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Crohn's disease and ulcerative colitis are heterogeneous inflammatory bowel diseases, and therapeutic requirements vary among patients. We have a limited capacity to predict disease progression for individual patients, therefore it is important that they are evaluated for the presence of active disease when symptoms are mild or even absent, when patients are more likely to respond to new treatment interventions. It then is important to monitor responses to treatment, to quickly identify those therapies that are ineffective, modify or change therapy, and avoid disease complications. Studies are underway to assess the effects of different monitoring strategies. Because of the heavy burden of severe inflammatory bowel disease on patients' health and quality of life, and the association between intestinal healing and disease progression in high-risk patients, a treat-to-target strategy (based on tissue healing) is likely to be optimal.

It is important to have clear goals for treating inflammatory bowel disease in clinical practice and in research. Conventional end points for trials in ulcerative colitis and Crohn's disease have been based on composite indices, such as the Mayo Clinic Score and the Crohn's Disease Activity Index; these indices incorporate symptoms, signs, and findings from laboratory tests and sometimes endoscopic assessments. Although definitions of clinical response and remission have been based on these indices for regulatory purposes, they are difficult to apply to practice because they are complex and not intuitive to clinicians. This has caused a disconnect between clinical trials and practice. Recently, the use of composite indices in trials has been reevaluated in Food and Drug Administration-sponsored Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics workshops due to concerns about the validity of the indices. Alternative measures of outcome and definitions of response are being developed. Patient-reported outcomes are psychometric instruments created and defined by patients to quantify symptoms. A combination of end points, comprising patient-reported outcomes and objective evaluation of inflammation by endoscopy, offers a clinically meaningful and scientifically valid alternative to existing composite indices. Unlike composite indices, response definitions based on endoscopy and patient-reported outcomes can be readily applied in practice. This convergence of outcome assessment in clinical trials and practice could expedite implementation of "treat-to-target" algorithms, in which therapy is progressively intensified until a specific treatment goal is reached. This approach could improve patient care by reducing rates of disease-related complications, surgery, and hospitalization.

Geboes-Structural 0.70 (0.60 0.79) 0.80 (0.74 0.86) Geboes-Chronic inflammatory infiltrate 0.64 (0.54 0.74) 0.81 (0.75 0.86) Geboes-Lamina propria eosinophils 0.26 (0.18 0.37) 0.59 (0.52 0.66) Geboes & Modified Riley-Lamina propria neutrophils 0.37 (0.27 0.49) 0.59 (0.51 0.68) Modified Riley-Neutrophils in epithelium 0.47 (0.37 0.59) 0.71 (0.64 0.78) Geboes-Crypt destruction 0.34 (0.24 0.47) 0.61 (0.54 0.69) Geboes-Erosion or ulceration 0.56 (0.45 0.67) 0.78 (0.73 0.84)

Introduction: During infliximab(IFX) therapy for IBD anti-drug antibody formation can lead to loss of response(LOR) to the drug. Data for adalimumab is limited. Karmiris et al.1 demonstrated that adalimumab resulted in sustained clinical benefit in two thirds of Crohn's disease(CD) patients during 2 year follow-up. We performed additional analyses on this cohort using the homogeneous mobility shift assay(HMSA)2, focusing on the inter-relationship of serum concentrations of adalimumab, antibodies-to-adalimumab(ATA) and CRP. Methods: 536 prospectively collected serum samples were available from 148/168 patients in the Karmiris cohort for additional analysis. Serum adalimumab and ATA at pre-defined time points were measured using HMSA. Samples were classified as ATA negative, ATA detectable(non-zero ATA levels below the lower limit of quantitation, LLOQ of 1.7 U/ml) or ATA positive(ATA ≥ LLOQ). The LLOQ for adalimumab was ≥ 1.0 μg/ml. We studied the role of week 4 adalimumab levels on ATA formation with a Cox proportional hazards model of time-to-ATA vs. adalimumab. Repeated measures mixed regression modeling was performed to assess the independent effects of ATA and adalimumab on CRP. Results: ATA were positive(above LLOQ) in 20.2 % of patients (n = 30/148) after a median of 34 weeks(IQR 12.4 60.5 weeks). Samples with adalimumab in the lower two quartiles were more often ATA positive compared to samples in the 3rd and 4th adalimumab quartile(p LLOQ) were associated with lower median adalimumab levels than ATA negative samples(p 5 μg/ml(HR = 11.13, p = 0.0002). Regression modeling showed a negative correlation between CRP and adalimumab levels(p=0.0013) and a positive association with ATA(p=0.042). When the model was used to predict CRP one observation in the future, ATA was strongly associated with future CRP increase (p=0.002; median 7.8 weeks between samples; IQR 4.0 15.8), while adalimumab levels were not(p=0.176). Per-patient median CRP was significantly higher in patients who eventually failed adalimumab therapy (median 8.34 mg/L vs. 4.35 mg/L; p=0.026). Conclusion: Using HMSA, ATA were detected in 20% of patients in this cohort on adalimumab maintenance therapy, compared to 9% as previously reported2. Risk of ATA formation increased with lower early drug levels. Interestingly ATA was strongly associated with CRP in the future while drug levels were only informative of present CRP levels. These data suggest that early drug and antibody level monitoring and subsequent dose optimization would help prevent ATA and improve patient outcomes. References: 1. Gastroenterology 2009;137(5):1628-40. 2. Wang J Pharm Biomed Anal. 2013;78-79:39-44.

end points were time to surgery and time to tx failure (defined as either need for surgery, biologic therapy stopped or switched due to lack of efficacy or adverse events).Specific MRE findings ; 1. penetrating complications e.g fistulae, 2. Small bowel stenosis (SBS) +/dilatation, 3. Small bowel wall thickening (SBWT) and 4. Relative contrast enhancement (RCE) were then correlated to primary and secondary end points. RESULTS: In total,353 patients were commenced on aTNFtx for CD(182 adalimumab and 171 infliximab).Of these 54 patients had an MRE prior to commencing aTNFtx(23 infliximab;31 adalimumab).The median time from MRE to aTNFtx was 66.2 days (+/58.4). 13/54(24.1%) had surgery within the following year due to tx failure.The proportion of patients with SBS on MRE was significantly greater in those who went on to have surgery within 1 year;10/13 (76.9%) vs 3/ 41(7.3%)respectively (chi-square p,0.001).The frequency of penetrating complications, SBWT and RCE was not significantly different in the group who required early surgery.Time to surgery was significantly shorter in patients with SBS on MRE (log rank p=0.001).34 patients were defined as tx responders vs 20 who experienced tx failure. In a multivariate analysis using cox proportional hazards model, the MRE variables independently associated with time to tx failure were SBS (p ,0.001, hazard ratio 17.9, 95% CI 4.5-71.4) and penetrating complications (p,0.027, hazard ratio 14.5 95% CI 1.4-155.3) . CONCLUSION: The presence of SBS on MRE can help predict need for early surgery and is associated with tx failure in patients who commence aTNFtx. These findings demonstrate the utility of MRE in planning tx and suggest that aTNFtx may be more effective when commenced early in disease course, prior to onset of fibrostenotic or penetrating complications.

Background: We estimated the cost-effectiveness of evaluating small-bowel Crohn's disease with magnetic resonance enterography (MRE) as an alternative to computed tomographic enterography (CTE) in Medicare-eligible patients. We assessed the potential cancer risk averted by using MRE. Methods: We developed a Markov model to compare the lifetime costs, benefits (measured in quality-adjusted life-years [QALYs] and cancers averted) and cost-effectiveness of using MRE rather than CTE for routine disease monitoring in a hypothetical cohort of 100,000 patients with Crohn's disease beginning at age 65. We assumed each CT-radiation exposure conferred an incremental annual risk of developing cancer using the linear, no-threshold model. We varied scan frequency, dose equivalent per scan, and risk of cancer per dose equivalent of exposure. Results: In the base case, using MRE instead of CTE every 5 years until age 85 has an incremental cost-effectiveness ratio (ICER) of $1,458,000/QALY. Two hundred ninety-five additional cancers in the simulated cohort were averted by using MRE alone. High-frequency scanning with two MRE scans per year up to age 85 resulted in an ICER of $1,112,000/QALY. In sensitivity analyses, only if the cost of MRE were less than $200 more than CTE, testing with MRE until age 70 would be costeffective, with an ICER of $75,000. Results were not sensitive to either patients' previous number of CTEs prior to age 65 or the effective dose (up to 24 mSv per CTE) per scan. Conclusions: MRE is not a cost-effective alternative to CTE among patients in this simulated population with Crohn's disease.

Background: The cost-effectiveness of alternative approaches to the diagnosis of Crohn's disease is unknown. Objective: To evaluate the cost-effectiveness (CE) of ileocolonoscopy, small-bowel follow-through (SBFT), CT enterography (CTE), and capsule endoscopy for the diagnosis of small-bowel Crohn's disease. Methods: A Markov model was developed to compare the life-time costs and benefits of each diagnostic strategy for a cohort of suspected Crohn's disease patients using a societal perspective. Test characteristics, disease natural history parameters, costs, and utilities were estimated from the literature and Medicare reimbursement rates. Effectiveness was measured in quality-adjusted life-years (QALYs) gained. All assumptions were tested with sensitivity analyses. Results: The cost-effectiveness of strategies depended critically on the pretest probability of Crohn's disease and whether or not the terminal ileum is successfully examined at ileocolonoscopy. For patients with a pretest probability of less than 70%, the strategy of CTE after a negative ileocolonoscopy with ileal biopsies had an incremental CE ratio exceeding $100,000 per QALY-gained. CTE dominated SBFT. When colonoscopy failed to intubate the terminal ileum, using SBFT to follow-up of any patient with pretest probability greater than 20% had a CE ratio of less than $100,000 per QALY-gained. The incremental CE of performing CTE instead of SBFT for these patients was greater than $100,000 per QALY-gained unless the pretest probability of Crohn's disease surpassed 70%. Capsule endoscopy cost more than $500,000 per QALYgained when performed as a follow-up to negative SBFT or negative CTE, even in patients with high (80%) pretest probabilities of Crohn's disease. Our results were sensitive to the diagnostic accuracy of the tests and the life-time cost of misdiagnosing a patient with disease. Threshold analysis revealed that if a new test had a conditional sensitivity after ileocolonoscopy greater than 60% and a specificity greater than 98% its cost-effectiveness ratio would be less than $100,000 per QALY-gained at a test cost of $5000. It is not yet known if MR-enterography or double-balloon enteroscopy will have these, or better, test characteristics. Conclusion: CTE and SBFT are cost-effective additions to ileocolonoscopy only in selected patients with suspected Crohn's disease. After a negative ileocolonoscopy with ileal biopsies, CTE is a cost-effective follow-up diagnostic only when there is a greater than 70% chance that the patient has Crohn's disease. The low specificity of capsule endoscopy makes it expensive relative to other diagnostic technologies.