Quantitative relationship between infliximab exposure and inhibition of C‐reactive protein synthesis to support inflammatory bowel disease management

Aim Quantitative and kinetic insights into the drug exposure‐disease response relationship might enhance our knowledge on loss of response and support more effective monitoring of inflammatory activity by biomarkers in patients with inflammatory bowel disease (IBD) treated with infliximab (IFX). This study aimed to derive recommendations for dose adjustment and treatment optimisation based on mechanistic characterisation of the relationship between IFX serum concentration and C‐reactive protein (CRP) concentration. Methods Data from an investigator‐initiated trial included 121 patients with IBD during IFX maintenance treatment. Serum concentrations of IFX, antidrug antibodies (ADA), CRP, and disease‐related covariates were determined at the mid‐term and end of a dosing interval. Data were analysed using a pharmacometric nonlinear mixed‐effects modelling approach. An IFX exposure‐CRP model was generated and applied to evaluate dosing regimens to achieve CRP remission. Results The generated quantitative model showed that IFX has the potential to inhibit up to 72% (9% relative standard error [RSE]) of CRP synthesis in a patient. IFX concentration leading to 90% of the maximum CRP synthesis inhibition was 18.4 μg/mL (43% RSE). Presence of ADA was the most influential factor on IFX exposure. With standard dosing strategy, ≥55% of ADA+ patients experienced CRP nonremission. Shortening the dosing interval and co‐therapy with immunomodulators were found to be the most beneficial strategies to maintain CRP remission. Conclusions With the generated model we could for the first time establish a robust relationship between IFX exposure and CRP synthesis inhibition, which could be utilised for treatment optimisation in IBD patients

Toll-like receptor 4 and NOD2/CARD15 mutations in Hungarian patients with Crohn's disease: Phenotype-genotype correlations

AIM: To determine common NOD2/CARD15 mutations and TLR4 D299G polymorphism in Hungarian patients with CD. METHODS: A total of 527 unrelated patients with CD (male/female: 265/262, age: 37.1 (SD 7.6) years) and 200 healthy subjects were included. DNA was screened for possible NOD2/CARD15 mutations by denaturing high-performance liquid chromatography (confirmed by direct sequencing). TLR4 D299G was tested by PCR-RFLP. RESULTS: NOD2/CARD15 mutations were found in 185 patients (35.1%) and in 33 controls (16.5%, P< 0.0001). SNP8/R702W (10.8% vs 6%, P = 0.02), SNP13/3020insC (19.4% vs 5%, P< 0.0001) and exon4 R703C (2.1% vs 0%, P = 0.02) mutations were more frequent in CD, while the frequency of SNP12/G908R was not increased. The frequency of TLR4 D299G was not different (CD: 9.9% vs controls: 12.0%). Variant NOD2/CARD15 allele was associated with an increased risk for CD (OR(het) = 1.71, 95% CI = 1.12-2.6, P = 0.0001, OR(two-risk alleles) = 25.2, 95% CI = 4.37-, P< 0.0001), early disease onset (carrier: 26.4 years vs non-carrier: 29.8 years, P = 0.0006), ileal disease (81.9% vs 69.5%, OR = 1.99, 95% CI = 1.29-3.08, P = 0.02, presence of NOD2/CARD15 and TLR4: 86.7% vs 64.8%), stricturing behavior (OR = 1.69, 95% CI = 1.13-2.55, P = 0.026) and increased need for resection (OR= 1.71, 95% CI: 1.13-2.62, P = 0.01), but not with duration, extraintestinal manifestations, familial disease or smoking. TLR4 exhibited a modifier effect: age of onset in wt/TLR4 D299G carriers: 27.4 years vs NOD2mut/TLR D299G: 23 years (P = 0.06), in NOD2mut/wt: 26.7 years. CONCLUSION: These results confirm that variant NOD2/CARD15 (R702W, R703C and 3020insC) alleles are associated with earlier disease onset, ileal disease, stricturing disease behavior in Hungarian CD patients. In contrast, although the frequency of TLR4 D299G polymorphism was not different from controls, NOD2/TLR4 mutation carriers tended to present at earlier age. (C) 2005 The WJG Press and Elsevier Inc. All rights reserved

External Model Performance Evaluation of Twelve Infliximab Population Pharmacokinetic Models in Patients with Inflammatory Bowel Disease

Infliximab is approved for treatment of various chronic inflammatory diseases including inflammatory bowel disease (IBD). However, high variability in infliximab trough levels has been associated with diverse response rates. Model-informed precision dosing (MIPD) with population pharmacokinetic models could help to individualize infliximab dosing regimens and improve therapy. The aim of this study was to evaluate the predictive performance of published infliximab population pharmacokinetic models for IBD patients with an external data set. The data set consisted of 105 IBD patients with 336 infliximab concentrations. Literature review identified 12 published models eligible for external evaluation. Model performance was evaluated with goodness-of-fit plots, prediction- and variability-corrected visual predictive checks (pvcVPCs) and quantitative measures. For anti-drug antibody (ADA)-negative patients, model accuracy decreased for predictions > 6 months, while bias did not increase. In general, predictions for patients developing ADA were less accurate for all models investigated. Two models with the highest classification accuracy identified necessary dose escalations (for trough concentrations < 5 µg/mL) in 88% of cases. In summary, population pharmacokinetic modeling can be used to individualize infliximab dosing and thereby help to prevent infliximab trough concentrations dropping below the target trough concentration. However, predictions of infliximab concentrations for patients developing ADA remain challenging

Clinical efficacy of the Toll-like receptor 9 agonist cobitolimod using patient-reported-outcomes defined clinical endpoints in patients with ulcerative colitis

Abstract Background The Toll-like-receptor 9 (TLR-9) agonist cobitolimod (DIMS0150, Kappaproct®) is a promising therapeutic option for ulcerative colitis (UC) patients. Aims The objectives of this post-hoc analysis using the COLLECT study data was to investigate the clinical effects of cobitolimod using patient-reported-outcomes (PRO) defined endpoints. Methods Dual topical administration of cobitolimod was studied in a randomised, multicentre clinical trial named COLLECT in moderate-to-severe UC patients. Symptomatic remission (SR) was studied in 104 patients based on their e-diary records and was defined as absence of blood in stool and a mean daily stool frequency (SF)  Results SR was achieved at week 4 in 17.1% of cobitolimod vs. 5.9% of placebo treated patients (p = 0.13), at week 8 in 35.7% vs. 17.6% (p = 0.07), and at week 12 in 38.6% vs. 17.6% (p = 0.04) of the patients, respectively. SR rates with cobitolimod and placebo in anti-TNFα experienced patients were smaller but with a broadly similar relative effect-size to anti-TNFα naive patients. Clinical efficacy was higher in patients with moderate compared to severe disease. Conclusions Application of the Toll-like-receptor 9 (TLR-9) agonist cobitolimod is able to induce remission as assessed by PRO measures in UC patients with moderate-to-severe activity as well as in anti-TNFα experienced and naive patients supporting the overall efficacy of the substance

Agreement of site and central readings of ileocolonoscopic scores in Crohn's disease: comparison using data from the EXTEND trial

Background and AimsCentralized endoscopic scoring may reduce variability, but evidence is lacking in patients with Crohn’s disease. We assessed the agreement of endoscopic scorings between site endoscopists and one central reader by using data from the adalimumab Crohn’s disease clinical trial EXTEND.MethodsAgreement between readers for Crohn’s Disease Endoscopic Index of Severity (CDEIS)–scored endoscopies from 6 sites and Simple Endoscopic Score for Crohn’s Disease (SES-CD)–scored endoscopies from 19 sites in EXTEND was evaluated at baseline and weeks 12 and 52. Agreement on total scores was calculated by using intraclass correlation coefficient (ICC). Kappa statistic or Spearman correlation coefficient measured the agreement between readers for each ileocolonic segment on CDEIS variables including deep ulceration, surface involved, and ulcerated surface and SES-CD variables including ulcerated surface, size of ulcers, and affected surface.ResultsICCs on mean scores at baseline and weeks 12 and 52 were 0.78, 0.92, and 0.86 (CDEIS), and 0.77, 0.86, and 0.82 (SES-CD), respectively. Site endoscopists consistently reported higher scores. High agreement was observed for most segments and all time points for CDEIS variables and SES-CD large ulcers. Weak agreement occurred for the right side of the colon at all time points for CDEIS deep ulceration and SES-CD large ulcers and at baseline and week 12 for CDEIS ulcerated surface. Fair/moderate agreement occurred for SES-CD ulcerated surface and moderate/high agreement for affected surface for all segments and time points.ConclusionsSite and central readers showed high agreement on total CDEIS and SES-CD scores overall, whereas variability for individual segments was observed. Weakest agreement occurred at baseline, with a greater difference for SES-CD than for CDEIS score. (Clinical trial registration number: NCT00348283.

Placebo response rate in clinical trials of fistulizing crohn's disease: systematic review and meta-analysis

Background & Aims: It is important to determine the magnitude and identify modifiers of the rate of response to placebo in clinical trials of fistulizing Crohn’s disease (CD), to understand disease progression, and to calculate sample size. We conducted a systematic review and meta-analysis of rates of response to placebo in trials of patients with fistulizing CD. Methods: We searched MEDLINE, EMBASE, EMBASE CLASSIC, and the Cochrane central register of controlled trials for randomized controlled trials (RCTs) comparing pharmacologic agents with placebo in adults with fistulizing CD. We identified studies that reported complete fistula closure, partial closure, or response. Data were extracted as intention-to-treat analyses and pooled by using a random-effects model. Proportions of patients who received placebo and had complete or partial fistula(e) closure were calculated, with 95% confidence intervals (CIs). The effects of trial characteristics on the magnitude of response to placebo were examined. Results: Thirteen RCTs were eligible for our analysis; these included 579 patients assigned to placebo groups. The pooled rate of response to placebo, among all RCTs, for complete fistula closure was 15.6% (95% CI, 10.9%–20.9%), with significant heterogeneity (I2 = 62.5%, P = .001). The pooled rate of response to placebo for partial fistula closure or response in 9 trials, comprising 423 patients, was 18.3% (95% CI, 14.8%–22.1%). Rates of response to placebo were significantly lower in trials with shorter durations of therapy and shorter intervals to assessment of fistula closure. Neither exposure to the pharmacologic agent during the induction phase of the same (or related) RCT nor concomitant medications had any effect. Conclusions: In a meta-analysis of rate of response to placebo in patients with fistulizing CD, we found that fistulae closed in almost 1/6 patients given placebo in RCTs of pharmacologic agents. Future research should identify characteristics of patients that predict response to placebo

Factors Associated With Short- and Long-Term Outcomes of Therapy for Crohn’s Disease

Background & AimsOur post hoc analysis assessed the association of early (at weeks 26–30) clinical, endoscopic, biologic, and pharmacokinetic outcomes with corticosteroid-free remission at week 50 (CSFR50); CSFR50 was observed in 55.2% and 65.4% of patients treated with infliximab, alone or in combination with azathioprine, respectively.MethodsWe analyzed data from 203 patients: 96 received infliximab monotherapy and 107 received combination therapy. Receiver operating characteristic analysis was used to set cut-off points for the week 30 trough serum infliximab concentration (SIC30) and percentage change, from baseline, in the C-reactive protein (CRP) level at week 26, to predict CSFR50. Univariate and multivariate procedures analyzed predictive parameters of CSFR50 (odds ratio [OR] and 95% confidence interval [CI]). Mucosal healing (MH, zero ulcers) and CRP normalization (<8.0 mg/L) also were assessed.ResultsTrough SIC30 was higher in patients with than without CSFR50. Patients given combination therapy had higher trough SIC30s than those given monotherapy. Median trough SIC30 was significantly higher in patients with than without CSFR50 among those on infliximab monotherapy (2.14 vs 0.80 μg/mL; P = .006), but not for those on combination therapy (3.56 vs 3.54 μg/mL; P=.31). In patients with increased baseline levels of CRP (n = 120), corticosteroid-free remission at week 26 (CSFR26) (OR, 4.09; 95% CI, 1.65–10.11), and trough SIC30s of 3.0 μg/mL or greater (OR, 3.20; 95% CI, 1.38–7.42) were associated significantly with CSFR50. In patients evaluable for MH (n = 123), trough SIC30s of 3.0 μg/mL or greater (OR, 3.34; 95% CI, 1.53–7.28) and CRP normalization (OR, 2.69; 95% CI, 1.10–6.54) were associated significantly with MH at week 26 (MH26). Furthermore, CSFR26 (OR, 4.43; 95% CI, 1.81–10.82) and MH26 (OR, 3.01; 95% CI, 1.33–6.81) were associated significantly with CSFR50.ConclusionsTrough SIC30 is associated positively with MH26; CSFR26 and MH26 are independent predictors of CSFR50. Trough SIC30 of 3.0 μg/mL or greater early during maintenance treatment is an important determinant of clinical and endoscopic Crohn’s disease outcomes. ClinicalTrials.gov number, NCT00094458

Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohn's Disease

Ileal Crohn's Disease (CD), a chronic small intestinal inflammatory disorder, is characterized by reduced levels of the antimicrobial peptides DEFA5 (HD-5) and DEFA6 (HD-6). Both of these α-defensins are exclusively produced in Paneth cells (PCs) at small intestinal crypt bases. Different ileal CD–associated genes including NOD2, ATG16L1, and recently the β-catenin–dependant Wnt transcription factor TCF7L2 have been linked to impaired PC antimicrobial function. The Wnt pathway influences gut mucosal homeostasis and PC maturation, besides directly controlling HD-5/6 gene expression. The herein reported candidate gene study focuses on another crucial Wnt factor, the co-receptor low density lipoprotein receptor-related protein 6 (LRP6). We analysed exonic single nucleotide polymorphisms (SNPs) in a large cohort (Oxford: n = 1,893) and prospectively tested 2 additional European sample sets (Leuven: n = 688, Vienna: n = 1,628). We revealed an association of a non-synonymous SNP (rs2302685; Ile1062Val) with early onset ileal CD (OR 1.8; p = 0.00034; for homozygous carriers: OR 4.1; p = 0.00004) and additionally with penetrating ileal CD behaviour (OR 1.3; p = 0.00917). In contrast, it was not linked to adult onset ileal CD, colonic CD, or ulcerative colitis. Since the rare variant is known to impair LRP6 activity, we investigated its role in patient mucosa. Overall, LRP6 mRNA was diminished in patients independently from the genotype. Analysing the mRNA levels of PC product in biopsies from genotyped individuals (15 controls, 32 ileal, and 12 exclusively colonic CD), we found particularly low defensin levels in ileal CD patients who were carrying the variant. In addition, we confirmed a direct relationship between LRP6 activity and the transcriptional expression of HD-5 using transient transfection. Taken together, we identified LRP6 as a new candidate gene in ileal CD. Impairments in Wnt signalling and Paneth cell biology seem to represent pathophysiological hallmarks in small intestinal inflammation and should therefore be considered as interesting targets for new therapeutic approaches

New Gastrointestinal Symptoms Are Common in Inflammatory Bowel Disease Patients With COVID-19: Data From an International Registry

Coronavirus disease 2019 (COVID-19) can cause gastrointestinal (GI) symptoms. A prior meta-analysis suggested that up to 17.6% of COVID-19 patients have GI symptoms. Data are conflicting on the association of GI symptoms with COVID-19 outcomes, with some reports suggesting worse prognosis among those with GI symptoms while others finding improved outcomes. There are limited data on COVID-19 and GI symptoms among inflammatory bowel disease (IBD) patients. A single-center study of 80 IBD patients with COVID-19 observed that they were more likely to present with abdominal pain and diarrhea than non-IBD controls. In addition, a prior systematic review on just over 400 patients found nearly one-quarter of IBD patients with COVID-19 had diarrhea.6 Using a large, international database, we aimed to describe new onset GI symptoms and their association with clinical outcomes in patients with IBD who develop COVID-19

Development of Red Flags Index for Early Referral of Adults with Symptoms and Signs Suggestive of Crohn's Disease: An IOIBD Initiative

International audience; BACKGROUND AND AIMS:Diagnostic delay is frequent in patients with Crohn's disease (CD). We developed a tool to predict early diagnosis.METHODS:A systematic literature review and 12 CD specialists identified 'Red Flags', i.e. symptoms or signs suggestive of CD. A 21-item questionnaire was administered to 36 healthy subjects, 80 patients with irritable bowel syndrome (non-CD group) and 85 patients with recently diagnosed (<18 months) CD. Patients with CD were asked to recall symptoms and signs they experienced during the 12 months before diagnosis. Multiple logistic regression analyses selected and weighted independent items to construct the Red Flags index. A receiver operating characteristic curve was used to assess the threshold that discriminated CD from non-CD. Association with the Red Flags index relative to this threshold was expressed as the odds ratios (OR).RESULTS:Two hundred and one subjects, CD and non-CD, answered the questionnaire. The multivariate analysis identified eight items independently associated with a diagnosis of CD. A minimum Red Flags index value of 8 was highly predictive of CD diagnosis with sensitivity and specificity bootstrap estimates of 0.94 (95% confidence interval 0.88-0.99) and 0.94 (0.90-0.97), respectively. Positive and negative likelihood ratios were 15.1 (9.3-33.6) and 0.066 (0.013-0.125), respectively. The association between CD diagnosis and a Red Flags index value of ≥8 corresponds to an OR of 290 (p < 0.0001).CONCLUSIONS:The Red Flags index using early symptoms and signs has high predictive value for the diagnosis of CD. These results need prospective validation prior to introduction into clinical practice