Prospective Observational Evaluation of the Time-Dependency of Adalimumab Immunogenicity and Drug Concentration in Ulcerative Colitis Patients: the POETIC II Study.

BACKGROUND AND AIMS: Home self-injection of the human anti-tumour necrosis alpha [anti-TNFα] monoclonal adalimumab complicates prospective serial-sampling studies. Although a recent study examined adalimumab levels and immunogenicity in Crohn's disease [CD] patients, prospective real-world data from ulcerative colitis [UC] patients are lacking. METHODS: A three-monthly home-visit programme from induction was established prospectively for UC patients. Clinical scores were determined at each visit, and sera were obtained for assessment of drug and anti-adalimumab antibody levels. Calprotectin was measured using a smartphone-based app. This cohort was compared to a parallel prospective cohort of adalimumab-treated CD patients [POETIC1]. RESULTS: Fifty UC patients starting adalimumab [median follow-up 28 weeks] were compared to 98 adalimumab-treated CD patients [median follow-up 44 weeks]. Only 11/50 UC patients [22%] continued treatment to the end of the follow-up compared with 50/98 [51%] CD patients (odds ratio [OR] = 0.27, p = 0.001). Loss of response was significantly more common in UC patients [OR = 3.2, p = 0.001]. Seventeen patients [34%] in the UC cohort developed anti-adalimumab antibodies, 9/17 [52.9%] as early as week 2. There was no difference between patient cohorts in the overall development of anti-adalimumab antibodies [34% vs 30.6%, respectively, OR = 1.67, p = 0.67], nor was there a difference in early immunogenicity [OR = 1.39, p = 0.35]. There was no difference in low drug levels [<3 µg/mL] between the two cohorts [OR = 0.87, p = 0.83]. CONCLUSIONS: Loss of response to adalimumab therapy was significantly more common in the UC compared to the CD cohort and was driven by a higher rate of non-immunogenic, pharmacodynamic parameters.

Outcome of inflammatory bowel disease patients with prior malignancy.

Background: Inflammatory bowel disease (IBD) treatment options, such as anti-tumor necrosis factor (TNF) agents and thiopurines, are associated with an increased risk of certain malignancies. However, the management of IBD patients with prior malignancy is not well defined and the literature is scarce. The main aim of this study was to describe the outcome of IBD patients with prior malignancy, or malignancy before first exposure to IBD-related biologic or immunosuppressive treatment. Methods: The study cohort included adult IBD patients followed in a tertiary academic center, with at least one malignancy diagnosed before IBD diagnosis or before initiation of IBD-related treatment. The main outcome of interest was a relapse of the previous malignancy or development of a second malignancy. Results: Our database included 1112 patients with both IBD and malignancy. Of these, 86 (9%) who had their malignancy diagnosed before IBD-related treatment initiation were identified, while 10/86 patients (9%) were further diagnosed with a second primary malignancy. Twenty patients, (20/86, 23%) had recurrence of a previous malignancy, most commonly non-melanoma skin cancer (NMSC), found in 9/20 patients (45%). Treatment with infliximab was found to be significantly associated with recurrence of NMSC (P=0.003). Conclusions: Anti-TNF treatment may be associated with an increased risk of NMSC recurrence. This underscores the importance of rigorous dermatological follow up in IBD patients with previous NMSC treated with anti-TNFs.

Do Vedolizumab trough Levels Predict the Outcome of Subsequent Therapy in Inflammatory Bowel Disease?

Background: Vedolizumab trough serum levels have been associated with clinical and endoscopic response in patients with inflammatory bowel disease (IBD). A recent study demonstrated that higher trough levels before dose escalation are associated with favorable outcomes. Objectives: We aimed to identify whether vedolizumab trough levels predict outcome of subsequent therapy. Methods: This retrospective study included IBD patients consecutively receiving vedolizumab therapy between November 2014 and June 2021. Only patients with a loss of response (LOR) to vedolizumab and available trough drug levels prior to therapy cessation were included. Clinical and endoscopic scores were recorded at 6 and 12 months post switching therapy. Results: Overall, 86 IBD patients (51 Crohn's disease, 35 ulcerative colitis) who discontinued vedolizumab were included; of those, 72 (83.7%) were due to LOR. Upon vedolizumab discontinuation, 66.3% of patients were switched to another biologic therapy. Trough vedolizumab levels at discontinuation due to LOR did not differ between patients with clinical response and LOR regarding subsequent therapy at 6 months [median 33.8 µg/mL (IQR 13.2-51.6) versus 31.7 µg/mL (IQR 9.1-64.8), p = 0.9] and at 12 months [median 29.6 µg/mL (IQR 14.3-51.6) versus 34.1 µg/mL (IQR 12.2-64.7), p = 0.6]. Patients progressing to subsequent surgery had numerically lower vedolizumab trough levels at LOR compared with patients who were treated with an additional medical therapy (median 14.3, IQR 4-28.2 µg/mL versus 33.5, IQR 13-51.6 µg/mL, p = 0.08). Conclusions: Vedolizumab trough levels upon LOR do not predict response to subsequent medical therapy; however, lower drug levels may suggest a more aggressive disease pattern and future need for surgery.

Distal Fecal Wash Host Transcriptomics Identifies Inflammation Throughout the Colon and Terminal Ileum.

BACKGROUND & AIMS: Noninvasive modalities for assessing active endoscopic and histologic inflammation in Crohn's disease and ulcerative colitis patients are critically needed. Fecal wash host shed-cell transcriptomics has been shown to be a robust classifier of endoscopic and histologic inflammation in inflammatory bowel disease patients with distal colitis. Whether such fecal washes can inform on inflammatory processes occurring in more proximal intestinal segments is currently unknown. METHODS: Fifty-nine inflammatory bowel disease patients and 50 controls were prospectively enrolled. Biopsy specimens and fecal washes from the distal colon, proximal colon, and terminal ileum were compared. Host transcriptomics were performed on the biopsy specimens and fecal washes obtained during colonoscopy at predefined locations throughout the colon and terminal ileum and results were associated with concurrent clinical, endoscopic, and histologic parameters. RESULTS: We found that host transcriptomics of distal fecal washes robustly classify histologic inflammation in ileal and proximal colonic Crohn's disease, even without distal colonic involvement (area under the receiver operating characteristic curve, 0.94 ± 0.09). We further found that fecal washes consist of modules of co-expressed genes of immune, stromal, and epithelial origin that are indicative of endoscopic disease severity. Fecal wash host transcriptomics also captures expression of gene modules previously associated with a lack of response to biological therapies. CONCLUSIONS: Our study establishes the accuracy of distal colonic fecal washes for identifying and scoring inflammatory processes throughout the entire ileal-colonic axis.

Ustekinumab and vedolizumab for extraintestinal manifestations in inflammatory bowel disease - a retrospective study.

INTRODUCTION: Extraintestinal manifestations (EIM) are associated with diminished quality of life. The efficacy of Ustekinumab and vedolizumab for EIM treatment is not well established. The aim was to compare the effectiveness of ustekinumab and vedolizumab for treatment of EIM in IBD. METHODS: We included IBD patients treated with vedolizumab or ustekinumab in the Gastroenterology department, Sheba Medical Center, for up to 52 weeks between 2015 and 2021. Patients with active EIM before treatment initiation were included. RESULTS: 111 patients were included. 53 patients (48%) were treated with ustekinumab; 88% (n-99) had CD. The most common EIM was arthralgia (95/111, 84%). Patients treated with ustekinumab were more likely to be anti-TNF experienced (n-51/53 [96%] compared with vedolizumab n = 36/58 [62%], p < 0.001). Clinical response of EIM at week 52 was achieved in 36% of patients treated with ustekinumab (n-18/50) and 34% of patients (n-19/54) treated with vedolizumab, with no statistically significant difference (p = 0.9). No statistical significance was achieved for patients presented with arthralgia. Clinical response of arthralgia at week 52 was seen in 34% (n-19/55) and 36% (n-18/46) of the patients treated with vedolizumab and ustekinumab, respectively, (p = 0.3). CONCLUSION: In this study, no difference was found between vedolizumab and ustekinumab regarding their effect on EIM in IBD patients for up to 52 weeks.

Patency Capsule: A Novel Independent Predictor for Long-Term Outcomes Among Patients With Quiescent Crohn's Disease.

INTRODUCTION: Patency capsule (PC) is a recommended procedure to rule out small bowel stenosis before video capsule endoscopy (VCE). We examined future clinical outcomes among patients with a failed PC vs patients in whom the PC had passed (passed PC). METHODS: A post hoc analysis of 2 prospective cohort studies of adult patients with quiescent small bowel Crohn's disease (CD) who underwent PC between 2013 and 2020. The primary composite outcome was the need for intestinal surgery or endoscopic dilation during follow-up in patients with or without a failed PC. RESULTS: A total of 190 patients were included (47: failed PC and 143: passed PC, median follow-up 34.12 months). Patients with a failed PC had higher rates of the primary composite outcome (21.3% vs 1.4%, hazard ratio [HR] 20.3, 95% confidence interval [CI] 4.4-93.7, P < 0.001) and also secondary outcomes including intestinal surgery (14.9% vs 0.70%, P < 0.001), endoscopic dilation (14.9% vs 0.70%, P < 0.001), admissions (23.3% vs 5.7%, P < 0.001), and clinical flares (43.9% vs 27.7%, P = 0.005) during follow-up compared with controls. Failed PC was the only statistically significant factor for surgery and/or endoscopic dilation, regardless of a B2/B3 phenotype at baseline. In sensitivity analyses restricted only to patients with a stricturing phenotype (n = 73), a failed PC still predicted the long-term composite outcome (HR 8.68, 95% CI 1.72-43.68, P = 0.002). Of the 190 patients ingesting a PC, only 1 patient with a failed PC had 48 hours of self-limiting mild symptoms. DISCUSSION: Patients with clinically stable CD with a failed PC have worse long-term clinical outcomes than those without, independently of the CD phenotype. Standalone PC may serve as a novel, safe, and affordable prognostic examination to identify patients with quiescent CD who have a higher risk for future worse clinical outcomes.

Computer-Aided Imaging Analysis of Probe-Based Confocal Laser Endomicroscopy With Molecular Labeling and Gene Expression Identifies Markers of Response to Biological Therapy in IBD Patients: The Endo-Omics Study.

BACKGROUND: We aimed to predict response to biologics in inflammatory bowel disease (IBD) using computerized image analysis of probe confocal laser endomicroscopy (pCLE) in vivo and assess the binding of fluorescent-labeled biologics ex vivo. Additionally, we investigated genes predictive of anti-tumor necrosis factor (TNF) response. METHODS: Twenty-nine patients (15 with Crohn's disease [CD], 14 with ulcerative colitis [UC]) underwent colonoscopy with pCLE before and 12 to 14 weeks after starting anti-TNF or anti-integrin α4ß7 therapy. Biopsies were taken for fluorescein isothiocyanate-labeled infliximab and vedolizumab staining and gene expression analysis. Computer-aided quantitative image analysis of pCLE was performed. Differentially expressed genes predictive of response were determined and validated in a public cohort. RESULTS: In vivo, vessel tortuosity, crypt morphology, and fluorescein leakage predicted response in UC (area under the receiver-operating characteristic curve [AUROC], 0.93; accuracy 85%, positive predictive value [PPV] 89%; negative predictive value [NPV] 75%) and CD (AUROC, 0.79; accuracy 80%; PPV 75%; NPV 83%) patients. Ex vivo, increased binding of labeled biologic at baseline predicted response in UC (UC) (AUROC, 83%; accuracy 77%; PPV 89%; NPV 50%) but not in Crohn's disease (AUROC 58%). A total of 325 differentially expressed genes distinguished responders from nonresponders, 86 of which fell within the most enriched pathways. A panel including ACTN1, CXCL6, LAMA4, EMILIN1, CRIP2, CXCL13, and MAPKAPK2 showed good prediction of anti-TNF response (AUROC >0.7). CONCLUSIONS: Higher mucosal binding of the drug target is associated with response to therapy in UC. In vivo, mucosal and microvascular changes detected by pCLE are associated with response to biologics in inflammatory bowel disease. Anti-TNF-responsive UC patients have a less inflamed and fibrotic state pretreatment. Chemotactic pathways involving CXCL6 or CXCL13 may be novel targets for therapy in nonresponders.

Host transcriptome signatures in human faecal-washes predict histological remission in patients with IBD.

BACKGROUND: Colonoscopy is the gold standard for evaluation of inflammation in inflammatory bowel diseases (IBDs), yet entails cumbersome preparations and risks of injury. Existing non-invasive prognostic tools are limited in their diagnostic power. Moreover, transcriptomics of colonic biopsies have been inconclusive in their association with clinical features. AIMS: To assess the utility of host transcriptomics of faecal wash samples of patients with IBD compared with controls. METHODS: In this prospective cohort study, we obtained biopsies and faecal-wash samples from patients with IBD and controls undergoing lower endoscopy. We performed RNAseq of biopsies and matching faecal-washes, and associated them with endoscopic and histological inflammation status. We also performed faecal mass-spectrometry proteomics on a subset of samples. We inferred cell compositions using computational deconvolution and used classification algorithms to identify informative genes. RESULTS: We analysed biopsies and faecal washes from 39 patients (20 IBD, 19 controls). Host faecal-transcriptome carried information that was distinct from biopsy RNAseq and faecal proteomics. Transcriptomics of faecal washes, yet not of biopsies, from patients with histological inflammation were significantly correlated to one another (p=5.3×10-12). Faecal-transcriptome had significantly higher statistical power in identifying histological inflammation compared with transctiptome of intestinal biopsies (150 genes with area under the curve >0.9 in faecal samples vs 10 genes in biopsy RNAseq). These results were replicated in a validation cohort of 22 patients (10 IBD, 12 controls). Faecal samples were enriched in inflammatory monocytes, regulatory T cells, natural killer-cells and innate lymphoid cells. CONCLUSIONS: Faecal wash host transcriptome is a statistically powerful biomarker reflecting histological inflammation. Furthermore, it opens the way to identifying important correlates and therapeutic targets that may be obscured using biopsy transcriptomics.

Risk of consecutive immunogenic failure in switchers of anti-tumor necrosis factor alpha among patients with inflammatory bowel diseases.

BACKGROUND: Evidence regarding the risk of immunogenicity in patients with inflammatory bowel disease (IBD) who switched anti-tumor necrosis factor alpha (anti-TNFα) therapies to a subsequent anti-TNFα (either infliximab or adalimumab) is conflicting. We aimed to assess the risk of consecutive immunogenicity to anti-TNFα in a large cohort of patients. METHODS: This was a multicenter retrospective study. Medical records of adult and pediatric IBD switchers who had pharmacokinetic data for both agents between 2014 and 2020 were retrieved. Data including age, sex, disease type, duration of therapies, and concomitant use of immunomodulators (IMMs) were recorded. RESULTS: Overall, 164 patients were included [52% female; 88% Crohn's disease; mean age = 24.4 ± 14.6 years; 108 (66%) switched from infliximab to adalimumab and 56 (34%) vice versa]; 120 (73.1%) patients switched due to an immunogenic failure. Among patients switching therapy from infliximab to adalimumab due to an immunogenic failure immunogenicity to infliximab was significantly associated with consecutive immunogenicity to adalimumab (p = 0.026). Forthy four out of 120 patients (36.6%) with an immunogenic failure to the first anti-TNFα started an IMM with the second anti-TNFα. This combination with IMM was not associated with reduction of consecutive immunogenicity (p = 0.31), but it was associated with longer drug retention (p = 0.007). Multivariate analysis demonstrated that older age at second anti-TNFα, adjusted to the chronology of therapy and sex, was associated with increased immunogenicity to the second anti-TNFα. CONCLUSION: Patients with IBD who switch from infliximab to adalimumab following an immunogenic failure are at increased risk for consecutive immunogenicity to adalimumab. IMM use after a switch prolongs drug retention.

Differential Serum-intestinal Dynamics of Infliximab and Adalimumab in Inflammatory Bowel Disease Patients.

BACKGROUND AND AIMS: Therapeutic drug monitoring is used to guide anti-tumour necrosis factor [TNF] therapy. However, the associations between serum drug levels [SDL], TNF-bound, and free anti-TNF in the target tissue are incompletely defined. We aimed to assess the interactions between these parameters in inflammatory bowel disease [IBD] patients. METHODS: ENZYME-LINKED IMMUNOSORBENT: assays [ELISA assays] were used to detect free drug and TNF-drug complexes in intestinal tissues. Concurrent SDL, anti-drug antibodies [ADA], pharmacotherapy, clinical response, endoscopic appearance, and histological severity were determined. Comparisons between anti-TNFs and paired inflamed/non-inflamed tissue were performed. Variables were correlated and potential interactions detected using multivariate analysis. RESULTS: A total of 95 biopsies taken from 49 anti-TNF treated IBD patients [26 receiving infliximab and 23 adalimumab] were studied. Free drug levels were higher in inflamed compared with non-inflamed paired specimens. Tissue free-drug and TNF-drug complexes levels were higher in adalimumab-treated patients. In adalimumab-treated patients, SDL were correlated with free drug, but not TNF-drug complex levels, in both inflamed and non-inflamed segments. In infliximab-treated patients, higher SDL were associated with the presence of tissue free drug in both inflamed and non-inflamed segments, whereas TNF-drug complexes were mostly detected in non-inflamed but not in inflamed tissue. In the presence of ADA, neither free drug nor TNF-infliximab complexes were measured in the tissue. Tissue levels did not correlate well with clinical, endoscopic, or histological scores. CONCLUSIONS: SDL correlated with tissue free drug levels; however, different dynamics were observed for TNF-drug complex levels. Infliximab and adalimumab tissue drug dynamics differ. Better understanding of these interactions may allow future therapeutic optimisation.

Incidentally Diagnosed Asymptomatic Crohn's Disease: A Retrospective Cohort Study of Long-Term Clinical Outcomes.

Background: Crohn's disease (CD) is occasionally diagnosed in asymptomatic patients who have undergone colonoscopy or imaging for other reasons. The clinical outcome and optimal management of these patients remain poorly defined. Methods: This was a retrospective cohort study of asymptomatic patients with incidental diagnosis of CD from the electronic patient registry of the IBD Unit of Sheba Medical Center in Israel. The primary outcome was defined as the occurrence of a clinical flare. Results: Of the 2700 CD patients in Sheba IBD registry, 60 asymptomatic patients with incidental diagnosis of CD were identified (31/60 males, median age 50.5, 25%-75% interquartile range [IQR] 43.5-57.25 years, median follow-up 4.5 years, 25-75% IQR 2.5-6.75, range 1-15 years). Most of the patients did not receive any treatment after diagnosis (53/60-88.33%). Of these, 5 patients (9.43%) experienced a flare during follow-up (median 4.5 years, IQR 2.5-6.75, range 1-15 years). Patients with subsequent flare had numerically higher CRP at diagnosis than patients who did not flare (2.2, IQR 2.0-3.0 vs 1.04, IQR 1.0-2.2, P = .09). When comparing the group of patients who received treatment immediately after diagnosis (n = 7) with the group who did not receive treatment (n = 53), there was no difference with respect to the survival time without a flare (P = .3). For other secondary outcomes, 3/40 progressed from B1 phenotype to B2, and 3/53 (6%) patients underwent surgery during the follow-up. Conclusions: The majority of patients with an incidental diagnosis of asymptomatic CD can probably be followed-up without immediate treatment. Although most remain asymptomatic and without complications during follow-up, close monitoring for disease progression is prudent.

Dose optimisation for Loss of Response to Vedolizumab- Pharmacokinetics and Immune Mechanisms.

BACKGROUND: Real life data regarding pharmacokinetics of vedolizumab in patients needing dose optimisation are scarce. We set to examine whether pre-optimisation vedolizumab levels associate with therapy outcomes and which mechanisms explain the associations. METHODS: A multicentre observational study assessed the outcome of dose increase in association with pre-escalation levels in vedolizumab-treated patients. SubsequentIy, α4ß7 occupancy on peripheral blood [PB] and intestinal lamina propria [LP] tissues was investigated on various cellular subsets in patients undergoing lower endoscopy on infusion day. Cellular localisation of vedolizumab-bound α4ß7 and effects on M1 and M2 macrophages were also explored. RESULTS: A total of 161 inflammatory bowel disease [IBD] patients were included. Among 129/161 patients intensified during maintenance [Week 14 onward], pre-intensification trough levels were comparable or higher among those subsequently attaining post-optimisation clinical, biomarker, and endoscopic remission, compared with non-remitting patients [p = 0.09, 0.25, 0.04, respectively]. Similar results were demonstrated for those dose-optimised during induction [Week 6, n = 32]. In the immune sub-study [n = 43], free α4ß7 receptors at trough were similarly low among patients with/without mucosal healing, on PB T cells [p = 0.15], LP T cells [p = 0.88], and on PB eosinophils [p = 0.08]. Integrin receptors on M1 and M2 macrophages were also saturated by low levels of vedolizumab and anti-inflammatory cytokine secretion was not increased. Co-localisation and dissociation experiments demonstrated membranal α4ß7 receptors of two origins: non-internalised and newly generated α4ß7, but re-binding was still complete at very low concentrations. CONCLUSIONS: These results do not support pharmacokinetics as the mechanism responsible for loss of response to vedolizumab, nor do they support a need for higher drug concentration to enhance vedolizumab's immune effects. Higher pre-escalation levels may indicate less clearance [less severe disease] and higher likelihood of subsequent re-gained response, regardless of therapy escalation.

Qualitative sonographic assessment of transmural ileal inflammation in Crohn's disease: a comparison with MRI activity score.

BACKGROUND: Intestinal ultrasound (IUS) is an accurate tool for monitoring Crohn's disease. To date, there is no clinically used validated quantitative ultrasonographic score for assessing disease activity. For magnetic resonance enterography (MRE), the magnetic resonance index of activity (MaRIA) is most used. The goal of this study was to devise a new quantitative IUS score for assessing Crohn's disease inflammation, by using a partial MaRIA score as a reference. METHODS: This was a retrospective cohort study. The study cohort included patients with Crohn's disease followed between January 2016 and December 2018. Inclusion criteria were age >18 and <3 months between MRE and IUS. Linear/logistic regression was performed for the correlation of ultrasonographic parameters with MaRIA score. Ultrasonograpic features included: bowel wall thickness, disrupted bowel wall stratification, mesenteric fat proliferation, presence of lymph nodes, hypervascularity present on color Doppler flow, and the presence of complications (strictures, inflammatory mass, and fistula). RESULTS: Forty-two patients were included. A stepwise multiple regression model was constructed to predict MaRIA score using ultrasound features. Two variables were found to be independently significant: terminal ileum (TI) thickness (r = 0.68, P = 0.001) and mesenteric fat proliferation (r = 0.45, P = 0.019). A model was constructed as follows: MaRIA = 7 + 2.5 * TI US thickness (mm) + 7 * US fat proliferation (0 = no, 1 = yes). This model has an R2 of 0.51 for explaining the variability in the results. CONCLUSIONS: IUS measurements are significantly correlated with MaRIA score in the terminal ileum and a simple computational model can be constructed.

Duration of combination therapy and risk of treatment failure in patients with inflammatory bowel disease.

BACKGROUND: Patients who receive infliximab (IFX) combined with a thiopurine, for inflammatory bowel disease, have a better clinical response and less frequent immunization towards IFX than those treated with IFX alone. The benefits of combination therapy must be weighed against the risks of infection and cancer. We studied the association between the duration of combination therapy and the risk of treatment failure by two year from initiation. METHODS: Participants had Crohn's disease or ulcerative colitis and were in clinical and biological remission, 6 months after initiation of combination therapy. The risk of subsequent treatment failure (i.e., undetectable trough IFX levels and/or clinical relapse followed by surgical treatment or switch of maintenance treatment) was estimated using Kaplan-Meier method and adjusted Hazard Ratios (aHRs), in patients whohadreceived 6 to 11 months vs. 12 months or more of combination therapy. We performed a similar analysis in which the follow-up was started at discontinuation of the immunosuppressant. RESULTS: Among 139 patients (48% women; median age 31.1), with a median follow-up of 18.9 months, we observed 26 treatment failures (including 15 patients with undetectable trough IFX levels). After adjustment for gender and type of immunomodulator, a shorter duration of combination therapy was not associated with a higher risk of treatment failure (aHR=0.42; 95% confidence interval (95%CI): 0.13-1.40; p=0.16). When the follow-up was started at discontinuation of the immunosuppressant, a combination therapy of 6-11 months was associated with a numerically lower risk of treatment failure as compared with a longer combination therapy (HR=0.12; 95%CI: 0.01-1.05; p=0.055). CONCLUSION: Our results do not show any benefit for continuation of combination therapy for more than 12 months after achieving clinical remission in IBD patients.

Infliximab clearance decreases in the second and third trimesters of pregnancy in inflammatory bowel disease.

BACKGROUND: Infliximab therapy during pregnancy in inflammatory bowel disease is challenged by a dilemma between maintaining adequate maternal disease control while minimizing fetal infliximab exposure. We investigated the effects of pregnancy on infliximab pharmacokinetics. METHODS: The study population comprised 23 retrospectively identified pregnancies. Patients with inflammatory bowel disease were generally in clinical remission at pregnancy conception (74%) and received steady infliximab maintenance therapy (5 mg/kg q8w n = 17; q6w n = 4; q10w n = 1; 10 mg/kg q8w n = 1). Trough blood samples had been obtained in the same patients prior to pregnancy (n = 119), the first trimester (n = 16), second trimester (n = 18), third trimester (n = 7), and postpregnancy (n = 12). Data were analyzed using nonlinear mixed-effects population pharmacokinetic modeling. RESULTS: Dose-normalized infliximab concentrations were significantly higher during the second trimester (median 15 mg/ml/kg, interquartile range 10-21) compared to prepregnancy (7, 2-12; p = 0.003), the first trimester (9, 1-12; p = 0.04), or postpregnancy (6, interquartile range 3-11; p > 0.05) in patients with inflammatory bowel disease. Similar trends were observed in the third trimester (13, 7-36; p > 0.05). A one-compartment model with linear elimination described the pharmacokinetics of infliximab (volume of distribution n = 18.2 L; clearance 0.61 L/day). Maternal infliximab exposure was influenced by the second and third trimester of pregnancy and anti-infliximab antibodies, and not by pregnancy-imposed physiological changes in, for example, body weight or albumin. Infliximab clearance decreased significantly during the second and third trimesters by up to 15% as compared to pre- and postpregnancy and the first trimester. The increased maternal infliximab exposure was weakly associated with lowered clinical disease activity. Pharmacokinetic model simulations of virtual patients indicated the increased maternal infliximab trough concentrations imposed by pregnancy will not completely counteract the decrease in infliximab concentration if therapy is paused in the third trimester. CONCLUSION: Infliximab clearance decreases significantly in the second and third trimesters, leading to increasing maternal infliximab concentrations in any given regimen. Maternal infliximab levels may thus be maintained as constant in a de-intensified regimen by therapeutic drug monitoring guidance in inflammatory bowel disease.

Terminal Ileum Thickness During Maintenance Therapy Is a Predictive Marker of the Outcome of Infliximab Therapy in Crohn Disease.

BACKGROUND: Mucosal healing has been associated with long-term response to therapy for Crohn disease (CD). However, little is known about the significance of terminal ileum (TI) transmural thickness in predicting clinical outcomes. METHODS: In this retrospective observational cohort study, we examined the association of an index ultrasonographic assessment of TI thickness during the maintenance phase and the subsequent clinical outcome of CD in a cohort of patients treated with infliximab (IFX). Treatment failure was defined as treatment discontinuation because of lack of efficacy, a need for dose escalation, or surgery. Clinical response was defined as treatment continuation in the absence of any of the aforementioned failure criteria. RESULTS: Sixty patients with CD receiving IFX therapy were included in the study. The patients were followed for a median of 16 months (5-24 months) after an index intestinal ultrasound. Thirty-eight patients (63.3%) maintained response to the therapy and 22 patients (36.6%) failed the treatment, with a mean follow up of 10.5 months (6.5-17 months) vs 9.25 months (1-10.25 months), respectively. On univariate analysis, the only variables differing between treatment response and failure were a TI thickness of 2.8 vs 5 mm (P < 0.0001) and an IFX trough level of 6.6 vs 3.9 µg/mL (P = 0.008).On multivariable analysis, only a small bowel thickness of ≥4 mm was associated with the risk of treatment failure (odds ratio, 2.9; 95% CI, 1.49-5.55; P = 0.002). CONCLUSIONS: Our findings suggest that transmural thickness of ≥4 mm can predict subsequent treatment failure in patients with CD treated using IFX, indicating transmural thickness <4 mm as a potential novel valuable therapeutic target.

Vedolizumab is effective and safe in elderly inflammatory bowel disease patients: a binational, multicenter, retrospective cohort study.

BACKGROUND: Immune modulating therapies are associated with an increased risk of infections and malignancies. This is of particular concern in elderly inflammatory bowel disease patients. This study aims to compare the safety and efficacy of vedolizumab between young and elderly inflammatory bowel disease patients. METHODS: A binational, multicentre, retrospective, cohort study was performed from 2015 to 2019. Patients who underwent treatment with vedolizumab and were followed for at least 14 weeks were studied. They were divided according to age into groups: 40 years or less or 60 years or older. Clinical and endoscopic responses at weeks 14 and 52 and infection development were compared between young and elderly inflammatory bowel disease patient groups. RESULTS: There were 144 patients (82 Crohn's disease and 62 ulcerative colitis) in the elderly cohort and 140 patients (83 Crohn's disease and 57 ulcerative colitis) in the young cohort. The average age was 70.2 ± 7.3 years and 29.6 ± 5.7 years, respectively. Clinical and endoscopic responses were comparable between the groups (week 52 remission of Crohn's disease: 40% vs. 35%, P = 0.7; week 52 remission of ulcerative colitis: 48% vs. 51%, P = 0.84). Previous anti-tumour necrosis factor biological therapy was independently associated with poor clinical remission rates at week 52 (Crohn's disease: odds ratio 0.23, 95% confidence interval 0.06-0.79; P = 0.02 and ulcerative colitis: odds ratio 0.10 95% confidence interval 0.01-0.74; P = 0.024). There were significantly more infections in the elderly cohort (2% vs. 12%, P = 0.002), none of which were fatal. CONCLUSIONS: Vedolizumab is equally effective in elderly and young inflammatory bowel disease patients. The findings of this study demonstrate an increased risk of infections among the elderly treated with vedolizumab, which may be related to their age and underlying diseases.

Propagation of EBV-driven Lymphomatous Transformation of Peripheral Blood B Cells by Immunomodulators and Biologics Used in the Treatment of Inflammatory Bowel Disease.

BACKGROUND: Immunomodulators and anti tumor-necrosis-α antibodies (anti-TNFs) have been implicated in increased risk of Epstein-Barr virus (EBV)-driven B-cell lymphoproliferative disorders in inflammatory bowel disease (IBD) patients. However, the underlying mechanisms are poorly understood. METHODS: An in-vitro model of lymphoblastoid cell line (LCL) was established by co-incubation of EBV-infected human peripheral blood mononuclear cells (PBMC) with Cyclosporin-A (CSA). After 4 weeks, the resultant LCLs were analyzed by flow cytometry, telomerase activity assay, and next generation sequencing. Subsequently, LCLs were explored in the presence of therapeutic agents for IBD (anti-TNFs, vedolizumab, 6-Mercaptopurine [6MP], methotrexate). Epstein-Barr virus titers were quantitated by real-time polymerase chain reaction. RESULTS: In cultures of PBMC with EBV and CSA, LCLs were characterized as an expanded, long lived population of CD58+CD23hi B-cells with high telomerase activity and clonal expansion. Upon addition to the cell cultures, LCL percentages were higher with infliximab (median 19.21%, P = 0.011), adalimumab (median 19.85%, P = 0.003), and early washed-out 6MP (median 30.57%, P = 0.043) compared with PBMC with EBV alone (median 9.61%). However, vedolizumab had no such effect (median 8.97%; P = 0.435). Additionally, LCL expansion was accompanied by increase in intracellular, rather than extracellular, EBV viral copies. Compared with PBMC with EBV alone, high levels of LCL were subsequently observed after triple depletion of NK cells, CD4+ T cells, and CD8+ T cells (median 52.8% vs 16.4%; P = 0.046) but also in cultures depleted solely of CD4+ T cells (median 30.7%, P = 0.046). CONCLUSIONS: These results suggest that both anti-TNFs and 6MP, but not vedolizumab, propagate EBV-driven lymphoblastoid transformation in an in vitro model of lymphoma. This model may prove useful for studying mechanisms underlying proneoplastic viral immune interactions of novel drugs in IBD therapy.