OBJECTIVES: Infliximab is effective in patients with ulcerative colitis (UC); however, one-third of patients do not respond and require additional therapies such as other biologic agents. Therefore, the aim of this study was to analyze the association between pro-inflammatory molecules and clinical efficacy to elucidate possible mechanisms for the non-response to infliximab to aid in treatment selection.
MATERIALS AND METHOD: Patients with moderate-to-severe active UC receiving infliximab in our hospital between 2010 and 2016 for whom pre-treatment serum samples were available were retrospectively evaluated. We analyzed the association between serum interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) and the clinical efficacy of infliximab. The primary endpoint was clinical response at the end of the induction period.
RESULTS: Forty-one patients were included in this study. After induction therapy, 27 patients (65.9%) showed a clinical response. Serum IL-6 levels were significantly lower in responders than in non-responders (p = .012), whereas no significant differences were noted in other factors including sMAdCAM-1 and TNF-α. Multivariate analysis identified that serum IL-6 level (odds ratio = 0.72; 95% confidence interval, 0.54-0.96; p = .027) was independently associated with response to infliximab.
CONCLUSIONS: Serum IL-6 level is associated with response to infliximab in UC. Elevated concentrations of IL-6 may provide insight to the mechanism of non-response to infliximab.
Ulcerative Colitis (3), Necrosis (2), Neoplasms (2), more mentions
BACKGROUND: Clinical guidelines are generated to preserve high-quality evidence-based care. Data on the implementation of guidelines into clinical practice are scarce, despite that guideline adherence prevents over- and undertreatment and correlates with survival. Therefore, we investigated guideline adherence for the systemic treatment in high-risk stage II and stage III colon cancer and metastatic colorectal cancer.
PATIENTS AND METHODS: In all Dutch hospitals (n = 88) 1 medical oncologist involved in colorectal cancer care was approached to participate. An online survey was conducted regarding the local standard of care for adjuvant chemotherapy in high-risk stage II and stage III colon cancer and first-line treatment regimens in metastatic colorectal cancer. Frequency tables were provided for categorical variables and compared for differences in guideline adherence according to hospital type (academic/teaching/regional).
RESULTS: The overall response rate was 70% (62 of 88). Reported guideline adherence was at least 60% of all presented settings. For high-risk stage II and stage III colon cancer, treatment strategies agreed with national guidelines in 66% and 84% of hospitals, and overtreatment patterns were identified in 28% and 13%, respectively. Targeted therapy was not routinely administered as first-line treatment in metastatic colorectal cancer (range from 63% to 71% in different settings). No differences in guideline adherence were observed among different hospital types.
CONCLUSION: Guideline adherence as reported by medical oncologists in The Netherlands is suboptimal. Possible explanations include unawareness or disagreement with the guidelines, or local financial restrictions. Our results recommend additional support of guideline implementation and monitoring in clinical practice, and investigating underlying causes in case of nonadherence.
Oncology (9) Colorectal Neoplasms (7), Colonic Neoplasms (3), more mentions
BACKGROUND: The optimal timing for performing appendectomy in adults remains controversial.
METHOD: A one-year retrospective review of adult patients with acute appendicitis who underwent appendectomy. The cohort was divided by time-to-intervention into two groups: patients who underwent appendectomy within 8 h (group 1), and those who had surgery after 8 h (group 2). Outcome measures including perioperative morbidity and mortality, post-operative length of stay, and the 30-day readmission rate were compared between the two groups.
RESULTS: A total of 116 patients who underwent appendectomy met the inclusion criteria: 75 patients (65%) in group 1, and 41 (35%) in group 2. There were no differences between group 1 & 2 in perioperative complications (6.7% vs. 9.8%, P = 0.483), postoperative length of stay (median [IQR]; 19.5 [11.5-40.5] vs. 20.0 [11.25-58.5] hours, P = 0.632), or 30-day readmission rate (2.7% vs. 4.9%, P = 0.543). There were no deaths in either group.
CONCLUSION: Delayed appendectomy performed more than 8 h was not associated with increased perioperative complications, postoperative length of stay, 30-day readmission rate, or mortality.
SUMMARY: This is a retrospective analysis of patients presenting with acute appendicitis. Outcome measures including mortality and morbidity (complications), 30-day readmission rate, and postoperative length of stay were compared in patients who underwent early appendectomy (within 8 h from time of arrival, to emergency department, to skin incision), and those who underwent delayed appendectomy (after 8 h). No reported mortality. No differences were observed between the two groups regarding complications, 30-day readmission rates, or postoperative length of stay.
INTRODUCTION: Several European studies suggest that some patients with appendicitis can be treated safely with antibiotics. A portion of patients eventually undergo appendectomy within a year, with 10%-15% failing to respond in the initial period and a similar additional proportion with suspected recurrent episodes requiring appendectomy. Nearly all patients with appendicitis in the USA are still treated with surgery. A rigorous comparative effectiveness trial in the USA that is sufficiently large and pragmatic to incorporate usual variations in care and measures the patient experience is needed to determine whether antibiotics are as good as appendectomy.
OBJECTIVES: The Comparing Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial for acute appendicitis aims to determine whether the antibiotic treatment strategy is non-inferior to appendectomy.
METHODS/ANALYSIS: CODA is a randomised, pragmatic non-inferiority trial that aims to recruit 1552 English-speaking and Spanish-speaking adults with imaging-confirmed appendicitis. Participants are randomised to appendectomy or 10 days of antibiotics (including an option for complete outpatient therapy). A total of 500 patients who decline randomisation but consent to follow-up will be included in a parallel observational cohort. The primary analytic outcome is quality of life (measured by the EuroQol five dimension index) at 4 weeks. Clinical adverse events, rate of eventual appendectomy, decisional regret, return to work/school, work productivity and healthcare utilisation will be compared. Planned exploratory analyses will identify subpopulations that may have a differential risk of eventual appendectomy in the antibiotic treatment arm.
ETHICS AND DISSEMINATION: This trial was approved by the University of Washington's Human Subjects Division. Results from this trial will be presented in international conferences and published in peer-reviewed journals.
TRIAL REGISTRATION NUMBER: NCT02800785.
BACKGROUND: Postoperative recurrence (POR) of Crohn's disease (CD) is common. Guidelines on POR management have recently been issued, but clinical practice may vary.
AIMS: To examine the current clinical practice of POR management in the USA METHODS: A web-based survey was sent to all members of the American Gastroenterological Association and the American College of Gastroenterology. The survey consisted of multiple-choice questions with clinical scenarios to assess how participants manage POR.
RESULTS: A total of 189 responses were received from practices in 34 states. 44% of participants were from academic settings. The median number of CD patients seen each month was 20-30 patients per participant. The majority of participants considered smoking, prior intestinal surgery, penetrating disease, perianal fistula, early disease onset, and long extent of disease as high-risk factors for POR. To diagnose and grade endoscopic recurrence, 57% of participants used an endoscopic scoring system; 86% defined clinical recurrence using a combination of symptoms and endoscopic findings; and 79% of participants routinely performed colonoscopy after surgery. In high-risk patients, 65% offered medical prophylaxis-most often biologics and/or immunomodulators-immediately after surgery, while 34% offered medical prophylaxis regardless of the patient's risk of POR. 64% of participants never stopped medical prophylaxis once initiated.
CONCLUSIONS: Most gastroenterologists routinely perform colonoscopy to guide POR management. The majority of these providers continue medical prophylaxis indefinitely regardless of subsequent endoscopic findings. Further research is needed to determine the risks and benefits of continuing versus deescalating therapy in patients with potentially surgically induced remission.
Immune System Diseases (2) Inflammatory Bowel Diseases (1), Fistula (1), more mentions
BACKGROUND: Prior studies have shown poor compliance with quality measures for IBD at academic and private practices. We sought to provide focused interventions to improve compliance and documentation with the IBD measures.
METHODS: Two centers, academic practice (AP) and private practice (PP), initially reviewed their compliance with eight established IBD quality measures in consecutive charts. A multi-faceted intervention was developed to improve awareness and documentation of these measures. The initial data and the quality measures were reviewed at a group meeting. Following this, a handout summarizing the measures was placed in each exam room. The AP added a new screen to the EHR that summarized the relevant IBD history, while the PP added a new template that was filled out and imported into the charts. Three months after this intervention, charts were reviewed for compliance with the measures.
RESULTS: The intervention cohort consisted of 768 patients (AP = 569/PP = 199) compared to the initial cohort of 566 patients (AP = 367/PP = 199). Improvement was seen throughout all measures compared to the initial cohort. The AP reported compliance with all relevant measures in 21% and the PP in 60% compared to 7 and 10% in the initial cohort. PP had ≥ 75% compliance with every measure, of which only assessment for bone loss and pneumococcal vaccination was under 80%. In contrast, the AP compliance ranged from 35 to 100% with assessment for bone loss, influenza, and pneumococcal vaccination scoring lowest.
CONCLUSION: Our study demonstrates that focused low-cost interventions can significantly improve compliance with IBD quality measures in different practice settings.
Muscular and Skeletal Diseases (2) Inflammatory Bowel Diseases (2), Ulcerative Colitis (1), Human Influenza (1), more mentions
Intestinal microbiome dysbiosis has been consistently described in patients with IBD. In the last decades, Escherichia coli, and the adherent-invasive E coli (AIEC) pathotype in particular, has been implicated in the pathogenesis of IBD. Since the discovery of AIEC, two decades ago, progress has been made in unravelling these bacteria characteristics and its interaction with the gut immune system. The mechanisms of adhesion of AIEC to intestinal epithelial cells (via FimH and cell adhesion molecule 6) and its ability to escape autophagy when inside macrophages are reviewed here. We also explore the existing data on the prevalence of AIEC in patients with Crohn's disease and UC, and the association between the presence of AIEC and disease location, activity and postoperative recurrence. Finally, we highlight potential therapeutic strategies targeting AIEC colonisation of gut mucosa, including the use of phage therapy, bacteriocins and antiadhesive molecules. These strategies may open new avenues for the prevention and treatment of IBD in the future.
Immune System Diseases (1) Inflammatory Bowel Diseases (2), Ulcerative Colitis (1), more mentions
BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a chronic disease usually diagnosed after the appearance of gastrointestinal symptoms. Little is known about IBD progression during its early and even preclinical phases. We aimed to determine the number of new incidental diagnoses of IBD in an older population, and evaluate disease progression from its early stages.
METHODS: We performed a retrospective analysis of 31,005 colonoscopies performed during colorectal cancer screening of patients with positive results from fecal immunochemical tests, at 11 centers in the Basque Country (Spain) from 2009 through 2014. We collected clinical and laboratory data from all asymptomatic individuals suspected to have IBD during screening colonoscopies, with histologic confirmation.
RESULTS: Colonoscopy screening led to 79 new diagnoses of ulcerative colitis, 24 of Crohn's disease, and 7 of unclassified colitis (average patient age, 57 years old; interquartile range, 52-62 years; 57% male). Eleven patients had symptoms before colonoscopy and were excluded from the analysis. Among those patients were asymptomatic at diagnosis, 36% developed symptoms after a follow-up period of 25 months (interquartile range, 10.5-42 months), mostly rectal bleeding and diarrhea. Treatment was prescribed for 81 patients (88%) and 2 cases required surgery.
CONCLUSION: We analyzed data from a large cohort of patients with IBD diagnosed at early or even preclinical stages, from an older population. New incidental diagnoses of IBD were made in 0.35% of individuals undergoing a population-based screening colonoscopy-most were classified as ulcerative colitis. Approximately one-third of patients developed symptoms during the follow-up period.
Oncology (1), Immune System Diseases (1) Ulcerative Colitis (3), Inflammatory Bowel Diseases (2), Colorectal Neoplasms (1), more mentions
OBJECTIVES: The therapy of the inflammatory bowel diseases is quite complex. A partial compliance increases the relapse probability and the health expenditure. The aim of the study is to correctly study the adherence to the therapy in a single centre eliminating the bias of a different relationship of trust with different doctors.
MATERIALS AND METHODS: We conducted a blind prospective study on the adherence evaluated for mesalazine.
RESULTS: Three hundred and seventy-six patients were included in the final analysis. Of the patients, 57.4% never missed a single dose of mesalazine, 29.3% missed one or two doses, 7.4% missed three to four doses, 5.9% missed more than five doses. A greater adherence among males (p = .015) and, in ulcerative colitis, among the group with a disease duration of <2 years compared to the one with a disease duration between 2 and 5 years (p = .04) were found. In Crohn's diseases, among the patients who had never undergone to surgical interventions, the adherence was 49.6%, compared to 51.9% among patients who underwent to one surgical resection and 78.6% among patients underwent to multiple surgical resections (p = .001).
CONCLUSIONS: The factors influencing the adherence to the therapy are only partly related to the prescribed therapy, but also to factors affecting the patient life: to increase the adherence rate it would be necessary not only interventions on the posology but also the psychological support to the patient at the time of the visit.
Inflammatory Bowel Diseases (2), Ulcerative Colitis (1), more mentions
BACKGROUND AND AIM: Microscopic colitis (MC) has been associated with increased paracellular permeability. Therefore, we aimed to investigate potential associations between MC and several genes encoding tight junction (TJ) proteins reported to interact with each other.
METHODS: The association between MC and single nucleotide polymorphisms (SNP; n = 63) within TJ genes (F11R, MAGI1, MAGI2, MAGI3, PARD3, PTEN, and TJP1) were investigated in a case-control study (n MC patients = 104 and n controls = 423). The genes that exhibited an association with MC were further investigated for gene expression related to genotype, MC phenotype, and gender using colonic biopsies from MC patients (n = 25) and controls (n = 58).
RESULTS: Based on the number of investigated genes and after correction for multiple testing, an association was detected between a SNP marker in PTEN (rs1234224) and both MC overall (OR = 1.70, 95% CI 1.23-2.34, p = 0.001) and collagenous colitis (CC; OR = 1.79, 95% CI 1.22-2.62, p = 0.003). Further, SNP markers in MAGI1 (rs17417230) and F11R (rs790055) were associated with MC overall (OR = 1.58, 95% CI 1.14-2.19, p = 0.006) and with CC (OR = 2.58, 95% CI 1.27-5.25, p = 0.007), respectively. However, none of the associated SNPs contributed markedly to the expression of the respective genes. Nonetheless, decreased MAGI1 (p = 3.47 × 10-4) and PTEN (p = 0.004) expression was associated with lymphocytic colitis (LC) and CC, respectively, compared to controls.
CONCLUSIONS: Decreased expression of PTEN and MAGI1 in the colonic mucosa might contribute to the pathogenesis of MC and its sub-phenotypes. Furthermore, our study indicates that genetic variants of TJ components are predisposing factors in the etiology of MC. Finally, F11R, MAGI1, and PTEN are new candidate genes that exhibit an association with MC.
OBJECTIVE: Compare efficacy and safety of vonoprazan and lansoprazole for secondary prevention of low-dose aspirin (LDA)-associated peptic ulcers in a 24-week study and long-term extension therapy in separate study.
DESIGN: Double-blind, randomised, non-inferiority study; single-blind extension study at 104 Japanese sites, including 621 patients (439 in extension) with a history of peptic ulcers who required long-term LDA therapy. Randomised (1:1:1, computer generated) patients received lansoprazole 15 mg (n=217), vonoprazan 10 mg (n=202) or vonoprazan 20 mg (n=202) once daily for 24 weeks (double blind) and ≤2 years (extension). The following measurements were made: 24-week (primary outcome; double blind) and 12-week peptic ulcer recurrence rate, 24-week GI bleeding rate, cumulative incidences of peptic ulcer recurrence and GI bleeding, treatment-emergent adverse events, laboratory results, serum gastrin and pepsinogen I/II concentrations.
RESULTS: The 24-week peptic ulcer recurrence rate was 2.8%, 0.5% and 1.5% in the lansoprazole 15 mg, vonoprazan 10 mg and vonoprazan 20 mg groups, respectively. Vonoprazan was non-inferior (Farrington and Manning test: margin 8.7%, significance level 2.5%) to lansoprazole. In the post hoc analyses of the extension study, peptic ulcer recurrence rates were significantly lower with vonoprazan 10 mg (log-rank test, P=0.039), but not vonoprazan 20 mg (P=0.260), compared with lansoprazole 15 mg. GI bleeding rates were higher with lansoprazole compared with two doses of vonoprazan in both 24-week study and extension study.
CONCLUSION: Vonoprazan (10 and 20 mg) was as effective as lansoprazole (15 mg) in preventing peptic ulcer recurrence during LDA therapy, had a similar long-term safety profile and was well tolerated.
TRIAL REGISTRATION NUMBERS: NCT01452763; NCT01456247.
Thiopurine drugs, including azathioprine and 6-mercaptopurine, are used commonly in patients with inflammatory bowel disease for maintenance of remission. Although generally well tolerated, adverse effects lead to discontinuation in a significant minority of patients. Pharmacogenomic studies have suggested that metabolic breakdown of azathioprine in an individual is genetically determined. Coupled with the fact that certain thiopurine metabolites, notably 6-thioguanine nucleotide and 6-methylmercaptopurine, are associated with antiinflammatory effects and adverse effects, respectively, some investigators have examined intentionally shunting the metabolism of azathioprine toward increasing 6-thioguanine nucleotide levels by using low doses of the xanthine oxidoreductase inhibitor allopurinol to improve efficacy and decrease toxicity of azathioprine in patients with inflammatory bowel disease. We performed a search of the Medline and Embase databases for basic and clinical research reports of this modality. Pertinent articles were retrieved, reviewed, and assessed by the authors. Case series, cohort studies, and one randomized trial have investigated adding allopurinol to azathioprine therapy in patients with inflammatory bowel disease. Most reports primarily examined metabolite levels in these patients. In general, the literature suggests that this modality was successful at significantly increasing 6-thioguanine nucleotide levels while decreasing 6-methylmercaptopurine levels. Several small reports have suggested that patients with increased 6-thioguanine nucleotide levels had improved symptoms or symptom remission. Adverse effects and discontinuation rates remained similar or were improved in patients who were taking a thiopurine and started allopurinol. In conclusion, the addition of allopurinol may be an option for optimizing thiopurine metabolite production in select patients with low 6-thioguanine nucleotide levels. Appropriate care and monitoring of these patients is mandatory to prevent neutropenia or other adverse effects. This article is protected by copyright. All rights reserved.
Muscular and Skeletal Diseases (1) Inflammatory Bowel Diseases (4), Neutropenia (1), more mentions
We investigated the role of HFE C282Y, H63D and TMPRSS6 A736V variants in the pathogenesis of iron deficiency anemia (IDA) in celiac disease (CD) patients, at diagnosis and after 1-year of gluten free diet (GFD). Demographic and clinical features were prospectively recorded for all CD patients between 2013 and 2017. C282Y, H63D and A736V variants were evaluated for CD patients and controls. Finally, 505 consecutive CD patients and 539 age-matched control subjects were enrolled. At diagnosis, 229 CD subjects had IDA (45.3%), with a subgroup of anemic patients (45.4%) presented persistent IDA at follow-up. C282Y allele frequency was significantly increased in CD compared with controls (1.1% vs 0.2%, P=0.001), whereas H63D and A736V allele frequencies were similar among patients and controls (P=0.92 and 0.84, respectively). At diagnosis, C282Y variant in anemic CD patients was significantly increased compared to non-anemic group (2% and 0.5%, P=0.04). At follow-up, A736V was significantly increased in IDA persistent than in IDA not persistent (57.7% vs 35.2%, P<0.0001). CD patients with H63D mutation showed higher Hb, MCV, serum iron and ferritin levels than subjects without HFE mutations. Decreased hepcidin values were observed in anemic compared to non-anemic subjects at follow-up (1.22±1.14 vs 2.08±2.15, P<0.001). This study suggests a protective role of HFE in IDA CD patients and confirms the role of TMPRSS6 in predicting oral iron response modulating hepcidin action on iron absorption. Iron supplementation therapeutic management in CD could depend on TMPRSS6 genotype that could predict persistent IDA despite iron supplementation and GFD. This article is protected by copyright. All rights reserved.
Blood Disorders and Hematology (2) Anemia (2), Celiac Disease (2), more mentions
BACKGROUND: Fecal calprotectin (FC) correlates with clinical and endoscopic activity in ulcerative colitis (UC), and it is a good predictor of relapse. However, its use in clinical practice is constrained by the need for the patient to deliver stool samples, and for their handling and processing in the laboratory. The availability of hand held devices might spread the use of FC in clinical practice.
OBJECTIVES: To evaluate the usefulness of a rapid semi-quantitative test of FC in predicting relapse in patients with UC in remission.
MATERIALS AND METHODS: Prospective, multicenter study that included UC patients in clinical remission for ≥6 months on maintenance treatment with mesalamine. Patients were evaluated clinically and semi-quantitative FC was measured using a monoclonal immunochromatography rapid test at baseline and every three months until relapse or 12 months of follow-up.
RESULTS: One hundred and ninety-one patients had at least one determination of FC. At the end of follow-up, 33 patients (17%) experienced clinical relapse. Endoscopic activity at baseline (p = .043) and having had at least one FC > 60 μg/g during the study period (p = .03) were associated with a higher risk of relapse during follow-up. We obtained a total of 636 semi-quantitative FC determinations matched with a three-month follow-up clinical assessment. Having undetectable FC was inversely associated with early relapse (within three months), with a negative predictive value of 98.6% and a sensitivity of 93.9%.
CONCLUSIONS: Serial, rapid semi-quantitative measurement of FC may be a useful, easy and cheap monitoring tool for patients with UC in remission.
Vedolizumab is a gut-selective humanized monoclonal antibody that binds selectively to the α4 β7 integrin and acts as a lymphocyte-homing antagonist. It is indicated in ulcerative colitis and Crohn disease. We report a case of acute interstitial nephritis following vedolizumab infusion in a 55-year-old white woman treated for severe Crohn disease resistant to several therapies. Other kidney disease causes were ruled out. Glucocorticoids were administrated, leading to full renal recovery. In the absence of other therapeutic options, vedolizumab was re-administered along with transient corticosteroids; this treatment was well tolerated. Fewer than 10 cases of immunoallergic acute interstitial nephritis following treatment with monoclonal antibody have previously been reported in the literature. The pathophysiology of delayed-type hypersensitivity secondary to monoclonal antibody therapeutics is discussed in this case report.