Daniel A. Sussman

Inflammatory Bowel Disease Is Associated With an Increased Incidence of Cardiovascular Events

OBJECTIVES:Patients with inflammatory bowel disease (IBD) present with several extraintestinal manifestations, including systemic inflammation and hypercoagulability. Limited studies have shown that patients with IBD may have a higher risk of developing atherosclerosis. The incidence of coronary artery disease (CAD) and the role of traditional CAD risk factors in IBD patients remain unclear. We sought to compare the rates of CAD events in patients with IBD with matched controls.METHODS:We performed a longitudinal cohort study of patients with IBD compared with matched controls. The primary outcome was the development of CAD events. Traditional and nontraditional CAD risk factors were assessed. Cox proportional hazards model was used to assess the impact of each CAD risk factor on the outcomes.RESULTS:A total of 356 IBD patients and 712 matched controls were followed for a median of 53 and 51 months, respectively. The unadjusted hazard ratio (HR) for developing CAD in the IBD group was 2.85 (95% confidence interval (CI) 1.82–4.46). IBD patients had significantly lower rates of selected traditional CAD risk factors (hypertension, diabetes, dyslipidemia, and obesity; P<0.01 for all). Adjusting for these factors, the HR for developing CAD between groups was 4.08 (95% CI 2.49–6.70). Among nontraditional risk factors, an elevated white blood cell (WBC) count was a risk factor for CAD development in the IBD group (HR 1.23; 95% CI 1.15–1.33).CONCLUSIONS:An increased incidence of CAD events was noted in IBD patients despite having a lower burden of traditional risk factors. Additionally, these risk factors had a lower impact on CAD development in the IBD group. Further investigation into how nontraditional risk factors, including WBC count, and the effect of attenuating systemic inflammation in IBD patients change CAD risk is warranted.

Systematic review with network meta‐analysis: the efficacy of anti‐tumour necrosis factor‐alpha agents for the treatment of ulcerative colitis

Antibodies against tumour necrosis factor‐alpha (anti‐TNF) are effective therapies in the treatment of ulcerative colitis (UC), but their comparative efficacy is unknown.

The association of tissue anti-TNF drug levels with serological and endoscopic disease activity in inflammatory bowel disease: the ATLAS study

Objective The aim of this study was to assess the correlation between serum and intestinal anti-tumour necrosis factor (TNF) levels, and their relationship to endoscopic disease activity and levels of TNF. Design Cross-sectional study of 30 patients receiving treatment with infliximab or adalimumab for Crohns disease or UC. For each patient, a sample of serum was matched to tissue biopsies. Endoscopic and histological disease activity was recorded for each tissue sample. Results There was a significant positive correlation between anti-TNF in serum and tissue (r=0.3920, p=0.002), especially in uninflamed tissue (r=0.50, p<0.001), but not with those samples that had inflammation (r=0.19, p=0.54). Anti-TNF concentration in tissue correlated with degree of endoscopic inflammation, except for tissue with severe inflammation in which anti-TNF levels were again lower (mean normalised anti-TNF in tissue: uninflamed=0.93, mild=2.17, moderate=13.71, severe=2.2 inflammation (p=0.0042)). The ratio of anti-TNF-to-TNF in tissue was highest in uninflamed areas and lowest in severely inflamed areas. Patients with active mucosal disease had a higher rate of serum to tissue drug level mismatch when compared to those in remission (73.3% vs 33.3%, respectively; p=0.03). Conclusions Our data suggest that local tissue inflammation characterised by high levels of TNF serves as a sink for anti-TNF. We further postulate that some patients with high serum anti-TNF levels have active disease because tissue levels of anti-TNF are insufficient to neutralise local TNF production.

Systematic review with network meta-analysis: the efficacy of anti-TNF agents for the treatment of Crohn's disease

Anti‐tumour necrosis factor‐alpha agents (anti‐TNF) are effective therapies for the treatment of Crohns disease (CD), but their comparative efficacy is unknown.

Concentrations of 6-thioguanine nucleotide correlate with trough levels of infliximab in patients with inflammatory bowel disease on combination therapy.

BACKGROUND & AIMS In patients with inflammatory bowel diseases, the combination of infliximab and thiopurines (such as 6-thioguanine) is more effective treatment than monotherapy. We assessed the correlation between serum levels of 6-thioguanine (6-TGN) and infliximab levels or antibodies to infliximab (ATI). METHODS We performed a cross-sectional study of 72 patients receiving maintenance therapy with infliximab and a thiopurine for inflammatory bowel disease at the Crohns and Colitis Center of the University of Miami, FL. We collected clinical, endoscopic, and biochemical data, and levels of thiopurine metabolites. The primary outcomes were trough level of infliximab and the presence of ATI. RESULTS Levels of 6-TGN correlated with those of infliximab (ρ, 0.53; P < .0001). The cut-off point of 6-TGN that best predicted a higher level of infliximab was 125 pmol/8 × 10(8) red blood cells (RBCs) (area under receiver operating characteristic, 0.86; P < .001). Patients in the lowest quartile of 6-TGN had infliximab levels that were similar to patients on no thiopurines (4.3 vs. 4.8 mcg/mL, respectively; P = .8). An infliximab level of 8.3 mcg/mL or greater was associated with mucosal healing. Only 8 patients (11%) had detectable ATI. Patients with 6-TGN levels less than 125 pmol/8 × 10(8) RBCs were significantly more likely to have ATI (odds ratio, 1.3; 95% confidence interval, 2.3-72.5; P < .01). CONCLUSIONS Although 6-TGN levels of greater than 230 pmol/8 × 10(8) RBCs have been associated with improved outcomes in patients on monotherapy, a level of 6-thioguanine of 125 pmol/8 × 10(8) RBCs or greater may be adequate to achieve therapeutic levels of infliximab. In the long term, this may minimize the toxicity for patients on combination therapy.

TLR4 Activates the β-catenin Pathway to Cause Intestinal Neoplasia

Colonic bacteria have been implicated in the development of colon cancer. We have previously demonstrated that toll-like receptor 4 (TLR4), the receptor for bacterial lipopolysaccharide (LPS), is over-expressed in humans with colitis-associated cancer. Genetic epidemiologic data support a role for TLR4 in sporadic colorectal cancer (CRC) as well, with over-expression favoring more aggressive disease. The goal of our study was to determine whether TLR4 played a role as a tumor promoter in sporadic colon cancer. Using immunofluorescence directed to TLR4, we found that a third of sporadic human colorectal cancers over-express this marker. To mechanistically investigate this observation, we used a mouse model that over-expresses TLR4 in the intestinal epithelium (villin-TLR4 mice). We found that these transgenic mice had increased epithelial proliferation as measured by BrdU labeling, longer colonic crypts and an expansion of Lgr5+ crypt cells at baseline. In addition, villin-TLR4 mice developed spontaneous duodenal dysplasia with age, a feature that is not seen in any wild-type (WT) mice. To model human sporadic CRC, we administered the genotoxic agent azoxymethane (AOM) to villin-TLR4 and WT mice. We found that villin-TLR4 mice showed an increased number of colonic tumors compared to WT mice as well as increased β-catenin activation in non-dysplastic areas. Biochemical studies in colonic epithelial cell lines revealed that TLR4 activates β-catenin in a PI3K-dependent manner, increasing phosphorylation of β-cateninSer552, a phenomenon associated with activation of the canonical Wnt pathway. Our results suggest that TLR4 can trigger a neoplastic program through activation of the Wnt/β-catenin pathway. Our studies highlight a previously unexplored link between innate immune signaling and activation of oncogenic pathways, which may be targeted to prevent or treat CRC.

The incidence and risk factors for developing depression after being diagnosed with inflammatory bowel disease: a cohort study.

Studies have found that depression is more frequent in patients with inflammatory bowel disease (IBD) than the general population. Clinicians are now trying to pinpoint risk factors for psychological impairment in the IBD population.

Higher Adalimumab Levels Are Associated with Histologic and Endoscopic Remission in Patients with Crohn's Disease and Ulcerative Colitis

Background:Optimal levels of adalimumab (ADA) have not been defined according to the ultimate goal of inflammatory bowel disease treatment—histologic and/or endoscopic healing. The aim of this study was to assess the relationship between random serum ADA levels and histologic and endoscopic healing in patients with inflammatory bowel disease. Methods:This was a cross-sectional study including 66 patients receiving maintenance therapy with ADA for Crohns disease or ulcerative colitis. ADA levels and anti-adalimumab antibodies (AAA) were measured at the time of colonoscopy. The primary outcome was histologic healing (lack of endoscopic and histologic inflammation) and the secondary outcomes were endoscopic healing and serum levels of C-reactive protein, tumor necrosis factor, ICAM, VCAM, and interleukins 1&bgr;, 6, and 8. Results:Sixty-six patients (59 with Crohns disease) were included. Mean random ADA levels were significantly lower in patients with histologic and endoscopic inflammation (9.2 [SD: 8.4] versus 14.1 [6.4] &mgr;g/mL, P = 0.03 and 8.5 [SD: 7.8] versus 13.3 [SD: 7.7], P = 0.02, respectively). The ADA level that was best associated with histologic healing was 7.8 &mgr;g/mL (receiver operating characteristic: 0.76 [P = 0.04]), whereas the ADA level that was best associated with endoscopic healing was 7.5 &mgr;g/mL (receiver operating characteristic: 0.73 [P = 0.02]). The presence of AAA was associated with lower random ADA levels (5.7 versus 12.5 &mgr;g/mL, P = 0.002) and higher C-reactive protein levels (30.3 versus 12.0, P = 0.01). Conclusions:Achievement of histologic and endoscopic healing may require higher levels of ADA than previously described for endoscopic remission. The measurement of random ADA levels and anti-drug antibodies may guide therapy and edify the course of incomplete responses.

Phenotypic Manifestations of Inflammatory Bowel Disease Differ Between Hispanics and Non-Hispanic Whites: Results of a Large Cohort Study

OBJECTIVES:Hispanics are the fastest growing minority in the United States, yet few studies have examined the phenotypes of inflammatory bowel disease (IBD) in this population. No studies compare IBD presentation between foreign and US-born Hispanics. Our aim was to compare phenotypic characteristics of IBD between Hispanics and non-Hispanic Whites (NHWs), as well as between US-born and foreign-born Hispanics.METHODS:We retrospectively identified cohorts of adult IBD patients from 1998 to 2009 and compared ethnic variation in phenotype, including disease type (Crohns disease or ulcerative colitis (UC)), extra-intestinal manifestations (EIMs), Montreal classification, surgeries, hospitalizations, and medication prescription.RESULTS:A total of 325 patients were included; 208 were Hispanics. Foreign-born Hispanics, accounting for 68% of the total, were diagnosed at an older age than US-born Hispanics and NHWs (45 vs. 25 and 27, respectively, P<0.05). Foreign-born Hispanics manifested more UC than US-born Hispanics or NHWs (59.9% vs. 41% and 28.2%, respectively, P<0.05). No difference was noted in the prevalence of EIMs between Hispanics and NHWs. More upper gastrointestinal tract Crohns was observed in NHWs (12.5% vs. 3.9%, P<0.05). The incidence density rate of IBD-related surgeries in NHWs was higher than in Hispanics (22.9 vs. 7.3 surgeries/100 person-years, P<0.01, hazard ratio: 0.3, 95% confidence interval: 0.14–0.5). Hispanic patients had fewer prescriptions for biologics and immunomodulators than NHWs (22.2% vs. 55.6%, P<0.01 and 35.7% vs. 53.8%, P<0.01, respectively).CONCLUSIONS:This study demonstrates differences in IBD presentation among NHW, US-born Hispanic, and foreign-born Hispanic groups. Further investigation to identify environmental and genetic differences between ethnic groups affected by IBD is warranted.

Cancer in Inflammatory Bowel Disease: lessons from animal models

Purpose of review Human colitis-associated cancers (CAC) represent a heterogeneous group of conditions in which multiple oncogenic pathways are involved. In this article, we review the latest studies using genetic, chemical, bacterial and innate immune-mediated experimental models of CAC. Recent findings Using the azoxymethane-dextran sodium sulfate model, wound healing pathways seem to be required in the development of CAC. There is also an emerging understanding that commensal and/or pathogenic bacteria can promote tumorigenesis, through T cell and TLR-mediated inflammation. Using specific transgenic mice (villin-CD98, T cell SMAD7, villin-TLR4) or specific knockout mice, investigators have determined that derangements in epithelial or innate and adaptive immune pathways can result in CAC. Subtle perturbations in epithelial repair – both too little or too exuberant – can render mice susceptible to tumorigenesis. Summary With the aid of animal models, we have witnessed a rapid expansion of our knowledge of the molecular and immunologic mechanisms underlying inflammatory cancers. Though animal models have contributed a discrete amount of information to our understanding of tumorigenesis in the setting of intestinal inflammation, it is clear that no single animal model will be able to adequately recapitulate the pathogenesis of complex colorectal cancers, but each model gets us one step closer to comprehending the nature of CAC.