关键词： Intestinal Diseases   Immunomodulators   drug antibody   Infliximab   Adalimumab   Inflammatory Bowel Diseases  

摘要： Background Loss of response to anti-tumour necrosis factor (TNF) therapy in patients with inflammatory bowel disease (IBD) is often caused by anti-drug antibody formation with neutralisation of drug effect. Addition of an immunomodulator has been suggested to reduce immunogenicity, leading to regained response. Aim To investigate whether addition of an immunomodulator to anti-TNF monotherapy could lead to anti-drug antibody suppression and regained clinical response in IBD patients. Methods We retrospectively collected measurements of infliximab or adalimumab serum concentrations and anti-drug antibodies to identify anti-drug positive patients with loss response who were given an immunomodulator. Results Anti-drug antibodies against infliximab and adalimumab were detected in 98/376 (26%) and in 61/226 (27%) patients, respectively. Immunomodulators were given to 17/159 patients. Clinical response was recaptured in 6/10 patients receiving a thiopurine and in all (7/7) patients receiving methotrexate. In 7/8 patients on infliximab, serum concentrations increased (median 2.84 g/mL;IQR: 1.19-4.98) and in 6/9 patients on adalimumab (median 3.10 g/mL;IQR: 1.45-4.45). This was accompanied by a decrease in anti-drug antibodies to undetectable levels (median 11 months for both anti-TNF agents). In 23 patients, no immunomodulator was added but anti-TNF interval was shortened (17/23) or dosage was increased (6/23), which resulted in a clinical response in 10/17 and 2/6 patients, respectively. Conclusion In 77% of IBD patients with loss of response due to immunogenicity, addition of immunomodulator resulted in undetectable anti-drug antibody levels, increased serum drug concentrations and regained clinical response. This strategy should be considered in this patient population before switching to other agents.

关键词： antibodies to infliximab   infliximab levels   inflammatory bowel disease   infliximab   loss of response  

摘要： Background: Infliximab (IFX) is an effective treatment for the management of moderate to severe inflammatory bowel disease (IBD). Low-serum IFX levels are associated with the development of antibodies to IFX (ATI), which subsequently associated with clinical relapse and increased morbidity. The primary purpose of this study is to examine the relation between dose and interval to IFX level. Secondary goal is to evaluate the relation between IFX level and ATI in a pediatric IBD population. Methods: We performed a retrospective chart review of all children diagnosed with IBD and treated with IFX at a tertiary care pediatric IBD center. We performed our analysis based on prescribed dosing intervals and rounded dose up to 5 or 10mg/kg as indicated in clinical practice. Results: Our study included 278 samples from 129 children on IFX. ATI were detected in 37 samples (13.3%). Low IFX levels (<3 mu g/mL) were detected in 37.2% of children receiving IFX. Samples with ATI present had significantly lower levels of IFX than samples in which ATI were not present. For the dose 5mg/kg, Q6 dosing had significantly higher IFX levels than Q8 dosing (P = 0.009). Higher IFX levels were seen with interval shortening rather than dose escalation. Conclusions: We demonstrate that low IFX levels are associated with development of immunogenicity to IFX as measured by ATI. We demonstrate that interval shortening rather than dose escalation results in higher IFX levels. We suggest that given the high number of IFX levels below 3 mu g/mL in patients, early IFX level evaluation or primary initiation of Q6 week dosing be considered.

关键词： high endothelial venules   inflammatory bowel disease   lymphocyte homing   T lymphocytes   tertiary lymphoid organ  

摘要： Naive and central memory T lymphocytes (T-N and T-CM) can infiltrate the inflamed gut mucosa in inflammatory bowel disease (IBD) patients. Homing of these subsets to the gut might be explained by ectopic formation of tertiary lymphoid organs (TLOs), containing high endothelial venules (HEVs). We aimed to evaluate the presence of HEVs and TLOs in inflamed intestinal mucosa of newly diagnosed, untreated IBD patients in relation to the presence of T-N and T-CM lymphocytes. IBD patients (n=39) and healthy controls (n=8) were included prospectively. Biopsy samples of inflamed and normal intestine, respectively, were analysed by immunohistochemistry for lymphocytes (CD3/CD20), blood vessels (CD31) and peripheral lymph node addressin (PNAd) expression (MECA-79). T-N and T-CM lymphocyte subsets were identified by flow cytometric immunophenotyping. A higher number of HEVs was found in the inflamed colon of patients with ulcerative colitis [median 305 HEV/mm(2);interquartile range (IQR)=0-639] and ileum of Crohn's disease patients (140;0-434) compared to healthy controls (both 0;P=0033). A high density of colonic HEVs (HEVhigh) was associated with increased infiltration of T-N and T-CM in the inflamed gut (median 87%;IQR=82-93% of T cell population), compared to HEVlow patients (58%;38-81%;P=0003). The number of colonic follicles was higher in HEVhigh patients (median 054/mm(2);IQR 028-084) compared to HEVlow patients (025/mm(2);008-045;P=0031) and controls (031/mm(2);023-045;P=0043). Increased homing of T-N and T-CM lymphocytes to inflamed gut tissue in IBD patients might be facilitated by ectopic formation of extrafollicular HEVs and TLOs in a subgroup of patients.

关键词： Inflammatory Bowel Disease   Treg Cell   Ipilimumab   Abatacept   Intestinal Inflammation  

摘要： Checkpoint inhibitors blocking CTLA-4 (ipilimumab) and PD-1 (nivolumab, pembrolizumab) have transfigured our cancer treatment paradigm. However, these drugs can induce immune-related adverse events that share clinical and pathological characteristics with immune-mediated diseases. One of the most severe immune-related adverse event observed with anti-CTLA-4 is an enterocolitis that mirrors naturally occurring inflammatory bowel disease. This paper reviews the clinical, immunological, and microbiota data associated with the immune-related enterocolitis induced by the cancer immunotherapy blocking CTLA-4, ipilimumab. A parallel analysis of the mechanisms underlying inflammatory bowel diseases on the one hand, and anti-CTLA-4-induced colitis on the other hand, stresses the crucial role of the gut microbiota and of resident T-reg in the genesis of both iatrogenic and spontaneous inflammatory bowel diseases.

关键词： Guidelines   Inflammatory bowel disease   Medical treatments   Safety  

摘要： Inflammatory bowel diseases are chronic conditions of unknown etiology, showing a growing incidence and prevalence in several countries, including Italy. Although the etiology of Crohn's disease and ulcerative colitis is unknown, due to the current knowledge regarding their pathogenesis, effective treatment strategies have been developed. Several guidelines are available regarding the efficacy and safety of available drug treatments for inflammatory bowel diseases. Nevertheless, national guidelines provide additional information adapted to local feasibility, costs and legal issues related to the use of the same drugs. These observations prompted the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) to establish Italian guidelines on the safety of currently available treatments for Crohn's disease and ulcerative colitis. These guidelines discuss the use of aminosalicylates, systemic and low bioavailability corticosteroids, antibiotics (metronidazole, ciprofloxacin, rifaximin), thiopurines, methotrexate, cyclosporine A, TNF alpha antagonists, vedolizumab, and combination therapies. These guidelines are based on current knowledge derived from evidence-based medicine coupled with clinical experience of a national working group. (C) 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

关键词： Anemia   Crohn's disease   Inflammatory bowel disease   Ulcerative colitis  

摘要： Background: The prevalence, characteristic and determinants of anemia, at the time of inflammatory bowel disease (IBD) diagnosis have yet to be fully elucidated. Methods: Retrospective cross-sectional study. Analytical data and disease characteristics obtained upon diagnosis of 1278 IBD patients [Crohn's disease/ulcerative colitis (CD/UC): 718/560] were collected. Results: Anemia was present in 41.2% of patients at diagnosis (47% and 33.8% of CD and UC patients, respectively;p < 0.001), being severe in 5.5%. Iron deficiency anemia represented 69.6% of cases, with no differences between CD and UC. Female sex was the strongest risk factor for anemia in both CD and UC (OR 7.11;95% CI 4.18-12.10 and 6.55;95% CI 3.39-12.63, respectively), followed by elevated (>= 2 mg/dL) C-reactive protein (OR 4.08;95% CI 2.39-6.97 and 4.58;95% CI 2.26-9.27, respectively). Current smoking was a risk factor for anemia in CD (OR 2.23;95% CI 1.24-4.02), but a protective one in UC (OR 0.36;95% CI 0.14-0.92). A penetrating CD behavior increased the risk of anemia (OR 3.34;95% CI 1.36-8.21);in UC, anemia increased with disease extension (E2 + E3) (OR 1.80;95% CI 1.13-2.86). Conclusions: Female sex and disease activity are major determinants of anemia at IBD diagnosis. Anemia is associated with disease behavior in CD and with disease extension in UC. (C) 2016 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.

关键词： Inflammatory bowel disease   Paradoxical reaction   Anti-tumor necrosis factor  

摘要： Inflammatory bowel disease (IBD) is a complex entity that includes Crohn disease and ulcerative colitis. It is characterized by a chronic proinflammatory state of varying intensity that often leads to considerable morbidity. In the last decade, several therapeutic targets have been identified that are susceptible to the use of biological agents, including anti-tumor necrosis factor alpha antibodies, which are associated with paradoxical psoriasiform reactions in 5% of patients. Decision-making in the management of these cases requires close collaboration between the dermatologist and gastroenterologist. Inflammatory bowel disease is also associated with various other dermatologic and rheumatologic manifestations, and presents a genetic and pathogenic association with psoriasis that justifies both the interdisciplinary approach to these patients and the present review. (C) 2016 AEDV. Published by Elsevier Espana, S.L.U. All rights reserved.

关键词： Epidemiology   Risk Factor   Dental Care   Microbiota  

摘要： BACKGROUND & AIMS: The hygiene hypothesis (a lack of childhood exposure to microorganisms increases susceptibility to allergic diseases by altering immune development) has been proposed as an explanation for the increasing incidence of inflammatory bowel disease (IBD). However, there are few data on the relationship between oral hygiene and development of IBD, and study results have been inconsistent. We investigated the association between poor oral health and risks of IBD, ulcerative colitis (UC), and Crohn's disease (CD). METHODS: We performed a population-based cohort study of 20,162 individuals followed for 40 years (from 1973 to 2012). Residents of 2 municipalities of Uppsala County, Sweden (N = 30,118), 15 years or older, were invited, and among them 20,333 were examined for tooth loss, dental plaques, and oral mucosal lesions at the time of study entry. Other exposure data were collected from questionnaires. Patients who later developed IBD (UC or CD) were identified by international classification codes from Swedish National Patient and Cause of Death Registers. Cox proportional hazards regression was used to estimate hazard ratios for IBD, UC, and CD. RESULTS: From National Patient and Cause of Death Registers, we identified 209 individuals who developed IBD (142 developed UC and 67 developed CD), with an incidence rate of 37.3 per 100,000 person-years. We found an inverse relationship between poor oral health and IBD, especially in individuals with severe oral problems. Loss of 5-6 teeth of the 6 teeth examined was associated with a lower risk of IBD (hazard ratio, 0.56;95% confidence interval, 0.32-0.98). Having dental plaques that covered more than 33% of tooth surface was negatively associated with CD (hazard ratio, 0.32;95% confidence interval, 0.10-0.97). CONCLUSIONS: In a population-based cohort study of more than 20,000 people in Sweden, we associated poor oral health with reduced risk of future IBD.

关键词： Intestinal Diseases   IgG1   vedolizumab   Pregnancy Outcome   Clinical Study   Inflammatory Bowel Diseases   Pregnancy  

摘要： BackgroundVedolizumab is a gut-selective immunoglobulin G(1) monoclonal antibody to (47) integrin for the treatment of Crohn's disease (CD) and ulcerative colitis (UC). Prospective clinical studies of vedolizumab in pregnancy have not been conducted;therefore, existing safety data of vedolizumab in pregnancy were examined. AimTo assess pregnancy outcomes in females and partners of males who received vedolizumab. MethodsAll pregnancy data collected during the clinical programme (from 14 May 2007 to 27 June 2013) and in the post-marketing setting (to 19 November 2015) were analysed. ResultsAcross six studies, there were 27 pregnancies in female participants and 19 pregnancies in partners of male participants. Among 24 vedolizumab-treatedfemales (23 with CD/UC, one healthy volunteer), there were 11 live births, five elective terminations, four spontaneous abortions and four undocumented outcomes. A congenital corpus callosum agenesis anomaly was reported in one live birth from a healthy volunteer with extensive obstetric history exposed to single-dose vedolizumab 79days before estimated conception. Of 19 pregnancies in partners of male participants, there were 11 live births, two spontaneous abortions, three elective terminations and three undocumented outcomes. Post-marketing reports recorded 81 pregnancies, resulting in four live births, 11 spontaneous abortions and 66 pregnancies that were on-going or reported undocumented outcomes. ConclusionsInitial analysis, limited by sample size and follow-up, identified no new safety concerns for pregnancy outcomes in females directly or indirectly exposed to vedolizumab. However, vedolizumab should be used during pregnancy only if the benefits to the mother outweigh the risks to the mother/unborn child.

关键词： disease severity   Immune System Diseases   Inflammatory Bowel Diseases   Intestinal Diseases   index tests  

摘要： Linked Content This article is linked to Ananthakrishnan and Conway et al papers. To view these articles visit https://***/10.1111/apt.13998 and https://***/10.1111/apt.13940. [ABSTRACT FROM AUTHOR]