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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