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Background & Aims Bacterial flagellin is an important antigen in inflammatory bowel disease, but the role of flagellin-specific CD4+ T cells in disease pathogenesis remains unclear. Also unknown is how changes in intestinal microbiome intersect with those in microbiota-specific CD4+ T cells. We aimed to quantify and characterize flagellin-specific CD4+ T cells in Crohn’s disease (CD) and ulcerative colitis (UC) patients and study their relationship with intestinal microbiome diversity. Methods Blood was collected from 3 cohorts that included CD patients, UC patients, and healthy controls. Flow cytometry analyzed CD4+ T cells specific for Lachnospiraceae-derived A4-Fla2 and Escherichia coli H18 FliC flagellins, or control vaccine antigens. Serum antiflagellin IgG and IgA antibodies were detected by enzyme-linked immunosorbent assay and stool samples were collected and subjected to 16S ribosomal DNA sequencing. Results Compared with healthy controls, CD and UC patients had lower frequencies of vaccine-antigen–specific CD4+ T cells and, as a proportion of vaccine-specific cells, higher frequencies of flagellin-specific CD4+ T cells. The proportion of flagellin-specific CD4+ T cells that were CXCR3negCCR4+CCR6+ Th17 cells was reduced in CD and UC patients, with increased proportions of CD39+, PD-1+, and integrin β7+ cells. Microbiome analysis showed differentially abundant bacterial species in patient groups that correlated with immune responses to flagellin. Conclusions Both CD and UC patients have relative increases in the proportion of circulating Fla2-specific CD4+ T cells, which may be associated with changes in the intestinal microbiome. Evidence that the phenotype of these cells strongly correlate with disease severity provides insight into the potential roles of flagellin-specific CD4+ T cells in inflammatory bowel disease., Graphical abstract

Background & Aims. T-regulatory (Treg) cells suppress immune responses to maintain homeostasis. There are two main subsets of Treg cells, FOXP3-positive Treg cells that do not produce high levels of effector cytokines and Type 1 Treg (Tr1) cells that are FOXP3-negative and secrete interleukin 10 (IL10). IL10 is an important anti-inflammatory cytokine, therefore Tr1 cells might be uniquely suited for development as a treatment for inflammatory bowel diseases. We aimed to develop methods to isolate and expand human Tr1 cells and define their functions. Methods. We obtained blood samples and colon biopsies from patients with Crohn’s disease or ulcerative colitis or healthy individuals (controls). CD4+ T cells were isolated from blood samples, stimulated with anti-CD3/CD28 beads and Tr1 cells purified using an IL10 cytokine capture assay and cell sorting. FOXP3-positive Treg cells were sorted as CD4+CD25highCD127low cells from unstimulated cells. Tr1 and FOXP3-positive Treg cells were expanded, and phenotypes and gene expression profiles were compared. T cells in peripheral blood mononuclear cells from healthy donors were stimulated with anti-CD3/CD28 beads and the suppressive abilities of Tr1 and FOXP3-positive Treg cells were measured. Human colonic organoid cultures were established then cultured with Tr1 or FOXP3-positive Treg cell culture supernatants and analyzed by immunofluorescence and flow cytometry. T84 cells (human colonic adenocarcinoma epithelial cells) were incubated with Tr1 or FOXP3-positive Treg cell culture supernatants and trans-epithelial electrical resistance was measured to determine epithelial cell barrier function. Results. Phenotypes of Tr1 cells isolated from healthy subjects or patients with Crohn’s disease or ulcerative colitis did not differ significantly following expansion. Tr1 cells and FOXP3-positive Treg cells suppressed proliferation of effector T cells, but only Tr1 cells suppressed secretion of IL1beta (IL1B) and TNF from myeloid cells. Tr1 cells, but not FOXP3-positive Treg cells, isolated from healthy subjects and IBD patients secreted IL22, which regulated repair of the epithelium and promoted barrier function of human intestinal epithelial cells. Tr1 cell culture supernatants promoted differentiation of mucin-producing goblet cells in intestinal organoid cultures. Conclusion. Human Tr1 cells suppress proliferation of effector T cells (adaptive immune response) and production of IL1B and TNF by myeloid cells (innate immune response). They also secrete IL22 to regulate repair of the epithelium and promote barrier function. They might be developed as a cell-based therapy for intestinal inflammatory disorders.

Infliximab is a monoclonal antibody therapy used to treat several chronic immune-mediated diseases, including Crohn’s disease, ulcerative colitis, and rheumatoid arthritis. Infliximab acts by binding to tumor necrosis factor and, thus, inhibiting the inflammatory cascade. While it is a highly effective therapy, a subset of patients on infliximab will develop a loss of response to therapy. In these circumstances, therapeutic drug monitoring of infliximab offers a rational approach to clinical decision making and is associated with improved outcomes. While infliximab has most commonly been measured by immunometric approaches, mass spectrometric approaches offer the opportunity to improve test accuracy and reduce test costs. Herein, we describe a simple, bottom-up high performance liquid chromatography tandem mass spectrometry (LC–MS/MS) approach for quantitation of infliximab in serum. Method development included pre-digestion and digestion experiments to determine critical sample preparation steps, optimization of the workflow and selection of rapidly produced proteolytic peptide(s) for quantitation. The workflow was further improved by automating all sample preparation steps on a robotic liquid handler, facilitating implementation in routine clinical use. A method comparison was performed against a Health Canada and US Food and Drug Administration licensed enzyme-linked immunosorbent assay. Our LC–MS/MS assay accurately reported concentrations based on drug manufacturer targets and demonstrated no interference from endogenous antibodies to infliximab; immunoassay methods did not share these performance characteristics. This LC–MS/MS method provides a workflow amenable to implementation in a clinical laboratory and desired performance characteristics for guiding clinical decision making.

Background A primary goal in IBD management is achieving disease remission; however, patient (pt)-physician alignment on this goal is unclear. International online surveys were conducted to gain insights into pts’ and physicians’ perspectives on real-world management of IBD. Herein, we report survey findings pertaining to their understanding and perceptions of disease remission in IBD. Methods Surveys were completed online by pts and physicians in Canada, France, Germany, Italy, Spain, UK, and US. Using a mixed-recruitment method, pts were identified by physicians, pt advocacy groups, and panels, while physicians were identified by recruitment agencies and panels. Eligible pts were aged ≥18 y who were diagnosed with and received treatment for Crohn’s disease (CD) or ulcerative colitis (UC) and had not undergone surgery for UC. Eligible physicians were gastroenterologists who had treated pts with CD or UC (≥12 each) in the last month, were responsible for treatment decisions of their IBD pts, and for whom ≥30% of their IBD pts had moderate or severe disease per prespecified clinical criteria. A 1:1 CD:UC ratio was targeted for the pt survey. Alignment between pts and physicians on remission definitions and pt-physician communication about remission was assessed. Physicians’ estimates of remission rates in their moderate/severe IBD pts receiving biologic therapy and their satisfaction (1=very dissatisfied to 7=very satisfied) with remission rates with current IBD treatments also were reported. Results A total of 2398 IBD pts (1368 CD [40% male], 1030 UC [45% male]) and 654 physicians completed the surveys. Mean pt age was 42 y (CD) and 44 y (UC). Physicians had mean monthly caseloads of 42.9 (CD) and 43.3 (UC). The most common primary care settings were university/teaching hospitals (41%), private practices (31%), and regional/community hospitals (20%). Nearly one quarter of pts reported never having discussed remission with their physician; only 7% of physicians reported that they typically did not discuss remission with their pts. Pts most commonly defined remission as symptom resolution (45%), whereas most physicians defined remission through test results (64% CD, 70% UC), including colonoscopies (56% CD, 58% UC), biopsies (36%, 37%), and biochemical tests (8%, 6%). Most pts (62% CD, 64% UC) had never heard of the term “mucosal healing.” Despite low physician-reported remission rates (CD: 37%–54%; UC: 37%–55%), 25% and 36% of physicians reported high satisfaction (score ≥6) with CD and UC remission rates, respectively. Conclusions This international survey demonstrated differences in pts’ and physicians’ definitions of IBD remission and in their understanding of the role of histologic remission in IBD. The findings highlight the need for improved pt-physician communication and education regarding remission, which may improve adherence and outcomes.

Randomized controlled trials (RCTs) have demonstrated that therapies targeting tumor necrosis factor (TNF) and α₄β₇ integrin are effective when given as monotherapy in inducing and/or maintaining remission in patients with ulcerative colitis (UC) or Crohn's disease (CD), but data from RCTs are less clear on whether concomitant immunomodulator (IM) therapy confers additional benefit. In CD, RCT data are mixed,1,2 as are results of systematic reviews and meta-analyses, showing no benefit overall,3 minimal benefit with individual agents,4 and comparative benefit over some monotherapies but not others.5 For example, concomitant azathioprine with infliximab is more effective than either drug alone in patients with CD naive to both drugs,2 but whether combination therapy is more effective than monotherapy with infliximab in nonnaive patients, or with other approved biologic drugs in any population, remains unknown. In UC, RCTs have shown that the benefit may be limited to specific populations,6 whereas systematic reviews suggest no benefit at all.7.

Background & Aims The availability of tests for blood concentrations of anti–tumor necrosis factor (TNF) agents and antibodies against these drugs could improve dose selection for patients with inflammatory bowel disease (IBD). However, there is little consensus on when to test and how to interpret test results. We used the RAND/UCLA Appropriateness Method to determine when these tests are appropriate and how to clinically interpret their results. Methods We conducted a systematic literature search in November 2013 to identify observational or experimental studies of the measurement of anti-TNF drug and antibody concentrations in patients with IBD and interpretation of their results. We developed 35 scenarios that assessed the appropriateness of testing and 143 scenarios that addressed clinical strategies in response to test results, and presented the findings to an expert panel. The appropriateness of each scenario was rated before and after an in-person meeting with the panel. Panelists rated the appropriateness of various clinical management options including changing therapy within class, switching out of class, adjusting drug dose or interval, adding or adjusting concomitant immune modulators, and doing nothing for each of 6 permutations of high versus low drug concentrations and high, low, or undetectable antibody concentrations. Disagreement was assessed using a validated index. Results Assessment of anti-TNF drug and antibody concentrations was rated appropriate at the end of induction therapy in primary nonresponders, in secondary nonresponders, at least once during the first year of maintenance therapy, and following a drug holiday. Routine assessment in responders at the end of induction was rated uncertain. In nearly all scenarios, escalation of drug dosing was rated appropriate when drug concentration was low in the absence of antibodies, and switching within class was rated appropriate when antibodies were present. Other recommendations depended on the specific clinical scenario for which the test was obtained. Conclusions Based on the RAND/UCLA Appropriateness Method of analysis, an expert panel recommends testing for drug and antibody concentrations in many clinical scenarios. The appropriate timing and best way to respond to anti-TNF drug and antibody testing for IBD depends on the specific clinical scenario. These recommendations can help guide clinicians to best optimize anti-TNF therapy.

Summary Background Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohn's disease. Methods In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohn's Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohn's disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohn's disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov, number NCT01030809. Findings This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% [SD 14·0] and 61·9% [16·9]; adjusted difference 2·5%, 95% CI −5·2% to 10·2%, p=0·5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27·7% and 35·1%, absolute difference [AD] 7·3%, hazard ratio [HR]: 0·73, 95% CI 0·62 to 0·86, p=0·0003). There were no differences in serious drug-related adverse events. Interpretation Although ECI was not more effective than conventional management for controlling Crohn's disease symptoms, the risk of major adverse outcomes was lower. The latter finding should be considered hypothesis-generating for future trials. ECI was not associated with an increased risk of serious drug-related adverse events or mortality. Funding AbbVie Pharmaceuticals.

Background & aims Therapeutic drug monitoring (TDM) is widely available for biologic therapies in patients with inflammatory bowel disease (IBD). We reviewed current data and provided expert opinion regarding the clinical utility of TDM for biologic therapies in IBD. Methods We used a modified Delphi method to establish consensus. A comprehensive literature review was performed regarding the use of TDM of biologic therapy in IBD and presented to international IBD specialists. Subsequently, 28 statements on the application of TDM in clinical practice were rated on a scale of 1 to 10 (1 = strongly disagree and 10 = strongly agree) by each of the panellists. Statements were accepted if 80% or more of the participants agreed with a score ≥7. The remaining statements were discussed and revised based on the available evidence followed by a second round of voting. Results The panel agreed on 24 (86%) statements. For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics. Reactive TDM was appropriate for all agents both for primary non-response and secondary loss of response. The panellists also agreed on several statements regarding TDM and appropriate drug and anti-drug antibody (ADA) concentration thresholds for biologics in specific clinical scenarios. Conclusion Consensus was achieved towards the utility of TDM of biologics in IBD, particularly anti-TNF therapies. More data are needed especially on non-anti-TNF biologics to further define optimal drug concentration and ADA thresholds as these can vary depending on the therapeutic outcomes assessed.

Background Universal access to medical procedures is deemed an advantage of the Canadian health care system. The purposes of this prospective study were to determine the degree to which the practice of colon cancer screening by colonoscopy differed among socioeconomic classes and to assess adherence to screening guidelines. Methods Consecutive patients scheduled to undergo colonoscopy at a single center between August 2000 and August 2002 completed a questionnaire that determined patient characteristics and indications for the procedure. The patients were divided into two groups: screening patients, defined as individuals who indicated they were undergoing colonoscopy for screening purposes and were asymptomatic, and a control group, which comprised patients undergoing colonoscopy because of symptoms. Statistical analysis was performed to determine if patients in the screening group had different characteristics with respect to socioeconomic class, compared with the control group. Results A total of 1088 patients completed the questionnaire: 707 (65%) had colonoscopy because of symptoms, compared with 381 (35%) who underwent a screening examination. Mean age and marital status were similar in both groups. Of all colonoscopy procedures, there was a significantly greater proportion of men undergoing colonoscopy for screening purposes: 199 (52.2%) vs. 294 (41.6%) in the symptomatic group ( p =0.001). Based on the Cochran-Armitage test, patients in the screening group had significantly higher education levels ( p =0.004) and household incomes ( p =0.001). Conclusions Income and education level, two indices of socioeconomic status, are statistically significantly higher in patients undergoing screening colonoscopy compared with those having colonoscopy for any other reason.

Background & Aims: Colonoscopy contains an inherent miss rate for colorectal cancer. Although miss rates from academic centers or units known for their endoscopic expertise have been previously reported, the colorectal cancer miss rate of colonoscopy performed in usual clinical practice is unknown. We conducted a population-based study to estimate the proportion of right-sided colon cancers missed during colonoscopy in Ontario. Methods: All persons ≥20 years old with a new diagnosis of right-sided colon cancer admitted to the hospital for surgical resection in Ontario from April 1, 1997, to March 31, 2001, were identified. Patients who had a colonoscopy within 3 years of their diagnosis were divided into 2 groups: detected cancers (those who had a colonoscopy up to 6 months before the diagnosis) and missed cancers (those who had a colonoscopy between 6 and 36 months before the diagnosis). Data were obtained from the Canadian Institute for Health Information Discharge Abstract Database, the Ontario Health Insurance Plan database, and the Registered Persons Database. Results: Between April 1, 1997, and March 31, 2001, we identified 4920 persons with a new diagnosis of right-sided colon cancer, of whom 2654 (53.9%) had had at least 1 colonoscopy within 3 years of their admission for surgical resection. Most (96.0%) had had their most recent colonoscopy up to 6 months before admission (detected cancers). However, 105 patients (4.0%) had their most recent colonoscopy between 6 and 36 months before admission to the hospital (missed cancers). Conclusions: Among persons undergoing resection for right-sided colon cancer, the miss rate of colonoscopy for detecting cancer in usual clinical practice was 4.0%.

International audience; Background & AimsThere is debate over whether patients with Crohn’s disease who start anti–tumor necrosis factor (TNF) therapy after failed immunomodulator therapy should continue to receive concomitant immunomodulators. We conducted a meta-analysis of subgroups from randomized controlled trials (RCTs) of anti-TNF agents to compare the efficacy and safety of concomitant immunomodulator therapy vs anti-TNF monotherapy.MethodsWe performed a systematic review of literature published from 1980 through 2008 and identified 11 RCTs of anti-TNF agents in patients with luminal or fistulizing Crohn’s disease. We excluded RCTs of patients who were naive to anti-TNF and immunomodulator therapy. The primary end points were clinical response at weeks 4–14 and 24–30 and remission at weeks 24–30. Secondary end points included infusion site or injection site reactions and selected adverse events. A priori subgroup analyses were performed to evaluate fistula closure and the efficacy and safety of combination therapy with different anti-TNF agents.ResultsOverall, combination therapy was no more effective than monotherapy in inducing 6-month remission (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.80–1.31), inducing a response (OR, 1.08; 95% CI, 0.79–1.48), maintaining a response (OR, 1.53; 95% CI, 0.67–3.49), or inducing partial (OR, 1.25; 95% CI, 0.84–1.88) or complete fistula closure (OR, 1.10; 95% CI, 0.68–1.78). In subgroup analyses of individual anti-TNF agents, combination therapy was not more effective than monotherapy in inducing 6-month remission in those treated with infliximab (OR, 1.73; 95% CI, 0.97–3.07), adalimumab (OR, 0.88; 95% CI, 0.58–1.35), or certolizumab (OR, 0.93; 95% CI, 0.65–1.34). Overall, combination therapy was not associated with an increase in adverse events, but inclusion of infliximab was associated with fewer injection site reactions (OR, 0.46; 95% CI, 0.26–0.79.)ConclusionsOn the basis of a meta-analysis, continued use of immunomodulator therapy after starting anti-TNF therapy is no more effective than anti-TNF monotherapy in inducing or maintaining response or remission. RCTs are needed to adequately assess the efficacy of continued immunomodulator therapy after anti-TNF therapy is initiated.

Background & Aims The medical management of ulcerative colitis (UC) has improved through the development of new therapies and novel approaches that optimize existing drugs. Previous Canadian consensus guidelines addressed the management of severe UC in the hospitalized patient. We now present consensus guidelines for the treatment of ambulatory patients with mild to severe active UC. Methods A systematic literature search identified studies on the management of UC. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a working group of specialists. Results The participants concluded that the goal of therapy is complete remission, defined as both symptomatic and endoscopic remission without corticosteroid therapy. The consensus includes 34 statements focused on 5 main drug classes: 5-aminosalicylate (5-ASA), corticosteroids, immunosuppressants, anti–tumor necrosis factor (TNF) therapies, and other therapies. Oral and rectal 5-ASA are recommended first-line therapy for mild to moderate UC, with corticosteroid therapy for those who fail to achieve remission. Patients with moderate to severe UC should undergo a course of oral corticosteroid therapy, with transition to 5-ASA, thiopurine, anti-TNF (with or without thiopurine or methotrexate), or vedolizumab maintenance therapy in those who successfully achieve symptomatic remission. For patients with corticosteroid-resistant/dependent UC, anti-TNF or vedolizumab therapy is recommended. Timely assessments of response and remission are critical to ensuring optimal outcomes. Conclusions Optimal management of UC requires careful patient assessment, evidence-based use of existing therapies, and thorough assessment to define treatment success.