Maria A. Quintero

Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids

Inflammatory T helper 17 cells in humans are distinguished by selective expression of MDR1 and are enriched in the gut of patients with Crohn’s disease.

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.

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.

Higher infliximab trough levels are associated with perianal fistula healing in patients with Crohn's disease

Infliximab has been found to be efficacious in the treatment of fistulas in the setting of Crohns disease, even though some patients do not benefit from therapy.

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.

Inflammatory bowel disease is presenting sooner after immigration in more recent US immigrants from Cuba

Despite a rising incidence of inflammatory bowel disease (IBD) in Hispanics in the United States, there are no studies examining the relationship between immigrant generation and IBD onset among Hispanics.

Development of Advanced Imaging Criteria for the Endoscopic Identification of Inflammatory Polyps

OBJECTIVES:Inflammatory polyps (IPs) are frequently encountered at colonoscopy in inflammatory bowel disease (IBD) patients and are associated with an increased risk of colon cancer. The aim of this prospective endoscopic image review and analysis was to describe endoscopic features of IPs in IBD patients at surveillance colonoscopy and determine the ability to endoscopically discern IPs from other colon polyps using high-definition white light (WL), narrow band imaging with magnification (NBI), and chromoendoscopy (CE).METHODS:Digital images of IPs using WL, NBI, and CE were reviewed by four attending gastroenterologists using a two-round modified Delphi method. The ability to endoscopically discern IPs from other colon polyps was determined among groups of gastroenterology fellows and attendings. IPs were classified by gross appearance, contour, surface pattern, pit pattern, and appearance of surrounding mucosa in IPs, as well as accuracy of diagnosis.RESULTS:Features characteristic of IPs included a fibrinous cap, surface friability and ulceration, an appendage-like appearance, the halo sign with CE, and a clustering of a multiplicity of IPs. The overall diagnostic accuracy for IP identification was 63% for WL, 42% for NBI, and 64% for CE. High degrees of histologic inflammation significantly improved the accuracy of diagnosis of IP with WL and CE, whereas the use of NBI significantly impaired IP accuracy.CONCLUSIONS:The overall diagnostic accuracy when applying these criteria to clinical images was modest, with incremental benefit with addition of CE to WL. CE showed promise predicting IP histology in actively inflamed tissue. Institutional Review Board approval was obtained. ClinicalTrials.gov Identifier: NCT01557387.

Serum Amyloid A as a Surrogate Marker for Mucosal and Histologic Inflammation in Patients with Crohn's Disease

Background: Serum amyloid A (SAA) is an acute-phase protein, but its role as a biomarker of disease activity in Crohns disease is unclear. The aim of the study was to assess the correlation between SAA, inflammatory cytokines, and mucosal inflammation in patients with Crohns disease and to investigate whether this marker might be useful in patients who do not have elevated C-reactive protein (CRP) levels despite having active disease. Methods: Cross-sectional study including patients with Crohns disease who underwent colonoscopies for assessment of disease activity. Predictive variables were recorded at the time of the procedure and included demographics, phenotype of disease, medications, and collection of serum for cytokine analysis (SAA, CRP, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and interleukins 8, 1&bgr;, and 6). The primary outcome was the presence of mucosal healing (MH) (absence of macroscopic and microscopic inflammation). Results: Ninety-four patients were included. Sixty-eight (72.3%) had not achieved MH. SAA, CRP, intercellular adhesion molecule, and interleukin-6 levels were significantly lower in those patients with MH. SAA was the only test that performed well in the sensitivity/specificity analysis (receiver operating characteristic: 0.81, P = 0.046). A high SAA was able to identify 70% of the patients with a normal CRP but active inflammation. Conclusions: High circulating SAA levels can correlate with lack of MH and may be used as a surrogate marker for disease activity, even in those patients in whom CRP levels do not correlate with disease activity.

Genetic Characterization and Influence on Inflammatory Bowel Disease Expression in a Diverse Hispanic South Florida Cohort

OBJECTIVES: Hispanics represent an understudied inflammatory bowel disease (IBD) population. Prior studies examining genetic predisposition to IBD in Hispanics are limited. In this study, we examined whether European‐derived IBD variants confer risk in Hispanics and their influence on IBD phenotype in Hispanics compared to non‐Hispanic whites (NHW). METHODS: Self‐identified Hispanics and NHWs with IBD were included. Hispanic controls were included for our genetic analyses. We performed single‐variant testing at previously identified Crohns disease (CD) and ulcerative colitis (UC) IBD variants in Hispanic cases and controls. These risk variants were used to compute individual genetic risk scores. Genetic risk scores and phenotype associations were compared between Hispanic and NHW. RESULTS: A total of 1,115 participants were included: 698 controls and 417 IBD patients (230 Hispanics). We found evidence of association within our Hispanic cohort at 22 IBD risk loci, with ˜76% of the risk loci demonstrating over‐representation of the European risk allele; these included loci corresponding to IL23R and NOD2 genes. CD genetic risk score for Hispanics (199.67) was similar to the score for NHW (200.33), P=0.51; the same was true in UC. Genetic risk scores did not predict IBD phenotype or complications in Hispanics or NHW except for a younger age of CD onset in Hispanics (P=0.04). CONCLUSIONS: This study highlights the fundamental importance of these loci in IBD pathogenesis including in our diverse Hispanic population. Future studies looking at non‐genetic mechanisms of disease are needed to explain differences in age of presentation and phenotype between Hispanics and NHW.

Hispanics Coming to the US Adopt US Cultural Behaviors and Eat Less Healthy: Implications for Development of Inflammatory Bowel Disease

IntroductionThe incidence of inflammatory bowel disease (IBD) among US Hispanics is rising. Adoption of an American diet and/or US acculturation may help explain this rise.AimsTo measure changes in diet occurring with immigration to the USA in IBD patients and controls, and to compare US acculturation between Hispanics with versus without IBD. Last, we examine the current diet of Hispanics with IBD compared to the diet of Hispanic controls.MethodsThis was a cross-sectional study of Hispanic immigrants with and without IBD. Participants were recruited from a university-based GI clinic. All participants completed an abbreviated version of the Stephenson Multi-Group Acculturation Scale and a 24-h diet recall (the ASA-24). Diet quality was calculated using the Healthy Eating Index (HEI-2010).ResultsWe included 58 participants: 29 controls and 29 IBD patients. Most participants were Cuban or Colombian. Most participants, particularly those with IBD, reported changing their diet after immigration (72% of IBD and 57% of controls). IBD participants and controls scored similarly on US and Hispanic acculturation measures. IBD patients and controls scored equally poorly on the HEI-2010, although they differed on specific measures of poor intake. IBD patients reported a higher intake of refined grains and lower consumption of fruits, whereas controls reported higher intake of empty calories (derived from fat and alcohol).ConclusionThe majority of Hispanics change their diet upon immigration to the USA and eat poorly irrespective of the presence of IBD. Future studies should examine gene–diet interactions to better understand underlying causes of IBD in Hispanics.