Magnetic Resonance Enterography and Histology in Patients With Fibrostenotic Crohn's Disease: A Multicenter Study.

INTRODUCTION: Magnetic resonance enterography (MRE) is useful for detecting bowel strictures, whereas a number of imaging biomarkers may reflect severity of fibrosis burden in Crohn's disease (CD). This study aimed to verify the association of MRE metrics with histologic fibrosis independent of inflammation. METHODS: This prospective European multicenter study performed MRE imaging on 60 patients with CD with bowel strictures before surgical resection. Locations of 61 histological samples were annotated on MRE examinations, followed by central readings using the Chiorean score and measurement of delayed gain of enhancement (DGE), magnetization transfer ratio, T2-weighted MRI sequences (T2R), apparent diffusion coefficient (ADC), and the magnetic resonance index of activity (MaRIA). Correlations of histology and MRE metrics were assessed. Least Absolute Shrinkage and Selection Operator and receiver operator characteristic (ROC) curve analyses were used to select composite MRE scores predictive of histology and to estimate their predictive value. RESULTS: ADC and MaRIA correlated with fibrosis (R = -0.71, P < 0.0001, and 0.59, P < 0.001) and more moderately with inflammation (R = -0.35, P < 0.01, and R = 0.53, P < 0.001). Lower or no correlations of fibrosis or inflammation were found with DGE, magnetization transfer ratio, or T2R. Least Absolute Shrinkage and Selection Operator and ROC identified a composite score of MaRIA, ADC, and DGE as a very good predictor of histologic fibrosis (ROC area under the curve = 0.910). MaRIA alone was the best predictor of histologic inflammation with excellent performance in identifying active histologic inflammation (ROC area under the curve = 0.966). DISCUSSION: MRE-based scores for histologic fibrosis and inflammation may assist in the characterization of CD stenosis and enable development of fibrosis-targeted therapies and clinical treatment of stenotic patients.

Rates of Postoperative Recurrence of Crohn's Disease and Effects of Immunosuppressive and Biologic Therapies.

BACKGROUND & AIMS: The Rutgeerts' scoring system is used to evaluate patients with Crohn's disease (CD) following ileocolic resection, based on endoscopic findings at the anastomosis and in the neoterminal ileum. We investigated rates of clinical and surgical recurrence of CD after surgery and effect of therapy modification based on post-operative endoscopic findings. METHODS: We collected data from 365 adults with CD (20% with Rutgeerts' score i0, 10% with score i1, 49% with score i2, 12% with score i3, 9% with score i4) who underwent ileocolonoscopy within 12 months of ileocolic resection with anastomosis from 2000 through 2013 at 2 centers in Belgium and France. Patients were followed for 3 y or more after the ileocolonoscopy. Clinical post-operative recurrence (POR) was defined as occurrence of CD symptoms along with biologic, radiologic, and/or endoscopic features of disease activity; modified surgical POR was defined as either an endoscopic or surgical intervention. RESULTS: After a median follow-up time of 88 months, 48% of patients had clinical POR and 26% had modified surgical POR. Rates of survival without clinical POR or a modified surgical POR were lower in patients with Rutgeerts' scores of i2, i3, or i4 compared to patients with scores of i0 or i1 (P < .001 and P = .02). New immunosuppressant or biological therapy was initiated following endoscopy in 129/254 patients (51%) with Rutgeerts' score of i2, i3, or i4 vs 7/111 patients (6%) with scores of i0 or i1 (odds ratio for new therapy, 14.9; 95% CI, 7.1-36.8; P < .001). A modest decrease in risk of clinical POR was observed for patients with Rutgeerts scores of i3 or i4 after initiation of immunosuppressive or biological therapy based on endoscopic findings (Breslow P = .03), but this was not observed for patients with scores of i2 (Breslow P = .46). CONCLUSIONS: Use of immunosuppressants and tumor necrosis factor antagonists to treat patients with an asymptomatic endoscopic post-operative recurrence of CD did not reduce long-term risk of clinical recurrence in patients with Rutgeerts' scores of i2, but it had a small effect in patients with scores of i3 or i4.

Worries and concerns of inflammatory bowel disease (IBD) patients in Belgium - a validation of the Dutch rating form.

OBJECTIVES: Worry is the most common psychological complaint among patients with Inflammatory Bowel Disease (IBD). This study aimed to translate and test the psychometric properties the Rating Form of IBD Patient Concerns (RFIPC) among Dutch-speaking patients with IBD in Belgium. It also aimed to describe worries and concerns, and to examine possible differences in worry patterns between patients with different disease types and disease activities. METHODS: The RFIPC was translated into Dutch following the guidelines of the Rome Foundation and was completed by patients with Crohn's disease (CD, n = 336) and ulcerative colitis (UC, n = 160). To test concurrent validity, the Depression Anxiety Stress Scales (DASS-21) were used. Factor structure was examined with confirmatory factor analysis. RESULTS: The four-factor structure including subscales 'impact of the disease', 'sexual intimacy', 'complications of the disease' and 'body stigma' was confirmed in the Dutch sample. All factors had high internal consistency (>.70). Correlations with DASS-21 suggest good concurrent validity, all rs>.30, ps<.001. No differences in the RFIPC scores were observed between patients with CD and UC. Patients with active disease (53%) had higher scores than patients in remission (47%). Across all groups, the order of top concerns was consistent and included worries about energy level, side effects of medication, having an ostomy bag/surgery, and uncertain nature of the disease. CONCLUSIONS: The Dutch version of the RFIPC is a valid and reliable measure of IBD-specific worries and concerns which can be used in both research and clinical settings.

Biological Therapy in Inflammatory Bowel Disease Patients Partly Restores Intestinal Innate Lymphoid Cell Subtype Equilibrium.

Patients with Crohn disease (CD) and ulcerative colitis (UC) suffer from chronic relapsing intestinal inflammation. While many studies focused on adaptive immunity, less is known about the role of innate immune cells in these diseases. Innate lymphoid cells (ILCs) are recently identified cells with a high cytokine-producing capacity at mucosal barriers. The aim was to study the impact of biological treatment on ILC in CD and UC. Patients initiating anti-tumor necrosis factor (TNF), ustekinumab, or vedolizumab treatment were prospectively followed up and peripheral and intestinal ILCs were determined. In the inflamed gut tissue of patients with inflammatory bowel disease, we found an increase of ILC1 and in immature NKp44- ILC3, whereas there was a decrease of mature NKp44+ ILC3 when compared to healthy controls (HCs). Similar but less pronounced changes in ILC1 were observed in blood, whereas circulating NKp44- ILC3 were decreased. Fifteen percent of CD patients had NKp44+ ILC3 in blood and these cells were not detected in blood of HCs or UC patients. Therapy with three different biologicals (ustekinumab targeting the IL-12/23 cytokines, anti-TNF and vedolizumab) partly restored intestinal ILC subset equilibrium with a decrease of ILC1 (except for ustekinumab) and an increase of NKp44+ ILC3. Anti-TNF also mobilized more NKp44+ ILC3 in circulation. As ILC1 are proinflammatory cells and as NKp44+ ILC3 contribute to homeostasis of intestinal mucosa, the observed effects of biologicals on ILCs might contribute to their clinical efficacy.

Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients With Crohn's Disease.

BACKGROUND & AIMS: We evaluated the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, in a randomized trial of patients with Crohn's disease (CD). METHODS: We performed a double-blind, phase 2 trial in adults with moderate to severe CD and inadequate response or intolerance to immunosuppressants or tumor necrosis factor antagonists. Patients were randomly assigned (1:1:1:1:1:1) to groups given placebo; or 3 mg, 6 mg, 12 mg, or 24 mg upadacitinib twice daily; or 24 mg upadacitinib once daily and were evaluated by ileocolonoscopy at weeks 12 or 16 of the induction period. Patients who completed week 16 were re-randomized to a 36-week period of maintenance therapy with upadacitinib. The primary endpoints were clinical remission at week 16 and endoscopic remission at week 12 or 16 using the multiple comparison procedure and modeling and the Cochran-Mantel-Haenszel test, with a 2-sided level of 10%. RESULTS: Among the 220 patients in the study, clinical remission was achieved by 13% of patients receiving 3 mg upadacitinib, 27% of patients receiving 6 mg upadacitinib (P < .1 vs placebo), 11% of patients receiving 12 mg upadacitinib, and 22% of patients receiving 24 mg upadacitinib twice daily, and by 14% of patients receiving 24 mg upadacitinib once daily, vs 11% of patients receiving placebo. Endoscopic remission was achieved by 10% (P < .1 vs placebo), 8%, 8% (P < .1 vs placebo), 22% (P < .01 vs placebo), and 14% (P < .05 vs placebo) of patients receiving upadacitinib, respectively, vs none of the patients receiving placebo. Endoscopic but not clinical remission increased with dose during the induction period. Efficacy was maintained for most endpoints through week 52. During the induction period, patients in the upadacitinib groups had higher incidences of infections and serious infections vs placebo. Patients in the twice-daily 12 mg and 24 mg upadacitinib groups had significant increases in total, high-density lipoprotein, and low-density lipoprotein cholesterol levels compared with patients in the placebo group. CONCLUSIONS: In a phase 2 trial of patients with CD, upadacitinib induced endoscopic remission in a significant proportion of patients compared with placebo. Upadacitinib's benefit/risk profile supports further development for treatment of CD. (Clinicaltrials.gov, Number: NCT02365649).

Influence of Drug Exposure on Vedolizumab-Induced Endoscopic Remission in Anti-Tumour Necrosis Factor [TNF] Naïve and Anti-TNF Exposed IBD Patients.

BACKGROUND AND OBJECTIVES: Vedolizumab has demonstrated efficacy and safety in patients with Crohn's disease [CD] and ulcerative colitis [UC]. Endoscopic outcome data are limited, especially in anti-tumour necrosis factor [TNF] naïve patients. The present study compared endoscopic outcome in anti-TNF naïve and exposed patients, and explored if this was affected by drug exposure. METHODS: We retrospectively analysed all patients initiating vedolizumab at our tertiary referral centre since 2015. For UC, endoscopic improvement was defined as a Mayo endoscopic subscore ≤1 at week 14. For CD, endoscopic remission was defined as absence of ulcerations at week 22. Vedolizumab trough concentrations were measured at week 6, week 14 and during maintenance. RESULTS: A total of 336 patients were identified [53.3% CD], 20% of them being anti-TNF naïve. Endoscopic improvement was achieved by 56.1% of UC patients and endoscopic remission by 39.1% of CD patients. Endoscopic outcomes were significantly better in anti-TNF naïve vs exposed patients [all: 67.2% vs 42.0%, p = 0.0002; UC: 74.4% vs 50.0%, p = 0.02; CD: 57.1% vs 35.8%, p = 0.03]. Achievement of endoscopic end points significantly impacted long-term treatment continuation [p = 9.7 × 10-13]. A better endoscopic outcome was associated with significantly higher drug exposure in both CD and UC. CONCLUSIONS: The results of this observational, single-centre real-life study suggest that vedolizumab may induce endoscopic remission in both CD and UC. Although anti-TNF naïve patients had a significantly better outcome, 42% of anti-TNF exposed patients still benefited endoscopically. A clear exposure-endoscopic response relationship exists, but not all patients will benefit from treatment intensification. Hence, predictive biomarkers remain necessary. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

Expression Levels of 4 Genes in Colon Tissue Might Be Used to Predict Which Patients Will Enter Endoscopic Remission After Vedolizumab Therapy for Inflammatory Bowel Diseases.

BACKGROUND & AIMS: We aimed to identify biomarkers that might be used to predict responses of patients with inflammatory bowel diseases (IBD) to vedolizumab therapy. METHODS: We obtained biopsies from inflamed colon of patients with IBD who began treatment with vedolizumab (n = 31) or tumor necrosis factor (TNF) antagonists (n = 20) and performed RNA-sequencing analyses. We compared gene expression patterns between patients who did and did not enter endoscopic remission (absence of ulcerations at month 6 for patients with Crohn's disease or Mayo endoscopic subscore ≤1 at week 14 for patients with ulcerative colitis) and performed pathway analysis and cell deconvolution for training (n = 20) and validation (n = 11) datasets. Colon biopsies were also analyzed by immunohistochemistry. We validated a baseline gene expression pattern associated with endoscopic remission after vedolizumab therapy using 3 independent datasets (n = 66). RESULTS: We identified significant differences in expression levels of 44 genes between patients who entered remission after vedolizumab and those who did not; we found significant increases in leukocyte migration in colon tissues from patients who did not enter remission (P < .006). Deconvolution methods identified a significant enrichment of monocytes (P = .005), M1-macrophages (P = .05), and CD4+ T cells (P = .008) in colon tissues from patients who did not enter remission, whereas colon tissues from patients in remission had higher numbers of naïve B cells before treatment (P = .05). Baseline expression levels of PIWIL1, MAATS1, RGS13, and DCHS2 identified patients who did vs did not enter remission with 80% accuracy in the training set and 100% accuracy in validation dataset 1. We validated these findings in the 3 independent datasets by microarray, RNA sequencing and quantitative PCR analysis (P = .003). Expression levels of these 4 genes did not associate with response to anti-TNF agents. We confirmed the presence of proteins encoded by mRNAs using immunohistochemistry. CONCLUSIONS: We identified 4 genes whose baseline expression levels in colon tissues of patients with IBD associate with endoscopic remission after vedolizumab, but not anti-TNF, treatment. We validated this signature in 4 independent datasets and also at the protein level. Studies of these genes might provide insights into the mechanisms of action of vedolizumab.

Evaluating Efficacy, Safety, and Pharmacokinetics After Switching From Infliximab Originator to Biosimilar CT-P13: Experience From a Large Tertiary Referral Center.

BACKGROUND: The use of infliximab biosimilar CT-P13 has increased in patients with inflammatory bowel disease. Nevertheless, doubts about switching from infliximab originator to biosimilar still exist among patients and health care professionals. METHODS: Our tertiary referral center underwent a mandatory switch from infliximab originator to CT-P13 in 2017. We investigated pharmacokinetics, efficacy, and safety of this switch. The primary endpoint was infliximab discontinuation within 6 months of switching. Secondary endpoints included loss of clinical remission, need for treatment optimization, adverse events, evolution of patient-reported outcome, C-reactive protein, infliximab trough levels, and antidrug-antibodies. RESULTS: A total of 361 patients (54.0% male, 70.0% Crohn's disease, 55.6% in clinical remission) were enrolled. Infliximab discontinuation within 6 months was observed in 4%. Loss of clinical remission, adverse events, and antidrug-antibodies were identified in only 2.0%, 2.2%, and 1.1% of patients, respectively. C-reactive protein concentrations and infliximab trough levels remained stable. Independent factors associated with remission at 6 months were lower PRO2 at switch (HR 6.024; 95% CI, 4.878-8.000; P < 0.0001) and higher hemoglobin levels (HR 1.383; 95% CI, 1.044-2.299; P = 0.018). CONCLUSIONS: Switching from infliximab originator to CT-P13 was not associated with an increased risk of treatment discontinuation, loss of clinical remission, or adverse events. No significant changes in infliximab trough levels or immunogenicity could be identified.

Ustekinumab Pharmacokinetics and Exposure Response in a Phase 3 Randomized Trial of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: The efficacy of antibody-based therapeutics depends on their pharmacokinetics. The pharmacokinetic and exposure response profiles of ustekinumab, a monoclonal antibody against interleukin 12/interleukin 23, are known in patients with Crohn's disease, yet there are few data from patients with ulcerative colitis. We characterized ustekinumab's pharmacokinetics, exposure response, and optimal serum concentrations in patients with ulcerative colitis. METHODS: We collected data from 2 phase 3 trials (1 induction and 1 maintenance), in which patients with moderate to severe ulcerative colitis received an intravenous induction dose of ustekinumab (130 mg, n = 320; or approximately 6 mg/kg, n = 322). Responders were assigned randomly to groups that received subcutaneous maintenance ustekinumab (90 mg) every 8 weeks (n = 176) or 12 weeks (n = 172), or placebo (n = 175). We evaluated the association between ustekinumab concentration and efficacy, serum based on clinical effects (Mayo score), histologic features, and inflammation (measurement of C-reactive protein, fecal calprotectin, and fecal lactoferrin), as well as safety (infections, serious infections, and serious adverse events), during induction and maintenance therapy. Optimal serum concentrations of ustekinumab were identified using receiver operating characteristic curve analyses. RESULTS: In patients with ulcerative colitis, dose-proportional serum concentrations of ustekinumab, unaffected by prior biologic or concomitant immunomodulator therapy, reached steady state by the second maintenance dose; the median trough concentration for dosing every 8 weeks was approximately 3-fold that of dosing every 12 weeks. Serum concentrations were associated with clinical and histologic features of efficacy and normalization of inflammation markers. The week-8 concentration threshold for induction of response was 3.7 µg/mL. A steady-state trough serum concentration of 1.3 µg/mL or higher was associated with a higher rate of clinical remission compared with patients who had lower serum concentrations. Serum concentrations of ustekinumab were not associated with infections, serious infections, or serious adverse events. CONCLUSIONS: In an analysis of data from 2 phase 3 trials of patients with ulcerative colitis, we found that serum concentrations of ustekinumab were proportional to dose, unaffected by prior biologic or concomitant immunomodulator therapies, associated with clinical and histologic efficacy and markers of inflammation, and were not associated with safety events at doses evaluated. Ustekinumab pharmacokinetics are consistent between patients with Crohn's disease vs ulcerative colitis.

The Ulcerative Colitis Response Index for Detection of Mucosal Healing in Patients Treated With Anti-tumour Necrosis Factor.

BACKGROUND: Surrogate markers that accurately detect mucosal healing [MH] in patients with ulcerative colitis [UC] are urgently needed. Several stool neutrophil-related proteins are currently used as biomarkers for MH. However, the sensitivity and specificity are not sufficient to avoid unnecessary endoscopic evaluations. METHODS: Novel serum neutrophil-related markers (neutrophil gelatinase B-associated lipocalin and matrix metalloproteinase-9 [NGAL-MMP-9 complex], cathelicidin LL-37 and chitinase 3-like 1 [CHI3L1]), together with C-reactive protein [CRP] and neutrophil counts were studied. Serum samples were obtained from 176 anti-tumour necrosis factor [anti-TNF]-treated UC patients (145 infliximab [IFX] and 31 adalimumab [ADM]) at baseline and after a median of 9.5 weeks. All patients had active disease prior to treatment (Mayo endoscopic subscore [MES] ≥ 2), and MH was defined as MES ≤ 1. Serum was also obtained from 75 healthy controls. Binary logistic regression analysis was used to generate the Ulcerative Colitis Response Index [UCRI]. The performance of individual markers and UCRI was tested with receiver operating characteristic analysis. RESULTS: All neutrophil-related markers were significantly higher in active UC patients compared to healthy controls. In the IFX cohort, CRP, NGAL-MMP-9, CHI3L1 and neutrophil count decreased significantly after treatment and all marker levels were significantly lower in healers compared to non-healers following IFX. In the ADM cohort, CRP, NGAL-MMP-9, CHI3L1 and neutrophil count decreased significantly only in healers. UCRI [including CRP, CHI3L1, neutrophil count and LL-37] accurately detected MH in both IFX-treated (area under the curve [AUC] = 0.83) and ADM-treated [AUC = 0.79] patients. CONCLUSIONS: The new UCRI index accurately detects MH after treatment with IFX and ADM. This panel is useful for monitoring MH in UC patients under anti-TNF treatment. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

Outcome of biological therapies in chronic antibiotic-refractory pouchitis: A retrospective single-centre experience.

Background: In limited retrospective series, infliximab, adalimumab and vedolizumab have demonstrated efficacy in chronic antibiotic-refractory pouchitis. Here, we report single-centre data of all biological therapies in refractory pouchitis. Methods: We retrospectively assessed all records from patients with ulcerative colitis and ileal pouch -anal anastomosis who received infliximab, adalimumab or vedolizumab for pouchitis. Clinically relevant remission, defined as a modified Pouchitis Disease Activity Index <5 and a reduction of modified Pouchitis Disease Activity Index ≥2 points from baseline, was assessed at week 14. Results: Thirty-three unique patients were identified. Prior to colectomy, patients had been exposed to cyclosporine (n = 14), infliximab (n = 12), adalimumab (n = 3), and/or vedolizumab (n = 3). All developed chronic antibiotic-refractory pouchitis, for which they received infliximab (n = 23), adalimumab (n = 13) or vedolizumab (n = 15). Clinically relevant remission was observed in 43.5% of patients in the infliximab group, and in 38.5% and 60.0% in the adalimumab and vedolizumab group, respectively. In the long-term, significantly more patients continued vedolizumab compared to anti-tumour necrosis factor (anti-TNF) therapy (hazard ratio 3.0, p = 0.04). Adverse events (mainly infusion reactions) explained 40.7% of the patients discontinuing anti-TNF therapy, whereas discontinuation of vedolizumab was only related to insufficient efficacy. Four patients eventually required a permanent ileostomy. Conclusion: In this case series of chronic antibiotic-refractory pouchitis, biological therapy was effective in the majority of patients and only a minority eventually required a permanent ileostomy. The use of anti-TNF agents was hampered by a high rate of adverse events, partly related to immunogenicity as some patients had been exposed to anti-TNF prior to colectomy. Vedolizumab was also efficacious and may provide a safe alternative in these chronic antibiotic-refractory pouchitis patients.

Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown. METHODS: We evaluated ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight-range-based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components). RESULTS: The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P<0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P<0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo. CONCLUSIONS: Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.).

Fibrogenesis in Chronic DSS Colitis is Not Influenced by Neutralisation of Regulatory T Cells, of Major T Helper Cytokines or Absence of IL-13.

Mechanisms underlying fibrogenesis in chronic colitis are largely unknown. There is an urgent need for clinical markers and identification of targets to prevent, treat and limit intestinal fibrosis. This study investigated the contribution of major T cell cytokines and T regulatory cells (Tregs) to inflammation and fibrosis induced in a model of experimental colitis by oral intake of dextran sodium sulphate (DSS) in wild type and IL-13 knock-out C57Bl/6 mice. Inflammation and fibrosis were scored by macroscopic and histological examination and fibrosis was quantified by hydroxyproline. Numbers of Tregs and IFN-γ+, IL-13+ and IL-17A+ CD4+ T helper (Th) cells in mesenteric lymph nodes increased during chronic DSS administration and mRNA for IFN-γ and IL-17 in the inflamed colon tissue was upregulated. However, antibody-mediated neutralisation of IFN-γ or IL-17A/F in a therapeutic setting had no effect on chronic intestinal inflammation and fibrosis. Antibody-mediated depletion of Tregs did not enhance fibrosis, nor did IL-13 deficiency have an effect on the fibrotic disease. These data argue against an important contribution of Tregs and of the cytokines IFN-γ, IL-13, IL-17A, IL-17F in the induction and/or control of fibrosis in this Crohn's disease like murine model.

Short Health Scale: a valid and reliable measure of quality of life in Dutch speaking patients with inflammatory bowel disease.

Objectives: Patient reported outcomes are widely used in today's clinical practice. The Short Health Scale has been proven to be an easy-to-use and reliable measure to evaluate quality of life in patients with inflammatory bowel disease. We aimed to validate this Short Health Scale in Dutch speaking patients. Methods: A total of 157 Crohn's disease and ulcerative colitis patients (46% male, median age 39 years) completed the Short Health Scale on a tablet during the outpatient clinic. Validity was assessed by correlating both individual and total Short Health Scale scores with short Inflammatory Bowel Disease Questionnaire dimensions and clinical disease activity. Test-retest reliability was assessed in eight patients in stable remission who completed the Short Health Scale a second time after 4-8 weeks. Results: All Short Health Scale items correlated with corresponding short Inflammatory Bowel Disease Questionnaire dimensions (correlation coefficients ranging from -0.403 to -0.833, all p < .01). Short Health Scale scores increased stepwise with increasing clinical disease activity (all p < .001). The results of the Short Health Scale questionnaire remained stable on repeated measurements in patients in remission (rs between 0.699 and 0.994, all p < .01 except for well-being). Conclusions: The Short health Scale is a rapid and valid instrument for measuring quality of life in Dutch speaking patients with Inflammatory Bowel Disease. Its simplicity and usability make it a good candidate for routine care and suitable for home-monitoring of patients.

Subcutaneous Absorption Contributes to Observed Interindividual Variability in Adalimumab Serum Concentrations in Crohn's Disease: A Prospective Multicentre Study.

BACKGROUND AND AIM: Therapeutic drug monitoring is used to optimise adalimumab therapy in patients with Crohn's disease [CD]. However, the interindividual variability in drug absorption and the quantitative effect on drug clearance of anti-adalimumab antibodies [AAA], measured with a drug-resistant assay, are unclear. We aimed to characterise adalimumab population pharmacokinetics [PopPK] and identify determinants of interindividual variability in patients with CD. METHODS: In a prospective multicentre open-label cohort study in 28 patients with CD starting adalimumab therapy peak, intermediate, and trough serum samples were analysed for adalimumab and AAA concentrations using a drug resistant assay. Adalimumab concentration-time data were analysed by non-linear mixed effects modelling and were adequately described by a PopPK model with first-order absorption and one-compartment disposition with linear elimination. Clinical remission at Week 12 [W12] was defined as a Harvey-Bradshaw index ≤4. RESULTS: The absorption rate, volume of distribution, and clearance estimates of a typical patient were respectively 0.343 /day, 7.8 L, and 0.330 L/day. A 4-fold difference in the range of adalimumab concentrations was observed 7 days after the first dose and found to be inversely correlated with baseline lean body weight [LBW], soluble tumour necrosis factor [s-TNF], and s-TNF receptor-1 whereas positive AAA and higher LBW were found to be important predictors of accelerated clearance. An adalimumab concentration at W12 of >7.3 µg/mL was significantly associated with achieving clinical remission at W12. CONCLUSION: Variability in subcutaneous drug absorption is an important contributor to the observed interindividual variability in adalimumab concentrations, in addition to drug clearance [ClinicalTrials.gov NCT02450513].

Ustekinumab Exposure-outcome Analysis in Crohn's Disease Only in Part Explains Limited Endoscopic Remission Rates.

BACKGROUND AND AIMS: Ustekinumab, an anti-IL12/23p40 monoclonal antibody, has been approved for Crohn's disease [CD]. Real-life data in CD patients receiving ustekinumab intravenously [IV] during induction, followed by subcutaneous [SC] maintenance, are lacking. We assessed efficacy of ustekinumab and studied exposure-response correlations. METHODS: We performed a prospective study in 86 CD patients predominantly refractory or intolerant to anti-tumour necrosis factor agents and/or vedolizumab. All received ustekinumab 6 mg/kg IV induction, with 90 mg SC every 8 weeks thereafter. Endoscopic response (50% decrease in Simple Endoscopic Score for CD [SES-CD] at Week 24), endoscopic remission [SES-CD ≤2], and clinical remission [daily stool frequency ≤2.8 and abdominal pain score ≤1] were assessed at weeks 4,8,16, and 24. Further serial analyses included patient-reported outcomes [PRO2], faecal calprotectin [fCal], and ustekinumab serum levels. RESULTS: SES-CD decreased from 11.5 [8.0-18.0] at baseline to 9.0 [6.0-16.0] at week [w]24 [p = 0.0009], but proportions of patients achieving endoscopic response [20.5%] or endoscopic remission [7.1%] were low. Clinical remission rates were 39.5% at w24. After IV induction, fCal dropped from baseline [1242.9 µg/g] to w4 [529.0 µg/g] and w8 [372.2 µg/g], but increased again by w16 [537.4 µg/g] and w24 [749.0 µg/g]. A clear exposure-response relationship was observed, both during induction and during maintenance therapy, with different thresholds depending on the targeted outcome. CONCLUSIONS: In this cohort of refractory CD patients, ustekinumab showed good clinical remission rates but limited endoscopic remission after 24 weeks. Our data suggest that higher doses may be required to achieve better endoscopic outcomes.

Impact of endoscopy system, high definition, and virtual chromoendoscopy in daily routine colonoscopy: a randomized trial.

BACKGROUND: To improve detection of mucosal lesions during colonoscopy a number of imaging modalities have been suggested, including high definition and virtual chromoendoscopy. Given the theoretical advantage of these new imaging techniques, we aimed to investigate their use for the detection of polyps in patients referred for colonoscopy in a large tertiary hospital. METHODS: Demographic, endoscopic, and histological data from 1855 consecutive patients undergoing colonoscopy were collected prospectively. Patients were randomly assigned to three endoscopy systems (Fujinon, Olympus, or Pentax) in combination with four modalities: conventional white-light colonoscopy (n = 505), high definition white-light colonoscopy (n = 582), virtual chromoendoscopy (n = 285) and high definition virtual chromoendoscopy (n = 483). RESULTS: The mean adenoma detection rate (ADR) was 34.9 %, and the adenoma per colonoscopy rate (APCR) was 2.1. No significant differences were noted between the three endoscopy systems. Moreover, no differences in ADR or APCR were observed between the four imaging modalities. High definition white-light colonoscopy resulted in a significantly higher detection of sessile serrated adenomas (8.2 % vs. 3.8 %; P < 0.01) and adenocarcinomas (2.6 % vs. 0.5 %; P < 0.05) compared with the conventional procedure. CONCLUSIONS: No significant differences in ADR or APCR between different endoscopy systems, high definition, and/or virtual chromoendoscopy could be observed in routine colonoscopies in the general population. High definition endoscopy was associated with a significantly higher detection rate of serrated adenomas and adenocarcinomas.

Efficacy, Pharmacokinetics, and Immunogenicity is Not Affected by Switching From Infliximab Originator to a Biosimilar in Pediatric Patients With Inflammatory Bowel Disease.

BACKGROUND: Rising evidence demonstrates that there are no differences in efficacy and safety between infliximab (IFX) originator and IFX biosimilar CT-P13 in the treatment of inflammatory bowel diseases (IBDs). However, most data are derived from adult patients, and data on pharmacokinetics are limited. The authors evaluated long-term IFX trough levels, immunogenicity, and remission rates in children with IBD who switched from IFX originator to biosimilar CT-P13. METHODS: In this single-center study, all children with Crohn disease and ulcerative colitis receiving maintenance IFX therapy were switched from originator to biosimilar CT-P13. Demographics, disease activity indices, and IFX drug levels were collected from 6 months before (baseline) till 6 months after switching to CT-P13. All data are presented as median (interquartile range). RESULTS: A total of 42 children (26 Crohn disease and 16 ulcerative colitis), with a median duration on IFX originator of 13.5 (6.8-35.5) months before switching to CT-P13, were included. No significant changes in IFX trough levels occurred after switching. The median baseline IFX trough level was 5.7 mcg/mL (3.8-9.3) versus 6.5 mcg/mL (3.9-8.6) at month 6 after switching (P = 0.900). Antibodies to IFX appeared in one patient after switching. The proportion of patients in clinical and/or biological remission did not significantly change after switching (all P > 0.05). No significant changes were observed in C-reactive protein, erythrocyte sedimentation rate, albumin, weight, and body mass index after the switch. Safety profile was also comparable. CONCLUSIONS: Pediatric patients with IBD on IFX originator can be successfully switched during maintenance to biosimilar CT-P13 without affecting efficacy, pharmacokinetics, immunogenicity, or safety.

Adequate Infliximab Exposure During Induction Predicts Remission in Paediatric Patients With Inflammatory Bowel Disease.

OBJECTIVES: Therapeutic drug monitoring has been proposed as a useful tool in the management of infliximab (IFX) treated patients with inflammatory bowel disease. The aim of this retrospective study was to determine whether IFX trough levels after induction therapy are predictive for outcome at week 52. METHODS: All pediatric patients with inflammatory bowel disease receiving maintenance IFX at our centre, with IFX trough level available at their first maintenance infusion and a follow-up of at least 52 weeks were included. IFX induction regimens could be intensified at the discretion of the treating physician. All children received proactive drug monitoring during maintenance with dose adaptation aiming to target a therapeutic window of 3 to 7 µg/mL. RESULTS: We included 35 children (23 with Crohn disease and 12 with ulcerative colitis). Median IFX trough levels just before the first maintenance infusion were significantly higher in children achieving clinical (4.6 µg/mL [2.7-11.8] vs 1.5 µg/mL [0.9-3.0]), biological (4.6 µg/mL [2.5-10.3] vs 2.6 µg/mL [0.3-3.2]) and combined clinical/biological remission (6.0 µg/mL [3.2-12.0] vs 2.6 µg/mL [1.1-3.2]) at week 52 compared to children not meeting these criteria (all P ≤ 0.002). Binary logistic regression identified these trough levels as the only predictor for the same outcomes with an odds ratio (95% confidence interval) of 2.083 (1.085-3.998), 2.203 (1.101-4.408), and 2.264 (1.096-4.680), respectively (all P < 0.05). CONCLUSIONS: Adequate IFX exposure during induction therapy is associated with better clinical and/or biological remission at week 52. Postinduction IFX trough levels were the only predictor for clinical and/or biological remission at week 52.

Optimising infliximab induction dosing for patients with ulcerative colitis.

AIMS: The therapeutic failure of infliximab therapy in patients with ulcerative colitis remains a challenge even 2 decades after its approval. Therapeutic drug monitoring (TDM) has shown value during maintenance therapy, but induction therapy has still not been explored. Patients may be primary nonresponders or underexposed with the standard dosing regimen. We aimed to: (i) develop a population pharmacokinetic-pharmacodynamic model; (ii) identify the best exposure metric that predicts mucosal healing; and (iii) build an exposure-response (ER) model to demonstrate model-based dose finding during induction therapy with infliximab. METHODS: Data were retrospectively collected from a clinical database. A total of 583 samples, from 204 patients, was used to develop a population pharmacokinetic model to generate exposure metrics for subsequent ER modelling. A subset of 159 patients was used to develop a logistic regression ER model, describing the relationship between infliximab exposure and ordered transitions between Mayo endoscopic subscore (MES) 3, 2 and ≤1 (baseline to post-induction). RESULTS: A 1-compartment population pharmacokinetic model with interindividual and interoccasion variability was found to fit the data best. Covariates influencing exposure were C-reactive protein, albumin, baseline MES, fat-free mass, concomitant corticosteroid use and pancolitis. The cumulative area under the infliximab concentration-time curve until endoscopy (CAUCendoscopy ) was found to be the best exposure metric for predicting mucosal healing (baseline MES >1 and post-induction MES ≤1). The model predicted that 70% of patients will attain mucosal healing with infliximab administered at days 0, 14 and 42 and a target CAUCendoscopy of 3752 mg/L*day at day 84. CONCLUSIONS: TDM-based dose individualisation targeting CAUCendoscopy has the potential to improve the effectiveness of infliximab during induction therapy.