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The aim of this study was to describe the impacts of inflammatory bowel disease (IBD) from the patients' perspective and to inform the development of a conceptual model.Focus groups and one-on-one interviews were undertaken in adult patients with IBD. Transcripts from the focus groups and interviews were analyzed to identify themes and links between themes, assisted by qualitative data software MaxQDA. Themes from the qualitative research were supplemented with those reported in the literature and concepts included in IBD-specific patient-reported outcome measures.Twenty-seven patients participated. Key physical symptoms included pain, bowel-related symptoms such as frequency, urgency, incontinence, diarrhea, passing blood, and systemic symptoms such as weight loss and fatigue. Participants described continuing and variable symptom experiences. IBD symptoms caused immediate disruption of activities but also had ongoing impacts on daily activities, including dietary restrictions, lifestyle changes, and maintaining close proximity to a toilet. More distal impacts included interference with work, school, parenting, social and leisure activities, relationships, and psychological well-being. The inconvenience of rectal medications, refrigerated biologics, and medication refills emerged as novel burdens not identified in existing patient-reported outcome measures.IBD symptoms cause immediate disruption in activities, but patients may continue to experience some symptoms on a chronic basis. The conceptual model presented here may be useful for identifying target concepts for measurement in future studies in IBD.

The causes for nonadherence to mesalamine in patients with inflammatory bowel disease (IBD) have been characterized using mostly indirect methods. Patient-reported barriers are lacking in this population.To identify patient-reported barriers to mesalamine adherence through direct interviews.Focus groups and one-on-one interviews were undertaken in adult patients with IBD. Transcripts from the focus groups and interviews were analyzed to identify themes and links between these themes, assisted by qualitative data software MaxQDA.Of 27 patients participating, 21 (78%) had ulcerative colitis, and 6 (22%) had Crohn's disease. Their self-reported adherence ranged from complete adherence (n = 3) to intermittent nonadherence (n = 24). Patients frequently indicated that they were resistant to taking medications for their condition. The barriers to adherence that emerged from interviews could be categorized under a number of themes: competing priorities, social stigma, refill inconvenience, costs, efficacy values, side effects, and pill characteristics. Efficacy values reported to influence adherence included doubts about efficacy, consequences of missed doses, and doubts about need for maintenance medication. Pill characteristics reported as barriers included pill size and pill frequency. Despite use of electronic prescribing, obtaining refills was reported as an obstacle to adherence in this cohort. Decanting of pills to multiple containers to increase accessibility was also reported.Patients with both ulcerative colitis and Crohn's disease report a number of common barriers to mesalamine adherence. Factors in medication-taking behavior and beliefs were reported in this study that may have implications for strategies to improve adherence by health care providers.

Poor adherence to mesalamine is common and driven by a combination of lifestyle and behavioral factors, as well as health beliefs. We sought to develop a valid tool to identify barriers to patient adherence and predict those at risk for future nonadherence.A 10-item survey was developed from patient-reported barriers to adherence. The survey was administered to 106 patients with ulcerative colitis who were prescribed mesalamine, and correlated with prospectively collected 12-month pharmacy refills (medication possession ratio (MPR)), urine levels of salicylates, and self-reported adherence (Morisky Medication Adherence Scale (MMAS)-8).From the initial 10-item survey, 8 items correlated highly with the MMAS-8 score at enrollment. Computer-generated randomization produced a derivation cohort of 60 subjects and a validation cohort of 46 subjects to assess the survey items in their ability to predict future adherence. Two items from the patient survey correlated with objective measures of long-term adherence: their belief in the importance of maintenance mesalamine even when in remission and their concerns about side effects. The additive score based on these two items correlated with 12-month MPR in both the derivation and validation cohorts (P0.05). Scores on these two items were associated with a higher risk of being nonadherent over the subsequent 12 months (relative risk (RR) =2.2, 95% confidence interval=1.5-3.5, P=0.04). The area under the curve for the performance of this 2-item tool was greater than that of the 10-item MMAS-8 score for predicting MPR scores over 12 months (area under the curve 0.7 vs. 0.5).Patients' beliefs about the need for maintenance mesalamine and their concerns about side effects influence their adherence to mesalamine over time. These concerns could easily be raised in practice to identify patients at risk of nonadherence (Clinical Trial number NCT01349504).

Induced regulatory T-cells (iT-reg) and T helper type 17 (Th17) in the mouse share common CD4 progenitor cells and exhibit overlapping phenotypic and functional features. Here, we show that human Th17 cells endowed with suppressor activity (supTh17) can be derived following exposure of iT-reg populations to Th17 polarizing conditions. In contrast to "pathogenic'' Th17, supTh17 display immune suppressive function and express high levels of CD39, an ectonucleotidase that catalyzes the conversion of pro-inflammatory extracellular nucleotides ultimately generating nucleosides. Accordingly, supTh17 exhibit nucleoside triphosphate diphosphohydrolase activity, as demonstrated by the efficient generation of extracellular AMP, adenosine and other purine derivatives. In addition supTh17 cells are resistant to the effects of adenosine as result of the low expression of the A2A receptor and accelerated adenosine catalysis by adenosine deaminase (ADA). These supTh17 can be detected in the blood and in the lamina propria of healthy subjects. However, these supTh17 cells are diminished in patients with Crohn's disease. In summary, we describe a human Th17 subpopulation with suppressor activity, which expresses high levels of CD39 and consequently produces extracellular adenosine. As these uniquely suppressive CD39(+) Th17 cells are decreased in patients with inflammatory bowel disease, our findings might have implications for the development of novel anti-inflammatory therapeutic approaches in these and potentially other immune disorders.

Goals and Background: Inflammatory bowel disease (IBD) serology testing is often used in patients with indeterminate colitis (IC) to help distinguish between ulcerative colitis (UC) and Crohn’s disease (CD). We investigated the performance of serology testing in predicting future diagnosis in this setting. Study: This was an observational study of individuals with IC at a single center who underwent IBD serology testing [anti-Saccharomyces cerevisiae antibody (ASCA), perinuclear anti-neutrophil cytoplasmic antibody (pANCA), and anti-outer membrane porin C antibody (anti-OmpC)] and had at least 12 months follow-up from the time of serology test results. Results: A total of 117 individuals with IC and with 1-year follow-up data were enrolled. All IC patients had endoscopic and histologic evidence of colitis at enrollment. One year after serology testing, 58 (50%) individuals with IC were diagnosed with UC, 49 (42%) with CD, and 10 (9%) remained labeled with IC. The sensitivity/specificity of an initial positive pANCA for a subsequent diagnosis of UC was 78%/44%. For ASCA and anti-OmpC, the results were 18%/84% and 27%/75%, respectively, for a subsequent diagnosis of CD. A positive pANCA test was associated with a likelihood ratio (LR) of 1.4 [95% confidence interval (CI), 1.1-1.8] for a subsequent diagnosis of UC at 1 year. Neither positive ASCA (LR 1.1; 95% CI, 0.5-2.5) nor anti-OmpC (LR 1.1; 95% CI, 0.6-2.0) was associated with a subsequent diagnosis of CD in patients with IC. Conclusions: The disease phenotype in the majority of individuals initially labeled with IC evolved to be more consistent with either UC or CD on follow-up. pANCA, ASCA, and anti-OmpC, individually, were of limited utility in predicting a patient’s subsequent disease phenotype.

Ulcerative colitis (UC) affects approximately 1 in 400 people internationally, with a higher prevalence in the Western hemisphere, although more recently incidence and prevalence rates have been rising in the rest of the world, particularly in Asia. The majority of UC patients are prescribed with medication for induction or maintenance of remission. In addition to standard therapies, recent developments in immunology have identified novel therapeutic pathways and biologic agents to treat inflammatory bowel disease. There are currently 11 drugs and biologic agents (including prednisolone, sulfasalazine, balsalazide, budesonide MMX, infliximab, adalimumab, golimumab, and different preparations of mesalamines) approved by the Food and Drug Administration (FDA) to treat UC. At present, there are 145 registered clinical trials evaluating therapeutics for managing adult UC, including drugs, biologic agents, and clinical tools for therapeutic monitoring of treatment response and disease activity.

Patients with inflammatory bowel disease have higher proportions of immunoglobulin G (IgG) antibodies lacking N-galactose, also called agalactosyl IgG, in their serum. Such agalactosyl IgGs have been associated with disease activity and the immunogenicity of biologics. The aim was to describe the relationship between circulating levels of a subset of agalactosyl IgGs (anti-α-Gal) and Crohn's disease (CD) phenotypes.Prospectively collected serum samples of a well-characterized cohort of patients with inflammatory bowel disease and controls were used. Serum anti-α-Gal levels were measured by a high-affinity enzyme-linked immunosorbent assay and referenced to a standard control.Serum samples from 167 subjects were tested; 62 with CD, 76 with ulcerative colitis, and 29 controls. Agalactosyl anti-α-Gal levels were significantly higher in active CD than in active ulcerative colitis (P = 0.0043) or healthy controls (P0.0001). Among patients with CD, agalactosyl anti-α-Gal levels were significantly higher in those with a history of arthritis, than those without (P = 0.0002), but lower in those taking immunomodulators (P = 0.03). There was no correlation between agalactosyl anti-α-Gal levels and indices of Crohn's severity, including C-reactive protein levels or Harvey-Bradshaw index. Patients who were primary or secondary nonresponders to infliximab had similar agalactosyl anti-α-Gal levels to clinical responders.Patients with CD have greater amounts of agalactosylated anti-α-Gal antibodies in their serum, particularly in those with associated joint disease. This increase seems to be independent of indices of disease activity, but is influenced by immunomodulator use.

Background & Aims Few studies have analyzed the safety of endoscopy in patients with inflammatory bowel disease (IBD). We aimed to determine the prevalence of procedure-related complications among these patients, compared with the general population, and estimate the lifetime risk of colonoscopy-related complications. Methods We collected data on complications in 685 patients with IBD and 17,000 patients without IBD (controls) using an automated system to track all emergency department visits to the Beth Israel Deaconess Medical Center within 14 days of an endoscopic procedure, from March 1, 2007, to November 30, 2007. We reviewed charts of all IBD patients to determine health care use (telephone calls or visits to a gastroenterologist or primary care physician and visits to other emergency departments or hospitals) after endoscopy. The lifetime risk of procedure-related complications was estimated using a Markov Monte Carlo model. Results Rates of complications were 1.17% among patients with IBD and 0.96% among controls ( P = .55). The chart review showed that 3.8% of the IBD cohort received medical care within 14 days of the endoscopic procedure. Based on a Markov Monte Carlo simulation model, the lifetime risk of complications after a surveillance colonoscopy protocol was 12.7% among patients with IBD and 2.0% in the general population undergoing screening colonoscopy ( P Conclusions Although the risk of adverse events after each endoscopic procedure was similar for patients with IBD and the general population, IBD patients have an increased lifetime risk of complications after colonoscopies. A higher percentage of patients with IBD also seek medical care after endoscopic procedures than controls.

Purinergic signaling and associated ectonucleotidases, such as CD39 and CD73, have been implicated in the pathogenesis of inflammatory bowel disease (IBD). CD39 is known to be a Treg memory cell marker, and here we determine the phenotype and function of CD73(+) CD4(+) T lymphocytes in patients with IBD. We describe elevated levels of CD73(+) CD4(+) T cells in the peripheral blood and intestinal lamina propria of patients with active IBD. The functional phenotype of these CD73(+) CD4(+) T cells was further determined by gene expression, ecto-enzymatic activity, and suppressive assays. Increased numbers of CD73(+) CD4(+) T cells in the periphery and lamina propria were noted during active inflammation, which returned to baseline levels following anti-TNF treatment. Peripheral CD73(+) CD4(+) T cells predominantly expressed CD45RO, and were enriched with IL-17A(+) cells. The CD73(+) CD4(+) cell population expressed higher levels of RORC, IL-17A, and TNF, and lower levels of FOXP3 and/or CD25, than CD73(-) CD4(+) T cells. Expression of CD73 by peripheral CD4(+) T cells was increased by TNF, and decreased by an anti-TNF monoclonal antibody (infliximab). In vitro, these peripheral CD73(+) CD4(+) T cells did not suppress proliferation of CD25(-) effector cells, and expressed higher levels of pro-inflammatory markers. We conclude that the CD73(+) CD4(+) T-cell population in patients with active IBD are enriched with cells with a T-helper type 17 phenotype, and could be used to monitor disease activity during treatment.

Background: The risk of viral infection is increased in immunosuppressed inflammatory bowel disease (IBD) patients. Varicella zoster virus (VZV) is of particular interest in IBD because of a number of reports of severe, disseminated, and occasionally fatal varicella infection in immunosuppressed IBD patients. Methods: We reviewed publications describing VZV infection in IBD patients and combined these data with a review of the current literature relating to both primary and secondary varicella in IBD. Results: Twenty cases of primary varicella infection and 32 cases of herpes zoster infection have been reported in IBD. Additional cases are reported in clinical trials. The risk of VZV infection is increased with all immunosuppressants used in IBD, but corticosteroids and combination immunosuppression appear to be a particular risk. Conclusions: Healthcare providers need to be aware of the various manifestations of primary and secondary VZV infection in immunosuppressed IBD patients. Patients should be screened for VZV immunity and vaccinated prior to commencing immunosuppression. (Inflamm Bowel Dis 2012;)

Infliximab (IFX) therapy escalation during maintenance treatment occurs frequently in clinical practice in patients with ulcerative colitis (UC). Outcomes for these patients have not been described.To describe the prevalence of, and outcomes after, IFX escalation during maintenance therapy in patients with moderate-severe UC.Retrospective observational study of clinical outcomes in ambulatory patients with moderate-severe UC treated with maintenance IFX.Fifty-six ambulatory patients received IFX for moderate-severe UC; fifty (89%) responded and proceeded to maintenance therapy. Mean duration of maintenance therapy was 14 months, with mean follow-up of 38 months. Twenty-seven patients (54%) required IFX therapy escalation after a mean of six maintenance infusions. Clinical remission was noted in 36% of the entire cohort (18/50) at 12 months; 19% in the escalation group and 56% in the non-escalation group. Patients who required IFX escalation were less likely to be in clinical remission at 12 months (OR 0.2, 95% CI 0.1-0.6, P = 0.01) when compared with those who did not. During the follow-up period, 27% of patients required a colectomy, and the mean time to colectomy was 17 months. Patients in the escalation group required a colectomy in 33% of cases, compared with 21% of non-escalation patients.A significant proportion of ambulatory patients with UC treated with maintenance infliximab required therapy escalation over time. This was associated with lower remission, and higher colectomy, rates.

In March 2008, a roundtable discussion was convened by the inflammatory bowel disease (IBD) specialist panel the BRIDGe (Building Resources and Research in IBD Globally) group, which consists of junior faculty gastroenterologists who have undergone advanced fellowship training at IBD referral centers in the United States, Canada, the United Kingdom, and Australia. An agenda was formulated to discuss three current controversies in Crohn's disease management: the role of 5-aminosalicylates, the use of biologic combination therapy versus monotherapy, and the use of step-up therapy versus top-down therapy for Crohn's disease. The aim of the meeting was three-fold: to review the data pertaining to each topic; to collect opinions from the participants as to their analysis of the literature and their current practice; and, where possible, to formulate recommendations of current best practice given the available evidence. This manuscript summarizes the discussions on these three areas of controversy in the current management of Crohn's disease.

Crohn's disease (CD) is a chronic inflammatory disorder that can often require surgical intervention due to complications such as strictures, fistulae, or perforation.1 Historically, 70% of patients require surgical resection within 10 years of initial CD diagnosis.2 Although surgery ostensibly leaves only healthy intestinal tissue behind, the majority of patients develop de novo mucosal inflammation at the anastomosis site. Endoscopic recurrence of CD is observed in >70% of patients within the first year, typically at the neoterminal ileum.3 The severity of endoscopic recurrence is predictive of subsequent clinical recurrence; 20% of patients show symptomatic recurrence within a year of endoscopic recurrence, and at least 50% experience clinical recurrence within 5 years.3,4 Given the morbidity associated with clinical CD recurrence after resection, a number of postsurgery treatments have been examined in randomized controlled trials (RCTs). Mesalamine, azathioprine, metronidazole, and infliximab have all demonstrated efficacy in preventing clinical or endoscopic recurrence of CD after resection. Recent meta-analyses confirmed the superiority of azathioprine to placebo, and to mesalamine.5,6 However, azathioprine is associated with frequent discontinuation due to adverse drug reactions (ADRs), and its long-term use is associated with a risk of lymphoma.5,7 While mesalamine has a safer side-effect profile than azathioprine, it has only modest efficacy in postoperative prevention. In addition, adherence to mesalamine maintenance therapy is reported to be as low as 40%.8 Infliximab was highly effective in preventing endoscopic recurrence of CD in a small prospective RCT, but its long-term prophylactic use is also limited by safety and cost concerns.9,10 Unfortunately, no head-to-head comparative studies between the prophylactic strategies to prevent clinical recurrence (mesalamine, azathioprine, metronidazole, and infliximab) have been published. Therefore, the optimal strategy, in terms of efficacy, safety, and cost-effectiveness, remains unclear. In addition, the relative impact of ADRs and costs of each treatment strategy is unknown. Based on this lack of data, expert groups have been unable to make definitive recommendations.11 The Institute of Medicine identified Comparative Effectiveness Research as a “national priority” for the United States recently in an era of increasing concerns of the costs of healthcare.12 In light of this uncertainty, and implications, we undertook a comprehensive economic evaluation, from a societal perspective, to define the comparative cost-effectiveness of each treatment strategy in order to identify the optimal prophylactic therapy (compared to “no prophlyaxis”) to prevent CD recurrence in patients in the U.S. during the first year after intestinal resection.

Background: Since the introduction of infliximab, anti-tumor necrosis factor alpha (anti-TNF-α) agents have been used with increasing frequency for the treatment of inflammatory bowel disease (IBD). Reactivation of latent Mycobacterium tuberculosis (TB) soon became recognized as a complication of therapy. More recently, reactivation of hepatitis B while on anti-TNF therapy has been documented. The aim of this study was to assess the adherence to screening for latent TB and hepatitis B by gastroenterologists prior to initiation of an anti-TNF. Methods: This is a retrospective analysis of all patients with IBD treated with an anti-TNF at a large urban academic hospital. In our population, 65% of patients were screened for latent TB prior to the initiation of anti-TNF therapy, while 25% of patients were screened for hepatitis B. Results: Failure to screen for latent TB was strongly correlated with prior exposure to an anti-TNF (odds ratio [OR]: 5.3; P < 0.0001) and initiation of treatment prior to 2006 (OR: 5.8; P < 0.0001). Failure to screen for hepatitis B was associated with lack of an abnormal alanine aminotransferase (OR: 2.6; P = 0.005) and treatment prior to 2010 (OR: 3.3; P = 0.02). Providers who had been in practice longer were less likely screen for TB or hepatitis B. Conclusions: The rate of screening for both latent TB and hepatitis B in this study was inadequate. While the rate of screening is increasing, further systems improvements and physician education is needed. (Inflamm Bowel Dis 2012;)

Aliment Pharmacol Ther 31, 802–809 Summary Background Enteric bacteria play an important early role in the pathogenesis of Crohn’s disease. Aim To perform a meta-analysis of trials testing antibiotics or probiotics for prevention of post-operative recurrence of Crohn’s disease. Methods Review of all randomized controlled trials comparing antibiotics or probiotics with placebo in prevention of endoscopic or clinical recurrence of Crohn’s disease after surgical resection. Fixed-effect meta-analysis was performed with dichotomous data summarized using relative risk with 95% confidence intervals, where appropriate. Results Seven studies were identified as suitable for inclusion (two comparing antibiotics with placebo, five comparing probiotics with placebo). The use of nitroimidazole antibiotics (metronidazole, ornidazole) reduced the risk of clinical (RR 0.23; 95% CI 0.09–0.57, NNT = 4) and endoscopic (RR 0.44; 95% CI 0.26–0.74, NNT = 4) recurrence relative to placebo. However, these agents were associated with higher risk of adverse events (RR 2.39, 95% CI 1.5–3.7) and patient withdrawal. Probiotic administration was not associated with any significant difference in risk of recurrence compared with placebo. Conclusions Nitroimidazole antibiotics are effective in the prevention of post-operative Crohn’s disease recurrence, but their side-effects limit acceptability. Probiotics have failed to show efficacy for post-operative prophylaxis, but may merit further study.

Background Recurrence of Crohn's disease is common after intestinal resection. A number of agents have been studied in controlled trials with the goal of reducing the risk of endoscopic or clinical recurrence of Crohn's disease following surgery. Objectives To undertake a systematic review of the use of medical therapies for the prevention of post-operative recurrence of Crohn's disease Search methods MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched to identify relevant studies. References from selected papers and abstracts from Digestive Disease Week were also searched. Selection criteria Randomised controlled trials that compared medical therapy to placebo or other medical agents for the prevention of recurrence of intestinal Crohn's disease were selected for inclusion. Data collection and analysis Two authors reviewed all abstracts containing search terms, and those meeting inclusion criteria were selected for full data abstraction. Dichotomous data were summarised using relative risk and 95% confidence intervals. A fixed-effects model was used, and sensitivity analysis performed. Main results Twenty-three studies were identified for inclusion. Probiotics were not superior to placebo for any outcome measured. The use of nitroimidazole antibiotics appeared to reduce the risk of clinical (RR 0.23; 95%CI 0.09 to 0.57, NNT=4) and endoscopic (RR 0.44; 95%CI 0.26 to 0.74, NNT = 4) recurrence relative to placebo. However, these agents were associated with higher risk of serious adverse events (RR 2.39, 95% CI 1.5 to 3.7). Mesalamine therapy was associated with a significantly reduced risk of clinical recurrence (RR 0.76; 95% CI 0.62 to 0.94, NNT = 12), and severe endoscopic recurrence (RR 0.50; 95% CI 0.29 to 0.84, NNT = 8) when compared to placebo. Azathioprine/6MP was also associated with a significantly reduced risk of clinical recurrence (RR 0.59; 95% CI 0.38 to 0.92, NNT = 7), and severe endoscopic recurrence (RR 0.64; 95% CI 0.44 to 0.92, NNT = 4), when compared to placebo. Neither agent had a higher risk than placebo of serious adverse events. When compared to azathioprine/6MP, mesalamine was associated with a higher risk of any endoscopic recurrence (RR 1.45, 95% CI 1.03 to 2.06), but a lower risk of serious adverse events (RR 0.51; 95% CI 0.30 to 0.89). There was no significant difference between mesalamine and azathioprine/6MP for any other outcome. Authors' conclusions There are insufficient randomised controlled trials of infliximab, budesonide, tenovil and interleukin-10 to draw conclusions. Nitro-imidazole antibiotics, mesalamine and immunosuppressive therapy with azathioprine/6-MP or infliximab all appear to be superior to placebo for the prevention of post-operative recurrence of Crohn's disease. The cost, toxicity and tolerability of these approaches require careful consideration to determine the optimal approach for post-operative prophylaxis.

Background & Aims There is no consensus on the appropriateness of concomitant immunomodulators with anti–tumor necrosis factor (TNF) therapy for Crohn's disease. Some patients benefit from concomitant immunomodulators, but concerns related to infections and lymphoma risk have dampened enthusiasm for this approach. We applied the RAND/University of California Los Angeles Appropriateness Method toward establishing appropriateness of concomitant immunomodulators and anti-TNF therapies for Crohn's disease. Methods A literature review was conducted regarding efficacy and safety of concomitant immunomodulators in the setting of anti-TNF therapy for Crohn's disease and presented to the Building Research in Inflammatory Bowel Disease Globally group, a globally diverse panel of 13 gastroenterologists clinically experienced in inflammatory bowel disease. A total of 134 scenarios were constructed using several clinical variables. Panelists used a modified Delphi method to rate the appropriateness of concomitant immunomodulators, and met to discuss and re-rate appropriateness. Disagreement was assessed using a validated index. Results Concomitant immunomodulators were generally rated appropriate for 63 scenarios, uncertain for 60 scenarios, and inappropriate for 11 scenarios. In general, concomitant immunomodulators were appropriate for those with extensive disease, shorter duration of disease, perianal involvement, prior surgery, females, and older patients (>26 y). Concomitant immunomodulators were generally rated inappropriate for young males, and in some scenarios involving uncomplicated disease. Smoking and the particular anti-TNF medication did not influence ratings. Disagreement was observed in 6 of 134 scenarios. Conclusions The appropriateness of concomitant immunomodulators with anti-TNF therapy for Crohn's disease was determined through a modified Delphi panel approach based on expert interpretation of the available literature. Clinicians should consider multiple factors when considering concomitant immunomodulators with anti-TNF treatment.

Ulcerative colitis is a chronic relapsing and remitting inflammatory disorder that can generally be managed successfully with maintenance oral medications. However, approximately 15% of patients with ulcerative colitis will develop a severe exacerbation and require hospitalization. While many patients with acute severe ulcerative colitis will respond to a short course of intravenous corticosteroids, up to a third will fail to improve. In these patients with steroid-refractory colitis, the choice is between rescue medical therapy with ciclosporin or infliximab, or surgery. Well-timed rescue medical therapy is generally safe when administered by experienced physicians, and is effective in the majority of cases. Surgery is unavoidable in some cases, but is the treatment of choice in others. While ileal pouch-anal anastomosis offers the prospect of life without a permanent ileostomy, there are issues with its long-term functional outcome.

Objectives In patients with suspected Crohn's disease (CD), little is known about the test characteristics of capsule endoscopy (CE) in the diagnosis of this condition. We sought to determine the utility of CE for the subsequent diagnosis of CD in patients suspected to have this condition. Methods All patients who underwent CE at a single tertiary-care center for investigation of suspected small bowel CD, and who had a 12-month follow-up, were included in the study. All patients had undergone other investigations that were normal or equivocal. The test characteristics of CE were determined on the basis of capsule findings of small bowel ulcers and a subsequent new diagnosis of CD within 12 months of CE. Results The study included 102 patients with 12-month follow-up data. The majority (75%) met the established criteria to define "suspected Crohn's disease" as an indication for CE. Most had undergone computed tomography scan or small bowel follow-through (92%) and colonoscopy (99%) before CE. There were abnormal CE findings suggestive of CD in 39 patients. The prevalence rate of a new diagnosis of CD by 12 months in the study population was 13%. Using the presence of more than 3 ulcers as the criterion for an abnormal CE study, the sensitivity of CE for the diagnosis of CD was 77%, the specificity was 89%, the positive predictive value (PPV) was 50%, and the negative predictive value (NPV) was 96%. Conclusions In patients with suspected CD, CE has a high sensitivity and a NPV for this condition. The PPV varies depending on the patient population and the criteria for a CE diagnosis of CD.

U lcerative colitis (UC) and Crohn’s disease (CD) have historically been grouped under the heading of inflammatory bowel disease (IBD) due to an overlap in pathogenesis, symptoms, and treatments. The wide range of clinical phenotypes seen within this spectrum raises the possibility that we are dealing with more than 2 distinct diseases. Molecular profiling suggests that IBD comprises a heterogeneous family of polygenic inflammatory disorders.1 For example, the discovery of the link between mutations in the NOD2/ CARD15 gene and stricturing ileal CD has provided a genetic basis for this distinct clinical phenotype. Indirect markers of IBD, such as anti-Saccharomyces cerevisiae antibody (ASCA), perinuclear-staining antineutrophil antibody (pANCA), and outer membrane porin C (OmpC) have also been associated with specific disease subtypes and risk of IBD.2,3 It is likely that further advances in molecular classification will provide clinicians with a molecular taxonomy based on specific transcriptional profiles, similar to the data from breast cancer and leukemia. In most cases, CD and UC are readily differentiated based on clinical, radiological, pathological, and endoscopic features. UC only affects the colon and is associated with mucosal inflammation that starts in the rectum and extends proximally in a continuous manner. In contrast, CD can affect any part of the gastrointestinal tract from the mouth to the anus, typically features “skip lesions” of transmural inflammation, yet often spares the rectum. Perianal involvement (fissures, fistulae, and abscesses), ileal involvement, and granulomas are highly specific to CD. Certain extraintestinal manifestations such as erythema nodosum and peripheral arthropathy are usually associated with CD rather than UC, although recent population-based studies have reported weaker associations.4,5 Other clinical clues useful in differentiating between CD and UC are smoking history and the absence of rectal bleeding. A case-control study of 21 patients initially diagnosed with UC who were later classified has having CD identified only nonbloody diarrhea and weight loss as independent predictors of change in diagnosis 6 However, despite these obvious differences between UC and CD, there are certain instances where the diagnosis is not so clear-cut. In addition, an individual’s clinico-pathological features may evolve over time. Consequently, a subset of patients with a label of UC may eventually be reclassified as CD and vice versa. In patients with UC a number of endoscopic and histological findings can create uncertainty about the diagnosis. Backwash ileitis, which can resemble the ileitis of CD, occurs in 10%–20% of patients with extensive colitis.7 It is usually associated with severe pancolitis, but may occasionally occur in those with left-sided disease. Endoscopy of patients with distal UC may also reveal proximal areas of colitis, in the cecum or ascending colon, which are distinct from the distal disease. These “skip lesions,” or cecal patches, have been reported in up to 20% of patients. Prospectively, these lesions have not been associated with the development of CD.8 Granulomas, which are highly specific to CD, can occur in up to 5% of UC biopsies in the setting of ruptured crypts (cryptolytic granulomas).9 The diagnostic accuracy of pathologists in classifying IBD type is 60%–74%, with uncertainty occurring in patients presenting with fulminant colitis, those with treated disease, and those seen at the earliest stages of disease.10 Finally, rectal sparing and patchy colitis may develop over time in patients with UC, although this usually represents differential healing due to treatment rather than a natural evolution of the disease. Due to this crossover of features, and despite extensive work-up, 10% of patients with chronic IBD do not fit either diagnostic category cleanly and are labeled as having an “indeterminate colitis.” Over time, as their clinical features continue to develop, most of these patients will acquire a diagnosis of UC or CD.11 However, the importance of the distinction between CD and UC has become less important in recent years, as the medical therapies have become less disease-specific. With the recent FDA approval of infliximab for UC, only methotrexate, natalizumab, and antibiotics remain specific therapies for CD. The distinction between the 2 diagnoses is particularly important, however, for surgical therapy and prognosis. The vast majority of patients with UC who undergo ileal pouch–anal anastomosis (IPAA) do well, as opposed to those patients with CD who undergo IPAA, up to 50% of whom require revision or diversion 12,13 There are few data examining how frequently patients From the Center for Inflammatory Bowel Disease, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Massachusetts, USA. Copyright © 2008 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1002/ibd.20593 Published online in Wiley InterScience (www.interscience.wiley.com).

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: Interferon gamma (IFNγ) responses and distinct CD8+ T cell transcriptional signatures can be linked to clinical manifestations of inflammatory bowl disease (IBD). CD39 is an ectonucleotidase and is typically associated with CD4+ T regulatory memory cells, which have the capacity to generate immunosuppressive adenosine. However, immunomodulatory effects of CD39 expression on CD8+ T cells, as in IBD, remain unknown. METHODS:CD39+CD8+ T cells were purified from peripheral blood (PB) and lamina propria (LP) of patients with Crohn's disease. Phenotypic features and functions of CD39+CD8+ T cells were assessed by flow cytometry and immunoblotting. RESULTS: CD39 expressing CD8+ T cells of patients with Crohn's disease are IFNγ-producing cells, and exhibited type 1 CD8+ T cell (Tc1) properties. CD3 and CD28-mediated synergistic stimulation of CD8+ T cells augment CD39 expression, boost reactive oxygen species (ROS) generation, and increase IFNγ production. CD39+CD8+ T cells preferentially express CD28, and exhibit robust ROS-JNK/NFkB signals and IFNγ production. Decreases in ROSmediated by inhibitors of NADPH oxidases (NOX) or knockdown of gp91phox (NOX2) in CD8+ T cells abrogate effects of TCR ligation, and decrease both CD39 expression and IFNγ production. Curiously, CD39+CD8+ T cells inhibit IFNγ production by CD39-CD8+ T cells via generation of adenosine, which is operational via the paracrine expression of Adenosine 2A (ADORA2A) receptor. CONCLUSIONS: CD8+ Tc1 cells express CD39, which is further boosted by cell activation and ROS, which in turn limit IFNg responses by these cells. Strategies to regulate ROS signal cascades and adenosine-mediated effects might have therapeutic potential in the treatment of Crohn's disease.

Article first published online 14 January 2015., Anti-TNF medications have revolutionized the care of patients with inflammatory bowel disease. However, despite an initial robust effect, loss of response is common and long-term results are disappointing. Much of this lack of durability may be due to inadequate dose optimization, and recent studies suggest a correlation between serum drug concentrations and clinical outcomes. Currently, in clinical practice, measurement of drug concentrations and antibodies to drug are typically performed only when a patient presents with active inflammatory bowel disease symptoms or during a potential immune-mediated reaction to anti-TNF (“reactive” setting). However, proactive monitoring of anti-TNF concentrations with titration to a therapeutic window (i.e., therapeutic concentration monitoring) represents a new strategy with many potential clinical benefits including prevention of immunogenicity, less need for IFX rescue therapy, and greater durability of IFX treatment. This review will cover the salient features of anti-TNF pharmacokinetics and pharmacodynamics and provide a rational approach for the use of anti-TNF concentration testing in both the reactive and proactive settings.

Background: Previous studies have suggested that there may be a defect in the control of immune responses locally in the intestines of patients with inflammatory bowel disease (IBD). Recently, we documented a failure to induce oral tolerance to a fed soluble protein antigen, keyhole limpet hemocyanin (KLH), in IBD patients. Both Crohn's disease (CD) and ulcerative colitis (UC) appear to be multigenic disorders with evidence of familial segregation. In this study, we analyzed multiplex IBD families to determine whether the defect in oral tolerance induction is genetically regulated. Methods: Patients and first-degree relatives from 6 multiplex families were fed KLH 50 mg on days 0 to 5 and 10 to 15, followed by subcutaneous immunizations on days 26 and 35. Blood was obtained and analyzed for KLH-specific T cell proliferative responses and cytokine production. Intestinal permeability was also assessed. Results: In contrast to normal controls, all IBD patients, save 1 (10 patients out of 11 tested P < .0001 versus normal controls), failed to develop oral tolerance to KLH. Furthermore, in 3 of the 4 CD families, at least 1 unaffected family member (total of 5/14 unaffected individuals, P = .002 versus normal controls) also failed to tolerize. This is in sharp contrast to unaffected individuals with no family history of IBD (1/31 tested to date). Conclusions: This failure of tolerance induction could not be attributed to increased intestinal permeability. In the UC families, the defect in tolerance segregated with disease. These data support a genetic defect in tolerance induction in CD.

Crohn's disease (CD) and ulcerative colitis (UC) are chronic and often debilitating inflammatory bowel diseases (IBD) without medical cures. Despite the existence of multiple therapies, the medical treatment of these diseases often has proven insufficient and surgery is frequently required. However, as our understanding of the pathogenesis of these disorders and other immune-mediated inflammatory diseases (eg, rheumatoid arthritis and psoriasis) has grown, new and more specific biologic therapies have been developed that are proving more effective than traditional agents. Infliximab is a genetically engineered monoclonal antibody that targets the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and represents the first effective biologic therapy for IBD and has largely revolutionized treatment. Infliximab initially was developed to be used in patients with moderate to severe luminal or fistulizing CD who are refractory to standard medical therapy. More and more practitioners now are using infliximab as first-line therapy because of its superior efficacy. Infliximab rapidly induces remission in CD, but when given chronically, it can provide long-term maintenance of remission. In addition, there are some data to support its use as a steroid-sparing agent and treatment for various extraintestinal manifestations of IBD and, although used predominantly to treat CD, recent data suggest that infliximab also may have a role in the management of UC. Overall, infliximab represents a clinically useful, cost-effective therapy that works well, even though careful patient monitoring is required to avoid rare but significant toxicities. The hope is that infliximab, together with other biologic agents that currently are in development, will allow us to modify the course of IBD, avoid complications such as strictures and abscesses, and reduce the need for surgery.

It has been proposed that defective activation of suppressor or regulatory T cells is one mechanism involved in the uncontrolled inflammatory process seen in inflammatory bowel disease (IBD). Because suppressor/regulatory T cells are thought to play a role in the promotion of oral tolerance, we attempted to induce oral tolerance in normal controls (n = 21) and patients with either Crohn's disease (CD; n = 12) or ulcerative colitis (UC; n = 13). In the first study, subjects were fed the neoantigen keyhole limpet hemocyanin (KLH) on days 1 to 5 and 11 to 15. Subcutaneous immunization with KLH was performed on day 26, with a booster immunization on day 35. Blood for KLH-induced T cell proliferation and serum for anti-KLH antibody production was obtained at baseline, on day 26 preimmunization (postfed), on day 35 after the first immunization, and again on day 42 after the second immunization. In normal individuals, KLH feeding prior to immunization and booster resulted in reduced KLH-specific T cell proliferation compared with the group that was not fed KLH. However, although on the same KLH-feeding protocol, both CD and UC patients demonstrated significantly enhanced proliferation without oral tolerance induction when compared with baseline values. These data suggest that oral tolerance induction is defective in patients with IBD. This may reflect an in vivo functional defect in mucosal suppression of immune responses in IBD. Both UC and CD appear to be multigenic disorders with evidence of familial segregation. We analyzed four multiplex Crohn's and two UC families to determine whether the defect in tolerance induction was genetically regulated. In three of the four CD families at least one unaffected family member also failed to tolerate (total 5 of 14 unaffected family members). In the UC families, the defect in tolerance segregated with disease. These data suggest a genetic defect in tolerance induction in Crohn's disease.

contrast, more objective measures, such as C-reactive protein (CRP) and haematocrit score, were, as one would predict, higher in Crohn’s patients. It is important to note that one half of all Crohn’s patients in this study appeared to be ‘active’ so one must be cautious in interpreting the application of their findings to Crohn’s patients in true remission. So where does this leave us? First and foremost, CDAI was never designed as a diagnostic tool for Crohn’s disease; to suggest otherwise is to erect a straw man. Its value lies in assessing the patient’s symptomatic response to treatment (we are, after all, treating patients, not blood tests or radiological images alone), but seems incapable, when expressed as a total score, of differentiating IBS from IBD; again no surprise. We contend that ‘IBStype symptoms’ in IBD should be regarded as representing IBD activity until proven otherwise. 6 In most instances, the differentiation is obvious; when uncertainty persists, sensitive biomarkers such as faecal calprotectin may be helpful.

To assess the incidence and management of infusion reactions to infliximab, a chimeric monoclonal antibody that targets human tumor necrosis factor-alpha, in patients with Crohn's disease treated at a large infusion center.A total of 165 consecutive patients who received 479 infliximab infusions in the Division of Clinical Immunology Infusion Center at Mount Sinai Medical Center from July, 1998 to January, 2001 were evaluated. Specific treatment protocols for initial and subsequent acute infusion reactions were followed and the outcomes documented.The overall incidence of infusion reactions to infliximab was 6.1% (29 of 479) of infusions, affecting 9.7% (16 of 165) of patients. Mild, moderate, or severe acute reactions occurred in 3.1% (15 of 479), 1.2% (six of 479), and 1.0% (five of 479) of infliximab infusions, respectively. Use of treatment protocols resulted in rapid resolution of all acute reactions to infliximab. With the prophylaxis protocol, all patients who experienced an initial mild or moderate acute reaction were able to receive additional infusions. Four patients experienced a total of five severe acute reactions. Three patients were retreated: two patients had no further problems, whereas one patient had a second severe acute reaction that rapidly resolved with treatment. Suggesting that acute infusion reactions are not type I hypersensitivity reactions, in 11 patients who experienced 14 acute infusion reactions, serum tryptase levels were normal. Delayed infusion reactions occurred in 0.6% (three of 479) of infusions.Infliximab infusions were accompanied by acute reactions in approximately 5% of infusions. These reactions did not seem to be true IgE-mediated type I hypersensitivity events. Using appropriate treatment protocols, these reactions were effectively treated and prevented upon retreatment in nearly all patients. Delayed reactions were rare, occurring in1% of infusions.