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Crohns Colitis. 2016 May 25.
Histological outcomes and predictive value of faecal markers in moderately to severely active ulcerative colitis patients receiving infliximab.
Magro F, Lopes SI, Lopes J, et al.

BACKGROUND AND AIMS: Histological healing has emerged as a promising therapeutic goal in ulcerative colitis. This is especially important in the context of biological therapies. The objectives of the present study were to investigate the ability of infliximab to induce histological remission in ulcerative colitis [UC] patients and to explore the utility of faecalcalprotectin and lactoferrin in predicting histological activity.

METHODS: Multi-centre, single-cohort, open-label, 52-week trial including moderately to severely biological-naïve UC patients receiving intravenous infliximab [5mg/kg]. The primary outcome was the proportion of patients with histological remission [Geboes index ≤3.0] after 8 weeks of treatment, scored by two independent pathologists.
RESULTS: Twenty patients were included. The rate of histological remission increased from 5% at baseline to 15% and 35% at Week 8 and Week 52, respectively. At Week 8, 40% of patients were in clinical remission [Mayo ≤2] and 45% achieved mucosal healing [Mayo endoscopy subscore 0-1]. At Week 52, 25% of patients had clinical, endoscopic and histological remission. Faecalcalprotectin and lactoferrin showed the highest correlation with histological activity at Week 8 (area under the curve [AUC] 94%, p = 0.017; and 96%, p = 0.013, respectively) and both markers revealed an excellent positive predictive value for this outcome at this time point [100%, p = 0.017; and 94%, p = 0.013, respectively].
CONCLUSIONS: Infliximab was able to induce histological remission. There was a good agreement between histology and faecal biomarkers. Faecalcalprotectin and lactoferrin were good predictors of histological remission. Our data support inclusion of histology as a treatment target complementary to endoscopy in clinical trials when evaluating therapeutic response in UC.

Aliment PharmacolTher. 2016 Jul;44(2):170-80.
The efficacy and safety of either infliximab or adalimumab in 362 patients with anti-TNF-α naïve Crohn's disease.
Narula N1, Kainz S2, Petritsch W3, et al.

BACKGROUND: TNFα antagonists, including infliximab (IFX) and adalimumab (ADA), have revolutionised treatment for Crohn's disease. Studies comparing efficacy in patients with Crohn's disease naïve to TNFα antagonists are lacking.METHODS: Consecutive TNFα antagonist-naïve patients with luminal or perianal Crohn's disease from four tertiary centres in Austria were assessed prospectively for induction and maintenance efficacy, and safety, of either IFX or ADA.
RESULTS: In a total of 362 patients, 251 (69.3%) started IFX and 111 (30.7%) started ADA. At baseline, the median Harvey-Bradshaw Index (HBI) score was 8 (range 5-29) and 8 (5-36), and the median C-reactive protein (CRP) was 1.07 (interquartile range (IQR) 1.36) mg/dL and 1.16 (IQR 1.23) mg/dL for IFX and ADA, respectively. At week 12, there was no difference between IFX and ADA among patients with luminal Crohn's disease in clinical remission (IFX 128/204; 62.7% vs. ADA 68/107; 63.6%, P = 0.47), clinical response (IFX 154/204; 75.5% vs. ADA 82/107; 76.6%, P = 0.82) and steroid-free remission (IFX 110/204; 53.9% vs. ADA 61/107; 57%, P = 0.60). At 12 months, there were similar numbers of patients treated with IFX and ADA who maintained clinical remission (IFX 77/154; 50.4% vs. ADA 47/82; 57.3%, P = 0.48) and steroid-free remission (IFX 68/154; 44.3% vs. ADA 44/82; 53.7%, P = 0.16). Baseline CRP >0.7 mg/dL (OR 0.24; 95% CI 0.07-0.77, P = 0.01) was the only predictor of clinical remission at 12 months in patients who did not have escalation of anti-TNFα therapy.
CONCLUSION: IFX and ADA appear comparable in clinical outcomes for patients with Crohn's disease who are naïve to TNFα antagonists.

J Gastrointest Surg. 2016 May 26.
Postoperative medical management of Crohn's disease: Prevention and surveillance strategies.
Regueiro M, Strong SA, Ferrari L, et al.

No abstract available.

BMJ Open Gastroenterol. 2016 May 3;3(1):e000093.
Cost-effectiveness of adalimumab, infliximab or vedolizumab as first-line biological therapy in moderate-to-severe ulcerative colitis.
Yokomizo L, Limketkai B, Park KT.

BACKGROUND: There are no head-to-head randomised controlled trials (RCTs) comparing the effectiveness of biologics in ulcerative colitis (UC). We aimed to assess the cost-effectiveness of adalimumab, infliximab and vedolizumab as first-line agents to induce clinical remission and mucosal healing (MH) in UC.
METHODS: We constructed a decision tree based on a payer's perspective in the USA to estimate the first year costs of adalimumab, infliximab or vedolizumab to achieve clinical remission and MH in patients with moderate-to-severe UC. Transition probabilities were derived from ACT, ULTRAand GEMINI RCT data. Costs were derived from Medicare reimbursement rates and wholesale drug prices.
RESULTS: Assuming a biological-naïve cohort, infliximab 5 mg/kg every 8 weeks was more cost-effective ( 171 per MH achieved) than adalimumab 40 mg every other week (6 378 per MH achieved) and vedolizumab every 8 weeks (1 969 per MH achieved) at 1 year. Non-drug administration cost of infliximab exceeding 74 per infusion would make adalimumab more cost-effective. First-line UC therapy with vedolizumab would be cost-effective if the drug acquisition price was <37 for each 300 mg administration during the 1-year time horizon.
CONCLUSIONS: If non-drug costs of infliximab administration are not excessive (<00), infliximab is the most cost-effective first-line biologic for moderate-to-severe UC. Exceeding this threshold infusion-related cost would make adalimumab the more cost-effective therapy. Considering its drug costs in the USA, vedolizumab appears to be appropriately used as a second-line biologic after antitumour necrosis factor failure.

World J Gastroenterol. 2016 Jun 7;22(21):5079-87.
Ulcerative colitis patients in clinical remission demonstrate correlations between fecal immunochemical test results, mucosal healing, and risk of relapse.
Nakarai A, Kato J, Hiraoka S, et al.

AIM: To assess the risk of relapse in ulcerative colitis (UC) patients in clinical remission using mucosal status and fecal immunochemical test (FIT) results.
METHODS: The clinical outcomes of 194 UC patients in clinical remission who underwent colonoscopy were based on evaluations of Mayo endoscopic subscores (MESs) and FIT results.
RESULTS: Patients with an MES of 0 (n = 94, 48%) showed a ten-fold lower risk of relapse than those with an MES of 1-3 (n = 100, 52%) (HR = 0.10, 95%CI: 0.05-0.19). A negative FIT result (fecal hemoglobin concentrations ≤100 ng/mL) was predictive of patients with an MES of 0, with a sensitivity of 0.94 and a specific of 0.76. Moreover, patients with a negative FIT score had a six-fold lower risk of clinical relapse than those with a positive score (HR = 0.17, 95%CI: 0.10-0.28). Inclusion of the distinguishing parameter, sustaining clinical remission > 12 mo, resulted in an even stronger correlation between negative FIT results and an MES of 0 with respect to the risk of clinical relapse (HR = 0.11, 95%CI: 0.04-0.23).
CONCLUSION: Negative FIT results one year or more after remission induction correlate with complete mucosal healing (MES 0) and better prognosis. Performing FIT one year after remission induction may be useful for evaluating relapse risk.

J Crohns Colitis.2016 Jun 9.
Predicting outcomes to optimize disease management in inflammatory bowel diseases.
Torres J, Caprioli F, Katsanos KH, et al.

BACKGROUND AND AIMS: Efforts to slow or prevent the progressive course of inflammatory bowel diseases [IBD] include early and intensive monitoring and treatment of patients at higherrisk for complications. It is therefore essential to identify high-risk patients - both at diagnosis and throughout disease course.
METHODS: As a part of an IBD Ahead initiative, we conducted a comprehensive literature review to identify predictors of long-term IBD prognosis and generate draft expert summary statements. Statements were refined at national meetings of IBD experts in 32 countries and were finalized at an international meeting in November 2014.
RESULTS: Patients with Crohn's disease presenting at a young age or with extensive anatomical involvement, deep ulcerations, ileal/ileocolonic involvement, perianal and/or severe rectal disease or penetrating/stenosingbehaviour should be regarded as high risk for complications. Patients with ulcerative colitis presenting at young age, with extensive colitis and frequent flare-ups needing steroids or hospitalization present increased risk for colectomy or future hospitalization. Smoking status, concurrent primary sclerosing cholangitis and concurrent infections may impact the course of disease. Current genetic and serological markers lack accuracy for clinical use.
CONCLUSIONS: Simple demographic and clinical features can guide the clinician in identifying patients at higher risk for disease complications at diagnosis and throughout disease course. However, many of these risk factors have been identified retrospectively and lack validation. Appropriately powered prospective studies are required to inform algorithms that can truly predict the risk for disease progression in the individual patient.

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Inflamm Bowel Dis. 2016 Apr 29.
Optimizing treatment with TNF inhibitors in inflammatory bowel disease by monitoring drug levels and antidrug antibodies.
Steenholdt C, Bendtzen K, Brynskov J, et al.

BACKGROUND: Biological tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory bowel disease and redefined treatment goals to include mucosal healing. Clinicians are faced with challenges such as inadequate responses, treatment failures, side effects, and high drug costs. The objective is to review optimization of anti-TNF therapy by use of personalized treatment strategies based on circulating drug levels and antidrug antibodies (Abs), i.e. therapeutic drug monitoring (TDM). Furthermore, to outline TDM-related pitfalls and their prevention.
METHODS: Literature review.
RESULTS: Circulating anti-TNF drug trough level is a marker for the pharmacokinetics (PK) of TNF inhibitors. Because of a number of factors, including antidrug antibodies, PK varies between and within patients across time leading to variable clinical outcomes. Differences in intestinal inflammatory phenotype influencing the pharmacodynamic (PD) responses to TNF inhibitors also affect treatment outcomes. As an alternative to handling anti-TNF-treated patients by empiric strategies, TDM identifies underlying PK and PD-related reasons for treatment failure and aids decision making to secure optimal clinical and economic outcomes. Although promising, evidence does not the support use of TDM to counteract treatment failure in quiescent disease. Use of TDM is challenged by methodological biases, difficulties related to differentiation between PK and PD problems, and temporal biases due to lack of chronology between changes in PK versus symptomatic and objective disease activity manifestations. Biases can be accommodated by knowledgeable interpretation of results obtained by validated assays with clinically established thresholds, and by repeated assessments over time using complimentary techniques.
CONCLUSIONS: TDM-guided anti-TNF therapy at treatment failure has been brought from bench to bedside.

Dig Dis Sci. 2016 Apr 28.
Timing of last preoperative dose of infliximab does not increase postoperative complications in inflammatory bowel disease patients.
Alsaleh A, Gaidos JK, Kang L, et al.

BACKGROUND: The association between preoperative use of infliximab and postoperative complications in patients with inflammatory bowel disease (IBD) is a subject of continued debate. Results from studies examining an association between the timing of last preoperative dose of infliximab and postoperative complications remain inconsistent. AIMS: To assess whether timing of last dose of infliximab prior to surgery affects the rate of postoperative complications in patients with Crohn's disease or ulcerative colitis.
METHODS: Retrospective chart review of IBD patients who have undergone surgery while receiving therapy with infliximab was conducted. Forty-seven patients were included in the analysis. RESULTS: No significant association was found between timing of infliximab and the rate of postoperative complications. Age, gender, disease type, steroid use, preoperative status, surgery type, or surgeon type was not associated with increased rate of postoperative complications.
CONCLUSION: Timing of last dose of infliximab does not affect the rate of postoperative complications in patients with Crohn's disease or ulcerative colitis.

Pharmacoeconomics. 2016 Apr 28.
A model-based economic evaluation of biologic and non-biologic options for the treatment of adults with moderately-to-severely active ulcerative colitis after the failure of conventional therapy.
Tappenden P, Ren S, Archer R, et al.

BACKGROUND: Ulcerative colitis (UC) is the most common form of inflammatory bowel disease in the UK. Medical management aims to induce and maintain remission and to avoid complications and the necessity for surgical intervention. Colectomy removes the source of inflammation but is associated with morbidity and mortality. Newer anti-tumour necrosis factor (TNF)-α therapies may improve medical outcomes, albeit at an increased cost.
OBJECTIVE: Our objective was to assess the incremental cost effectiveness of infliximab, adalimumab and golimumab versus conventional therapy and surgery from a National Health Service (NHS) and Personal Social Services (PSS) perspective over a lifetime horizon.
METHODS: A Markov model was developed with health states defined according to whether the patient is alive or dead, current treatments received, history of colectomy and level of disease control. Transition probabilities were derived from network meta-analyses (NMAs) of trials of anti-TNF-α agents in the moderate-to-severe UC population. Health utilities, colectomy rates, surgical complications and resource use estimates were derived from literature. Unit costs were drawn from standard costing sources and literature and were valued at year 2013/2014 values.
RESULTS: For patients in whom surgery is an option, colectomy is expected to dominate all medical treatment options. For patients in whom colectomy is not an option, infliximab and golimumab are expected to be ruled out due to dominance, whilst the incremental cost-effectiveness ratio (ICER) for adalimumab versus conventional treatment is expected to be approximately £50,278 per quality-adjusted life-year (QALY) gained.
CONCLUSIONS: Based on the NMAs, the ICERs for anti-TNF-α therapy versus conventional treatment or surgery are expected to be at best, in excess of £50,000 per QALY gained. The cost effectiveness of withdrawing biologic therapy upon remission and re-treating relapse is unknown.

Dig Liver Dis. 2016 Apr 11.
French national consensus clinical guidelines for the management of ulcerative colitis.
Peyrin-Biroulet L, Bouhnik Y, Roblin X, et al.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease of multifactorial etiology that primarily affects the colonic mucosa. The disease progresses over time, and clinical management guidelines should reflect its dynamic nature. There is limited evidence supporting UC management in specific clinical situations, thus precluding an evidence-based approach.
AIM: To use a formal consensus method - the nominal group technique (NGT) - to develop a clinical practice expert opinion to outline simple algorithms and practices, optimize UC management, and assist clinicians in making treatment decisions.
METHODS: The consensus was developed by an expert panel of 37 gastroenterologists from various professional organizations with experience in UC management using the qualitative and iterative NGT, incorporating deliberations based on the European Crohn's and Colitis Organisation recommendations, recent reviews of scientific literature, and pertinent discussion topics developed by a steering committee. Examples of clinical cases for which there are limited evidence-based data from clinical trials were used. Two working groups proposed and voted on treatment algorithms that were then discussed and voted for by the nominal group as a whole, in order to reach a consensus.

J Crohns Colitis. 2016 May 18.
The ulcerative colitis Endoscopic Index of Severity (UCEIS) is useful to predict medium to long-term prognosis in ulcerative colitis patients with clinical remission.
Arai M, Naganuma M, Sugimoto S, et al.

BACKGROUND: The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) is a validated scoring system. Nevertheless, few studies have investigated its usefulness in clinical settings. In this study, we aimed to predict the clinical prognosis of patients with ulcerative colitis (UC) in clinical remission using the UCEIS.
METHODS: A total of 285 UC patients who underwent a colonoscopy between April 2012 and March 2013 were enrolled. We reviewed clinical characteristics and endoscopic scores at the time of the colonoscopy and checked the clinical remission rate of the patients through September 2015. Clinical remission and recurrence were defined as a partial Mayo of ≤1 and ≥3, respectively.
RESULTS: UCEIS was strongly correlated with the Mayo endoscopic score (r=0.93), moderately correlated with clinical severity (r=0.64), and mildly correlated with C-reactive protein (r=0.34). The recurrence rate increased gradually as it became more endoscopically severe (5.0% for UCEIS=0, 22.4% for UCEIS=1, 27.0% for UCEIS=2, 35.7% for UCEIS=3, and 75.0% for UCEIS=4-5) in patients with clinical remission. UCEIS and the concomitant use of thiopurine were independent factors predicting clinical recurrence. A multivariate analysis indicated that the absence of bleeding (p<0.001) and the absence of mucosal damage (p<0.001) in a colonoscopy were independent factors for prolongation of clinical remission.
CONCLUSION: The UCEIS is useful to predict the medium to long-term outcomes of UC patients with clinical remission. The absence of bleeding or mucosal damage is important for maintaining clinical remission.

Inflamm Bowel Dis. 2016 Apr 26.
Anti-infliximab antibodies with neutralizing capacity in patients with inflammatory bowel disease: distinct clinical implications revealed by a novel assay.
Weisshof R, Ungar B, Blatt A, et al.

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.

Clin Gastroenterol Hepatol. 2016 May 14.
Biologic therapies and risk of infection and malignancy in patients with inflammatory bowel disease: a systematic review and network meta-analysis.
Bonovas S, Fiorino G, Allocca M, et al.

BACKGROUND & AIMS: Safety issues are a major concern for patients considering treatments for inflammatory bowel disease (IBD). We performed a systematic review and meta-analysis to determine whether biologic agents affect the risk of infection or malignancy in adults with IBD.
METHODS: We searched PubMed, Embase, Scopus, Cochrane IBD Group Specialized Trials Register, World Health Organization International Clinical Trials Registry Platform, and through March 2016 for randomized placebo-controlled or head-to-head trials of biologic agents approved for treatment of adults with IBD (i.e., adalimumab, certolizumab, golimumab, infliximab, natalizumab, or vedolizumab). Two reviewers independently extracted study data and outcomes (serious infections, opportunistic infections, tuberculosis, any infection, and malignancies) and rated each trial's risk of bias. We used conventional meta-analysis to synthesize direct evidence, and a network meta-analysis for adjusted indirect treatment comparisons.
RESULTS: We identified 49 randomized placebo-controlled studies comprising 14,590 participants. Synthesis of the evidence indicated that patients treated with biologics had a moderate increase in risk of any infection (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.10-1.29) and a significant increase in risk of opportunistic infections (OR, 1.90; 95% CI, 1.21-3.01). Risk of serious infections was not increased in patients treated with biologics (OR, 0.89; 95% CI, 0.71-1.12). On the contrary, biologics appeared to significantly reduce risk of serious infections in studies with low risk of bias (OR, 0.56; 95% CI, 0.35-0.90). We did not find an increased risk of malignancy with use of biologic agents (OR, 0.90; 95% CI, 0.54-1.50), but data were insufficient in terms of exposure and follow-up times. None of the indirect comparisons, either among the individual agents or between the anti-tumor necrosis factor and anti-integrin classes, reached significance for any of the outcomes analyzed.
CONCLUSIONS: Based on a systematic review and meta-analysis, biologic agents increase the risk of opportunistic infections in patients with IBD, but not the risk of serious infections. It is necessary to continue to monitor the comparative and long-term safety profiles of these drugs.

Int J Cancer. 2016 May 11.
Inflammatory bowel disease, cancer and medication: cancer risk in the Dutch population based IBDSL cohort.
van den Heuvel TR, Wintjens DS, Jeuring SF, et al.

The management of inflammatory bowel disease (IBD) has changed since the mid-1990s (e.g. use of thiopurines/anti-TNFα agents, improved surveillance programs), possibly affecting cancer risk. To establish current cancer risk in IBD, updates are warranted from cohorts covering this time span, and detailed enough to study associations with phenotype and medication. We studied intestinal-, extra-intestinal- and overall cancer risk in the Dutch population based IBDSL cohort. In total, 1157 Crohn's Disease (CD) and 1644 ulcerative colitis (UC) patients were diagnosed between 1991 and 2011, and followed until 2013. Standardized incidence ratios (SIR) were calculated for CD and UC separately, as well as for gender-, phenotype-, disease duration-, diagnosis era-, and medication groups. We found an increased risk for colorectal cancer in CD patients with colon involvement (SIR 2.97; 95%CI 1.08-6.46), but not in the total CD or UC population. In addition, CD patients were at increased risk for hematologic- (2.41; 1.04-4.76), overall skin- (1.55; 1.06-2.19), skin squamous cell- (SCC; 3.83; 1.83-7.04), and overall cancer (1.28; 1.01-1.60), whereas UC patients had no increased risk for extra-intestinal- and overall cancer. Finally, in a medication analysis on CD and UC together, long term immunosuppression exposure (>12 months) was associated with an increased risk for hematologic cancer, non-Hodgkin lymphoma, SCC and overall cancer, and this increase was mainly attributed to thiopurines. IBD patients with long term immunosuppression exposure can be considered as having a higher cancer risk, and our data support the advice in recent IBD guidelines to consider skin cancer screening in these patients.

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Gastroenterology. 2016 Mar 23. [Epub ahead of print]
Efficient early drug development for ulcerative colitis.
Khanna R, Jairath V, Vande Casteele N, et al.
No abstract available.

Gastroenterology. 2016 Mar 24.
How failure can fuel improvements in early drug development for inflammatory bowel diseases.
Schreiber S, Vermeire S.
No abstract available.

Am J Gastroenterol. 2016 Mar 22. [Epub ahead of print]
The risk of relapse after anti-TNF discontinuation in inflammatory bowel disease: systematic review and meta-analysis.
Gisbert JP, Marín AC, Chaparro M.

Dig Liver Dis. 2016 Mar 2. [Epub ahead of print]
Treatment satisfaction, preferences and perception gaps between patients and physicians in the ulcerative colitis CARES study: A real world-based study.
Peyrin-Biroulet L, Van Assche G, Sturm A, et al.

BACKGROUND: Ulcerative colitis (UC) is a life time disease and issues with therapy may impact on patient satisfaction and treatment preferences. AIMS: To assess disease and treatment perception gaps from patients' and physicians' perspectives in UC patients.
METHODS: Adult patients with moderate-to-severe UC (Mayo score ≥6) naïve to biologic therapy were enrolled in a European, observational, cross-sectional, retrospective study. Treatment satisfaction was assessed by the TSQM questionnaire and treatment preferences and patient's knowledge with pre-defined questions. Physicians' and patients' perceptions were compared through the level of agreement.
RESULTS: 256 patients from 11 European countries were included. 48.0% of patients were dissatisfied with their current treatment. Effectiveness, long lasting action, rapid start of action, and fewer side effects were the attributes more frequently considered important or very important by patients (96.9%, 89.1%, 83.8%, and 81.8%, respectively). 26.2% patients rated their overall disease knowledge as very knowledgeable. The agreement between patients' and physicians on disease severity was good (kappa=0.62).
CONCLUSION: Half patients with moderate-to-severe UC managed with conventional therapy, are dissatisfied with their treatments. Effectiveness, long lasting action and rapidity of action were the most frequently rated items in treatment preferences. There are major gaps between physicians and patients when evaluating disease burden.

J Crohns Colitis. 2016 Mar 28. [Epub ahead of print]
Long-term outcome of patients with ulcerative colitis and primary non-response to infliximab.
Papamichael K, Rivals-Lerebours O, Billiet T, et al.

BACKGROUND AND AIMS: We studied the long-term outcome of patients with ulcerative colitis [UC] and primary non response [PNR] to infliximab and searched for predictors of colectomy in these patients.
METHODS: This retrospective, multi-centre study included UC patients from three European referral centres, with PNR to infliximab defined as a lack of clinical improvement after the induction therapy, leading to drug discontinuation. Relapse, for patients who continued on biologicals after PNR to infliximab, was defined as drug discontinuation for PNR, loss of response, or serious adverse event. Serum infliximab concentrations at Weeks 2 and 6 were evaluated using an enzyme-linked immunosorbent assay [ELISA] developed in house.
RESULTS: The study population consisted of 99 anti-tumour necrosis factor [TNF]-naïve patients with UC and PNR to infliximab. At the end of follow-up (median: 3.2 [interquartile range 1-6.3] years), 55 [55.6%] of these patients underwent colectomy. Multiple Cox regression analysis identified acute severe UC (hazard ratio [HR]: 24; 95% confidence interval [CI]: 2.5-231; p = 0.006], baseline C-reactive protein [CRP] > 5mg/l [HR: 11; 95% CI: 2.1-58.8; p = 0.005], baseline albumin < 40g/l [HR: 9.5; 95% CI: 1.3-71.4; p = 0.026], and infliximab concentration at Week 2 < 16.5 μg/ml [HR: 5.6; 95% CI: 1.1-27.8; p = 0.034] as independent predictors of colectomy. Regarding patients who continued on biologicals after PNR to infliximab, there was a marginally higher cumulative probability for relapse in patients switching to another anti-TNF agent compared with those swapping to vedolizumab [p logrank = 0.08].
CONCLUSIONS: About half of UC patients with PNR to infliximab will undergo colectomy. Patients with severe inflammation and low serum infliximab concentrations during the induction phase are at greatest risk.

Aliment Pharmacol Ther. 2016 Apr 19. [Epub ahead of print]
Induction infliximab levels among patients with acute severe ulcerative colitis compared with patients with moderately severe ulcerative colitis.
Ungar B, Mazor Y, Weisshof R, et al.

BACKGROUND: Infliximab is effective as salvage therapy for patients with steroid refractory acute severe ulcerative colitis (UC). Although current data suggest that the pharmacokinetics of infliximab are influenced by inflammatory burden in patients with acute severe UC, data comparing infliximab trough levels in patients with acute severe UC vs. moderately severe UC are scarce. AIM: To compare infliximab trough and anti-infliximab antibody levels at a standard fixed time-point during induction between patients with acute severe and moderately severe UC.
METHODS: A multi-centre retrospective study comparing infliximab drug and antibody levels 14 days after the first infusion in hospitalised acute severe UC versus out-patients with moderately severe UC was performed.
RESULTS: Sixteen acute severe UC patients, hospitalised between 2010-2015 and refractory to intravenous corticosteroids, were treated with infliximab 5 mg/kg salvage therapy. They were compared to 16 moderately severe UC out-patient controls. Mean infliximab trough levels at day 14 were significantly lower in patients with acute severe UC compared to moderately severe UC (7.15 ± 5.3 vs. 14.4 ± 11.2 μg/mL, P = 0.007). Seven patients (three acute severe and four moderate severe UC) were primary nonresponders to infliximab induction therapy. Infliximab level at day 14 did not differ between responders and nonresponders (9.8 ± 9 vs. 12.1 ± 10.6 μg/mL, respectively, P = N.S.). However, week 2 median antibody-to-infliximab levels were numerically higher among primary nonresponders (3.4 ± 5.7 vs. 1.2 ± 4 μg/mL-eq, respectively, P = 0.06).
CONCLUSIONS: Infliximab trough levels at day 14 were lower in patients with acute severe UC compared to moderately severe UC, possibly due to a higher inflammatory burden and/or increased drug clearance. However, drug levels at day 14 were not lower among nonresponders compared with responders. Controlled trials are warranted to examine whether an a-priori-intensified infliximab induction protocol will lead to an improved outcome in acute severe UC.

Inflamm Bowel Dis. 2016 Apr 6. [Epub ahead of print]
Serum infliximab, antidrug antibodies, and tumor necrosis factor predict sustained response in pediatric Crohn's disease.
Stein R, Lee D, Leonard MB, et al.

BACKGROUND: Serum infliximab (s-IFX) levels, antibodies to IFX (ATI), and inflammatory markers are important in predicting clinical outcomes in adults, but their roles in pediatric Crohn's disease (CD) require further study. The primary aim of this study was to determine the association between serologic parameters during induction and ongoing IFX therapy at 12 months in pediatric CD.
METHODS: S-IFX, ATI, serum tumor necrosis factor alpha (s-TNF-α), and C-reactive protein were measured at IFX initiation, 10 weeks, 6 months, and 12 months in a prospective cohort study of children with CD at a single tertiary care center.
RESULTS: At 12 months, 60 of 77 participants (78%) remained on IFX. Participants who completed 12 months of IFX had higher 10-week median s-IFX levels (20.40 μg/mL; interquartile range [IQR], 11.20-35.00] versus 8.70 μg/mL; IQR 0.90-16.90; P = 0.01), a greater proportion with undetectable 10-week ATI (P = 0.008), and a greater median change in s-TNF-α between baseline and week 10 (-5.96 pg/mL; IQR, -8.73 to -4.17 versus -1.76 pg/mL; IQR, -5.60 to 0.30; P = 0.006). Receiver operating characteristic analysis to predict ongoing IFX at 12 months showed area under the curve (95% confidence interval) for 10-week s-IFX and change in s-TNF-α from baseline to 10 weeks to be 0.71 (0.54-0.88) and 0.74 (0.58-0.91), respectively. C-reactive protein was not associated with ongoing therapy.
CONCLUSIONS: ATI, s-IFX, and s-TNF-α during IFX induction are associated with 12-month clinical outcomes in pediatric CD. Future studies are needed to further define the clinical role of s-TNF-α measurement and to compare the clinical utility of 10 and 14-week ATI and s-IFX levels.

Ther Drug Monit. 2016 Apr 26. [Epub ahead of print]
A comparison of three assays to quantify infliximab, adalimumab and etanercept serum concentrations.
van Bezooijen JS, Koch BC, Doorn MV, et al.

BACKGROUND: To optimize treatment of inflammatory diseases, interest in the measurement of anti- tumor necrosis factor alpha (anti-TNFα) serum drug concentrations is increasing. Preferably, assays for the detection of these drugs should be compared using the same reference material. In the current study two commercially available ELISAs and a commercially available bioassay for the determination of anti-TNFα drugs are compared.
METHOD: Serum samples from infliximab-, adalimumab- and etanercept-treated patients, control samples from ustekinumab-treated patients and healthy donors were obtained. Enzyme-linked immunosorbent assay (ELISAs) manufactured by Sanquin and Theradiag, and the iLite reporter gene-based bioassay from Biomonitor were compared.
RESULTS: Sanquin, Theradiag and iLite assays concordantly (100%) detected infliximab, adalimumab and etanercept in the relevant patient groups. The Sanquin ELISAs specifically detected the anti-TNFα drug they were designed for, whereas the Theradiag and iLite showed cross-reactivity with other anti-TNFα drugs. Ustekinumab was not detected in any of the assays. Sanquin, Theradiag and iLite exhibited linear quantitative correlation for all drug concentration assays. However, there were statistically significant quantitative differences in measured concentrations.
CONCLUSIONS: All three commercially available assays appear suitable for therapeutic drug monitoring of anti-TNFα drugs, allowing sensitive and comparable detection of infliximab, adalimumab and etanercept concentrations, however with differences in specificity and recovery.

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Gastroenterology. 2016 Mar 2.
Infliximab reduces endoscopic, but not clinical, recurrence of Crohn's disease following ileocolonic resection.
Regueiro M, Feagan BG, Zou B, et al.

BACKGROUND & AIMS: Most patients with Crohn's disease (CD) eventually require an intestinal resection. However, CD frequently recurs following resection. We performed a randomized trial to compare the ability of infliximab vs placebo to prevent CD recurrence.
METHODS: We evaluated the efficacy of infliximab in preventing post-operative recurrence of CD in 297 patients at 104 sites worldwide, from November 2010 through May 2012. All study patients had undergone ileocolonic resection within 45 days before randomization. Patients were randomly assigned (1:1) to groups given infliximab (5 mg/kg) or placebo every 8 weeks for 200 weeks. The primary endpoint was clinical recurrence a composite outcome consisting of a CD Activity Index score above 200 and a ≥70 point increase from baseline, and endoscopic recurrence (Rutgeerts score greater than or equal to i2, determined by a central reader), or development of a new or re-draining fistula or abscess, before or at week 76. Endoscopic recurrence was a major secondary endpoint.
RESULTS: A smaller proportion of patients in the infliximab group had a clinical recurrence before or at week 76 compared with the placebo group, but this difference was not statistically significant (12.9% vs 20.0%; absolute risk reduction [ARR] with infliximab, 7.1%; 95% confidence interval [CI], -1.3% to 15.5%; P=.097). A significantly smaller proportion of patients in the infliximab group had endoscopic recurrence compared to the placebo group (30.6% vs 60.0%; ARR with infliximab, 29.4%; 95% CI, 18.6% to 40.2%; P<.001). Additionally, a significantly smaller proportion of patients in the infliximab group had endoscopic recurrence based only on Rutgeerts scores greater than or equal to i2 (22.4% vs 51.3%; ARR with infliximab, 28.9%; 95% CI, 18.4% to 39.4%; P<.001). Patients previously treated with anti-tumor necrosis factor agents or those with more than 1 resection were at greater risk for clinical recurrence. The safety profile of infliximab was similar to that from previous reports.
CONCLUSIONS: Infliximab is not superior to placebo in preventing clinical recurrence following CD-related resection. However, infliximab does reduce endoscopic recurrence.

Dig Dis Sci. 2016 Feb 26.
Long-term follow-up of patients treated with infliximab for ulcerative colitis: predictive factors of response-an observational study.
García-Bosch O, Aceituno M, Ordás I, et al.

AIM: To evaluate the early and long-term efficacy of infliximab in ulcerative colitis and to determine predictors of response and colectomy.
METHODS: This is an ambidirectional cohort study in a tertiary referral center including patients who started infliximab within 2005 and 2008 and monitored until 2014. Efficacy was evaluated by partial Mayo scores at weeks 2, 4, 8, 30, and 54. Long-term treatment maintenance with infliximab and colectomy requirements were recorded.
RESULTS: Fifty-three patients were included with a median follow-up of 69.5 months. Clinical remission at the time point assessments was 40.8, 47.2, 54.7, 54.7, and 49.1 %. At the time of maximal follow-up, the proportion of patients under infliximab maintenance was 24.5 %. A higher level of albumin (OR 1.4, CI 95 % 1.06-1.8; p = 0.017) was predictive of a higher remission rate at week 8. Concomitant immunomodulators beyond 6 months were predictive of infliximab's long-term maintenance (OR 15.8, CI 95 % 1.8-135.4; p = 0.012). Colectomy was required in 41.5 %. Factors associated with a higher rate of colectomy at week 54 were previous treatment with cyclosporine (OR 3.4, CI 95 % 1.2-9.7; p = 0.012), absence of response at week 8 (OR 10.3, CI 95 % 3.3-31.7; p < 0.001), and not receiving concomitant immunomodulators (OR 4.1, CI 95 % 1.8-9; p = 0.002). Colectomy rates within the first 54 weeks were closely dependent on the number of variables present: none (0 %), 1 (26.3 %), 2 (71.4 %), or 3 (100 %) of them (log rank <0.0001).

J Crohns Colitis. 2016 Feb 23.
Ulcerative colitis remission status after induction with mesalazine predicts maintenance outcomes: the MOMENTUM trial.
Rubin DT, Bradette M, Gabalec L, et al.

BACKGROUND AND AIMS: This study assessed the efficacy of maintenance treatment with multimatrix mesalazine following achievement of complete or partial remission after induction treatment with high-dose multimatrix mesalazine.
METHODS: In this phase 3b/4 open-label, multicenter, prospective, single-arm study, patients with mild-to-moderate ulcerative colitis were treated with multimatrix mesalazine 4.8 g/day once daily for 8 weeks (induction phase). At Week 8, those who achieved complete or partial remission based on predefined clinical and endoscopic criteria were eligible to receive 12 months of multimatrix mesalazine 2.4 g/day once daily maintenance therapy. The primary endpoint was the proportion of patients in complete remission at Month 12.
RESULTS: 717 patients received induction treatment; 25.9% and 39.3% of patients achieved complete and partial remission, respectively, at Week 8. A total of 461 patients entered the maintenance phase. The likelihood of remaining in/achieving complete remission at Month 12 was higher for patients who entered the maintenance phase in complete remission compared with those who began maintenance in partial remission (47.8% vs 26.0%; P <0.001). At Month 12, mucosal healing (endoscopy score ≤1) was demonstrated in 76.4% (139/182) and 63.5% (176/277) of those who were in complete and partial remission, respectively, at the end of induction.
CONCLUSION: Patients achieving complete remission prior to dose reduction were more likely to remain in remission at Month 12.

Dig Liver Dis. 2016 Jan 29.
Burden of disease and patient-reported outcomes in patients with moderate to severe ulcerative colitis in the last 12 months - Multicenter European cohort study.
Van Assche G, Peyrin-Biroulet L, Sturm A, et al.

BACKGROUND: Treatment of ulcerative colitis (UC) is aimed at maintaining corticosteroid-free remission and improving quality of life (QoL). AIM: Assess patients' perception of disease burden and unmet clinical needs in moderate/severe UC patients.
METHODS: Adults surgery-free conventionally treated patients with Mayo score ≥6 were enrolled in an observational, cross-sectional, retrospective study in 11 European countries. Disease control was defined as Mayo score ≤2 with no sub-score >1. No corticosteroid was used the previous two months. Unmet clinical needs were defined as: non-controlled disease, self-perception of 'moderate'/'severe' disease, and dissatisfaction with treatments. Disease burden on QoL and work productivity were assessed (EuroQol-5D-5L, Short Inflammatory Bowel Disease Questionnaire (SIBDQ) and Work Productivity and Activity Impairment (WPAI) in UC questionnaire).
RESULTS: UC patients (n=253) with mean Mayo score at enrolment of 4.9, 44.3% of patients had Mayo score ≥6. Main treatment was 5-ASA (75%). Overall, 25% met the composite endpoint for unmet clinical needs. Mean (SD) questionnaire scores were: EQ-5D-5L-VAS, 71 (19.1), EQ-5D-5L utility, 0.77 (0.19), SIBDQ, 4.8 (1.3), and WPAI, 26% (32%).
CONCLUSIONS: Patients with moderate/severe UC in the last 12 months treated with conventional therapies felt that their disease was not controlled and 25% reported unmet clinical needs. QoL and work productivity were seriously impaired

Inflamm Bowel Dis. 2016 Feb 24.
Risk of incident cancer in inflammatory bowel disease patients starting anti-TNF therapy while having recent malignancy.
Poullenot F, Seksik P, Beaugerie L, et al.

BACKGROUND: Patients with inflammatory bowel disease (IBD) and history of malignancy within the last 5 years are usually contraindicated for receiving anti-tumor necrosis factor (anti-TNF) agents. The aim of this study is to assess survival without incident cancer in a cohort of IBD patients exposed to anti-TNF while having previous malignancy within past 5 years.
METHODS: Data from IBD patients with previous malignancy diagnosed within the last 5 years before starting an anti-TNF agent were collected through a Groupe d'Etude Thérapeutiques des Affections Inflammatoires du tube Digestif multicenter survey. Inclusion date corresponded to the first anti-TNF administration after cancer diagnosis.
RESULTS: Twenty centers identified 79 cases of IBD patients with previous malignancy diagnosed 17 months (median; range: 1-65) before inclusion. The most frequent cancer locations were breast (n = 17) and skin (n = 15). After a median follow-up of 21 (range: 1-119) months, 15 (19%) patients developed incident cancer (8 recurrent and 7 new cancers), including 5 basal-cell carcinomas. Survival without incident cancer was 96%, 86%, and 66% at 1, 2, and 5 years, respectively. Crude incidence rate of cancer was 84.5 (95% CI, 83.1-85.8) per 1000 patient-years.
CONCLUSIONS: In a population of refractory IBD patients with recent malignancy, anti-TNF could be used taking into account a mild risk of incident cancer. Pending prospective and larger studies, a case-by-case joint decision taken with the oncologist is recommended for managing these patients in daily practice.

Crohns Colitis. 2016 Mar 1.
Inflammatory bowel disease phenotype as risk factor for cancer in a prospective multicenter nested case-control IG-IBD study.
Biancone L, Armuzzi A, Scribano ML, et al.

BACKGROUND AND AIMS: Cancer risk in Inflammatory Bowel Disease (IBD) is still debated. In a prospective, multicenter, nested case-control study, we aimed to characterize incident cases of cancer in IBD. The role of immunomodulators versus clinical characteristics of IBD as risk factors for cancer was also investigated.
MATERIALS AND METHODS: From January 2012 to December 2014, each IBD patient with incident cancer was matched with 2 IBD patients without cancer for: IBD type, gender, age. Risk factors were assessed by multivariate regression analysis.
RESULTS: IBD patients considered were 44,619: 21,953 Crohn’s Disease (CD), 22,666 Ulcerative Colitis (UC). Cancer occurred in 174 patients: 99 CD (CD-K), 75 UC (UC-K). Controls included 198 CD (CD-C), 150 UC (UC-C). Cancer incidence in IBD was 3.9/1000, higher in CD (4.5/1000 [99/21,953]) than in UC (3.3/1000 [75/22,666]; p=0.042). Cancers involved: digestive system (36.8%), skin (13.2%), urinary tract (12.1%), lung (8.6%), breast (8%), genital tract (6.9%), thyroid (4.6%), lymphoma (3.5%), others (6.3%). In CD, penetrating behavior and combined thiopurines and TNFα antagonists were risk factors for cancer overall (OR [95% CI]: 2.33 [1.01-5.47]; 1.97 [1.1-3.5]) and for extracolonic cancers (OR 3.9 [1.56-10.1]; 2.15 [1.17-4.1]). In UC, risk factors were: pancolitis and disease-related surgery for cancer overall (OR: 2.52 [1.26-5.1]; 5.09 [1.73-17.1]); disease-related surgery for CRC (OR 3.6 [1.0-12]); extensive and left-sided vs distal UC for extracolonic cancers (OR: 2.55 [1.15-5.9]; 2.6 [1.04-6.6]).
CONCLUSIONS: In a multicenter study, penetrating CD and extensive UC were risk factors for cancer overall. Cancer incidence was higher in CD than in UC.

Dig Dis Sci. 2016 Mar 12]
Long-term outcomes of infliximab treatment in 582 Korean patients with Crohn's disease: a hospital-based cohort study.
Park SH, Hwang SW, Kwak MS, et al.

BACKGROUND AND AIMS: To date, no large-scale studies have evaluated long-term outcomes of infliximab (IFX) treatment in Korean patients with Crohn's disease (CD). METHODS: We analyzed long-term clinical responses to IFX in 582 Korean CD patients who received scheduled IFX treatments at Asan Medical Center. Clinical responses were defined as maintaining IFX without major abdominal surgery (MAS) or dose intensification.
RESULTS: Between February 2002 and July 2015, a total of 11,990 IFX infusions were administered to 582 Korean patients with CD over a median period of 36 months. At the end of follow-up, 316 (54.3 %) were still receiving IFX without MAS (71 patients, 12.2 %) or dose intensification (86 patients, 14.8 %). IFX was stopped in 109 (18.7 %) patients because of a loss of response (48 patients, 8.2 %), adverse events (30 patients, 5.2 %), or patient preferences or problems with reimbursement (31 patients, 5.3 %). The cumulative survival for maintenance of IFX without MAS or dose intensification was 89.0, 75.9, 68.3, and 50.8 % at 1, 2, 3, and 5 years, respectively. Multivariate regression analysis identified older age at the initiation of IFX (≥40 years, P = 0.006) and a longer disease duration (≥3 years, P = 0.020) as independent positive predictors of a poorer response to IFX.
CONCLUSIONS: The long-term efficacy of IFX in a large, real-life cohort of Korean patients with CD appears to be similar to that in previously published Western studies. Our findings support the early use of IFX to obtain better clinical outcomes.

Curr Med Res Opin. 2016 Mar 30:1-9.
Comparison of real-world outcomes of adalimumab and infliximab for patients with ulcerative colitis in the United States.
Sandborn WJ, Sakuraba A, Wang A, et al.

OBJECTIVE: We compared the real-world effectiveness of initiating adalimumab and infliximab among patients in the US who were naïve to tumor necrosis factor (TNF) inhibitors.
METHODS: A retrospective chart review was conducted to evaluate the real-world effectiveness among adults with ulcerative colitis (UC) initiating adalimumab or infliximab. Charts of patients with UC were abstracted by treating physicians (randomly selected from a nationally representative panel) in April 2014. Patient eligibility criteria included: adalimumab or infliximab initiation on/after 1 October 2012; no prior anti-TNF therapy, history of Crohn's disease, or colectomy; and ≥6 months of follow-up. Information on clinical outcomes (partial Mayo score, remission rate, physician global assessment (PGA), stool frequency, and rectal bleeding) and treatment patterns (dose escalations, discontinuations, switches, and treatment augmentations) were retrospectively reported by treating physicians. Kaplan-Meier curves and multivariate Cox proportional hazards regression models were used to assess the time to clinical outcomes and treatment changes for each therapy.
RESULTS: Overall, 170 physicians participated, contributing data on 380 and 424 patients who initiated adalimumab and infliximab, respectively. Baseline clinical characteristics were similar between groups. Both adalimumab- and infliximab-treated patients showed substantial improvements from baseline to follow-up in effectiveness measures; results of these measures were similar between the adalimumab and infliximab cohorts. Time to remission (p = 0.5241), no rectal bleeding (p = 0.7648), normal stool count (p = 0.9941), and normal PGA (p = 0.7697) showed no significant differences between therapies in unadjusted and adjusted comparisons. Unadjusted and adjusted time to event analysis of discontinuation (p = 0.7151), dose escalation (p = 0.6310), treatment augmentation (p = 0.1209), and switching (p = 0.7975) showed no significant differences between the two cohorts.
LIMITATIONS: Retrospective, observational design.
CONCLUSIONS: Adalimumab and infliximab were similarly effective in the treatment of moderate-to-severe UC in the real-world clinical setting.

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Clin Gastroenterol Hepatol. 2016 Feb 2.
The Crohn's disease-ulcerative colitis clinical appraisal.
D'Haens G, Bressler B, Danese S, et al.

No abstract available


Crohns Colitis. 2016 Jan 22.
Use of anti-TNFα agents and time to first-time surgery in paediatric patients with ulcerative colitis and Crohn's disease.
Larsen MD, Qvist N, Nielsen J, et al.

BACKGROUND AND AIMS: It is debated whether the need for surgery has changed following introduction of anti-TNFα agents in the treatment of paediatric ulcerative colitis [UC] and Crohn's disease [CD]. We aimed to describe the implementation of anti-TNFα agents in paediatric patients, and the need of first-time surgery before and after introduction of anti-TNFα agents.
METHODS: In the Danish National Patient Registry, we identified incident paediatric patients diagnosed from 1998. We calculated the proportion of patients receiving anti-TNFα agents within 5 years from diagnosis, and the cumulative 5 year proportion of surgery, according to calendar periods of diagnosis.
RESULTS: At the end of our study period [2007 and 2008], 29-41% of CD children were treated with anti-TNFα agents within 5 years, and for UC children 17-19%. In 1278 CD patients, the 5 year cumulative proportions of surgery were 14.6-15.6% for children diagnosed in 1998-2008 and 9.7% (95% confidence interval [CI]: 6.7-13.7) for those diagnosed in 2009-2013. In 1468 UC patients, the cumulative proportion of surgery suggested a decline in patients diagnosed after mid 2005, and the hazard ratio of surgery was 0.64 [95% CI: 0.47-0.86] after the introduction of anti-TNFα agents compared with before. For UC patients diagnosed in 2009-2013, the 5 year cumulative proportion of surgery was 7.6% [95% CI: 5.2-11.2].
CONCLUSIONS: This nationwide study showed an extensive use of anti-TNFα agents at the end of our study period. For UC children, our data suggest a decline in the proportion of surgery in the period of increasing use of anti-TNFα agents.


J Crohns Colitis. 2016 Jan 22. [Epub ahead of print]
Anti-TNF monotherapy for Crohn's disease: a 13-year multicentre experience.
Peyrin-Biroulet L, Salleron J, Filippi J, et al.


BACKGROUND: Anti-tumour necrosis factor [TNF] therapy in combination with thiopurine is the most effective strategy for Crohn's disease, but raises safety concerns.
METHODS: In a retrospective multicentre study, we investigated long-term outcome of patients starting anti-TNF monotherapy for Crohn's disease and investigated whether introducing an immunomodulator in patients losing response to anti-TNF monotherapy is effective for resetting immunogenicity.
RESULTS: A total of 350 adult patients with Crohn's disease received either infliximab [n = 178, 51%] or adalimumab [n = 172, 49%] monotherapy. Mean duration of follow-up was 42 months. An immunomodulator was initiated in 53 patients [15%]. At last follow-up, 73.1% [n = 38] were in clinical remission [one patient with missing data]. Multivariate analysis identified anti-TNF type [higher need for starting immunomodulator for infliximab than for adalimumab; p = 0.0058] and first- vs second-/third-/fourth-line anti-TNF therapy [p = 0.014] as predictors of immunomodulator initiation. Among the 18 patients with available data, introduction of an immunomodulator was able to restore infliximab trough level within the therapeutic range and to induce clinical remission in 10 patients [55%]. Cumulative probability of remaining on anti-TNF therapy was 57.9% at 5 years among the 297 patients not starting an immunomodulator during follow-up.
CONCLUSION: An immunomodulator was initiated in 15% of patients with Crohn's disease starting anti-TNF monotherapy. Independent predictors of immunomodulator initiation were infliximab use and second-/third-/fourth-line anti-TNF therapy. Resetting immunogenicity with an immunomodulator was effective in half of patients in a sub-study. Persistence of anti-TNF treatment at 5 years was observed in half of the 297 patients not starting an immumodulator in a real-life setting.


Inflamm Bowel Dis. 2016 Jan 27.
Anti-TNF therapy within 2 years of Crohn's disease diagnosis improves patient outcomes: a retrospective cohort study.
Ma C, Beilman CL, Huang VW, et al.


BACKGROUND: Although biological agents targeting tumor necrosis factor (TNF) alpha are effective in the management of Crohn's disease (CD), use of anti-TNF agents is often delayed until after failure of other treatment modalities, resulting in potentially long delays between diagnosis and initiation of infliximab or adalimumab. We aim to determine if early treatment with anti-TNF agents reduces the rate of surgical resection and clinical secondary loss of response in CD patients.
METHODS: A retrospective cohort study was conducted evaluating CD outpatients who were primary responders to anti-TNF therapy, on a maintenance regimen with infliximab or adalimumab from 2003 to 2014. Patients were stratified by time to first dose of anti-TNF therapy; early initiation was defined as starting anti-TNF therapy within 2 years of diagnosis. The primary outcome was occurrence of surgical resection or clinical secondary loss of response requiring dose escalation. Kaplan-Meier analysis was used to assess time to the primary outcomes.
RESULTS: One hundred ninety CD patients met inclusion criteria (100 infliximab, 90 adalimumab). Median follow-up duration was 154.4 weeks (inter quartile range, 106.4-227.8). Fifty-three patients (27.9%) had early initiation of anti-TNF therapy. Fewer patients in the early initiation group required surgery (5.7% versus 30.7%, P < 0.001) or experienced clinical secondary loss of response (45.3% versus 67.2%, P = 0.006). In Kaplan-Meier analysis, early initiation of anti-TNF therapy prolonged time to surgery (P = 0.001) and secondary loss of response (P = 0.006).
CONCLUSIONS: In CD patients, early initiation of infliximab or adalimumab within the first 2 years of diagnosis reduces the rate of surgery and secondary loss of response requiring dose escalation


J Crohns Colitis. 2016 Jan 28.
Identifying patients at high risk of loss of response to infliximab maintenance therapy in paediatric Crohn's disease.
Dupont-Lucas C, Sternszus R, Ezri J, et al.


BACKGROUND AND AIMS: Loss of response (LOR) to infliximab (IFX) resulting in discontinuation of therapy is a frequent problem encountered in paediatric Crohn's disease. Although identifying patients at risk of failure could have important implications for follow-up, literature in this area remains sparse. Our primary aim was to identify predictors of LOR to IFX among patients who were responders to induction. Secondary aim was to identify predictors of non-response to induction.
METHODS: A retrospective cohort of patients with paediatric Crohn's disease treated with IFX between 2000 and 2013 was followed until LOR to IFX or transfer to adult care. Predictors of response to induction therapy were studied by multivariate logistic regression. Time to treatment failure was analysed by multivariate Cox model.
RESULTS: Two-hundred-and-forty-eight patients were eligible for the study. Of these, 196 (79%) were responders to induction (57% clinical remission and 22% clinical response) and 52 (21%) were non-responders. Steroid resistance was the only variable independently associated with primary non-response (OR 4.57 (95% CI 1.67 - 12.50), p=0.002). Thirty-one of the 196 responders discontinued IFX due to LOR after a mean 1.6 ± 1.3 years of treatment. Predictors of LOR were: level of response to induction (clinical response vs. clinical remission: HR 3.74 (95% CI 1.80 - 7.80), p=0.0004 and isolated colonic disease: HR 2.72 (95% CI 1.30 - 5.71), p=0.008.
CONCLUSIONS: Patients who fail to achieve clinical remission after induction and/or who have isolated colonic disease are at increased risk of LOR to IFX.


Inflamm Bowel Dis. 2016 Jan 27.
Comparison of fecal inflammatory markers in Crohn's disease.
Wright EK, Kamm MA, De Cruz P, et al.


BACKGROUND: Fecal biomarkers are used increasingly to monitor Crohn's disease (CD). However, the relative accuracy of different markers in identifying inflammation has been poorly evaluated. We evaluated fecal calprotectin (FC), lactoferrin (FL), and S100A12 (FS) using endoscopic validation in a prospective study of the progression of CD after intestinal resection.
METHODS: Data were collected from 135 participants in a prospective, randomized, controlled trial aimed at preventing postoperative CD recurrence. Three hundred nineteen stool samples were tested for FC, FL, and FS preoperatively and 6, 12, and 18 months after resection. Colonoscopy was performed at 6 and/or 18 months. Endoscopic recurrence was assessed blindly using the Rutgeerts score. C-reactive protein (CRP) and Crohn's Disease Activity Index (CDAI) were assessed.
RESULTS: FC, FL, and FS concentrations were elevated preoperatively (median: 1347, 40.9, and 8.4 μg/g, respectively). At 6 months postoperatively, marker concentrations decreased (166, 3.0, 0.9 μg/g) and were higher in recurrent disease than remission (275 versus 72 μg/g, P < 0.001; 5.7 versus 1.6 μg/g, P = 0.007; 2.0 versus 0.8 μg/g, P = 0.188). FC > 135 μg/g, FL > 3.4 μg/g, and FS > 10.5 μg/g indicated endoscopic recurrence (score ≥ i2) with a sensitivity, specificity, and negative predictive value (NPV) of 0.87, 0.66, and 91%; 0.70, 0.68, and 81%; 0.91, 0.12, and 71%, respectively. FC and FL correlated significantly with the presence and severity of endoscopic recurrence, whereas FS, CRP and CDAI did not.
CONCLUSIONS: FC was the optimal fecal marker for monitoring disease activity in postoperative CD and was superior to CRP and CDAI. FL offered modest sensitivity for detecting recurrent disease, whereas S100A12 was sensitive but had low specificity and NPV.


Am J Gastroenterol. 2016 Feb 9.
Systematic review and meta-analysis: infliximab or cyclosporine as rescue therapy in patients with severe ulcerative colitis refractory to steroids.
Narula N, Marshall JK, Colombel JF, et al.


OBJECTIVES: Acute severe steroid-refractory ulcerative colitis (UC) carries a poor prognosis and requires optimal management. A systematic review and meta-analysis were conducted to assess cyclosporine and infliximab (IFX) as rescue agents in patients with steroid-refractory UC.
METHODS: A literature search identified studies that investigated IFX and cyclosporine in steroid-refractory UC patients. The primary outcome was short-term response to treatment. Secondary outcomes included the rates of colectomy at 3 months and 12 months, adverse drug reactions, post-operative complications in those who received rescue therapy but underwent colectomy subsequently, and mortality. Odds ratios (ORs) with 95% confidence intervals (CIs) are reported.
RESULTS: Overall, 16 studies with 1,473 participants were eligible for inclusion. Among three randomized controlled trials, no significant difference was seen with IFX compared with cyclosporine with regard to treatment response and 3- or 12-month colectomy. Among 13 non-randomized studies, IFX was associated with significantly higher rates of treatment response (OR 2.96 (95% CI 2.12-4.14, χ2=6.50, I2=0%)) and a lower 12-month colectomy rate (OR 0.42 (95% CI 0.22-0.83, χ2=30.94, I2=71%)), with no significant difference seen in the 3-month colectomy rate (OR 0.53 (95% CI 0.22-1.28, χ2=22.73, I2=69%)) compared with cyclosporine. There were no significant differences between IFX and cyclosporine in adverse drug-related events, post-operative complications, or mortality.
CONCLUSIONS: In the management of steroid-refractory severe UC, no definitive difference between IFX and cyclosporine is demonstrated by randomized trials, but non-randomized studies suggest that IFX is associated with better treatment response and lower risk of colectomy at 12 months. Prospective studies comparing dose-optimized IFX with cyclosporine are needed.


J Crohns Colitis. 2016 Jan 27.
Similar short- and long-term colectomy rates with ciclosporin and infliximab treatment in hospitalised ulcerative colitis patients.
Duijvis N, Ten Hove A, Ponsioen C, et al.


BACKGROUND AND AIMS: Ciclosporin A (CsA) and infliximab (IFX) are similarly effective in preventing short-term colectomy in ulcerative colitis (UC) patients, but long-term data are scarce. We aimed to compare short- and long-term efficacy of CsA and IFX by analysing colectomy rates and failure of remission-induction treatment as outcome parameters for treatment success.
METHODS: We retrospectively studied hospitalised UC patients who received CsA or IFX for moderate-to-severe UC, between January 2000 and April 2014. The primary end point was time to colectomy, and treatment failure (defined as colectomy or another remission-induction treatment with corticosteroids, CsA or IFX) was used as secondary end point. Variables possibly affecting colectomy outcomes were analysed.
RESULTS: Fifty-five patients were studied for colectomy outcome and 58 patients for treatment failure. A significantly longer follow-up duration was available for CsA-treated patients (P<0.001, both subcohorts). Patients showed comparable patient- and disease-specific characteristics. Colectomy rates did not differ significantly at 3, 12 and 36 months: 36% versus 29%, 58% versus 48%, and 64% versus 67% for CsA- and IFX-treated patients, respectively. Multivariate Cox regression analysis revealed the lowest hazard ratio for colectomy in patients concomitantly using thiopurines (HR 0.28 (CI 0.13-0.64), P=0.002). Treatment failure rates were not significantly different at 3, 12 and 36 months: 35% versus 48%, 51% versus 68%, and 62% versus 83% for CsA- and IFX-treated patients, respectively.
CONCLUSION: Treatment with CsA and IFX is similarly effective in preventing short- and long-term colectomy in hospitalised UC patients. Furthermore, failure rates of these remission-induction treatments were comparable.


Eur J Gastroenterol Hepatol. 2016 Jan 29.
Colectomy rates in patients with ulcerative colitis following treatment with infliximab or ciclosporin: a systematic literature review.
Thorne K, Alrubaiy L, Akbari A, et al.


This review aimed to compile all available published data on colectomy rates following treatment using infliximab or ciclosporin in adult ulcerative colitis patients and to analyse colectomy rates, timing to colectomy and postcolectomy mortality for each treatment. We systematically reviewed the literature after 1990 reporting colectomy rates in ulcerative colitis patients treated with infliximab or ciclosporin, excluding articles on paediatric patients, patients with indeterminate colitis or Crohn's disease and bowel surgery not related to ulcerative colitis. We presented weighted mean colectomy rates and mortality rates. Cox's regression was used to assess time to colectomy adjusting for colitis severity, patient age and sex. We tabulated 78 studies reporting on ciclosporin and/or infliximab and colectomy rates or postcolectomy mortality rates. Not all studies reported data in a standardized manner. Infliximab had a significantly lower colectomy rate than ciclosporin at 36 months when analysing all studies, studies directly comparing infliximab and ciclosporin and studies using severe colitis patients, but not at 3, 12 or 24 months. Severity and age were key indicators in the likelihood of undergoing colectomy after treatment. Postcolectomy mortality rates were less than 1.5% for both drugs. This review indicates that long-term colectomy rates following infliximab are significantly lower than ciclosporin in the longer term, and that postcolectomy mortality following infliximab and ciclosporin is very low. However, many key data items were missing from research articles, reducing our ability to establish with more confidence the actual impact of these two drugs on colectomy rates and postcolectomy mortality rates.


Scand J Gastroenterol. 2016 Jun;51(6):700-5.
Comparison of the therapeutic efficacy and safety between tacrolimus and infliximab for moderate-to-severe ulcerative colitis: a single center experience.
Nuki Y, Esaki M, Asano K, et al.


OBJECTIVE: Both tacrolimus (Tac) and infliximab (IFX) are effective for moderate-to-severe ulcerative colitis (UC). The aim of this study was to compare the therapeutic efficacy and safety of both drugs.
MATERIALS AND METHODS: We performed a retrospective analysis of 46 patients with moderate-to-severe UC who were treated either by Tac (n = 21) or IFX (n = 25). We compared the remission and response rates for 10 weeks between the two groups. In patients who achieved a clinical response, the subsequent relapse rate was compared. The overall adverse events were also compared between the two groups.
RESULTS: The remission and response rates at week 10 did not differ between patients treated with Tac (67% and 86%, respectively) and patients treated with IFX (76% and 92%, respectively). Among 41 patients showing a clinical response, eight of 23 patients treated with IFX and eight of 18 patients treated with Tac showed a subsequent relapse. The risk of relapse was not different between the two groups. While no serious adverse events were observed, the incidence of adverse events was higher in patients treated with Tac than in those treated with IFX.
CONCLUSION: Tac and IFX may be equally efficacious for the induction and maintenance of remission in patients with UC while minor adverse events are more frequent with the former treatment


Clin Gastroenterol Hepatol. 2016 Jan 29.
Mucosal healing is associated with improved long-term outcomes of patients with ulcerative colitis: a systematic review and meta-analysis.
Shah SC, Colombel JF, Sands BE, et al.


BACKGROUND & AIMS: The paradigm for treatment for ulcerative colitis (UC) is shifting from resolving symptoms toward objective measures such as mucosal healing (MH). However, it is unclear whether MH is associated with improved long-term outcomes. We performed a systematic review and meta-analysis to identify and analyze studies comparing long-term outcomes of patients with MH compared to those without MH.
METHODS: We performed a systematic search of 3 large databases to identify prospective studies of patients with active UC that included outcomes of patients found to have MH at the first endoscopic evaluation after initiation of UC therapy (MH1) compared to those without MH1. The primary outcome was clinical remission after at least 52 weeks. Secondary outcomes included proportions of patients who were free of colectomy or corticosteroids, and rate of MH, after at least 52 weeks.
RESULTS: We analyzed 13 studies comprising 2073 patients with active UC. Patients with MH1 had pooled odds-ratio of 4.50 for achieving long-term (after at least 52 weeks) clinical remission (95% confidence interval [CI], 2.12-9.52), 4.15 for remaining free of colectomy (95% CI, 2.53-6.81), 8.40 for achieving long-term MH (95% CI, 3.13-22.53), and 9.70 for achieving long-term corticosteroid-free clinical remission (95% CI, 0.94-99.67), compared to patients without MH1. We found no difference in outcomes if patients achieved MH1 while receiving biologic versus non-biologic therapy.
CONCLUSIONS: In a meta-analysis, we associated MH with long-term clinical remission, avoidance of colectomy, and corticosteroid-free clinical remission. MH is therefore appropriate goal of UC therapy.


Crohns Colitis. 2016 Jan 22.
Consecutive measurements by fecal immunochemical test in quiescent ulcerative colitis patients can detect clinical relapse.
Hiraoka S, Kato J, Nakarai A, et al.


BACKGROUND: We have reported that results of the quantitative fecal immunochemical test (FIT), hemoglobin concentrations in feces measured by using an antibody for human hemoglobin, effectively reflect the mucosal status of ulcerative colitis (UC). The aim of this study was to evaluate the predictability of flare-up in quiescent UC patients by consecutive FIT evaluation.
METHODS: UC patients who fulfilled the following criteria by the index colonoscopy were enrolled: clinical remission, mucosal healing (Mayo endoscopic subscore; 0), and negative FIT (less than 100 ng/mL). These patients were followed-up prospectively every 1-3 months by monitoring patient symptoms and FIT results between index and subsequent colonoscopies.
RESULTS: The periods between two colonoscopies (median 2.51 years) of 83 patients (49 males, median age at onset 34 years, median disease duration 9.74 years) were analyzed. None of the 43 (52%) patients who maintained negative FIT throughout the observation period exhibited clinical relapse. On the other hand, 25/40 (63%) patients who showed positive conversion of FIT during the period experienced relapse. The cutoff FIT value of 450 ng/mL could predict relapse with 73% positive predictive value, and 96% negative predictive value. Moreover, positive conversion of FIT preceded occurrence of symptoms by one month or more in nearly one third of patients with relapse.
CONCLUSIONS: Consecutive measurements of FIT in quiescent UC patients who achieved mucosal healing with negative FIT would help identify patients with clinical relapse whose symptoms had not presented yet. Further investigations are required for more precise prediction of relapse with this modality.


Crohns Colitis. 2016 Jan 22.
Tuberculosis in anti-tumor necrosis factor treated inflammatory bowel disease patients after the implementation of preventive measures: compliance with recommendations and safety of retreatment.
Carpio D, Jauregui-Amezaga A, de Francisco R, et al.


INTRODUCTION: Despite having adopted preventive measures, tuberculosis (TB) in anti-tumor necrosis factor (anti-TNF) treated inflammatory bowel disease (IBD) patients may still occur. Data about the causes and characteristics of TB cases in this scenario are lacking.
AIMS & METHODS: Our aim is to describe the characteristics of TB in anti-TNF treated IBD patients after the publication of the Spanish prevention guidelines and to evaluate the safety of restarting anti-TNF after a TB diagnosis. In this multicenter retrospective descriptive study, TB cases from Spanish hospitals were collected. Continuous variables were reported as mean and standard deviation or median and interquartile range. Categorical variables were described as absolute and relative frequencies and their confidence intervals when necessary.
RESULTS: We collected 50 TB cases in anti-TNF treated IBD patients, 60% male, median age 37.3 years (IQR 30.4-47). Median latency between anti-TNF initiation and first TB symptoms was 155.5 days (IQR 88-301); 34% of TB cases were disseminated TB and 26% extra-pulmonary TB. In 30 patients (60%), TB cases developed despite following the recommended preventive measures; not performing PPD or booster was the main failure in compliance with recommendations. In 17 patients (34%), anti-TNF was restarted after a median of 13 months (IQR 7.1-17.3) and there were no cases of TB reactivation.
CONCLUSION: In anti-TNF treated IBD patients, tuberculosis may still occur despite following recommended preventive measures, though a significant number of cases developed when these recommendations were not followed. Restarting anti-TNF treatment in these patients seems to be safe.


Dig Surg. 2016 Feb 10;33(3):182-189.
Prolonged medical therapy increases the risk of surgical complications in patients with severe ulcerative colitis.
Kimura H, Kunisaki R, Tatsumi K, et al.


AIMS: To determine the risk factors of surgical complications and the optimal timing of surgery for patients with severe ulcerative colitis (UC). METHODS: One hundred one UC patients who had undergone surgery for a severe indication were retrospectively reviewed. Indications included severe disease unresponsive to medical therapy, massive bleeding, toxic megacolon, and colon perforation. Outcomes were compared based on the occurrence or absence of surgical complications. Patients with severe disease unresponsive to medical therapy were investigated separately to determine the optimal timing of surgery. RESULTS: There was no significant difference regarding the use of rescue therapy. The duration of all medical therapy for a severe attack was the only significant factor associated with a surgical complication (p = 0.032). In patients with severe disease unresponsive to medical therapy, the receiver operating characteristic curve analysis showed that 30.5 days was the length of medical therapy after which the risk of surgical complications significantly increased. CONCLUSIONS: In patients with severe UC, rescue therapy itself was not related to an increased risk of surgical complications. However, prolonged medical therapy increased the risk of surgical complications. Patients should undergo surgery within 30 days from the institution of medical therapy for a severe attack.


Curr Treat Options Gastroenterol. 2016 Feb 11.
Treat to target in inflammatory bowel disease.
Bossuyt P, Vermeire S.


OPINION STATEMENT: With the expanding armamentarium in IBD the current treatment targets can be reached. By optimally using our drugs we can avoid long-term complications in IBD. For this the therapeutic strategy has to be changed from a clinically driven approach to a target-driven strategy. Currently mucosal healing, normalization of biomarkers, histological healing, and healing on abdominal imaging are proposed targets. Correct phenotyping of the patient before initiation of therapy is mandatory. Once treatment is initiated a continuous re-evaluation with consequent adaptation of the treatment when goals are not (yet) reached is needed. Both escalation and de-escalation should be considered. Drug levels can be used as a guidance to reach these targets.


J Crohns Colitis. 2016 Feb 19.
Mechanism of action of anti-TNF therapy in inflammatory bowel disease.
Levin AD, Wildenberg ME, van den Brink GR.


Several anti-TNF blocking strategies have been evaluated in patients with Crohn's disease. Compounds that have been tested included the full monoclonal IgG1 antibodies infliximab and adalimumab, the pegylated anti-TNF F(ab')2 fragment certolizumab, an IgG4 anti-TNF CDP571 with reduced affinity for the Fc receptor, the soluble TNF receptor I onercept and the TNF receptor II-Fc fusion protein etanercept. The endpoints of these studies suggest that not all methods of blocking TNF are equal. Here we will review the differences in the clinical, biochemical and endoscopic endpoints of the major clinical studies. Collectively the data suggest that only IgG1 monoclonal antibodies have the ability to induce complete clinical, biochemical and endoscopic remission. We discuss the potential multiple modes of action that may contribute to the response to full IgG1 anti-TNFs focusing on the rapid induction of lamina propria T cell apoptosis and Fc receptor dependent induction of M2 type wound healing macrophages. We discuss how novel insights into the mechanism of action of anti-TNFs in Crohn's disease may contribute to the development of novel anti-TNFs with improved efficacy.


Aliment Pharmacol Ther. 2016 Feb 19.
Relapse after withdrawal from anti-TNF therapy for inflammatory bowel disease: an observational study, plus systematic review and meta-analysis.
Kennedy NA, Warner B, Johnston EL, et al.


BACKGROUND: Infliximab and adalimumab have established roles in inflammatory bowel disease (IBD) therapy. UK regulators mandate reassessment after 12 months' anti-TNF therapy for IBD, with consideration of treatment withdrawal. There is a need for more data to establish the relapse rates following treatment cessation. AIM: To establish outcomes following anti-TNF withdrawal for sustained remission using new data from a large UK cohort, and assimilation of all available literature for systematic review and meta-analysis.
METHODS: A retrospective observational study was performed on 166 patients with IBD (146 with Crohn's disease (CD) and 20 with ulcerative colitis [UC) and IBD unclassified (IBDU)] withdrawn from anti-TNF for sustained remission. Meta-analysis was undertaken of all published studies incorporating 11 further cohorts totalling 746 patients (624 CD, 122 UC). RESULTS: Relapse rates in the UK cohort were 36% by 1 year and 56% by 2 years for CD, and 42% by 1 year and 47% by 2 years for UC/IBDU. Increased relapse risk in CD was associated with age at diagnosis [hazard ratio (HR) 2.78 for age <22 years="" white="" cell="" count="" hr="" 3="" 22="" for="">5.25 × 109 /L) and faecal calprotectin (HR 2.95 for >50 μg/g) at drug withdrawal. Neither continued immunomodulators nor endoscopic remission were predictors. In the meta-analysis, estimated 1-year relapse rates were 39% and 35% for CD and UC/IBDU respectively. Retreatment with anti-TNF was successful in 88% for CD and 76% UC/IBDU.
CONCLUSIONS: Assimilation of all available data reveals remarkable homogeneity. Approximately one-third of patients with IBD flare within 12 months of withdrawal of anti-TNF therapy for sustained remission.


Gastroenterol. 2016 Feb 20.
Fecal calprotectin: its scope and utility in the management of inflammatory bowel disease.
Ikhtaire S, Shajib MS, Reinisch W, et al.


Gastrointestinal symptoms such as abdominal pain, dyspepsia, and diarrhea are relatively nonspecific and a common cause for seeking medical attention. To date, it is challenging for physicians to differentiate between functional and organic gastrointestinal conditions and it involves the use of serological and endoscopic techniques. Therefore, a simple, noninvasive, inexpensive, and effective test would be of utmost importance in clinical practice. Fecal calprotectin (FC) is considered to be a reliable biomarker that fulfills these criteria. FC can detect intestinal inflammation, and its level correlates well with macroscopic and histological inflammation as detected by colonoscopy and biopsies, respectively. FC has a decent diagnostic accuracy for differentiating organic diseases and functional disorders because of its excellent negative predictive value in ruling out inflammatory bowel disease (IBD) in symptomatic undiagnosed patients. There is accumulating evidence that FC has been effectively used to monitor the natural course of IBD, to predict relapse, and to see the response to treatment. This novel biomarker has the ability to assess mucosal healing (MH), which is a therapeutic goal in IBD management. A literature search was carried out using PubMed with the keywords FC, IBD, intestinal inflammation, and MH. In our review, we provide an overview of the utility and scope of FC as a biomarker in patients with IBD as well as undiagnosed patients with lower gastrointestinal symptoms.


Scand J Gastroenterol. 2016 Feb 19:1-6.
Effect of mucosal healing (Mayo 0) on clinical relapse in patients with ulcerative colitis in clinical remission.
Kim JH, Cheon JH, Park Y, et al.


OBJECTIVE: The aim of this study was to identify the effect of mucosal healing (MH) on clinical relapse in patients with ulcerative colitis (UC) who are in clinical remission, with special reference to Mayo endoscopic subscore 0.
METHODS: Between November 2005 and December 2013, medical records from a total of 215 patients with UC who underwent colonoscopic examination at the time of clinical remission were retrospectively reviewed. Endoscopic MH was defined as a '0 point' of Mayo endoscopic subscore (Mayo 0). Patients were categorized into two groups according to Mayo endoscopic subscore and then analyzed.
RESULTS: The baseline characteristics of both groups (MH vs. no-MH), including age at diagnosis, gender, and initial clinical and colonoscopic findings, were not significantly different. The median follow-up duration was 80 (12-118) months. Factors predictive of longer clinical remission duration were age .30 years at diagnosis (.30 years vs. < 30 years; hazard ratio [HR] 3.16, 95% CI 1.88-5.30, p < 0.001), shorter interval between diagnosis and clinical remission (< 15 months vs. .15 months; HR 1.93, 95% CI 1.13-3.28, p = 0.015), and presence of MH at clinical remission (HR 1.95, 95% CI 1.15-3.32, p = 0.014). With a Cox regression model, patients with MH at clinical remission were more likely to have longer duration of clinical remission than patients without MH.
CONCLUSION: The achievement of MH, Mayo 0 in particular, in patients with UC who are in clinical remission is important in predicting a favorable disease course prognosis.

Saiba mais

Dig Dis Sci. 2015 Dec 15.
Pharmacokinetics of infliximab and reduction of treatment for inflammatory bowel diseases.
Williet N, Paul S, Peyrin-Biroulet L, et al.

Local or national policy, patients' preferences, safety and/or economic concerns, or reimbursement issues may dictate stopping drug in inflammatory bowel diseases (IBD) patients. Sustained deep remission is an important predictor of a better outcome after anti-tumor necrosis (TNF) factor therapy discontinuation, including infliximab (IFX) in IBD patients, but this is not sufficient to prevent future relapse in these patients. In IBD patients under combotherapy, trough level of infliximab (TRI) could be helpful to choose stopping one of the two drugs. In patients on IFX monotherapy, TRI could help to decide reduction of drug dosing, particularly in IBD patients with supratherapeutic trough levels. Incidental findings of undetectable TRI in patients with deep remission may identify a subset of patients who may be considered for IFX cessation. Controlled trials further assessing this issue are eagerly awaited. Pending these trials, clear international recommendations for discontinuing anti-TNF therapy are needed.

J Crohns Colitis. 2016 Jan 6.
Non-adherence to anti-TNF therapy is associated with illness perceptions and clinical outcomes in outpatients with inflammatory bowel disease: results from a prospective multicentre study.
Have MV, Oldenburg B, Kaptein AA, et al.


BACKGROUND AND AIMS: Non-adherence to anti-tumor necrosis factor (TNF) agents in patients with inflammatory bowel disease (IBD) is a serious problem. In this study, we assessed risk factors for non-adherence and examined the association between adherence to anti-TNF agents and loss of response (LOR).
METHODS: In this multicentre, 12-month observational study, outpatients with IBD were included. Demographic and clinical characteristics were recorded. Adherence was measured with the Modified Morisky Adherence Scale-8 (MMAS-8) and 12-month pharmacy refills (medication possession ratio, MPR). Risk factors included demographic and clinical characteristics, medication beliefs and illness perceptions. Cox regression analysis was performed to determine the association between MPR and LOR to anti-TNF, IBD-related surgery or hospitalization, dose intensification or discontinuation of anti-TNF.
RESULTS: In total, 128 patients were included (67 infliximab, 61 adalimumab), mean age 37 (±SD 14) years, 71 (56%) females. Median disease duration was 8 (IQR 4-14) years. Clinical disease activity was present in 41/128 (32%) patients, 36/127 (28%) patients had a MMAS-8 < 6 ("low adherence") and 25/99 (25%) patients had a MPR<80% (non-adherence). Risk factors for non-adherence included adalimumab use (OR 10.1, 95%CI 2.62-40.00), stronger emotional response (OR 1.16, 95%CI 1.02-1.31) and shorter timeline perception, i.e. short perceived illness duration (OR 0.60, 95%CI 0.38-0.96). Adherence is linearly and negatively (OR 0.14, 95%CI 0.03-0.63) associated with LOR.
CONCLUSION: Non-adherence to anti-TNF agents is strongly associated with LOR to anti-TNF agents, adalimumab use and illness perceptions. The latter may provide an important target for interventions aimed at improving adherence and health outcomes.

World J Gastroenterol. 2015 Dec 28;21(48):13566-73.
Fecal calprotectin correlated with endoscopic remission for Asian inflammatory bowel disease patients.
Lin WC, Wong JM, Tung CC, et al.

AIM: To evaluate the correlation between fecal calprotectin (fC), C-reactive protein (CRP), and endoscopic disease score in Asian inflammatory bowel disease (IBD) patients.
METHODS: Stool samples were collected and assessed for calprotectin levels by Quantum Blue Calprotectin High Range Rapid test. Crohn's disease endoscopic index of severity (CDEIS) and ulcerative colitis endoscopic index of severity (UCEIS) were used for endoscopic lesion scoring.
RESULTS: A total of 88 IBD patients [36 patients with Crohn's disease (CD) and 52 with ulcerative colitis (UC)] were enrolled. For CD patients, fC correlated with CDEIS (r = 0.465, P = 0.005) and CRP (r = 0.528, P = 0.001). fC levels in UC patients correlated with UCEIS (r = 0.696, P < 0.0001) and CRP (r = 0.529, P = 0.0005). Calprotectin could predict endoscopic remission (CDEIS < 6) with 50% sensitivity and 100% specificity (AUC: 0.74) in CD patients when using 918 μg/g as the cut-off. When using 191 μg/g as the cut-off in UC patients, calprotectin could be used for predicting endoscopic remission (UCEIS < 3) with 88% sensitivity and 75% specificity (AUC: 0.87).
CONCLUSION: fC correlated with both CDEIS and UCEIS. fC could be used as a predictor of endoscopic remission for Asian IBD patients.


2015 Dec 15;314(23):2524-34.
Autologous hematopoetic stem cell transplantation for refractory Crohn disease: a randomized clinical trial.
Hawkey CJ, Allez M, Clark MM, et al.


IMPORTANCE: Case reports and series suggest hematopoietic stem cell transplantation (HSCT) may benefit some patients with Crohn disease.
OBJECTIVE: To evaluate the effect of autologous HSCT on refractory Crohn disease.
DESIGN, SETTING, AND PARTICIPANTS: Parallel-group randomized clinical trial conducted in 11 European transplant units from July 2007 to September 2011, with follow-up through March 2013. Patients were aged 18 to 50 years with impaired quality of life from refractory Crohn disease not amenable to surgery despite treatment with 3 or more immunosuppressive or biologic agents and corticosteroids.
INTERVENTIONS: All patients underwent stem cell mobilization before 1:1 randomization to immunoablation and HSCT (n = 23) or control treatment (HSCT deferred for 1 year [n = 22]). All were given standard Crohn disease treatment as needed.
MAIN OUTCOMES AND MEASURES: Sustained disease remission at 1 year, a composite primary end point comprising clinical remission (Crohn Disease Activity Index (CDAI) < 150 [range, 0-600]), no use of corticosteroids or immunosuppressive or biologic drugs for at least the last 3 months, and no endoscopic or radiological evidence of active (erosive) disease anywhere in the gastrointestinal (GI) tract. Secondary outcomes were individual components of the primary composite outcome and other measures of disease activity, laboratory results, quality of life and functional status, and GI tract imaging.
RESULTS: Twenty-three patients underwent HSCT and 22 received standard Crohn disease treatment (controls). Sustained disease remission was achieved in 2 patients undergoing HSCT (8.7%) vs 1 control patient (4.5%) (absolute difference, 4.2% [95% CI, -14.2% to 22.6%]; P = .60). Fourteen patients undergoing HSCT (61%) vs 5 control patients (23%) had discontinued immunosuppressive or biologic agents or corticosteroids for at least 3 months (difference, 38.1% [95% CI, 9.3% to 59.3%]; P = .01). Ten vs 2 patients had a CDAI less than 150 (remission) at the final evaluation, 8 (34.8%) vs 2 (9.1%) for 3 or more months (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .052). Eight (34.8%) vs 2 (9.1%) patients were adjudicated free of active disease on endoscopy and radiology at final assessment (difference, 25.7% [95% CI, 1.1% to 47.1%]; P = .054). There were 76 serious adverse events in patients undergoing HSCT vs 38 in controls. One patient undergoing HSCT died.
CONCLUSIONS AND RELEVANCE: Among adult patients with refractory Crohn disease not amenable to surgery who had impaired quality of life, HSCT, compared with conventional therapy, did not result in a statistically significant improvement in sustained disease remission at 1 year and was associated with significant toxicity. These findings do not support the widespread use of HSCT for patients with refractory Crohn disease.


Clin Gastroenterol Hepatol. 2015 Dec 8.
Infliximab concentration thresholds during induction therapy are associated with short-term mucosal healing in patients with ulcerative colitis.
Papamichael K, Van Stappen T, Casteele NV, et al.


BACKGROUND & AIMS: Mucosal healing is an independent predictor of sustained clinical remission in patients with ulcerative colitis (UC) treated with infliximab. We investigated whether infliximab concentrations during induction therapy are associated with short-term mucosal healing (STMH) in patients with UC.
METHODS: We performed a retrospective, single-center analysis of data collected from a tertiary referral center, from 101 patients with UC who received scheduled induction therapy with infliximab at weeks 0, 2, and 6 and had an endoscopic evaluation at baseline and after induction therapy. STMH was defined as Mayo endoscopic sub-score ≤1, assessed at weeks 10-14, with baseline sub-score ≥2. In a prospective study, infliximab concentrations were evaluated in serum samples collected at weeks 0, 2, 6, and 14 of infliximab therapy, using an ELISA we developed.
RESULTS: Fifty-four patients (53.4%) achieved STMH. Patients with STMH had a higher median infliximab concentration at weeks 2, 6, and 14 than patients without STMH. A receiver operating characteristic (ROC) analysis identified infliximab concentration thresholds of 28.3 (area under the ROC curve [AUROC], 0.638), 15 (AUROC, 0.688), and 2.1 μg/ml (AUROC, 0.781) that associated with STMH at weeks 2, 6 and 14, respectively. Multiple logistic regression analysis identified infliximab concentration ≥15 at week 6 (P=.025; odds ratio, 4.6; 95% confidence interval, 1.2-17.1) and ≥2.1 μg/ml at week 14 (P=.004; odds ratio, 5.6; 95% confidence interval, 1.7-18) as independent factors associated with STMH.
CONCLUSIONS: In an analysis of data from real-life clinical practice, we associated infliximab concentrations during the induction therapy with STMH in patients with UC.


Aliment Pharmacol Ther. 2016 Feb;43(4):482-513.
Review article: the practical management of acute severe ulcerative colitis.
Seah D, De Cruz P.


BACKGROUND: Acute severe ulcerative colitis (ASUC) is a life-threatening condition for which optimal management strategies remain ill-defined. AIM: To review the evidence regarding the natural history, diagnosis, monitoring and treatment of ASUC to inform an evidence-based approach to management.
METHODS: Relevant articles addressing the management of ASUC were identified from a search of MEDLINE, the Cochrane Library and conference proceedings.
RESULTS: Of ASUC, 31-35% is steroid-refractory. Infliximab and ciclosporin salvage therapies have improved patient outcomes in randomised controlled trials. Short-term response rates (within 3 months) have ranged from 40% - 54% for ciclosporin and 46-83% for infliximab. Long-term clinical response rates (≥1 year) have ranged from 42%-50% for ciclosporin and 50-65% for infliximab. Short-term and long-term colectomy rates have been respectively: 26-47% and 36-58% for ciclosporin, and 0-50% and 35-50% for infliximab. Mortality rates for ciclosporin and infliximab-treated patients have been: 0-5% and 0-2%, respectively. At present, management challenges include the selection, timing and assessment of response to salvage therapy, utilisation of therapeutic drug monitoring and long-term maintenance of remission.
CONCLUSIONS: Optimal management of acute severe ulcerative colitis should be guided by risk stratification using predictive indices of corticosteroid response. Timely commencement and assessment of response to salvage therapy is critical to reducing morbidity and mortality. Emerging pharmacokinetic models and therapeutic drug monitoring may assist clinical decision-making and facilitate a shift towards individualised acute severe ulcerative colitis therapies.


J Crohns Colitis. 2016 Jan 7.
Systematic review and meta-analysis: placebo rates in induction and maintenance trials of ulcerative colitis.
Jairath V, Zou G, Parker CE, et al.


BACKGROUND AN AIM: Minimization of the placebo responses in randomized controlled trials (RCTs) is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis (UC) clinical trials and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them.
METHODS: MEDLINE, EMBASE and the Cochrane Library were searched from inception through April 2014 for placebo controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool.
RESULTS: Fifty-one trials (48 induction and 10 maintenance phases) were identified. Placebo response and remission rates were pooled according to random-effects models and mixed effects meta-regression models used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7%-13%) and 33% (95% CI 29%-37%) respectively. Corresponding values for maintenance trials were 19% (95% CI 11%-30%) and 22% (95% CI 17%-28%). Trials enrolling patients with more active disease confirmed by endoscopy (endoscopy subscore ≥2) were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits.
CONCLUSIONS: Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials.


J Crohns Colitis. 2016 Jan 13.
Systematic review and meta-analysis: serum infliximab levels during maintenance therapy and outcomes in inflammatory bowel disease.
Moore C, Corbett G, Moss AC.


BACKGROUND & AIMS: A number of observational studies have reported an association between serum levels of infliximab at various thresholds, and clinical outcomes in IBD. This association has not previously been systematically analyzed.
METHODS: Systematic review of studies that reported serum infliximab levels according to outcomes in IBD. Primary outcome was clinical remission, and secondary outcomes included endoscopic remission, CRP levels and colectomy. Meta-analysis of raw data was performed where appropriate. A quality assessment was also undertaken.
RESULTS: Twenty two studies met the inclusion criteria, including 3483 patients. Twelve studies reported IFX levels in a manner suitable for determining effect estimates. During maintenance therapy, patients in clinical remission had significantly higher mean trough IFX levels than patients not in remission; 3.1 μg/ml versus 0.9 μg/ml. The standardized mean difference in serum IFX levels between groups was 0.6 μg/ml (95% CI 0.4-0.9, p=0.0002). Patients with an IFX level > 2 μg/ml were more likely to be in clinical remission (RR 2.9, 95% CI 1.8-4.7, p<0.001), or achieve endoscopic remission (RR 3, 95% CI 1.4 -6.5, p=0.004) than patients with levels < 2 μg/ml.
CONCLUSIONS: There is a significant difference between serum infliximab levels in patients with IBD in remission, compared to those who relapse. A trough threshold during maintenance >2 μg/ml is associated with a greater probability of clinical remission and mucosal healing.


Curr Gastroenterol Rep. 2016 Jan;18(1):5.
Understanding endoscopic disease activity in IBD: how to incorporate it into practice.
Christensen B, Rubin DT.


Endoscopic assessment of disease activity is an essential part of clinical practice in inflammatory bowel disease (IBD) and is used for diagnosis, prognosis, monitoring for dysplasia and increasingly for the evaluation of mucosal or endoscopic response to therapy. Recently, mucosal or endoscopic healing has emerged as a key goal of therapy as it has been found that patients who achieve endoscopic remission have improved outcomes compared to those who do not, and this may be independent of their clinical disease activity. However, there is currently no validated definition of mucosal healing and there are numerous endoscopic scoring systems proposed to define endoscopic activity and response to therapy in both ulcerative colitis and Crohn's disease. This article will discuss the most common endoscopic scores used to measure endoscopic disease activity in IBD, the pros and cons of each of these scoring systems and proposed definitions for endoscopic response or remission that exist for each. In addition, the role of endoscopy in prognosticating the disease course is discussed and how endoscopy can be utilized as part of a "treat-to-target" treatment strategy where endoscopy results direct decisions regarding medical strategies in clinical practice is highlighted.


Expert Rev Gastroenterol Hepatol. 2016 Jan 14.
Emerging therapeutic targets and strategies in Crohn's disease.
Furfaro F, Fiorino G, Allocca M, et al.


Crohn's disease (CD) is an immune-mediated inflammatory bowel disease, in which inflammation is driven by a complex interaction between the microbiota, immune cells, genes and mediators. New mechanisms of action and several cytokines have been identified as factors involved in the inflammatory process in CD, and many new molecules have been developed to treat this complex disease. New agents have been developed that target leukocyte trafficking, block or adhesion molecules for example, as well as the development of antibodies against classic inflammatory cytokines or therapies directed against IL-12/23 and Janus kinases. The development of selective mechanisms of action and targeting of different cytokines or inflammatory mediators for each patient presents the biggest challenge for the future in CD therapy. Such agents are currently at different phases of development. We aim to review the current literature data on a targeted approach in CD, which could be promising alternative approach for CD patients in the near future.


Aliment Pharmacol Ther. 2016 Jan 13.
Tacrolimus vs. anti-tumour necrosis factor agents for moderately to severely active ulcerative colitis: a retrospective observational study.
Yamamoto T, Shimoyama T, Umegae S, et al.


BACKGROUND: There have been no comparative studies of tacrolimus vs. anti-tumour necrosis factor (anti-TNF) agents to determine which treatment is safer or more effective in refractory ulcerative colitis (UC). AIM: To compare short-term safety and efficacy of tacrolimus vs. anti-TNF agents for active UC. METHODS: One hundred patients with moderate-to-severe active UC were studied. Fifty patients were treated with oral tacrolimus (TAC group). The other 50 patients were treated with anti-TNF agents (anti-TNF group): 40 with infliximab and 10 with adalimumab. Primary endpoints were clinical response and remission rates, colectomy rate, and the incidence of adverse events during 12 weeks. RESULTS: The incidence of adverse events was 12% in the TAC vs. 18% in the anti-TNF groups (P = 0.58). At week 12, clinical remission rate was 40% in the TAC vs. 28% in the anti-TNF groups (P = 0.29). Clinical response (including remission) rate was 62% in the TAC vs. 64% in the anti-TNF groups (P > 0.99). Five patients (10%) in the TAC and 8 (16%) in the anti-TNF groups required colectomy (P = 0.55). In a subgroup analysis restricted to severely active UC, the response rate was 50% in the TAC vs. 25% in the anti-TNF groups (P = 0.24). In severely active UC, the response rate tended to be higher in patients treated with tacrolimus, albeit not statistically significant. CONCLUSIONS: Both tacrolimus and anti-TNF agents appeared to be safe and effective in the management of moderate-to-severe active UC. However, randomised controlled trials are warranted to confirm the results obtained in this study.


J Crohns Colitis. 2016 Jan 11.
Anti-tumour necrosis factor α therapies and inflammatory bowel disease pregnancy outcomes: a meta-analysis.
Shihab Z, Yeomans ND, De Cruz P.


BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) commonly affects women during their reproductive years, leading to concerns regarding pregnancy outcomes and therapeutic safety. The aim of this study was to assess the risks associated with anti-tumour necrosis factor α (anti-TNFα) therapy for pregnancy outcomes, including rates of congenital abnormality, based on published studies.
METHODS: Published studies were screened from on-line databases and international meeting abstracts. A meta-analysis was performed for adverse pregnancy outcomes (APOs), congenital abnormalities (CAs), preterm birth (PTB) and low birth weight (LBW). The prevalence of CAs was compared with whole-population pooled registry data.
RESULTS: In women exposed to anti-TNFα the pooled odds ratio for APOs was 1.14 (95% confidence interval [CI] 0.73-1.78; p = 0.55) compared with disease-matched controls. The pooled odds ratios for CAs, PTB and LBW were 0.89 (0.37-2.13; p = 0.79), 1.21 (0.74-2.00; p = 0.45) and 1.36 (0.77-2.38; p = 0.29) respectively. The rate of CAs in TNFα-exposed women was not statistically different from that in population-wide registries (difference 0.4%, 95% CI -2.0 to +2.7).
CONCLUSIONS: Anti-TNFα therapy does not increase the risk of APOs, CAs, PTB or LBW compared with disease-matched controls. Furthermore, the risk of CAs is not increased when published prevalence data are compared with data for the general population. These findings may offer some reassurance for women and physicians regarding the safety profile of anti-TNFα during pregnancy in IBD.




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