Comparative evaluation of a language model and human specialists in the application of European guidelines for the management of inflammatory bowel diseases and malignancies.

BACKGROUND: Society guidelines on colorectal dysplasia screening, surveillance, and endoscopic management in inflammatory bowel disease (IBD) are complex, and physician adherence to them is suboptimal. We aimed to evaluate the use of ChatGPT, a large language model, in generating accurate guideline-based recommendations for colorectal dysplasia screening, surveillance, and endoscopic management in IBD in line with European Crohn's and Colitis Organization (ECCO) guidelines. METHODS: 30 clinical scenarios in the form of free text were prepared and presented to three separate sessions of ChatGPT and to eight gastroenterologists (four IBD specialists and four non-IBD gastroenterologists). Two additional IBD specialists subsequently assessed all responses provided by ChatGPT and the eight gastroenterologists, judging their accuracy according to ECCO guidelines. RESULTS: ChatGPT had a mean correct response rate of 87.8%. Among the eight gastroenterologists, the mean correct response rates were 85.8% for IBD experts and 89.2% for non-IBD experts. No statistically significant differences in accuracy were observed between ChatGPT and all gastroenterologists (P=0.95), or between ChatGPT and the IBD experts and non-IBD expert gastroenterologists, respectively (P=0.82). CONCLUSIONS: This study highlights the potential of language models in enhancing guideline adherence regarding colorectal dysplasia in IBD. Further investigation of additional resources and prospective evaluation in real-world settings are warranted.

Trends in Biochemical Parameters, Healthcare Resource and Medication Use in the 5 Years Preceding IBD Diagnosis: A Health Maintenance Organization Cohort Study.

BACKGROUND: Few data describing pre-diagnosis changes in patients with inflammatory bowel disease (IBD) exist. We aimed to determine if there is a pattern of change in use of health resources, medications and laboratory results in the years preceding diagnosis. METHODS: This retrospective study used electronic medical records of Maccabi Health Services (MHS). Patients with IBD ≥ 16 years of age and minimum of 5-years follow-up were identified by entry into the MHS IBD registry and included in the analysis. Demographic, clinical, medication and laboratory data were collected. Generalized estimating equation model was applied to study trends and compare between years. RESULTS: This study included 5643 patients with IBD. Of these, 3039 (53.8%) had Crohn's disease (CD), 2322 (41.1%) had ulcerative colitis (UC) and 282 (5%) had indeterminate colitis (IC). Laboratory parameters including white blood cells, platelets and C-reactive protein showed significant increases while haemoglobin and mean cell volume showed significant decreases in mean values in the 2 years prior to diagnosis with stable values prior to that (p < 0.0001). Parameters such as creatinine, total protein and albumin showed significant, progressive decreases in mean values starting 5 years prior to diagnosis (p < 0.0001). Patients with CD had distinct laboratory trends when compared with patients with UC. CONCLUSIONS: Changes in laboratory parameters, healthcare service and medication use occur during the 5-year period before IBD diagnosis. These data can have future clinical applicability by developing a composite score and referral algorithm introducing red flags into primary care visits and appropriate referral for specialist care.

Intermittent Appearance of Antibodies to Infliximab Is Not Associated With Reduced Efficacy in Patients With Inflammatory Bowel Diseases.

GOALS: To assess the clinical significance of antibodies to infliximab (ATI) formation in patients with inflammatory bowel disease (IBD). BACKGROUND: Infliximab therapy in patients with IBD is highly effective though up to 50% of patients lose response to infliximab. ATI formation occurs in 6% to 60% of patients on scheduled infliximab maintenance therapy. METHODS: Infliximab trough levels and ATI at trough were prospectively determined in patients with IBD on maintenance infliximab therapy. Patients on infliximab maintenance therapy with at least 3 ATI measurements were included. Patients were divided into 2 groups: sustained negative (<1 µg/mL) ATI levels, and fluctuating ATI levels (at least 1 sample with ATI <1 and at least one >1 µg/mL). RESULTS: Forty-eight patients with IBD with available clinical data and serum samples were included. 25 patients had sustained low ATI levels and 23 patients had fluctuating ATI levels. Both groups were similar in IBD subtype distribution (Crohn's disease in 73.9% and 60%), mean serum albumin levels (4.2 vs. 3.9 g/dL), and mean trough serum infliximab levels (3.3 vs. 4.6 µg/mL) in fluctuating ATI and low ATI groups, respectively. There were no significant differences in the rate of clinical response (64% vs. 76%) and mean serum C-reactive protein levels (9.4 vs. 8.5 mg/dL, ULN=5) in the fluctuating ATI and low ATI groups. Similar rates of clinical response in the fluctuating ATI and low ATI groups were observed in ulcerative colitis (33% vs. 40%) and Crohn's disease (76% vs. 100%). CONCLUSIONS: The fluctuating pattern of appearance of ATI in patients with IBD was not associated with loss of clinical response or a rise in C-reactive protein. The authors suggest that in clinical decision making, only sustained appearance of ATI should be considered as an adverse therapeutic factor.

Risk of Cancer in Paediatric onset Inflammatory Bowel Diseases: A Nation-wide Study From the epi-IIRN.

BACKGROUND: Paediatric onset IBD [PIBD] is characterised by a more extensive phenotype than adult-onset IBD and a higher utilisation of immunosuppressive medications; both may be associated with malignancy. We aimed to assess the risk of cancer in a nationwide cohort of PIBD and to explore the risks associated with medical treatments. METHODS: PIBD patients [<18 years old] were included from the epi-IIRN cohort, covering 98% of the Israeli population from 2005, linked to the national cancer registry. We matched PIBD children to non-IBD children for calculating the cumulative incidence of cancer. RESULTS: In all, 3944 PIBD cases were included (2642 [67%] Crohn's disease, 1302 [33%] ulcerative colitis) translating into 23 635 person-years of follow-up, individually matched to 13 005 non-IBD children. By 30 years of age, 14 IBD patients [0.35%, 5.9/10 000 patient-years] were diagnosed with cancer and one [0.03%] with haemophagocytic-lymphohistiocytosis [HLH], compared with 14 [0.11%, 1.9/10 000 patient-years] cases of cancer {relative risk (RR) 2.5 (95% confidence interval [CI] 1.05-6.2); p = 0.04} and no HLH in the comparison-group. There were no cases of hepatosplenic T cell lymphoma, adenocarcinoma, or cholangiocarcinoma. Cancer risk was 15.6 cases/10 000 person-years in those treated with thiopurines alone (RR compared with IBD patients never exposed to either thiopurines or anti-tumuor necrosis factor [TNF] 1.8 [95% CI 0.6-6.1]; p = 0.2), 11.1/10 000 in those treated with anti-TNF alone (RR 1.3 [95% CI 0.3-6.6]; p = 0.5), and 23.1/10 000 treated with combination therapy of anti-TNF and thiopurines (RR 2.8 [95% CI 0.6-13.8]; p = 0.2). CONCLUSIONS: PIBD confers an increased risk for malignancy compared with non-IBD in children. However, the absolute risk is very low and no differences in risk with specific therapies were apparent in our data.

Differential Serum-intestinal Dynamics of Infliximab and Adalimumab in Inflammatory Bowel Disease Patients.

BACKGROUND AND AIMS: Therapeutic drug monitoring is used to guide anti-tumour necrosis factor [TNF] therapy. However, the associations between serum drug levels [SDL], TNF-bound, and free anti-TNF in the target tissue are incompletely defined. We aimed to assess the interactions between these parameters in inflammatory bowel disease [IBD] patients. METHODS: ENZYME-LINKED IMMUNOSORBENT: assays [ELISA assays] were used to detect free drug and TNF-drug complexes in intestinal tissues. Concurrent SDL, anti-drug antibodies [ADA], pharmacotherapy, clinical response, endoscopic appearance, and histological severity were determined. Comparisons between anti-TNFs and paired inflamed/non-inflamed tissue were performed. Variables were correlated and potential interactions detected using multivariate analysis. RESULTS: A total of 95 biopsies taken from 49 anti-TNF treated IBD patients [26 receiving infliximab and 23 adalimumab] were studied. Free drug levels were higher in inflamed compared with non-inflamed paired specimens. Tissue free-drug and TNF-drug complexes levels were higher in adalimumab-treated patients. In adalimumab-treated patients, SDL were correlated with free drug, but not TNF-drug complex levels, in both inflamed and non-inflamed segments. In infliximab-treated patients, higher SDL were associated with the presence of tissue free drug in both inflamed and non-inflamed segments, whereas TNF-drug complexes were mostly detected in non-inflamed but not in inflamed tissue. In the presence of ADA, neither free drug nor TNF-infliximab complexes were measured in the tissue. Tissue levels did not correlate well with clinical, endoscopic, or histological scores. CONCLUSIONS: SDL correlated with tissue free drug levels; however, different dynamics were observed for TNF-drug complex levels. Infliximab and adalimumab tissue drug dynamics differ. Better understanding of these interactions may allow future therapeutic optimisation.

Early Indolent Course of Crohn's Disease in Newly Diagnosed Patients Is Not Rare and Possibly Predictable.

BACKGROUND & AIMS: The early stages of Crohn's disease (CD) course are heterogeneous, and it is a challenge to predict the course of disease in patients with new diagnosis. METHODS: We performed an observational longitudinal study of 156 adults (79 male; median age, 27.7 years; 57 treatment naïve) with newly diagnosed CD (within 6 months of enrollment), referred from medical centers and community clinics in Israel from 2013 through 2017. Study participants each received semi-annual scheduled evaluations. Indolent disease was defined as a disease course without need for strict interventions to control complicated course of CD (hospitalization or surgery, or decision to start steroid, immunomodulator, or biologic therapy). Cox regression and receiver operating characteristic analyses were used to identify factors associated with early indolent or complicated course of CD. We validated our findings in an independent cohort of patients with CD from a separate medical center in Israel in 2018. RESULTS: Over a median follow-up period of 17.2 months (interquartile range, 8.8-23.8 months), 52 patients (33.3%) had an indolent course of CD, 29 (18.5%) required hospitalizations, and 75 (48%) were recommended to start steroid, immunomodulator, or biologic therapies. The median time to first intervention was 3.4 months (95% CI, 2.4-4.4). We developed a model based on clinical factors that identified 4 factors associated with complicated course in treatment-naïve patients: body mass index <25 kg/m2 (hazard ratio [HR], 2.45; 95% CI, 1.07-5.43; P = .033), serum level of vitamin B12 <350 pg/mL (HR, 2.78; 95% CI, 1.21-6.41; P = .016), white blood cells ≥7 × 103/µL (HR, 2.419; 95% CI, 1.026-5.703; P = .044), and serum level of ALT ≥25 IU/L (HR, 2.680; 95% CI, 1.186-6.058; P = .018). This model discriminated between patients with vs without a complicated course of disease with 90% and 89% accuracy at 6 and 12 months after diagnosis, respectively. A validation cohort demonstrated a discriminatory ability of 79% at 3 months after diagnosis, and a nomogram was constructed. CONCLUSIONS: In an observational longitudinal study of 156 patients with newly diagnosed CD, we found that one third have an early indolent course of disease. We identified factors that can be measured at diagnosis to identify patients at risk for an early complicated course-these might be used in patient management and selection of treatment.

Physician adherence to societal guidelines following colonoscopy with polypectomy.

BACKGROUND: Colorectal cancer is a significant cause of mortality and morbidity in western countries. Polypectomy reduces the incidence and mortality of colorectal cancer. Following polypectomy, recommendations regarding the frequency and duration of surveillance rely mostly on features of the resected polyps and are summarized in various gastroenterological societal guidelines. In this study, we aimed to delineate the accuracy of current post-polypectomy surveillance recommendations and to check whether active intervention would lead to an improvement in accuracy and consistency with societal guidelines. METHODS: We prospectively collected polypectomy reports over a 3-month period in 2 tertiary medical centers. We then performed an intervention that included: 1) presentation of results from 1st phase; 2) re-affirming the guidelines in a departmental meeting; 3) addition of a dedicated reporting form for post-polypectomy surveillance recommendations in the patients' electronic medical file. Finally, we conducted a second prospective collection of post-polypectomy recommendations, over a second 3-month period. RESULTS: Prior to the intervention, 76% of the colonoscopies with polypectomy had a recommendation for surveillance, compared to 85% after the intervention (P=0.003). Prior to the intervention, 65% of patients received a recommendation consistent with societal guidelines, compared with 78% after the intervention (P=0.001). CONCLUSION: Intervention, including re-affirmation of the current guidelines and creation of a dedicated reporting platform, significantly increases the number of follow-up recommendations after polypectomy and their consistency with societal guidelines.

Safety and effectiveness of ustekinumab for induction of remission in patients with Crohn's disease: A multicenter Israeli study.

INTRODUCTION: Ustekinumab is an effective treatment of Crohn's disease (CD). Real-world data addressing the efficacy and safety of ustekinumab are scarce. AIM: Our aim was to assess the safety and efficacy of ustekinumab in a large national patient cohort. METHODS: A prospective multicenter study, in which we followed patients with active CD treated with ustekinumab for 24 weeks. Induction dose was intravenous ranging from 260 to 520 mg, according to body weight, followed by 90 mg doses given subcutaneously every 8 weeks. Clinical response was defined as a reduction of at least 1 severity category, as defined by Harvey-Bradshaw index (HBI). Patients with HBI < 5 were considered to be in clinical remission. Patients who stopped needing steroids at week 24 were defined as being in steroid-free clinical remission. RESULTS: A total of 106 CD patients from eight Israeli centers were included. All patients were previously exposed to at least one biological agent. Our cohort consisted of 65 (61.3%) females. Mean age was 41 ± 14 years with an average disease duration of 12.2 ± 8 years. A total of 96 (90.5%) patients continued treatment throughout week 24. Clinical response was observed in 52% of these patients with mean HBI reduction from 8.34 ± 3.8 to 6.8 ± 4.4 at week 24 (p = 0.001). Clinical remission was achieved in 33 patients (31.1%). Moreover, the number of patients requiring steroid treatment was reduced by 66% at week 24. Out of 106 patients, 11 patients (10.4%) discontinued treatment: 3 due to adverse events (2.8%), 7 due to a lack of response, and 1 who was lost to follow-up. Following 24 weeks of treatment, 15 patients reported minor adverse events. CONCLUSIONS: In a large real-world Israeli cohort of non-naïve-to-biological-treatment CD patients, ustekinumab was effective and safe in induction of clinical remission with a significant reduction in the number of patients requiring steroid treatment.

Cell-centred meta-analysis reveals baseline predictors of anti-TNFα non-response in biopsy and blood of patients with IBD.

OBJECTIVE: Although anti-tumour necrosis factor alpha (anti-TNFα) therapies represent a major breakthrough in IBD therapy, their cost-benefit ratio is hampered by an overall 30% non-response rate, adverse side effects and high costs. Thus, finding predictive biomarkers of non-response prior to commencing anti-TNFα therapy is of high value. DESIGN: We analysed publicly available whole-genome expression profiles of colon biopsies obtained from multiple cohorts of patients with IBD using a combined computational deconvolution-meta-analysis paradigm which allows to estimate immune cell contribution to the measured expression and capture differential regulatory programmes otherwise masked due to variation in cellular composition. Insights from this in silico approach were experimentally validated in biopsies and blood samples of three independent test cohorts. RESULTS: We found the proportion of plasma cells as a robust pretreatment biomarker of non-response to therapy, which we validated in two independent cohorts of immune-stained colon biopsies, where a plasma cellular score from inflamed biopsies was predictive of non-response with an area under the curve (AUC) of 82%. Meta-analysis of the cell proportion-adjusted gene expression data suggested that an increase in inflammatory macrophages in anti-TNFα non-responding individuals is associated with the upregulation of the triggering receptor expressed on myeloid cells 1 (TREM-1) and chemokine receptor type 2 (CCR2)-chemokine ligand 7 (CCL7) -axes. Blood gene expression analysis of an independent cohort, identified TREM-1 downregulation in non-responders at baseline, which was predictive of response with an AUC of 94%. CONCLUSIONS: Our study proposes two clinically feasible assays, one in biopsy and one in blood, for predicting non-response to anti-TNFα therapy prior to initiation of treatment. Moreover, it suggests that mechanism-driven novel drugs for non-responders should be developed.

Efficacy and Safety of Vedolizumab for Induction of Remission in Inflammatory Bowel Disease-the Israeli Real-World Experience.

BACKGROUND: Vedolizumab (VDZ) is an anti-integrin monoclonal antibody effective in ulcerative colitis (UC) and Crohn's disease (CD). The aim of this study was to examine the "real world" efficacy and safety of VDZ in a large national patient cohort. METHODS: Patients with inflammatory bowel disease treated with VDZ were prospectively followed for 14 weeks. Patients who completed the induction protocol (week 0/2/6/14) or discontinued the treatment before week 14 for adverse events (AEs) or primary nonresponse were included. The primary outcome was induction of clinical remission at week 14; secondary outcomes included clinical response and corticosteroid-free clinical remission. RESULTS: A total of 204 patients (CD-130, UC-69, inflammatory bowel disease-unclassified-5) from 8 centers in Israel were included. Fifteen (7.4%) of the patients were anti-tumor necrosis factor naive and 46 (35.4%) had a previous surgery. For patients with CD, 69/130 (53.1%) responded to treatment; 45 (34.6%) achieved clinical remission; and 38 (29.2%) achieved corticosteroid-free remission at week 14. Fourteen (10.7%) patients discontinued VDZ before week 14 due to primary nonresponse or AEs. For UC, 32/74 (43.2%) responded to treatment; 20 (28.4%) achieved clinical remission, and 18 (24.3%) achieved corticosteroid-free remission at week 14. Fifteen (20.3%) patients with UC did not complete the induction due to primary nonresponse or AEs. AEs were reported by 29 (14.2%) patients (CD and UC combined), most common being nasopharyngitis and skin eruptions. CONCLUSIONS: In a large real-world Israeli cohort of anti-tumor necrosis factor-experienced patients with inflammatory bowel disease, VDZ was effective and safe in induction of clinical remission and steroid-free clinical remission.

Prevention of Antidrug Antibody Formation to Infliximab in Crohn's Patients With Prior Failure of Thiopurines.

BACKGROUND & AIMS: Combination thiopurine-infliximab (IFX) therapy is associated with reduced generation of antidrug antibodies (ADA) compared with IFX monotherapy. Whether past clinical response to thiopurine therapy bears an effect on ADA prevention is unknown. METHODS: This was a retrospective observational multicenter study of patients with Crohn's disease (CD) treated by IFX and thiopurines who had serial ADA measurements. Therapy was classified into past thiopurine response or its lack of, de novo combination, or IFX monotherapy. The primary endpoint was risk of ADA appearance. RESULTS: Out of 494 patients with serial ADA measurements 207 eligible patients were included in the final analysis. The 1-year cumulative risk of ADA development was similar in past thiopurine responders (19.3%) compared with past thiopurine failures (16.1%) (log rank P = .54). ADA was found in 46.6% of the monotherapy group and was significantly different compared with past thiopurine responders (P = .007) and past thiopurine failures (P = .007). The adjusted hazards for ADA development were significantly lower in past responders and past failures compared with the monotherapy group (hazard ratio, 0.47 [95% CI, 0.22-1.00] and 0.32 [95% CI, 0.11-0.93], respectively). CONCLUSIONS: Thiopurines-IFX cotherapy in patients with Crohn's disease is associated with reduced ADA formation compared with IFX monotherapy. This is probably regardless of initial thiopurine therapeutic effect.

The association of the MTHFR C677T polymorphism with inflammatory bowel diseases in the Israeli Jewish population: An example of genetic heterogeneity.

MTHFR C677T is a common gene polymorphism that has been shown to be associated with hyperhomocysteinemia. Studies on the role of MTHFR in inflammatory bowel diseases (IBD) have yielded conflicting results, perhaps due in part to genetic heterogeneity. The prevalence of the MTHFR C677T variant allele varies according to Jewish subpopulations: Ashkenazi vs non-Ashkenazi. The aim of this study was to examine the association between MTHFR C677T genotype and IBD in the different Jewish populations.DNA samples were assessed for the presence of the MTHFR C677T variant allele in 445 Jewish Israeli IBD patients: 338 with Crohn's disease [CD] (214 Ashkenazi and 124 non-Ashkenazi Jews) and 107 with ulcerative colitis [UC] (73 Ashkenazi and 34 non-Ashkenazi Jews), and in 347 healthy controls: 173 Ashkenazi and 174 Non-Ashkenazi Jews. Possible genotype-phenotype associations were investigated.We showed a significantly higher frequency of MTHFR 677T variant genotypes in non-Ashkenazi CD patients: Odds ratio of 1.86 for heterozygotes (CT) and 2.89 for homozygotes (TT) compared to non-Ashkenazi healthy controls. No significant association was found for UC in non-Ashkenazi patients or for CD or UC in Ashkenazi patients.Our findings suggest that the MTHFR 677T variant may contribute to the risk of CD in non-Ashkenazi but not Ashkenazi Jews. This may result from genetic heterogeneity and highlights the complexity of the genetic etiology of IBD.

Anti-infliximab Antibodies with Neutralizing Capacity in Patients with Inflammatory Bowel Disease: Distinct Clinical Implications Revealed by a Novel Assay.

BACKGROUND: About 60% of infliximab (IFX)-treated patients develop antidrug antibodies (ADA), although their clinical significance remains disputed. The aim of this study was to develop an assay for assessing ADA-neutralizing potential, and clinical significance. METHODS: An immune assay was devised in which the inhibition of IFX binding to plated-tumor necrosis factor in the presence of patient sera or controls, was assessed and defined as IFX-tumor necrosis factor binding reduction ratio (ITBR). The assay was compared to a bioassay in which tumor necrosis factor-α-induced interleukin-8 secretion from HT-29 cells was assessed after addition of IFX to ADA-containing sera or control sera. RESULTS: Both assays detected neutralizing antibodies in 39 of 44 ADA-positive sera. The median ITBR was 3.66 (mean 4.9 ± 3.2) in 29 ADA-positive patients with loss of response (LOR), and 1.3 (mean 1.9 ± 1.3) in 15 patients without LOR (P = 0.001). ADA titers in both groups were similar (median 9.5 and 10.2 µg/mL, respectively P = 0.74). Using an ITBR of 1.65, the sensitivity for LOR detection was 86.2% and the specificity was 66.7%. (positive predictive value 83%; negative predictive value 71.4%; P = 0.001). When early ADA-IFX-sera from IFX-treated patients with or without subsequent LOR were compared, the median ITBRs were 1.1 and 0.57, respectively (P = 0.028). CONCLUSIONS: Detection of neutralizing antibody activity was superior to antibody quantization by enzyme-linked immunosorbent assay with respect to correlation with clinical LOR, and for prediction of subsequent LOR. These findings may assist in optimizing infliximab therapy in patients with inflammatory bowel disease.

Predictors of Outcome in Ulcerative Colitis.

BACKGROUND: Approximately 80% of patients with ulcerative colitis (UC) have intermittently active disease and up to 20% will require a colectomy, but little data available on predictors of poor disease course. The aim of this study was to identify clinical and genetic markers that can predict prognosis. METHODS: Medical records of patients with UC with ≥5 years of follow-up and available DNA and serum were retrospectively assessed. Immunochip was used to genotype loci associated with immune mediated inflammatory disorders (IMIDs), inflammatory bowel diseases, and other single nucleotide polypmorphisms previously associated with disease severity. Serum levels of pANCA, ASCA, CBir1, and OmpC were also evaluated. Requirement for colectomy, medication, and hospitalization were used to group patients into 3 prognostic groups. RESULTS: Six hundred one patients with UC were classified as mild (n = 78), moderate (n = 273), or severe disease (n = 250). Proximal disease location frequencies at diagnosis were 13%, 21%, and 30% for mild, moderate, and severe UC, respectively (P = 0.001). Disease severity was associated with greater proximal extension rates on follow-up (P < 0.0001) and with shorter time to extension (P = 0.03) and to prednisone initiation (P = 0.0004). When comparing severe UC with mild and moderate UC together, diagnosis age >40 and proximal disease location were associated with severe UC (odds ratios = 1.94 and 2.12, respectively). None of the single nucleotide polypmorphisms or serum markers tested was associated with severe UC, proximal disease extension or colectomy. CONCLUSIONS: Older age and proximal disease location at diagnosis, but not genetic and serum markers, were associated with a more severe course. Further work is required to identify biomarkers that will predict outcomes in UC.

Accuracy of capsule colonoscopy in detecting colorectal polyps in a screening population.

BACKGROUND & AIMS: Capsule colonoscopy is a minimally invasive imaging method. We measured the accuracy of this technology in detecting polyps 6 mm or larger in an average-risk screening population. METHODS: In a prospective study, asymptomatic subjects (n = 884) underwent capsule colonoscopy followed by conventional colonoscopy (the reference) several weeks later, with an endoscopist blinded to capsule results, at 10 centers in the United States and 6 centers in Israel from June 2011 through April 2012. An unblinded colonoscopy was performed on subjects found to have lesions 6 mm or larger by capsule but not conventional colonoscopy. RESULTS: Among the 884 subjects enrolled, 695 (79%) were included in the analysis of capsule performance for all polyps. There were 77 exclusions (9%) for inadequate cleansing and whole-colon capsule transit time fewer than 40 minutes, 45 exclusions (5%) before capsule ingestion, 15 exclusions (2%) after ingestion and before colonoscopy, and 15 exclusions (2%) for site termination. Capsule colonoscopy identified subjects with 1 or more polyps 6 mm or larger with 81% sensitivity (95% confidence interval [CI], 77%-84%) and 93% specificity (95% CI, 91%-95%), and polyps 10 mm or larger with 80% sensitivity (95% CI, 74%-86%) and 97% specificity (95% CI, 96%-98%). Capsule colonoscopy identified subjects with 1 or more conventional adenomas 6 mm or larger with 88% sensitivity (95% CI, 82%-93) and 82% specificity (95% CI, 80%-83%), and 10 mm or larger with 92% sensitivity (95% CI, 82%-97%) and 95% specificity (95% CI, 94%-95%). Sessile serrated polyps and hyperplastic polyps accounted for 26% and 37%, respectively, of false-negative findings from capsule analyses. CONCLUSIONS: In an average-risk screening population, technically adequate capsule colonoscopy identified individuals with 1 or more conventional adenomas 6 mm or larger with 88% sensitivity and 82% specificity. Capsule performance seems adequate for patients who cannot undergo colonoscopy or who had incomplete colonoscopies. Additional studies are needed to improve capsule detection of serrated lesions. Clinicaltrials.gov number: NCT01372878.

Serological markers associated with disease behavior and response to anti-tumor necrosis factor therapy in ulcerative colitis.

BACKGROUND AND AIM: Information is limited on the relationship between serological markers and disease behavior and anti-tumor necrosis factor-α (anti-TNF) therapy response in ulcerative colitis (UC). This study aimed to determine the association between serological markers and unfavorable UC behavior defined as need for colectomy or UC-related hospitalization. The association between serological markers and requirement for and outcome of anti-TNF therapy was also evaluated. METHODS: Two hundred thirty patients were studied. Requirement for colectomy, UC-related hospitalization, and anti-TNF therapy were documented. Response to anti-TNF therapy at 1 year and rates of therapy discontinuation were recorded. Titers of perinuclear anti-neutrophil cytoplasmic antibodies (pANCAs), anti-Saccharomyces cerevisiae antibody (ASCA), and antibody to Escherichia Coli outer membrane porin (anti-OmpC) were determined. Antibody reference ranges were used to dichotomize subjects into seropositive and seronegative groups. Where multiple tests were performed, P-values were Bonferroni corrected (pcorr). RESULTS: Extensive colitis was associated with requirement for colectomy and UC-related hospitalization, HR 7.7 (95% confidence interval [CI] 1.9-32.2) pcorr = 0.03 and HR 2.7 (95% CI 1.5-4.6), pcorr = 0.006, respectively. No serological variable was associated with unfavorable UC behavior. Anti-OmpC positivity was associated with a lack of response to anti-TNF therapy at 1 year (odds ratio 0.14 [95% CI 0.03-0.60], pcorr = 0.04) and increased likelihood of therapy discontinuation (HR 2.2 [95% CI 1.1-4.7], P = 0.03). CONCLUSION: Extensive colitis is associated with unfavorable disease course in UC. Anti-OmpC holds promise as a biomarker of anti-TNF therapy response in UC; however, prospective studies are required before it can be incorporated into routine clinical practice.

Distinctive histopathologic phenotype in resection specimens from patients with Crohn's disease receiving anti-TNF-α therapy.

Anti-tumor necrosis factor α (anti-TNF-α) therapy can result in endoscopic healing, reduction of symptoms, and reduced need for surgery and hospitalization in many patients with Crohn's disease (CD). Earlier data suggested that anti-TNF-α therapy may be associated with fibrosis and stricturing. We sought to determine whether anti-TNF-α therapy affects histologic inflammation, fibrosis, and granuloma formation. Hematoxylin and eosin sections from 62 patients with CD treated with either infliximab or adalimumab and 80 controls undergoing the same surgery but without prior exposure to anti-TNF-α therapy were compared. All patients with CD had undergone surgery within 6 months of therapy; CD controls were matched for steroid exposure, procedure, and indication for surgery and were subcategorized and case matched. Blinded histologic assessment of all slides was performed using a semiquantitative scoring system to assess inflammatory changes and fibrosis in all bowel layers. Compared with controls, the group treated with anti-TNF-α showed a reduction in mucosal and submucosal inflammation (P < .05), a decrease in granuloma formation (P < .05), and an increase in duplication of the muscularis mucosae (P < .05). A notable feature was a distinct pattern of hyalinizing submucosal fibrosis that was often devoid of inflammatory cells and that started directly below the muscularis mucosae; this pattern was not observed in the control group (P < .05). Resection specimens from patients with CD treated with anti-TNF-α therapy showed (a) reduced mucosal and submucosal inflammation; (b) a decrease in granuloma formation; and (c) a distinct pattern of submucosal hyaline fibrosis, with increased fibrosis in the muscularis mucosae and muscularis propria.

Thiopurine effectiveness in patients with Crohn's disease: a study of genetic and clinical predictive factors.

BACKGROUND: Thiopurines are efficacious in the treatment of Crohn's disease and were recently shown to induce T-cell apoptosis by modulation of Rac1 activation. To assess whether polymorphisms in Rac1 and other apoptosis-related genes, combined with clinical parameters, can predict response to thiopurines. METHODS: A retrospective cohort of 156 thiopurine-treated patients with Crohn's disease was genotyped for 11 single-nucleotide polymorphisms (SNPs): 9 SNPs in Rac1, 1 SNP in the Fas ligand -843 T>C, and 1 SNP in the Caspase-9 93 C>T. Clinical data were extracted from the medical charts. Odds ratios (ORs) and 95% confidence intervals (CIs) of the association between demographic, clinical, and genetic variables and thiopurine response rates were calculated. RESULTS: The overall response rate to thiopurines was 74% (115/156). The Rac1 SNP rs34932801 heterozygote genotype GC was associated with a lower response rate compared with the wild-type GG genotype (46% versus 76%; OR = 0.26; 95% CI, 0.08-0.91; P = 0.036). Only wild-type homozygotes were found for 5 Rac1 SNPs. None of the other 3 Rac1 SNPs were associated with response to thiopurines. Patients with Montreal B3 behavior pattern responded worse than those with a B1 behavior pattern (59%, versus 80%; OR = 0.37; 95% CI, 0.17-0.83; P = 0.016). Sephardic Jews had a lower response rate to thiopurines compared with Jews of Ashkenazi or mixed ancestry (60% versus 82%; OR = 0.32; 95% CI, 0.15-0.69, P = 0.003). CONCLUSIONS: Rac1 SNP rs34932801carriage, Montreal B3 disease behavior, and a Sephardic Jewish origin were associated with unfavorable response to thiopurines. Corroboration of these associations in larger cohorts is warranted.

Preoperative biological therapy and short-term outcomes of abdominal surgery in patients with inflammatory bowel disease.

OBJECTIVE: Previous investigations of short-term outcomes after preoperative exposure to biological therapy in inflammatory bowel disease (IBD) were conflicting. The authors aimed to assess postoperative outcomes in patients who underwent abdominal surgery with recent exposure to anti-tumour necrosis factor therapy. DESIGN: A retrospective case-control study with detailed matching was performed for subjects with IBD with and without exposure to biologics within 180 days of abdominal surgery. Postoperative outcomes were compared between the groups. RESULTS: 473 procedures were reviewed consisting of 195 patients with exposure to biologics and 278 matched controls. There were no significant differences in most postoperative outcomes such as: length of stay, fever (≥ 38.5°C), urinary tract infection, pneumonia, bacteraemia, readmission, reoperations and mortality. On univariate analysis, procedures on biologics had more wound infections compared with controls (19% vs 11%; p=0.008), but this was not significant in multivariate analysis. Concomitant therapy with biologics and thiopurines was associated with increased frequencies of urinary tract infections (p=0.0007) and wound infections (p=0.0045). Operations performed ≤ 14 days from last biologic dose had similar rates of infections and other outcomes when compared with those performed within 15-30 days or 31-180 days. Patients with detectable preoperative infliximab levels had similar rates of wound infection compared with those with undetectable levels (3/10 vs 0/9; p=0.21). CONCLUSION: Preoperative treatment with TNF-α antagonists in patients with IBD is not associated with most early postoperative complications. A shorter time interval from last biological dose is not associated with increased postoperative complications. In most cases, surgery should not be delayed, and appropriate biological therapy may be continued perioperatively.

Addition of an immunomodulator to infliximab therapy eliminates antidrug antibodies in serum and restores clinical response of patients with inflammatory bowel disease.

There are few therapeutic options for patients with inflammatory bowel disease who lose response to infliximab because they produced antibodies against the drug. We performed a retrospective analysis to investigate whether administration of immune modulators to 5 patients who developed antibodies to infliximab (ATI) restored response to this drug; 3 patients were given azathioprine/6-mercaptopurine and 2 patients were given methotrexate. Concentrations of infliximab and ATIs, and antitumor necrosis factor (TNF) activity, were analyzed using enzyme-linked immunosorbent assay-based competition assays of serum samples collected before and after patients were given the immunomodulator. In all patients, levels of ATIs gradually decreased and trough levels of infliximab increased; clinical responses were restored to all patients. In competition assays, immunomodulator-induced elimination of ATIs was associated with increased anti-TNF activity in serum. The addition of immunomodulators to therapy might be helpful to patients who have lost response to anti-TNF agents owing to formation of antidrug antibodies.