarkers are C-reactive protein(CRP) and fecal calprotectin(FC). This review summarizes the evidence for utilizing CRP and FC for monitoring IBD during clinical remission and after surgical resection. Endoscopic correlation with CRP and FC is evaluated in each disease state. Advantages and drawbacks of each biomarker are discussed with special consideration of isolated ileal CD. Fecal immunochemical testing,traditionally used for colorectal cancer screening,is mentioned as a potential new alternative assay in the evaluation of IBD. Based on a mixture of information gleaned from biomarkers,clinical status,and endoscopic evaluation,the best treatment decisions can be made for the patient with IBD.
Summary
Background
The effectiveness of vedolizumab as a treatment for extraintestinal manifestations (EIM) is questionable due to its gut‐specificity.
Aim
To assess effectiveness of vedolizumab for ...EIM in patients with inflammatory bowel disease (IBD) in a large real‐life experience cohort.
Methods
Between June and December 2014, 173 patients with Crohn's disease and 121 with ulcerative colitis were treated with vedolizumab. Patients were followed until week 54. EIM activity was assessed at weeks 0, 6, 14, 22, 30 and 54 by using a 3‐step scale: complete remission, partial response and no response.
Results
At baseline, 49 (16.7%) patients had EIMs of which 47 had inflammatory arthralgia/arthritis, four had cutaneous lesions and two had both rheumatologic and skin EIM. At week 54, 21 (44.7%) patients had complete remission for inflammatory arthralgia/arthritis and three (75%) for cutaneous EIM. In multivariate analysis, complete remission of inflammatory arthralgia/arthritis was associated with clinical remission of IBD (OR = 1.89, IC95% 1.05‐3.41, P = .03) and recent onset of inflammatory arthralgia/arthritis (OR = 1.99, IC95% 1.12‐3.52, P = .02). During the follow‐up period, 34 (13.8%) patients without any EIM at baseline, developed incident cases of inflammatory arthralgia/arthritis consisting mostly of peripheral arthralgia without evidence of arthritis and 14 (4.8%) incident cases of paradoxical skin manifestation.
Conclusion
Vedolizumab therapy is commonly associated with improvement in EIM. This was associated with quiescent IBD and recent EIM. However, paradoxical skin manifestation and inflammatory arthralgia/arthritis may occur upon vedolizumab therapy.
Linked Content
This article is linked to Barclay and Stamp paper. To view this article visit https://doi.org/10.1111/apt.14465.
Abstract
Summary
Gene-based supervised machine learning classification models have been widely used to differentiate disease states, predict disease progression and determine effective treatment ...options. However, many of these classifiers are sensitive to noise and frequently do not replicate in external validation sets. For complex, heterogeneous diseases, these classifiers are further limited by being unable to capture varying combinations of genes that lead to the same phenotype. Pathway-based classification can overcome these challenges by using robust, aggregate features to represent biological mechanisms. In this work, we developed a novel pathway-based approach, PRObabilistic Pathway Score, which uses genes to calculate individualized pathway scores for classification. Unlike previous individualized pathway-based classification methods that use gene sets, we incorporate gene interactions using probabilistic graphical models to more accurately represent the underlying biology and achieve better performance. We apply our method to differentiate two similar complex diseases, ulcerative colitis (UC) and Crohn's disease (CD), which are the two main types of inflammatory bowel disease (IBD). Using five IBD datasets, we compare our method against four gene-based and four alternative pathway-based classifiers in distinguishing CD from UC. We demonstrate superior classification performance and provide biological insight into the top pathways separating CD from UC.
Availability and Implementation
PROPS is available as a R package, which can be downloaded at http://simtk.org/home/props or on Bioconductor.
Supplementary information
Supplementary data are available at Bioinformatics online.
Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD
)-dependent protein deacetylase that is involved in various diseases, including cancers, metabolic diseases, and inflammation-associated ...diseases. However, the role of SIRT1 in ulcerative colitis (UC) is still confusing.
To investigate the role of SIRT1 in intestinal epithelial cells (IECs) in UC and further explore the underlying mechanisms.
We developed a coculture model using macrophages and Caco-2 cells. After treatment with the SIRT1 activator SRT1720 or inhibitor nicotinamide (NAM), the expression of occludin and zona occludens 1 (ZO-1) was assessed by Western blot analysis. Annexin V-APC/7-AAD assays were performed to evaluate Caco-2 apoptosis. Dextran sodium sulfate (DSS)-induced colitis mice were exposed to SRT1720 or NAM for 7 d. Transferase-mediated dUTP nick-end labeling (TUNEL) assays were conducted to assess apoptosis in colon tissues. The expression levels of glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, caspase-9, and caspase-3 in Caco-2 cells and the colon tissues of treated mice were examined by quantitative real-time PCR and Western blot.
SRT1720 treatment increased the protein levels of occludin and ZO-1 and inhibited Caco-2 apoptosis, whereas NAM administration caused the opposite effects. DSS-induced colitis mice treated with SRT1720 had a lower disease activity index (
< 0.01), histological score (
< 0.001), inflammatory cytokine levels (
< 0.01), and apoptotic cell rate (
< 0.01), while exposure to NAM caused the opposite effects. Moreover, SIRT1 activation reduced the expression levels of GRP78, CHOP, cleaved caspase-12, cleaved caspase-9, and cleaved caspase-3 in Caco-2 cells and the colon tissues of treated mice.
SIRT1 activation reduces apoptosis of IECs
the suppression of endoplasmic reticulum stress-mediated apoptosis-associated molecules CHOP and caspase-12. SIRT1 activation may be a potential therapeutic strategy for UC.
Pouchitis is the most common complication after colectomy with ileal pouch-anal anastomosis (IPAA) for UC and the risk is the highest within the 1st year after surgery. The pathogenesis is not ...completely understood but clinical response to antibiotics suggests a role for gut microbiota. We hypothesised that the risk for pouchitis can be predicted based on the faecal microbial composition before colectomy.
Faecal samples from 21 patients with UC undergoing IPAA were prospectively collected before colectomy and at predefined clinical visits at 1 month, 3 months, 6 months and 12 months after IPAA. The predominant microbiota was analysed using community profiling with denaturing gradient gel electrophoresis followed by quantitative real-time PCR validation.
Cluster analysis before colectomy distinguished patients with pouchitis from those with normal pouch during the 1st year of follow-up. In patients developing pouchitis, an increase of Ruminococcus gnavus (p<0.001), Bacteroides vulgatus (p=0.043), Clostridium perfringens (p=0.011) and a reduction of two Lachnospiraceae genera (Blautia (p=0.04), Roseburia (p=0.008)) was observed. A score combining these five bacterial risk factors was calculated and presence of at least two risk factors showed a sensitivity and specificity of 100% and 63.6%, respectively.
Presence of R. gnavus, B. vulgatus and C. perfringens and absence of Blautia and Roseburia in faecal samples of patients with UC before surgery is associated with a higher risk of pouchitis after IPAA. Our findings suggest new predictive and therapeutic strategies in patients undergoing colectomy with IPAA.
Abstract
Background
The Ulcerative Colitis (UC) Narrative is a global patient and physician survey aimed at identifying the impact of UC and comparing and contrasting perceptions of UC burden and ...management approaches.
Methods
Surveys of patients with UC (self-reported diagnosis; n = 2100) and physicians (n = 1254) were completed across 10 countries by The Harris Poll between August 2017 and February 2018. Questionnaires covered multiple aspects of UC, including diagnosis, treatment, and impact on patient quality of life, in addition to standard demographic information. Descriptive statistics are reported.
Results
The majority of patients (82%) had moderate to severe UC (based on medication history; those who had only ever taken 5-aminosalicylates were excluded); 67% described their UC as controlled with few to no symptoms. On average, patients experienced 4.3 flares (standard deviation, 7.4) in the past year. Diagnostic delay was on average 2.0 years (standard deviation, 5.4); 42% of patients waited ≥1 year. Most patients (65%) felt that UC controlled their life rather than them controlling their disease. Because of the fear of repercussions, many patients had not disclosed their UC to their employer. Discussion of the emotional impact of UC during routine appointments was less of a priority for physicians, compared with patients.
Conclusions
The data from this global survey highlight that patients with UC experience diagnostic delay, poor disease control, and adverse impact on their quality of life. Patients report UC to be a mentally exhausting condition; however, emotional and mental health issues are infrequently discussed at routine appointments.
Graphical Abstract
Graphical Abstract
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