Need For anti-TNF Therapy Research Articles

Pre-Diagnosis Diet Predicts Response to Exclusive Enteral Nutrition and Correlates with Microbiome in Pediatric Crohn Disease.

Exclusive enteral nutrition (EEN) is effective in inducing remission in pediatric Crohn disease (CD). EEN alters the intestinal microbiome, but precise mechanisms are unknown. We hypothesized that pre-diagnosis diet establishes a baseline gut microbiome, which then mediates response to EEN. We analyzed prospectively recorded food frequency questionnaires (FFQs) for pre-diagnosis dietary patterns. Fecal microbiota were sequenced (16SrRNA) at baseline and through an 18-month follow-up period. Dietary patterns, Mediterranean diet adherence, and stool microbiota were associated with EEN treatment outcomes, disease flare, need for anti-tumor necrosis factor (TNF)-α therapy, and long-term clinical outcomes. Ninety-eight patients were included. Baseline disease severity and microbiota were associated with diet. Four dietary patterns were identified by FFQs; a "mature diet" high in fruits, vegetables, and fish was linked to increased baseline microbial diversity, which was associated with fewer disease flares (p < 0.05) and a trend towards a delayed need for anti-TNF therapy (p = 0.086). Baseline stool microbial taxa were increased (Blautia and Faecalibacterium) or decreased (Ruminococcus gnavus group) with the mature diet compared to other diets. Surprisingly, a "pre-packaged" dietary pattern (rich in processed foods) was associated with delayed flares in males (p < 0.05). Long-term pre-diagnosis diet was associated with outcomes of EEN therapy in pediatric CD; diet-microbiota and microbiota-outcome associations may mediate this relationship.

Discovery and validation of mucosal TNF expression combined with histological score - a biomarker for personalized treatment in ulcerative colitis

BackgroundThere are no accurate markers that can predict clinical outcome in ulcerative colitis at time of diagnosis. The aim of this study was to explore a comprehensive data set to identify and validate predictors of clinical outcome in the first year following diagnosis.MethodsTreatment naive-patients with ulcerative colitis were included at time of initial diagnosis from 2004 to 2014, followed by a validation study from 2014 to 2018. Patients were treated according to clinical guidelines following a standard step-up regime. Patients were categorized according to the treatment level necessary to achieve clinical remission: mild, moderate and severe. The biopsies were assessed by Robarts histopathology index (RHI) and TNF gene transcripts.ResultsWe included 66 patients in the calibration cohort and 89 patients in the validation. Mucosal TNF transcripts showed high test reliability for predicting severe outcome in UC. When combined with histological activity (RHI) scores the test improved its diagnostic reliability. Based on the cut-off values of mucosal TNF and RHI scores from the calibration cohort, the combined test had still high reliability in the validation cohort (specificity 0.99, sensitivity 0.44, PPV 0.89, NPV 0.87) and a diagnostic odds-ratio (DOR) of 54.ConclusionsThe combined test using TNF transcript and histological score at debut of UC can predict severe outcome and the need for anti-TNF therapy with a high level of precision. These validated data may be of great clinical utility and contribute to a personalized medical approach with the possibility of top-down treatment for selected patients.

Tu1842 - Genetic Risk of IBD: Predictors of Loss of Response and Need for Anti-Tnf Therapy

Tu1842 - Genetic Risk of IBD: Predictors of Loss of Response and Need for Anti-Tnf Therapy

Diagnostic Delay Is Associated with a Greater Risk of Early Surgery in a French Cohort of Crohn's Disease Patients.

To investigate whether a diagnostic delay is associated with a poor outcome in Crohn's disease (CD). Medical and socioeconomic characteristics as well as medications and need for surgery of consecutive CD adults patients followed in three referral centers were prospectively recorded using an electronic database (Focus_MICI®). A long diagnostic delay was defined by the upper quartile. We compared patients with long diagnostic delay to those with earlier diagnosis regarding the time to: (1) first intestinal surgery, (2) first use of immunosuppressants (IMSs), and (3) first use of anti-tumor necrosis factor (anti-TNF) therapy using the Kaplan-Meier test and the log-rank test. A total of 497 patients with CD (53.6% women) were analyzed. Median diagnostic delay was 5months (IQR 25-75%: 2-13months). Median follow-up was 9years (IQR 4-16.2), and 148 (29.8%) patients had major surgery. There were no significant differences between patients with late and early diagnosis regarding age at diagnosis, disease phenotype, need for IMS therapy, and need for anti-TNF therapy. Time to first major surgery was shorter in patients with late diagnosis (p=0.05). In this large multicenter prospective cohort of French CD patients, a long diagnostic delay (>13months) increased the risk of early surgery. No associated factors could be identified in this study.

Hispanic Ethnicity is Associated With Milder Disease Severity in Crohn’s Disease but not Ulcerative Colitis

Introduction: Inflammatory bowel disease (IBD) is increasing among Hispanic patients; however few studies have examined differences in epidemiology, disease severity, and treatment course between Hispanic and non-Hispanic patients. Our aim was to evaluate ethnicity as a clinically significant variable influencing disease severity, need for anti-TNF ±immunomodulator therapy, rates of surgery, and hospitalizations. Methods: A cohort of adult IBD patients followed in a large urban safety-net hospital between January 2007 and December 2012 was identified. The following variables were extracted from the electronic medical record: age, gender, race/ethnicity, disease type and severity, treatment regimens, steroid-free remission at 26 weeks, receipt of IBD-related surgery, and hospitalizations. Fisher exact and Mann-Whitney rank sum tests were used to compare categorical and continuous variables between Hispanic and non-Hispanic patients respectively. Results: We identified a total of 291 adult IBD patients, including 148 with Crohn’s Disease (CD), and 143 with ulcerative colitis (UC). Our cohort was 54% male and median age was 44 years. Our cohort was racially diverse with 32% white, 37% black, 28% Hispanic, and 2% Asian. Hispanic patients appeared to have a more benign disease course, with significantly less IBD-related surgeries (mean 0.4 vs. 1.1; p=0.001) and total hospitalizations (mean 2.1 vs. 2.9; p=0.04). Treatment regimens were significantly different between Hispanics and non-Hispanics (p=0.04), as Hispanic patients were less likely to require anti-TNF ± immunomodulator therapy (27% vs. 39%). On subgroup analysis, these differences were primarily noted among those with CD but not those with UC. Hispanic UC patients had a similar number of IBD-related surgeries (p=0.17) and hospitalizations (p=0.62), whereas Hispanic CD had lower rates of both IBD-related surgeries (mean 0.8 vs. 1.8; p=0.01) and total hospitalizations (mean 2.4 vs. 3.8; p=0.04). Hispanic patients with CD also were significantly less likely to require anti-TNF ± immunomodulator therapy (38% vs. 57%; p=0.05). Conclusion: Hispanic CD patients appear to have less severe disease than non-Hispanic patients, with lower rates of IBD-related surgery, hospitalization, and need for anti-TNF therapy. In contrast, Hispanic ethnicity does not appear to be associated with disease course severity in UC patients.

O-035 Efficacy of Anti-inflammatory Monoclonal Secretory Immunoglobulin-A Antibodies after Oral Treatment in Preclinical Models of Inflammatory Bowel Disease

Treatment of inflammatory bowel disease (IBD) often depends on the form of the disease (e.g. Crohn's Disease (CD) or Ulcerative Colitis (UC)) and the extent and severity of the disease. Anti-TNF antibody therapy has been approved for treatment of patients with moderate to severe CD. Current anti-TNF antibodies (Abs) are IgG class and are administered intravenously or subcutaneously leading to high systemic exposure of the Abs and subsequent unwanted effects, e.g. systemic immunosuppression and opportunistic infections, injection site reactions, immunogenicity. There is an unmet medical need for anti-TNF therapy that combines (local) efficacy with less adverse effects. Here we describe the functional characteristics of anti-TNF secretory immunoglobulin-A antibodies (SIgAs), a new class of anti-inflammatory antibodies for topical treatment of IBD after oral administration. SIgA is a complex dimeric molecule consisting of 4 heavy chains, 4 light chains, 1 J-chain and 1 secretory component (SC) and having a molecular weight of approximately 430 kD. Monoclonal SIgAs were produced in the SYNLEX™ duckweed system (stably transfected Lemna minor containing the 4 genes required) and purified with affinity and size exclusion chromatography. Binding, neutralization and physical-chemical characteristics were determined in vitro using SDS-PAGE and chromatography techniques and using ELISA, L929 and CaCo-2 cells. Pharmacokinetics and biodistribution were studied using in vivo imaging and quantitative whole body autoradiography techniques in mice. In vivo efficacy after oral administration (5 mg/kg, 3 times weekly) was established in both DSS and TNBS IBD models in C57Bl/6 mice using a mini-endoscopy-based colitis scoring system. Anti-TNF-SIgA bound to TNF with an EC50 lower than 1 nM and inhibited TNF-induced apoptosis in an L929 assay. The stabilities of the anti-TNF-SIgA and human colostral SIgA in simulated intestinal fluid were similar. Confocal laser scanning experiments demonstrated apical uptake of anti-TNF-SIgA after overnight exposure by polarized Caco-2 monolayer cells. In vivo imaging with fluorescently-labeled antibodies after oral administration to mice showed SIgA in the intestine but not IgG at 24 hours post administration. Using an antibody with cross-reactivity to human but not mouse SC, co-localization of SIgA within epithelial cells and dendritic cells was demonstrated in the colon. In pharmacokinetic experiments no SIgA could be detected in plasma after oral administration, whereas after intravenous administration SIgA was rapidly cleared from the circulation with a half-life of only a few hours. These results were confirmed with quantitative whole body autoradiography using tritium-labeled antibodies. Biological activity after oral administration of anti-TNF SIgA was established in 2 IBD models (DSS- and TNBS-induced) where the colitis scoring was significantly reduced in anti-TNF-SIgA-treated animals. We have successfully generated a monoclonal anti-TNF-secretory IgA antibody in duckweed. The physical, chemical and biological characteristics of anti-TNF-SIgA support the molecule’s potential as an effective topical treatment for IBD patients avoiding adverse effects associated with systemic exposure and combining the convenience of oral treatment.

Predictors of favourable outcome in inflammatory Crohn's disease. A retrospective observational study

BackgroundNo studies have specifically searched for predictors of a favourable outcome that would allow a conservative therapeutic approach in adult Crohn's disease (CD). AimsTo identify predictors of a favourable disease course over time at CD diagnosis. MethodsWe identified and included all patients diagnosed with CD between January 1994 and December 2003, who had CD with an inflammatory pattern and no perianal disease at diagnosis, and who were followed up for at least 5 years. Clinical and therapeutic features until December 2008 and losses to follow-up were identified. We defined a favourable outcome as the absence of stricturing and penetrating complications of the disease (including perianal disease), together with the absence of need for anti-TNF therapy or resectional surgery during follow up. ResultsOne hundred and forty-five patients were included and followed up for a median of 96 months (IQR, 79–140). At diagnosis, location was ileal in 39%, colonic in 28%, and ileocolonic in 32%; 50% of the patients were active smokers, and 41% used immunomodulators. Eighty-two patients (57%) met the criteria for a favourable outcome at the end of follow-up. The only factor associated with a favourable outcome was isolated colonic involvement (P=0.022), with 73% of these patients meeting the criteria for a favourable outcome. ConclusionsA favourable outcome of initially uncomplicated CD is not easily predicted at disease diagnosis by means of clinical or epidemiologic factors. Nevertheless, patients with isolated colonic disease are less likely to have an aggressive course.

Sa1917 Efficacy of Allopurinol Added to 6MP or Azathioprine for Inflammatory Bowel Disease

INTRODUCTION Azathioprine (AZA) and 6-mercaptopurine (6MP) are indicated for the induction and maintenance of remission in patients with IBD. A drawback is their narrow therapeutic window. Therapeutic levels of the metabolite 6-thioguanine (6TGN) are associated with clinical remission. Adverse effects of 6-methylmercaptopurine ribonucleotide (6MMPN) include hepatotoxicity. Patients who selectively metabolize 6MP to 6MMPN can be identified and co-treated with allopurinol (allo), which shifts metabolism to 6TGN. The use of these measurements remains controversial as some experts maintain that outcomes are unchanged from standard therapy. We retrospectively reviewed charts of patients with toxic levels of 6MMPN who were treated with allo to determine if goals of therapy were achieved. METHODS A list of all patients who had 6MP/AZA metabolites measured in the last 4 years was obtained from Prometheus laboratory. The list included 32 patients, 14 met our criteria. Data was collected regarding age, sex, diagnosis, ESR, CRP, 6MMPN and 6TGN levels and need for anti-TNF therapy before and after initiation of allo, subjective improvement of patient's symptoms. RESULTS 14 patients were treated with allo due to toxic levels of 6MMPN (mean 11175 pmol/8X10^8RBC range 5936-22398). The average age was 49 yrs (range 22-90). 7(50%) were men. 8(57%) had Crohn's, 5(35%) had UC, and 1(7.1%) had indeterminate colitis. Following initiation of allo, all patients had normalization of 6MMPN levels (mean 996.5 range 979-1014). 4(25%) patients had therapeutic 6TGN levels prior to initiating allo. Following allo, 11(79%) reached therapeutic 6TGN levels, 1 achieved near therapeutic level (223) and 2 did not have follow up data. The average levels before and after therapy with allo was 191(range 117-355) and 330.1 pmol/8X10^8RBC (range 223-498), respectively. The average ESR before and after the initiation of allo was 24.7(range 1-111) and 18.7(range 1-76), respectively with an average decrease of 6 mm/ hr. 50% of the patients had a greater than 30% decrease in ESR. The average CRP before and after allo was 3.2 mg/L (range 0.1-18.6) and 0.56(range 0.1-2.4), respectively with an average decrease of 2.66. 57% of the patients had a greater than 40% decrease in CRP. 12 (86%) reported improvement in global symptoms following initiation of allo. 2 of the 3 patients who were on anti-TNF therapy prior to initiation of allo were able to discontinue it, 1 patient had to be switched to biologics due to pancytopenia and 1 required biologics due to lack of response to 6MP/allo . CONCLUSION Our study shows that initiation of allo in patients with elevated 6MMPN level results in normalization of 6MMPN level, achieves therapeutic levels of 6TGN, improvement of subjective symptoms, lab parameters used to assess inflammatory activity(ESR, CRP) and decrease in need for anti-TNF therapy.

Mannose-binding lectin polymorphisms are not associated with rheumatoid arthritis--confirmation in two large cohorts

In RA, conflicting results have been described on the association between genotypes of the complement factor mannose-binding lectin (MBL) and disease susceptibility and severity. This might be due to underpowerment of previous research work and the fact that no confirmation cohorts were used. Therefore a different approach is warranted. MBL2 gene polymorphisms were determined in two RA cohorts (378 and 261 cases) and 648 controls. Considering MBL polymorphisms, cases and controls were categorized in groups of high, intermediate and low MBL production. The total sample size allows detection of a potential association between RA susceptibility and MBL groups with an odds ratio of 1.37 (alpha < 0.05; 1-beta > 0.8). Disease severity as defined by the need for anti-TNF therapy was also analysed for possible associations with MBL groups. There was no difference in the frequencies between MBL genotypes of RA cases and controls that are associated with high (cases 54.4%, controls 57.0%), intermediate (cases 28.9%, controls 27.5%) or low (cases 16.7%, controls 15.5%) MBL production. Furthermore, there was no association between MBL groups and disease severity. MBL genotype groups are not associated with RA disease susceptibility or severity in this large study including a confirmation cohort. Compared with previous smaller studies these results add to more definite conclusions.