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Summary: Background: Fibrotic stricture is a common complication of Crohn's disease (CD) affecting approximately half of all patients. No specific anti‐fibrotic therapies are available; however, several therapies are currently under evaluation. Drug development for the indication of stricturing CD is hampered by a lack of standardised definitions, diagnostic modalities, clinical trial eligibility criteria, endpoints and treatment targets in stricturing CD. Aim: To standardise definitions, diagnosis and treatment targets for anti‐fibrotic stricture therapies in Chron's disease. Methods: An interdisciplinary expert panel consisting of 15 gastroenterologists and radiologists was assembled. Using modified RAND/University of California Los Angeles appropriateness methodology, 109 candidate items derived from systematic review and expert opinion focusing on small intestinal strictures were anonymously rated as inappropriate, uncertain or appropriate. Survey results were discussed as a group before a second and third round of voting. Results: Fibrotic strictures are defined by the combination of luminal narrowing, wall thickening and pre‐stenotic dilation. Definitions of anastomotic (at site of prior intestinal resection with anastomosis) and naïve small bowel strictures were similar; however, there was uncertainty regarding wall thickness in anastomotic strictures. Magnetic resonance imaging is considered the optimal technique to define fibrotic strictures and assess response to therapy. Symptomatic strictures are defined by abdominal distension, cramping, dietary restrictions, nausea, vomiting, abdominal pain and post‐prandial abdominal pain. Need for intervention (endoscopic balloon dilation or surgery) within 24‐48 weeks is considered the appropriate endpoint in pharmacological trials. Conclusions: Consensus criteria for diagnosis and response to therapy in stricturing Crohn's disease should inform both clinical practice and trial design. [ABSTRACT FROM AUTHOR]

Summary: Background: The presence of antibodies towards infliximab (ATI) is associated with lower infliximab (IFX) trough concentrations and loss of response. IFX treatment intensification is effective for restoring response in most, but not all patients with Crohn's disease (CD). Aim: To compare outcome, pharmacokinetics and immunogenicity of treatment intensification strategies in patients with CD who lost clinical response to IFX. Methods: A retrospective cohort study was conducted, including 103 patients with CD who lost clinical response during IFX maintenance therapy and therefore received a double dose IFX (10 mg/kg) and/or a next infusion after a shortened interval. IFX and ATI concentrations were measured in consecutive trough samples, just before (T0) and after (T+1) treatment intensification. Results: Clinical response (physicians' global assessment) and biological response and remission (CRP) were restored in 63%, 42% and 24% of patients (evaluated at T+1). Treatment intensification increased IFX trough concentrations from 1.2 μg/mL [0.3‐3.6] at T0 to 3.6 μg/mL [0.5‐10.2] at T+1 (P < .0001). Using a drug tolerant assay, ATI were detected in the T0 sample of 47% of patients. ATI negatively impacted the achieved IFX trough concentration (Spearman r −0.57, P < .0001) and the probability of clinical response (P = 0.034) at T+1. When ATI were quantifiable but <282 ng/mL eq. at T0, combined interval shortening and dose doubling was more effective for restoring therapeutic IFX trough concentrations (≥3 μg/mL at T+1) than dose doubling alone, which in turn was more effective than interval shortening alone (P < .001). Conclusion: Antibodies towards infliximab can guide clinical decision‐making on treatment intensification. [ABSTRACT FROM AUTHOR]

Background Data on dose de-escalation in patients with Crohn's disease (CD) are limited. Aim To evaluate outcomes of dose de-escalation from adalimumab (ADM) every other week (EOW) to every three weeks (ETW). Methods We selected patients with CD receiving maintenance therapy with ADM 40 mg ETW with serum levels (SL) available before and after dose de-escalation. Sex- and age-matched controls continuing ADM 40 mg EOW were identified. Patient reported outcome, C-reactive protein (CRP) and serum albumin were collected. Results Out of 898 patients, we identified 40 (11 male, median 37 years) who de-escalated to ADM 40 mg ETW for ADM-related adverse events (AE, n = 1), ADM SL >7 μg/mL ( n = 8), or both ( n = 31). Compared to controls, ADM SL dropped significantly within 4 months, without associated clinical or biochemical changes. In 53% of patients, dose de-escalation was associated with disappearance of AE (8/16 skin manifestation, 3/6 arthralgia, 5/7 frequent infectious episodes). During a median follow-up of 24 months, 65% of patients maintained clinical response, but 35% needed dose escalation back to ADM 40 mg EOW because of clinical relapse ( n = 8), ADM SL <4 μg/mL ( n = 2), or both ( n = 4). CRP <3.5 mg/L at dose de-escalation was independently associated with dose escalation-free survival [odds ratio 6.28 (95% CI 1.83-21.59), P = 0.004]. We could not define a minimal ADM SL to consider or maintain dose de-escalation. Conclusions Overall, 65% of patients who de-escalated to adalimumab 40 mg every 3 weeks remained in clinical remission for a median of 24 months. In 53% of patients, adalimumab-related adverse events disappeared after dose de-escalation. Regardless of adalimumab SL, disease remission should be assessed objectively prior to dose de-escalation. [ABSTRACT FROM AUTHOR]

Background The long-term efficacy of infliximab in patients with Crohn's disease is suboptimal. Aim To study prognostic factors for real-life long-term effcacy of infliximab in Crohn's disease. Methods All consecutive Crohn's disease patients treated with infliximab at a tertiary centre were retrospectively analysed. Only patients who received scheduled infliximab maintenance treatment were considered. Patient- and disease-related factors were used to identify independent predictors of infliximab failure-free survival using Cox proportional hazards regression. Results Of 1031 patients with Crohn's disease, 261 were eligible for inclusion. Median time on infliximab was 2.4 [ IQR 1.4-4.7] years, and 65 (24.9%) patients experienced infliximab failure. Estimated 5-year infliximab failure-free survival was 65.9% (95% CI 58.3-73.5). Multivariate Cox regression identified disease duration ≥1 year ( HR 2.5 (95% CI 1.2-5.2), P = 0.02), L1 disease location [ HR 2.0 (1.1-3.5), P = 0.02], prior anti- TNF use [ HR 2.3 (1.1-4.8), P = 0.03], haemoglobin <13.5 g/dL [ HR 2.3 (1.2-4.4), P = 0.02], not using therapeutic drug monitoring [ HR 8.0 (4.1-15.6), P = 1 × 10−9], and first dose optimisation within first year [ HR 3.7 (2.1-6.6), P = 5 × 10−6] as independent predictors of infliximab failure-free survival. Stratifying patients into risk groups resulted in estimated 3-year infliximab failure-free survival rates ranging from 95.3% (94.2-96.4) to 26.3% (8.6-44.0) depending on the number of risk factors ( P = 8 × 10−13). Conclusions This study identified several easy to obtain predictors of infliximab failure in patients with Crohn's disease, and these are in line with previous reports. Those with a high-risk profile for infliximab failure in whom infliximab initiation is considered, should be treated as early as possible making use of therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Background: A modified Michelassi strictureplasty over the ileocaecal valve or ileocolic anastomosis could be an alternative to ileocaecal resection. This study assessed the outcome of the modified Michelassi strictureplasty in patients with extensive stenotic terminal ileal Crohn's disease [CD]. Methods: This type of strictureplasty was proposed to all patients with an extensive strictured [neo-] terminal ileal segment [> 20 cm]. Short- and long-term outcome data were retrieved from a prospectively maintained database. Safety and medium-term efficacy were studied, using both postoperative magnetic resonance enterography [MRE] and ileocolonoscopy at 6 months. Results: Between June 2009 and September 2014, 29 CD patients had a modified strictureplasty [male 9/29, median age 38 [range: 16-64] years]. The median length of strictureplasty was 50 [27110] cm. Twelve patients underwent a total of 30 additional procedures during surgery, mainly additional short strictureplasties, but also segmental resections. The majority had a laparoscopic-assisted procedure. Median length of hospital stay was 9 [6-17] days. Two patients had an early rescue procedure to oversew a small anastomotic leak. MRE and ileocolonoscopy at follow-up showed a remarkable regression of inflammation and bowel wall thickness. Clinical recurrence, necessitating initiation or modification of medical therapy, and surgical recurrence were reported in 11 and 1 patient after a median follow-up of 21 [1-54] months, respectively. Conclusion: A modified long Michelassi strictureplasty appears to be safe in patients with extensive stricturing Crohn's ileitis. Significant mucosal and bowel wall healing is observed and suggests that clearance of microbial stasis may play a role in this process. [ABSTRACT FROM AUTHOR]

Background and Aims: Surgery for Crohn's disease [CD] can be complicated by an enhanced inflammatory response. This retrospective study aims to compare the inflammatory response measured by C-reactive protein [CRP] in patients operated for CD with patients undergoing similar surgery for colorectal cancer [CRC]. Methods: All CD patients undergoing an ileocaecal resection between February 2001 and December 2013 were retrieved from a prospectively maintained database. The same number of patients with a CRC of the ascending colon, undergoing a laparoscopic right hemicolectomy between March 2009 and June 2014, were retrieved from a CRC database. CRP level during the first 7 postoperative days was used as primary outcome. Results: Totals of 112 consecutive CD patients (male 40.2%; median age: 32.3 yrs; interquartile range [IQR]: 25.2-45.1) and 112 consecutive CRC patients [male 53.6%; median age 71.6 yrs; IQR: 64.7-77.5] were included. Postoperative CRP level in the CD group was on average 27% higher compared with the CRC group [p = 0.02]. The day-specific differences in CRP values were 21% (p = 0.021, 95% confidence interval [CI]: 3% 41%), 41% [p = 0.005, 95% CI: 11% - 79%], 49% [p = 0.007, 95% CI: 11% - 96%], and 49% [p = 0.006, 95% CI: 12% - 100%] higher for CD patients at Days 1, 4, 5, and 6 respectively. The difference in postoperative CRP level was partially due to differences in preoperative CRP level. Conclusion: CD patients develop a higher postoperative CRP level, probably reflecting an enhanced postoperative inflammatory response, which may be triggered by a higher preoperative inflammatory state. [ABSTRACT FROM AUTHOR]

Background The detrimental effect of smoking on development and progression of Crohn's disease ( CD) is generally accepted. Aim To evaluate the awareness of smoking risks in a Belgian inflammatory bowel disease ( IBD) population. Methods In the out-patient clinic of a tertiary referral centre, 625 consecutive patients with CD, 238 patients with ulcerative colitis ( UC) and 289 non- IBD controls, filled out a simple questionnaire. This questionnaire included data on smoking behaviour and awareness of smoking-related health effects, including effects on IBD. Results At diagnosis, more CD patients were active smokers compared to UC (40% vs. 17%, P < 0.001). Remarkably, smoking cessation rates after diagnosis were similar for CD and UC (both 56%, P = 0.997). The great majority recognised a detrimental influence of smoking on general health (98-99%), lung cancer (95-97%), myocardial infarction (89-92%) and stroke (78-87%). Although CD patients more frequently acknowledged risks of smoking on their disease, only 37% were aware of a link with CD development, 30% of increased surgical rates and 27% of increased post-operative CD recurrence. Active smokers more frequently denied an increased risk of surgery and higher post-operative CD recurrence. Intriguingly, within the active smokers with CD, those not willing to quit smoking most often denied a potential bad influence of smoking. Taking into account disease duration, previous surgery, education level, working status and nicotine dependence, we were unable to define specific subgroups of patients requiring extra education. Conclusion Although patients with Crohn's disease were better informed on the detrimental effects of smoking, the awareness rate was still low. [ABSTRACT FROM AUTHOR]

Abstract: The management of patients with IBD requires evaluation with objective tools, both at the time of diagnosis and throughout the course of the disease, to determine the location, extension, activity and severity of inflammatory lesions, as well as, the potential existence of complications. Whereas endoscopy is a well-established and uniformly performed diagnostic examination, the implementation of radiologic techniques for assessment of IBD is still heterogeneous; variations in technical aspects and the degrees of experience and preferences exist across countries in Europe. ECCO and ESGAR scientific societies jointly elaborated a consensus to establish standards for imaging in IBD using magnetic resonance imaging, computed tomography, ultrasonography, and including also other radiologic procedures such as conventional radiology or nuclear medicine examinations for different clinical situations that include general principles, upper GI tract, colon and rectum, perineum, liver and biliary tract, emergency situation, and the postoperative setting. The statements and general recommendations of this consensus are based on the highest level of evidence available, but significant gaps remain in certain areas such as the comparison of diagnostic accuracy between different techniques, the value for therapeutic monitoring, and the prognostic implications of particular findings. [Copyright &y& Elsevier]

Background Endoscopic dilatation of Crohn's diseaserelated strictures is an alternative to surgical resection in selected patients. The influence of disease activity and concomitant medical therapy on long-term outcomes is largely unknown. Aim and methods To study the long-term safety and efficacy of stricture dilatation in a single centre cohort. Results Between 1995 and 2006, 237 dilatations where performed in 138 patients (mean age 50.6613.4, 56% female) for a clinically obstructive stricture (<5 cm, 84% anastomotic). Immediate success of a first dilatation was 97% with a 5% serious complication rate. After a median follow-up of 5.8 years (IQR 3.0e8.4), recurrent obstructive symptoms led to a new dilatation in 46% or surgery in 24%. Niether elevated levels of C-reactive protein nor endoscopic disease activity predicted the need for new intervention. None of the concomitant therapies influenced the outcome. Conclusion This largest series ever reported confirms that long term efficacy of endoscopic dilatation of Crohn's disease outweighs the complication risk. Neither active disease at the time of dilatation nor medical therapy afterwards predict recurrent dilatation or surgery. [ABSTRACT FROM AUTHOR]

Background Adalimumab (ADA) and certolizumab pegol (CZP) have demonstrated efficacy in Crohn’s disease (CD) patients previously treated with infliximab (IFX). Aim To assess the efficacy and tolerability of a third anti-TNF in CD after failure of and/or intolerance to two different anti-TNF antibodies. Methods Crohn’s disease patients who received ADA or CZP after loss of response and/or intolerance to two anti-TNF agent were included in this retrospective study. Data were collected using a standardized questionnaire. Clinical response, duration, safety and reasons for discontinuation were assessed. Results Sixty-seven patients treated with CZP ( n = 40) or ADA ( n = 27) were included. A clinical response was observed in 41 (61%) at week 6 and 34 patients (51%) at week 20. The probability of remaining under treatment at 3 months, 6 months and 9 months was 68%, 60% and 45%, respectively. At the end of follow-up, the third anti-TNF had been stopped in 36 patients for intolerance ( n = 13), or failure ( n = 23). Two deaths were observed. Conclusions The treatment with a third anti-TNF (CZP or ADA) agent of CD patients, who have experienced loss of response and/or intolerance to two anti-TNF antibodies, has favourable short-term and long-term efficacy. It is an option to be considered in patients with no other therapeutic options. [ABSTRACT FROM AUTHOR]

Abstract: Perianal manifestations are common in patients with Crohn''s disease and include skin tags and haemorrhoids, fissures, ulcers, abscesses, fistulas, stenosis or cancer. Primary lesions include Crohn''s fissures and cavitating perianal ulcers. Secondary lesions include deep abscesses, fistulas and strictures. A good classification and anatomical description of these conditions is crucial before embarking on any kind of (medical or surgical) therapy, as this greatly influences management. This review analyses and discusses current classifications of any perianal form of Crohn''s disease. [Copyright &y& Elsevier]

Background The natural course of Crohn's disease is characterized by flare-ups altered with periods of remission. The majority of Crohn's disease patients need surgery within 10 years of diagnosis. Major advances in treatment options over the past years have made our treatment goals more ambitious and modification of the natural course has become the ultimate endpoint. Aim To review the evidence of existing therapies for Crohn's disease for changing the natural history. Methods A Medline search was undertaken by using ‘natural history’, ‘Crohn's disease’, ‘therapy’ (corticosteroids, azathioprine, methotrexate, infliximab and enteral feeding), ‘surgery’, ‘hospitalizations’ and ‘mucosal healing’. Results Corticosteroids do not alter the disease course and maintenance therapy with corticosteroids should be avoided given their side effects. The immunomodulators azathioprine and methotrexate heal the mucosa but their onset of action is slow. Infliximab therapy introduces rapid mucosal healing and is associated with decreased hospitalizations and surgical interventions. Despite the fact that immunomodulators and infliximab are effective in maintaining clinical and endoscopic remission, there is little hard evidence at present that these therapies alter the natural history of the disease. The main reason being the fact that these therapies have so far been used only in refractory patients and that early initiation in the right patient is crucial in order to change the disease course. Conclusion Prospective studies should validate predictors of complicated disease and randomized studies in high-risk groups should be performed to answer if early introduction of immunomodulators or biological therapies slows down disease progression and alters natural history. [ABSTRACT FROM AUTHOR]

Introduction: Interferon γ is a potent proinflammatory cytokine implicated in the inflammation of Crohn's disease (CD). We evaluated the safety and efficacy of fontolizumab, a humanised anti-interferon γ antibody, in patients with moderate to severe CD. Methods: A total of 133 patients with Crohn's disease activity index (CDAI) scores between 250 and 450, inclusive, were randomised to receive placebo or fontolizumab 4 or 10 mg/kg. Forty two patients received one dose and 91 patients received two doses on days 0 and 28. Investigators and patients were unaware of assignment. Study end points were safety, clinical response (decrease in CDAI of 100 points or more), and remission (CDAI ⩽ 150). Results: There was no statistically significant difference in the primary end point of the study (clinical response) between the fontolizumab and placebo groups alter a single dose at day 28. However, patients receiving two doses of fontolizumab demonstrated doubling in response rate at day 56 compared with placebo: 32% (9/28) versus 69% (22/32, p=0.02) and 67% (21/31, p=0.03) for the placebo, and 4 and 10 mg/kg fontolizumab groups, respectively. Stratification according to elevated baseline C reactive protein levels resulted in a decreased placebo response and pronounced differences in clinical benefit. Two grade 3 adverse events were reported and were considered to be related to CD. One death (during sleep) and one serious adverse event (an elective hospitalisation) occurred, both considered unrelated. Conclusion: Treating active CD with fontolizumab was well tolerated and resulted in increased rates of clinical response and remission compared with placebo. [ABSTRACT FROM AUTHOR]

Introduction: This study was designed to evaluate the safety of fontolizumab, a humanised anti-interferon y antibody, in patients with moderate to severe Crohn's disease (CD). Patients and methods: Forty five patients with a CD activity index (CDAI) of 250-450 were randomised in a double blind, placebo controlled, dose escalating fashion to receive single doses of fontolizumab (0.1, 1.0, and 4.0 mg/kg) or placebo. By day 29, patients with clinical response were re-randomised to receive three additional doses of one half their initial fontolizumab dose or placebo at four weekly intervals. Primary objectives were safety and tolerability. Secondary outcomes included assessments of immunogenicity, clinical activity, and potential pharmacodynamic surrogates. Results: Treatment was generally well tolerated. There were slightly more reports of chills, flu-like syndrome, asthenia, nausea, and vomiting in the 1.0 mg and 4.0 mg/kg fontolizumab cohorts. Two serious adverse events rated as worsening of CD occurred under fontolizumab. Antibodies to fontolizumab were confirmed in one patient. No differences in clinical activity parameters were noted between any of the active treatment groups and placebo, with the placebo group having a particularly favourable outcome (60% response and 40% remission). By day 29, a more enhanced decrease in median Crohn's disease endoscopic index of severity (p=0.02) and serum C reactive protein (p<0.001) was observed in the 4.0 mg/kg (n = 14) fontolizumab cohort compared with placebo (n = 10). Pharmacodynamic effects were observed by immunohistochemistry. Conclusions: Fontolizumab was well tolerated with minimal immunogenicity at doses of up to 4.0 mg/kg in patients with CD. A biological activity of fontolizumab is suggested. [ABSTRACT FROM AUTHOR]

Laboratory markers have been investigated in inflammatory bowel disease (IBD) for diagnostic and differential diagnostic purposes, for assessment of disease activity and risk of complications, for prediction of relapse, and for monitoring the effect of therapy. The introduction of biological therapies in IBD has renewed interest in inflammatory markers (especially C reactive protein (CRP)), given their potential to select responders to these treatments. Of all the laboratory markers, CRP is the most studied and has been shown to have the best overall performance. CRP is an objective marker of inflammation and correlates well with disease activity in Crohn's disease (CD). Increased CRP levels are associated with better response rates and normal CRP levels predict high placebo response rates in clinical trials with biologicals. However, despite the advantages of CRP over other markers, it is still far from ideal. Furthermore, CRP correlates less well with disease activity in patients with ulcerative colitis (UC) as compared with CD. Other laboratory markers, including erythrocyte sedimentation rate (ESR), leucocyte and platelet count, albumin, and α1 acid glycoprotein (orosomucoid), have been studied either less extensively in IBD or have proven to be less useful than CRP. Faecal markers seem promising and may be more specific in detecting gut inflammation in patients with established IBD. Promising results have been reported with the use of faecal calprotectin in CD as well as in UC. Recent data however suggest that the performance of the faecal calprotectin test is superior for UC than for CD. Taken together, laboratory markers are useful and should be part of the global management of our IBD patients. They are however not magic and until more data become available, the use of CRP and other laboratory markers should be seen as an additive tool to clinical observation and physical examination rather than a replacement. [ABSTRACT FROM AUTHOR]

Major depressive disorder is the most common psychiatric diagnosis in Crohn's disease. In other chronic diseases, evidence suggests that depression influences the course of the disease. Strong evidence of such a mediating role of major depressive disorder in Crohn's disease has never been found. To assess the relationship between major depressive disorder and outcome of treatment of luminal Crohn's disease with infliximab. In this prospective study, 100 consecutive unselected patients underwent assessment of psychosocial, demographical disease-related biological and clinical parameters at baseline and at 4 weeks after infliximab. Major depressive disorder was diagnosed using the Patient Health Questionnaire. Subsequently, the patients were followed up clinically until the next flare or during 9 months. The Crohn's disease responded in 75% of the patients, and remission was achieved in 60%. The presence of major depressive disorder at baseline predicted a lower remission rate (OR = 0.166, 95% CI = 0.049–0.567, P = 0.004). At follow-up, 88% of the patients needed retreatment. At univariate regression analysis, major depressive disorder significantly decreased time to retreatment ( P = 0.001). Multivariate Cox regression confirmed major depressive disorder as an independent determinant of active disease both at baseline and at re-evaluation (hazard ratio = 2.271, 95% CI: 1.36–3.79, P = 0.002). Major depressive disorder is a risk factor for failure to achieve remission with infliximab and for earlier retreatment in patients with active luminal Crohn's disease. Assessment and management of major depressive disorder should be part of the clinical approach to patients with Crohn's disease. [ABSTRACT FROM AUTHOR]

Introduction: Crohn's disease is a chronic inflammatory disorder of the gut. It is assumed that a defective interaction between the bacterial flora of the gut and the innate immune system plays a key role in the pathogenesis of the disease. This may lead to specific histological lesions. The epithelioid granuloma is particularly interesting in this regard as it is also observed in several bacterial infections of the gut. Aims and methods: We hypothesised that genetic or environmental factors with a known influence on inflammation or immunity would lead to an increased prevalence of granulomas. Therefore, surgical specimens from 161 patients were evaluated for the presence of granulomas. Patients were genotyped for the three single nucleotide polymorphisms in caspase recruitment domain 15 (CARD15)/NOD2 associated with CD and for Asp299Gly in Toll-like receptor 4 (TLR4). Results: The overall prevalence of granulomas was 68.9%. We did not find a significant correlation between granulomas and TLR4 or CAROl 5 variants. The frequency of granulomas increased with more distal disease (63% small bowel, 72% right colon, 88% left colon, 90% rectum; p =0.01). Granulomas were more frequent in younger patients (odds ratio 0.95 (95% confidence interval 0.92-0.98) p =0.007). Conclusion: In this study of 161 well documented CD patients, we found no significant association between CARD 15 and TLR4 variants and granulomas. This finding seems to refute our initial hypothesis. However, it may be that additional factors are needed for granuloma development. Granulomas may develop only when specific bacterial components are present. Therefore, future research on granuloma pathogenesis should be orientated towards detection and identification of bacterial components in these lesions. [ABSTRACT FROM AUTHOR]

: By temporarily suppressing the immune response, the anti-tumour necrosis factor agent, infliximab, may increase the risk of peri-operative complications. : To test this hypothesis for intestinal resection in a cohort of 313 Crohn's disease patients treated with infliximab. Forty received one or more infusions prior to intestinal resection (31/40 within 12 weeks). : The post-operative events of these patients were compared with those of a control group (infliximab naive) of 39 patients adjusted for age, gender and surgical procedure. Early (10 days) and late (3 months) major or minor complications were identified. : The incidence of early minor (15.0% vs. 12.8%) and major (12.5% vs. 7.7%) and late minor (2.5% vs. 5.1%) and major (17.5% vs. 12.8%) complications and the mean hospital stay after surgery (10.3 ± 4.0 days vs. 9.9 ± 5.5 days) were similar in both groups. A trend towards an increased early infection rate was found in infliximab pre-treated patients (6 vs. 1; P = 0.10), but more patients in this group received corticosteroids and/or immunosuppressives (29 vs. 16 patients; P < 0.05). : The use of infliximab before intestinal resection does not prolong the hospital stay and does not increase the rate of post-operative complications. [ABSTRACT FROM AUTHOR]

An imbalance of immunoregulatory factors and/or cells contributes to uncontrolled mucosal T cell activation and inflammation in Crohn's disease (CD). Bioactive interleukin (IL)-18 has been shown to be produced by macrophages in CD lesions. We report here that T cells freshly isolated from inflamed tissue of CD patients (and not T cells from control intestinal tissue) were responsive to IL-18. In the presence of IL-18, these T cells produced more interferon (IFN)- γ and less IL-10. To analyse further the role of IL-18 in this disease, an acute and a chronic model of murine colitis were used. IL-18 mRNA was significantly enhanced in trinitrobenzene sulphonic acid (TNBS) induced colitis, and treatment with IL-18 binding protein (IL-18BPa), which neutralizes IL-18 bioactivity, significantly reduced the severity of colitis. However, IL-18BPa did not affect the course of chronic colitis in CD45RBhighCD4+ T cell reconstituted SCID mice. Production of IFN- γ in lamina propria mononuclear cell cultures from IL-18BPa-treated SCID mice was decreased, but at the same time fewer lamina propria CD4+ T cells harvested from IL-18BPa-treated mice compared to non-treated mice were in apoptosis. We conclude that IL-18 clearly has a modulatory role in the inflammatory cascade of CD and experimental colitis by affecting IFN- γ and IL-10 production, and apoptosis. In view of the divergent effects of IL-18 neutralization in the two different murine colitis models, it is unlikely that IL-18 is at the top of this cascade. [ABSTRACT FROM AUTHOR]

Background: Anti-TNFα therapy with infliximab is effective for Crohn’s disease. Infliximab neutralizes the biological activities of TNFα, a cytokine involved in host-defence against certain infections. Aim: To evaluate the effects of infliximab on the gut and peripheral immune system functions. Methods: Biopsies and blood samples from three clinical trials of infliximab in Crohn’s disease were analysed. Pharmacokinetics, changes in leucocyte counts and T cell subsets, T cell function, and cytokine profiles of lamina propria mononuclear cells (LPMC) and peripheral blood mononuclear cells (PBMC) were analysed. Results: Infliximab has a serum half-life of 9.5 days and is still detectable in serum 8 weeks after infusion. Leucocyte counts showed consistent changes from baseline toward normal values after therapy. Monocytes and lymphocytes were modestly increased, while neutrophils were decreased 4 weeks after treatment. Lymphocyte subsets and T cell proliferative responses were not altered after therapy. The proportion of PBMCs capable of producing IFNγ and TNFα did not change, while Th1 cytokine production by stimulated LPMC was decreased after infliximab therapy. Conclusion: The clinical efficacy of infliximab is based on local anti-inflammatory and immunomodulatory effects in the bowel mucosa, without generalized suppression of systemic immune functions in Crohn’s disease patients. [ABSTRACT FROM AUTHOR]

The authors discuss the study conducted by E. Bultman and colleagues on the predictors of dose escalation in Crohn's disease patients treated with adalimumab. The authors say that clinical trials with infliximab and adalimumab in Crohn's disease have shown a response loss with need for dose optimization. They note that the study show 39% of 122 patients needed adalimumab dose optimization after a year. Moreover, the relation of body mass index (BMI) to adalimumab is discussed.