Anne E. Gifford

Histologic Markers of Inflammation in Patients With Ulcerative Colitis in Clinical Remission

BACKGROUND & AIMS Mucosal healing, based on histologic analysis, is an end point of maintenance therapy for patients with ulcerative colitis (UC). There are few data on how histologic signs of inflammation correlate with endoscopic and peripheral blood measures of inflammation in these patients. We investigated patterns of histologic features of inflammation in patients with UC in clinical remission, and correlated these with endoscopic and biochemical measures of inflammation. METHODS We performed a prospective observational study of 103 patients with UC in clinical remission undergoing surveillance colonoscopy while receiving maintenance therapy with mesalamine or thiopurines; 2674 biopsy specimens were collected from 708 colonic segments. Each colonic segment was evaluated based on the Mayo endoscopic subscore and the Geboes histology score (range, 0-5.4). Biomarkers were measured in peripheral blood samples. RESULTS Histologic features of inflammation were found in 54% of patients receiving maintenance therapy; 37% had at least moderate inflammation based on histology scores. Of the 52 patients with endoscopic evidence only of left-sided colitis, 34% had histologic features of inflammation in their proximal colon. Histology scores correlated with endoscopic scores for per-segment inflammation (Spearman ρ = 0.65; P < .001). Patients with histology scores greater than 3.1 had a significantly higher mean level of C-reactive protein than those with scores less than 3.1. There were no differences among treatment groups in percentages of patients with histologic scores greater than 3.1. CONCLUSIONS Patients in clinical remission from UC still frequently have histologic features of inflammation, which correlate with endoscopic appearance. Patients with at least moderate levels of inflammation, based on histologic grading (score >3.1), have higher serum levels of C-reactive protein, which could be used as a surrogate marker of histologic inflammation.

Predictors of endoscopic inflammation in patients with ulcerative colitis in clinical remission.

Background:Patients with ulcerative colitis (UC) who are in clinical remission may still have underlying endoscopic inflammation, which is associated with inferior clinical outcomes. The goal of this study was to determine the prevalence of active endoscopic disease, and factors associated with it, in patients with UC who are in clinical remission. Methods:Prospective observational study in a single center. Patients with UC in clinical remission (by Simple Clinical Colitis Activity Index) were enrolled prospectively at the time of surveillance colonoscopy. Disease phenotype, endoscopic activity (Mayo subscore), and histologic score (Geboes) were recorded, and blood was drawn for peripheral blood biomarkers. Results:Overall, 149 patients in clinical remission were prospectively enrolled in this cohort; 81% had been in clinical remission for >6 months, and 86% were currently prescribed maintenance medications. At endoscopy, 45% of patients in clinical remission had any endoscopic inflammation (Mayo endoscopy subscore >0), and 13% had scores >1. In a multivariate model, variables independently associated with a Mayo endoscopic score >1 were remission for <6 months (P = 0.001), white blood count (P = 0.01), and C-reactive protein level (P = 0.009). A model combining these 3 variables had a sensitivity of 94% and a specificity of 73% for predicting moderate-to-severe endoscopic activity in patients in clinical remission (area under the curve, 0.86). In an unselected subgroup of patients who had peripheral blood mononuclear cell messenger RNA profiling, GATA3 messenger RNA levels were significantly higher in patients with endoscopic activity. Conclusions:Duration of clinical remission, white blood count, and C-reactive protein level can predict the probability of ongoing endoscopic activity, despite clinical remission in patients with UC. These parameters could be used to identify patients who require intensification of treatment to achieve mucosal healing.

Systematic review: the quality of the scientific evidence and conflicts of interest in international inflammatory bowel disease practice guidelines.

Guidelines published by the international gastroenterology societies establish standards of care and seek to improve patient outcomes.

Systematic Analysis Underlying the Quality of the Scientific Evidence and Conflicts of Interest in Interventional Medicine Subspecialty Guidelines

OBJECTIVE To determine the validity of guidelines published by interventional medical societies. METHODS We reviewed the interventional medicine subspecialty society websites of the American Association for Bronchology and Interventional Pulmonology (AABIP), American Society of Diagnostic and Interventional Nephrology (ASDIN), American Society for Gastrointestinal Endoscopy (ASGE), and Society for Cardiovascular Angiography and Interventions (SCAI) as of November 15, 2012, for published interventional guidelines. The study was performed between November 15, 2012, and January 1, 2013. The AABIP did not publish guidelines, so American Thoracic Society and American College of Chest Physicians guidelines were reviewed. All the guidelines were reviewed for graded levels of evidence, methods used to grade the evidence, and disclosures of conflicts of interest (COIs). RESULTS Of 153 interventional guidelines evaluated, 4 were duplicates. Forty-six percent of guidelines (69 of 149) graded the quality of evidence using 7 different methods. The ASGE graded 71% of guidelines (46 of 65) compared with 29% (23 of 78) by the SCAI and 0 by the ASDIN (n=4) and the pulmonary societies (n=2). Of the 3425 recommendations reviewed, 11% (n=364) were supported by level A, 42% (n=1432) by level B, and 48% (n=1629) by level C. The mean age of the guidelines was 5.2 years. Additionally, 62% of the guidelines (92 of 149) failed to comment on COIs; when disclosed, 91% of guidelines (52 of 57) reported COIs. In total, 1827 COIs were reported by 45% of the authors (317 of 697), averaging 5.8 COIs per author. CONCLUSION Most of the interventional guidelines failed to grade the evidence. When present, most guidelines used lower-quality evidence. Furthermore, most guidelines failed to disclose COIs. When commented on, numerous COIs were present. Future guidelines should clearly state the quality of evidence, use a standard grading system, be transparent regarding potential biases, and provide frequent updates.

A Random Urine Test Can Identify Patients at Risk of Mesalamine Non-Adherence: A Prospective Study

OBJECTIVES:Mesalamine non-adherence is common among patients with ulcerative colitis (UC), and can be difficult to identify in practice. We sought to determine whether a random urine test for salicylates could be used as a marker of 5-aminosalicylic acid (5-ASA) ingestion and identify patients at risk of non-adherence. Our aim is to determine whether measurement of salicylates in a random urine sample correlates with 5-ASA levels, and predicts an individuals risk of mesalamine non-adherence.METHODS:Prospective observational study. Urinary salicylates (by colorimetry) and 5-ASA (by liquid chromatography and tandem-mass spectrometry) were measured in a random urine sample at baseline in patients and controls. Mesalamine adherence was quantified by patient self-reports at enrollment and pharmacy refills of mesalamine over 6 months.RESULTS:A total of 93 patients with UC taking mesalamine maintenance therapy were prospectively enrolled from the clinic. Random urine salicylate levels (by colorimetry) were highly correlated with urine 5-ASA metabolite levels (by mass spectrometry; R2=0.9). A random urine salicylate level above 15 mg/dl distinguished patients who had recently taken mesalamine from controls (area under the curve value 0.9, sensitivity 95%, specificity 77%). A significant proportion of patients (27%) who self-identified as “high adherers” by an adherence questionnaire (Morisky Medication Adherence Scale-8) had random levels of urine salicylate below this threshold. These patients were at higher risk of objectively measured non-adherence to mesalamine over the subsequent 6 months (RR: 2.7, 95% CI: 1.1–7.0).CONCLUSIONS:A random urine salicylate level measured in the clinic can identify patients who have not recently taken mesalamine, and who are at higher risk of longitudinal non-adherence. This test could be used to screen patients who may warrant interventions to improve adherence and prevent disease relapse.

Systematic Analysis Underlying the Quality of the Scientific Evidence and Conflicts of Interest in Gastroenterology Practice Guidelines

OBJECTIVES:The practice guidelines published by the American Gastroenterological Association (AGA) and the American College of Gastroenterology (ACG) are used to establish standards of care and improve patient outcomes. We examined the guidelines for quality of evidence, methods of grading evidence, and conflicts of interest (COIs).METHODS:All 81 (AGA and ACG) guidelines available online on 26 July 2012 were reviewed for the presence of grading of evidence and COIs. In total, 570 recommendations were evaluated for level of evidence and methods used to grade the evidence. The data were evaluated in aggregate and by society.RESULTS:Only 31% (n=25) of the guidelines graded the levels of evidence. A total of 12 systems were used to grade the quality of evidence in these 25 guidelines. Of the 570 recommendations reviewed, only 29% (n=165) were supported by the highest quality of evidence, level A; 37% (n=210) level B, 29% (n=165) level C, and 5% (n=30) level D. Since 2007, 87% (n=13/15) of the ACG guidelines graded the evidence compared with only 33% of the AGA guidelines (n=4/12). Furthermore, 70% (n=57/81) of the guidelines failed to disclose any information regarding COIs. Of the 24 articles commenting on COIs, 67% reported COIs.CONCLUSIONS:Although the majority of the gastroenterology guidelines fail to grade the quality of evidence, more recent ACG guidelines grade majority of their recommendations. When the evidence is graded, most of the supporting evidence is based on lower-quality evidence. In addition, most of the guidelines fail to comment on COIs, and when disclosed, numerous COIs were present. This study highlights the critical need to revise the guideline development process. Future guidelines should clearly state the quality of evidence for their recommendations, utilize a standard grading system, and be transparent regarding all COIs.

Rifaximin suppresses background intestinal 18F-FDG uptake on PET/CT scans.

BackgroundIdentification of cancer or inflammatory bowel disease in the intestinal tract by PET/computed tomography (CT) imaging can be hampered by physiological uptake of 18F-fluorodeoxyglucose (18F-FDG) in the normal colon. Previous work has localized this 18F-FDG uptake to the intestinal lumen, predominantly occupied by bacteria. We sought to determine whether pretreatment with an antibiotic could reduce 18F-FDG uptake in the healthy colon. Patients and methodsThirty patients undergoing restaging PET/CT for nongastrointestinal lymphoma were randomly selected to receive rifaximin 550 mg twice daily for 2 days before their scan (post-rifaximin). Their PET/CT images were compared with those from their prior study (pre-rifaximin). Cecal maximum standard uptake value (SUVmax) and overall colonic 18F-FDG uptake were compared between scans. All PET/CT images were blindly scored by a radiologist. The same comparison of sequential scans was also undertaken in 30 patients who did not receive antibiotics. ResultsThirty post-rifaximin scans were compared with 30 pre-rifaximin scans in the same patients. SUVmax in the cecum was significantly lower in the patient’s post-rifaximin scans than in their pre-rifaximin scans (P=0.002). The percentage of scans with greater than grade 1 colonic 18F-FDG uptake was significantly lower in the post-rifaximin scans than in the pre-rifaximin scans (P<0.05). In contrast, there was no significant difference in the paired sequential scans from control patients, nor a reduction in the percentage of scans with greater than grade 1 colonic 18F-FDG uptake. ConclusionThis pilot study shows that treatment with rifaximin for 2 days before PET/CT scanning can significantly reduce physiological 18F-FDG uptake in the normal colonic lumen.

Comment on Moshkovska et al

We read with great interest the article entitled Impact of a Tailored Patient Preference Intervention in Adherence to 5-Aminosalicylic Acid Medication in Ulcerative Colitis: Results from an Exploratory Randomized Controlled Trial by Moshkovska et al. The authors concluded that this tailored intervention ‘‘can enhance persistence with 5-ASA’’ among patients with inflammatory bowel disease (IBD). We would caution against making this conclusion based on the data presented in the study for two reasons. First, the authors used a spot urinary 5-ASA and N-acetyl-5-ASA concentration at 12 months as the primary outcome measure of mesalamine adherence in their intervention and control groups. Urine levels of 5-ASA and N-acetyl-5-ASA only reflect ingestion of mesalamine in the previous 24–96 hours, and do not reflect persistence of medication use over 12 months. Isolated measures of adherence collected at a scheduled study visit may be biased in favor of adherence (so-called ‘‘white coat adherence’’). We previously reported that longitudinal medication refill adherence was not significantly improved beyond standard care by a similar patient support program. Second, whether or not the tailored program ‘‘enhanced’’ adherence depends on whether or not it improved adherence in patients who were nonadherent at baseline. The authors report that 14/17 (82%) of the baseline nonadherent patients remained nonadherent at follow-up, suggesting the intervention did not improve adherence in most of these patients. Those reporting nonadherence at baseline are the critical group for such interventions. In conclusion, we commend Moshkovska et al for performing such a study. Although we do not agree that the intervention ‘‘enhanced persistence with 5-ASA,’’ it has some merit in maintaining adherence in alreadyadherent patients. ACKNOWLEDGMENTS Disclosures: Alan C. Moss has received grant support from Proctor & Gamble and Shire for studies on mesalamine adherence.

Tu1964 Upregulation of Melanin-Concentrating Hormone Receptor in Lamina Propria CD4+ Cells From Patients With Inflammatory Bowel Disease

G A A b st ra ct s increase of CD11c+ cells in the lamina propria of which are 90% CD11b+ and 40% β2-AR positive. Conclusion: Stimulation of the β2-AR expressed by BMDC results in a significant anti-inflammatory cytokine profile compared to the inflammatory phenotype with high levels of IL-12p70, IL-6, TNFα and low IL-10 of vehicle treated BMDC. In T cell dependant colitis there is a significant increase of CD11c+CD11b+ DC in the lamina propria which express the β2-AR. Treating IBD patients with β2-AR agonists might have the same effect on inflammatory DC as in BMDC and could potentially ameliorate disease activity.

Tu1966 Inhibition of CD4+ T-Helper Cells in Crohn's Disease by Imipramine is Mediated via Acid Sphingomyelinase Blockade

G A A b st ra ct s increase of CD11c+ cells in the lamina propria of which are 90% CD11b+ and 40% β2-AR positive. Conclusion: Stimulation of the β2-AR expressed by BMDC results in a significant anti-inflammatory cytokine profile compared to the inflammatory phenotype with high levels of IL-12p70, IL-6, TNFα and low IL-10 of vehicle treated BMDC. In T cell dependant colitis there is a significant increase of CD11c+CD11b+ DC in the lamina propria which express the β2-AR. Treating IBD patients with β2-AR agonists might have the same effect on inflammatory DC as in BMDC and could potentially ameliorate disease activity.