Early intestinal ultrasound in severe ulcerative colitis identifies patients at increased risk of 1-year treatment failure and colectomy.

BACKGROUND AND AIMS: Reliable and easily accessible objective markers of disease activity to predict long-term treatment outcomes in severe ulcerative colitis (UC) are missing. We aimed to investigate if intestinal ultrasound (IUS) might predict long-term outcomes in hospitalized patients with severe UC treated with intravenous corticosteroids. METHODS: Hospitalized patients with severe UC and IUS inflammation (bowel wall thickness (BWT)>3.0mm) starting IV corticosteroids were recruited at three university hospitals in Denmark. IUS was performed before treatment, 48±24 hours (h), 6±1 days, and 3 months after treatment initiation. Time until colectomy or need for new interventions was registered together with Mayo score at 3 months and partial Mayo score (pMayo) at 12-months. Follow-up time was 12 months. RESULTS: Fifty-six patients were included in the final analysis. Forty-five (80%) patients needed intervention, including 9 colectomies, during the 12-month follow-up. After 48±24h: No patient with a BWT<3mm needed a colectomy, p=0.04. BWT≥4mm showed an increased risk of colectomy (odds ratio 9.5 (95%CI 1.5-186), p=0.03), while a BWT≥3mm showed an increased risk of intervention (3.6 (1.1-12.5), p=0.03). A BWT≥4mm resulted in a significantly shorter time until both colectomy, p=0.03, and treatment intensification (mean days 75 (95%CI24-127) vs. 176 (119-233), p=0.005. However, neither IUS parameters nor pMayo score, CRP, hemoglobin, or p-albumin could predict remission at 3- and 12-months. CONCLUSION: BWT assessed at 48h post intravenous corticosteroid initiation in patients hospitalized with severe UC may identify patients with an increased risk of short- and long-term colectomy and predict a more aggressive short-term disease course.

Therapeutic drug monitoring of vedolizumab therapy in inflammatory bowel disease.

BACKGROUND: Therapeutic drug monitoring is effective for optimizing anti-tumor necrosis factor therapies in inflammatory bowel disease, but for vedolizumab, a gut-selective leucocyte migration inhibitor, data are scarce. METHODS: Observational cohort study including 116 bio-experienced inflammatory bowel disease patients treated with vedolizumab for active luminal disease. Biobanked trough blood samples (n = 676) covering 96% of patients were analyzed using a drug-binding immunofluorometric assay. Steroid-free treatment outcomes were classified by clinical disease activity indices and objective findings, primarily endoscopy. RESULTS: Patients with clinical remission to vedolizumab induction therapy (37%) had significantly higher trough levels than those without at weeks 6 (mean 34.1 vs 28.0 µg/mL, P = 0.03) and 10 (34.8 vs 27.5 µg/mL, P = 0.01). Optimal thresholds for discrimination were 32.4 µg/mL (AUCROC 0.66, P = 0.04) and 23.5 (AUCROC 0.67, P = 0.01), respectively. This positive association persisted during maintenance phase with 11.9 µg/mL (AUCROC 0.69, P < 0.01) associated with clinical remission (37%) and 15.3 (AUCROC 0.74, P < 0.001) for objective remission (46%). Stratification by temporal evolution of treatment effects revealed higher induction and maintenance vedolizumab levels in persistent and slow responders as compared to secondary or persistent failures. Pharmacokinetics was influenced by rare formation of anti-vedolizumab antibodies (2%), and to a lesser extent gender and albumin during induction, but not disease severity, concomitant steroids, or thiopurine metabolites. Switching to subcutaneous administrations resulted in 2.3-fold increase in steady-state trough levels. CONCLUSION: Our study supports maintaining adequate drug exposure being essential for sustained positive outcomes of vedolizumab and emphasizes individualized, therapeutic drug monitoring-based treatment regimens. Controlled trials and pharmacokinetic modeling are, however, needed.

Tofacitinib for Acute Severe Ulcerative Colitis: A Systematic Review.

BACKGROUND: Tofacitinib has emerged as a new potential treatment for acute severe ulcerative colitis [ASUC]. We conducted a systematic review to assess efficacy, safety and integration in ASUC algorithms. METHODS: Systematic searching was done in MEDLINE, EMBASE, Cochrane Library and Clinicaltrials.gov until August 17, 2022, including all studies reporting original observations on tofacitinib for ASUC, preferably defined according to Truelove and Witts criteria. The primary outcome was colectomy-free survival. RESULTS: Of 1072 publications identified, 21 studies were included of which three were ongoing clinical trials. The remaining comprised a pooled cohort originating from 15 case publications [n = 42], a GETAID cohort study [n = 55], a case-control study [n = 40 cases] and a paediatric cohort [n = 11]. Of these 148 reported cases, tofacitinib was used as second-line treatment after steroid failure in previous infliximab failures or third-line after sequential steroid and infliximab or cyclosporine failure, 69 [47%] were female, median age range was 17-34 years and disease duration was 0.7-10 years. Overall, 30-day colectomy-free survival was 85% [n = 123 of 145; n = 3 without colectomy had follow-up <30 days], 90-day 86% [n = 113 of 132; n = 16 follow-up <90 days] and 180-day 69% [n = 77 of 112; n = 36 follow-up <180 days]. Tofacitinib persistence at follow-up was 68-91%, clinical remission 35-69% and endoscopic remission 55%. Adverse events occurred in 22 patients, predominantly being infectious complications other than herpes zoster [n = 13], and resulted in tofacitinib discontinuation in seven patients. CONCLUSION: Tofacitinib appears promising for treatment of ASUC with high short-term colectomy-free survival among refractory patients who are otherwise deemed to require colectomy. However, large high-quality studies are needed.

Therapeutic drug monitoring in inflammatory bowel disease: implementation, utilization, and barriers in clinical practice in Scandinavia.

BACKGROUND AND AIMS: Therapeutic drug monitoring (TDM) may optimize biologic and thiopurine therapies in inflammatory bowel disease (IBD). The study aimed to investigate implementation and utilization of TDM in Scandinavia. METHODS: A web-based questionnaire on the use of TDM was distributed to Scandinavian gastroenterologists via the national societies. RESULTS: In total, 297 IBD physicians prescribing biologic therapies, equally distributed between community and university hospitals, were included (response rate 42%) (Norway 118 (40%), Denmark 86 (29%), Sweden 50 (17%), Finland 33 (11%), Iceland 10 (3%)). Overall, TDM was applied during biologic therapies by 87%, and for TNF-inhibitors >90%. Among the users, reactive and proactive TDM were utilized by 90% and 63%, respectively. Danish physicians were significantly less inclined to use TDM compared to other Scandinavian countries; (58% vs 98%); OR 0.03 [0.01-0.09], p < 0.001). Reactive TDM was commonly applied at primary (74%) and secondary (99%) treatment failure. Proactive TDM was used by 80% during maintenance therapy and 56% during induction and more commonly utilized in Norway (p < 0.001), and by physicians managing >10 IBD patients/week (p = 0.005). TDM scenarios were interpreted in accord with available evidence but with discrepancies for proactive TDM. The main barriers to TDM were lack of guidelines (51%) and time lag between sampling and results (49%). TDM of thiopurines was routinely used by 87%. CONCLUSION: TDM of biologic and thiopurine therapies has been broadly implemented into clinical practice in Scandinavia. However, physicians call for TDM guidelines detailing indications and interpretations of test results along with improved test response times.

Trajectories of health-related quality of life and fatigue during vedolizumab therapy in inflammatory bowel disease.

BACKGROUND AND AIM: Normalizing health-related quality of life (QoL) and fatigue are important long-term treatment targets in inflammatory bowel disease (IBD). We examined their evolution in relation to changes in disease activity during vedolizumab therapy. METHODS: Cohort study of biologically refractory IBD patients treated with vedolizumab. Patients were prospectively evaluated at all infusions by Short Health Scale (SHS) (QoL questionnaire covering four health dimensions) (n = 79), visual analogous scale for fatigue (VAS-F) (n = 30), and clinical disease activity. Objective disease assessment was carried out after 1 year or at treatment failure. RESULTS: Patients in steroid-free clinical remission at end of induction improved significantly in all SHS items already from week 2 with full implementation by week 14 ("Symptoms" 59% improvement, P < 0.001; "Function" 63%, P < 0.001; "Worries" 59%, P < 0.001; "Well-being" 40%, P < 0.01). Then, SHS remained stable at background levels (< 20) for 1 year (improvements 67%; 65%; 62%; 57%; P < 0.001). Combined clinical-objective remission at 1 year was associated with highest SHS improvements (64-72%; P < 0.001). Of note, early SHS improvements preceded manifestation of clinical remission in most patients (22 of 33; 67%). Clinical response materialized into late (week 6 or later) and minor SHS improvements (31-46%, P < 0.001). Fatigue improved steadily over 6 months to background levels (VAS-F < 4) among patients in clinical remission (45% decrease) or clinical-objective remission (41%). SHS and VAS-F impairment remained elevated in patients without effect of therapy. CONCLUSION: QoL rapidly improves and predicts later significant clinical-objective efficacies of vedolizumab at end of induction and 1 year. Fatigue improves slowly after remission is attained.

Identifying and understanding disease burden in patients with inflammatory bowel disease.

OBJECTIVE: Physicians tend to focus on biomedical targets while little is known about issues important to patients. We aimed to identify critical concepts impacting patients with inflammatory bowel disease (IBD). DESIGN: We performed a survey of patients with IBD in biologic therapy (n=172) and used a validated qualitative method called group concept mapping (GCM) in patient workshops. The survey included 13 questions on attitudes toward symptoms and issues related to IBD. In the eight workshops, patients (n=26) generated statements later clustered into concepts identifying issues impacting a patient's life. Patients ranked the statements. RESULTS: In the survey, patients' mean age were 40 years (SD 13), 53% were women, and 38% had ulcerative colitis. They identified fatigue (57%) and stool frequency (46%) as the most critical symptoms impacting their daily lives regardless of disease activity. In the GCM workshops with Crohn's disease (n=13) (median age 42 years (IQR 39-51) and 62% were women), 335 statements divided among 10 concepts were generated, and the three most important concepts were 'Positive attitudes', 'Accept and recognition', and 'Sharing knowledge and experiences in life with Crohn's disease'. In the workshops with ulcerative colitis (n=13) (median age 43 years (IQR 36-49) and 69% were women), 408 statements divided into 11 concepts were generated; the most important concepts were 'Take responsibility and control over your life', 'Medication', and 'Everyday life with ulcerative colitis'. CONCLUSION: Focusing solely on IBD symptoms, patients identified fatigue and stool frequency to impact daily life the most. However, when investigating the disease burden in a broader perspective beyond classic IBD symptoms, patients identified concepts with focus on emotional health to be most important. TRIAL REGISTRATION: The Copenhagen University Hospital, Herlev and Gentofte approved the questionnaire and methodology (work-zone no: 18015429).

Early Intestinal Ultrasound Predicts Intravenous Corticosteroid Response in Hospitalised Patients With Severe Ulcerative Colitis.

BACKGROUND AND AIMS: Our aim was to determine if transabdominal intestinal ultrasound changes after 48 ±â€…24 h of intravenous corticosteroids can predict treatment outcomes in hospitalised patients with severe ulcerative colitis. METHODS: We performed a blinded observational multicentre study. Ultrasound parameters were assessed before treatment initiation, after 48 ±â€…24 h, and 6 ±â€…1 days. Treatment response was determined within 7 days by two outcome measures: 1] partial Mayo score reduction; 2] no administration of rescue therapy. RESULTS: Out of 69 recruited patients, 56 were included in the final analysis, with 37 responders. The colon segment with the highest baseline bowel wall thickness was analysed, being the sigmoid in all patients. There was no difference in baseline bowel wall thickness between responders and non-responders in the partial Mayo score outcome. At 48 ±â€…24 h, a significant difference between responders and non-responders was identified in both absolute bowel wall thickness [median 3.1 mm vs 4.9 mm; p <0.0001], absolute reduction [-1.9 mm vs -0.2 mm; p <0.001], and relative reduction [-35.9% vs -4.1%; p <0.0001]. A ≤20% reduction had a sensitivity of 84.2% (95% confidence interval [CI] 60.4, 96.6%) and a specificity of 78.4% [61.8, 90.2%] for determining non-response [area under the curve 0.85]. In the multivariable analysis, a >20% reduction had the highest odds ratio (22.6 [4.2, 201.2]; p = 0.001) for determining response. Similar results were seen for the rescue therapy outcome. CONCLUSIONS: Changes in bowel wall thickness, after 48 ±â€…24 h following intravenous corticosteroid treatment in hospitalised patients with severe ulcerative colitis, identify responders with high accuracy and might be used as an early marker to guide accelerated rescue therapy.

Fatigue is a systemic extraintestinal disease manifestation largely independent of disease activity, chronicity, and nutritional deficiencies in inflammatory bowel disease on biologics.

BACKGROUND: Fatigue is a common symptom reported by patients with chronic immunoinflammatory diseases and with profound negative implications on health-related quality of life. This study aimed to delineate underlying components contributing to fatigue in patients with inflammatory bowel disease (IBD) receiving biologic therapy. METHODS: Cross-sectional questionnaire study of all patients with IBD receiving any biologic therapy at a tertiary IBD center. Fatigue was assessed by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Disease activity and quality of life were evaluated by generic questionnaires. Principal component analysis (PCA) was used to identify components of variables explaining fatigue. RESULTS: Three hundred patients with IBD were included. Moderate-to-severe fatigue defined as FACIT-F ≤ 39 was present in half of the included patients. PCA condensed variables associated with fatigue into three main components contributing to 49% of observed fatigue. The first component, explaining 21% of fatigue, included factors related to disease chronicity, e.g., long disease duration, high number of previously used biologic therapies, presence of previous intestinal surgery, and increasing age. The second component explained 14% of fatigue and comprised disease activity-related aspects, e.g., disease activity indices and C-reactive protein. The third explained 14% of fatigue and comprised various nutritional deficiencies. CONCLUSION: Fatigue can partly be explained by chronicity, disease activity, and nutritional deficits. However, the cause of fatigue is unexplained in approximately half of the patients with IBD supporting that fatigue can be an independent, systemic extraintestinal disease manifestation in IBD.

Low-dose azathioprine and allopurinol versus azathioprine monotherapy in patients with ulcerative colitis (AAUC): An investigator-initiated, open, multicenter, parallel-arm, randomised controlled trial.

Background: Retrospective studies suggest that for patients with ulcerative colitis (UC) combination therapy with low-dose azathioprine and allopurinol (L-AZA/ALLO) may result in higher remission rates than monotherapy with azathioprine (AZA). We prospectively investigated the effects of these drugs for remission in patients with moderate-to-severe UC. Methods: Open-label, unblinded, randomised, controlled, investigator-initiated, multicentre study conducted at eight hospital sites in Denmark. Adult patients with established UC, who were steroid dependent/refractory, thiopurine naïve, had a normal thiopurine methyltransferase, and achieved remission with steroids or infliximab were eligible for inclusion. Patients were randomly assigned by the investigators (1:1) to 52 weeks of treatment with once daily oral AZA (median dose 50 mg) combined with ALLO 100 mg versus AZA monotherapy (median dose 200 mg), using a computer-generated randomisation list with blocks of six. The trial was open without masking. All randomised patients who received at least one dose of study drug were included in primary and safety analyses (intention to treat population). The primary outcome was steroid and infliximab free remission after 52 weeks, defined as a Mayo Score of ≤1 and no rectal bleeding. The trial is completed and is registered in ClinicalTrials.gov (ClinicalTrials.gov NCT03101800). Findings: Between January 9, 2017 and February 10, 2021, 47 patients were randomised to l-AZA/ALLO and 42 to AZA and received at least one dose of the study drug. After 52 weeks, 20 of 47 (43%) patients in the l-AZA/ALLO group and nine of 42 (21%) patients in the AZA group achieved remission (odds ratio 2·54 [95% CI 1·00 to 6.78, p < 0·048]). Fourteen patients (30%) in the l-AZA/ALLO group and 16 (38%) in the AZA group were withdrawn from the study due to adverse events. Interpretation: This study suggests that after one year l-AZA/ALLO therapy may be associated with a beneficial effect on steroid- and infliximab-free clinical remission in patients with moderate-to-severe UC and should be considered as first line therapy. Funding: Funding for AAUC was provided by The Capital Region of Denmark (Regionernes Medicinpulje (6062/16)).

Patient Satisfaction of Propofol Versus Midazolam and Fentanyl Sedation During Colonoscopy in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Colonoscopy is essential for optimal management of inflammatory bowel disease. However, many patients opt out due to unpleasantness related to this procedure. We investigated if Nurse Administered Propofol Sedation (NAPS) would improve patient satisfaction and attitude towards future colonoscopies. METHODS: Randomized clinical trial of deep sedation with NAPS (n = 63) versus moderate midazolam and fentanyl sedation (n = 67). To assess the primary end point of patient satisfaction at discharge, we developed a Satisfaction Questionnaire comprising 13 items each rated by a 5-point Likert scale and with higher scores reflecting more positive outcomes (13-65 points). RESULTS: Fifty-six patients (43%) with ulcerative colitis, 48 (37%) with Crohn's disease, and 26 (20%) with high suspicion of inflammatory bowel disease were included. Most (88%) had previously had a colonoscopy and pre-procedure expectations were similar between groups. Patients receiving deep sedation had significantly higher satisfaction score (mean 60.1, SD 3.4) than those receiving moderate sedation (51.2, 8.4; P < .001). This was driven especially by less pain, more amnesia, sedation more to their liking, and better experience with the current than previous sedations. Importantly, these patients significantly more often preferred the same sedation for a future colonoscopy and were also inclined to accept more frequent colonoscopies. Assistance from another colonoscopist and disruption of the procedure due to pain occurred significantly more frequent in the moderate sedation group. There were no safety signals associated with NAPS. CONCLUSIONS: Patients with inflammatory bowel disease favor deep propofol sedation over moderate midazolam and fentanyl sedation. Availability of NAPS may facilitate patient adherence to endoscopy-based monitoring programs. Clinicaltrials.gov NCT01934088.

Drug Levels Associated With Optimal Discrimination Between Remission and Nonremission and Comparison of Antibody Assays During First Year of Stable Infliximab Maintenance Therapy in Inflammatory Bowel Disease.

BACKGROUND: To implement therapeutic drug monitoring-based strategies for infliximab (IFX) in inflammatory bowel disease, the authors assessed IFX levels for optimal discrimination between remission and nonremission and compared assays for anti-IFX antibodies (Abs). METHODS: The retrospective cohort comprised 163 bionaive patients with inflammatory bowel disease who received stable IFX maintenance therapy (5 mg/kg every 8 weeks [q8w]) for 1 year. The clinical and biochemical remission status was assessed at all infusions (weeks 14-22-30-38-46-54), and IFX and anti-IFX Abs were estimated using a time-resolved fluorometric assay (n = 690; 88% of infusions). Samples positive for anti-IFX Abs or IFX levels < limit of detection (n = 102) were analyzed by 2 binding assays [enzyme-linked immunosorbent assay (ELISA)] and functional reporter gene assay/drug-tolerant enzyme immunoassay. RESULTS: At all assessed time points, IFX levels were more than double in patients presenting clinical or biochemical remission. An IFX concentration of 4.5 mcg/mL was associated with clinical remission during the entire first year of therapy [sensitivity 54% (49-59), specificity 73% (67-78), AUCROC 0.65 (0.60-0.69), P < 0.0001]; these values were comparable with biochemical remission. Exploratory assessments for endoscopic remission (n = 131) were performed at the discretion of the treating physician. Anti-IFX Abs were associated with undetectable IFX and treatment failure [OR 2.9 (1.4-6.0), P < 0.01], irrespective of persistency or transiency. All performed assays detected anti-IFX Abs were picked up by all assays in ∼2/3 of samples. Binding assays demonstrated a higher sensitivity to anti-IFX Abs. CONCLUSIONS: IFX at ∼5 mcg/mL was associated with clinical and biochemical remission during the first year of maintenance therapy. During this phase of therapy, standard binding assays are appropriate for therapeutic drug monitoring.

A systematic monitoring approach to biologic therapies in inflammatory bowel disease: patients' and physicians' preferences and adherence.

OBJECTIVES: Treatment of patients with inflammatory bowel disease (IBD) should aim at achieving mucosal healing. However, monitoring schedules to support this goal remain undefined. We aimed to identify patients' and physicians' preferences regarding monitoring strategy and investigated the feasibility of such a strategy. METHODS: Elements considered relevant for monitoring were identified in questionnaire surveys among 1) patients with IBD receiving biologic agents (n = 172) and 2) their physicians (n = 87). Adherence to a monitoring strategy incorporating these elements was investigated in a retrospective cohort of patients with IBD treated with biologic agents (n = 139). RESULTS: Patients considered blood and stool samples, endoscopies, and magnetic resonance imaging (MRI) to be relevant aspects of monitoring their disease. However, patients also considered stool samples and endoscopies unpleasant. Physicians considered blood samples (99%), medical consultations (99%), fecal calprotectin (85%), endoscopy (78%), and MRI (71%) to be important aspects of IBD monitoring but considered endoscopies and MRI relevant only at clinical signs of relapse. A review of the clinical use of monitoring strategies including the elements identified above revealed high adherence for blood samples and disease activity indices (92%), but low adherence for fecal calprotectin (38%), therapeutic drug monitoring (38%), and endoscopies (32%). CONCLUSION: Important tools for evaluating mucosal healing (e.g., endoscopy) were rated highly unpleasant by patients, and physicians found endoscopies/MRI relevant only in case of relapse. These findings were reflected by low rates of adherence to use of these monitoring tools. In defining monitoring schedules to help achieve treatment goals, these important barriers must be addressed.

Discontinuation of Infliximab Therapy in Patients with Crohn's Disease.

BACKGROUND: Whether infliximab therapy can be successfully discontinued after patients with Crohn's disease have attained sustained, clinical, biochemical, and endoscopic remission is unknown. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled withdrawal study of infliximab in patients with Crohn's disease who were in clinical, biochemical, and endoscopic remission after standard infliximab maintenance therapy for at least 1 year. Patients were randomly assigned 1:1 to continue infliximab therapy or to receive matching placebo for 48 weeks. The primary end point was time to relapse. RESULTS: This study randomly assigned 115 patients to either the infliximab-continuation group or to the infliximab-discontinuation group. No relapses were observed among the 59 patients continuing infliximab, whereas 23 of 56 patients discontinuing infliximab experienced relapse. Time to relapse was significantly shorter among patients who discontinued infliximab than among those who continued infliximab (hazard ratio, 0.080; 95% confidence interval [CI], 0.035 to 0.186; P<0.001). At the end of the trial at week 48, relapse-free survival was 100% in the infliximab-continuation group and 51% in the infliximab-discontinuation group. The key secondary end point, time to loss of remission, was significantly shorter among patients discontinuing infliximab therapy than those continuing infliximab (hazard ratio, 0.025; 95% CI, 0.003 to 0.187; P<0.001). No unexpected adverse events were reported. CONCLUSIONS: Discontinuation of infliximab for patients with Crohn's disease receiving long-term infliximab therapy and in clinical, biochemical, and endoscopic remission leads to a considerable risk of relapse. (Funded by the Nordic Trial Alliance [NordForsk], the Medical Fund of the Danish Regions [Regionernes Medicin og Behandlingspulje], the Danish Colitis-Crohn Association, and the A.P. Moller Foundation; ClinicalTrials.gov number, NCT01817426; EudraCT number, 2012-002702-51.)

Vedolizumab clearance in neonates, susceptibility to infections and developmental milestones: a prospective multicentre population-based cohort study.

BACKGROUND: Little is known about the consequences of intrauterine exposure to, and the post-natal clearance of, vedolizumab. AIMS: To investigate the levels of vedolizumab in umbilical cord blood of newborns and rates of clearance after birth, as well as how these correlated with maternal drug levels, risk of infection and developmental milestones during the first year of life METHODS: Vedolizumab-treated pregnant women with inflammatory bowel disease were prospectively recruited from 12 hospitals in Denmark and Canada in 2016-2020. Demographics were collected from medical records. Infant developmental milestones were evaluated by the Ages and Stages Questionnaire (ASQ-3). Vedolizumab levels were measured at delivery and, in infants, every third month until clearance. Non-linear regression analysis was applied to estimate clearance. RESULTS: In 50 vedolizumab-exposed pregnancies, we observed 43 (86%) live births, seven (14%) miscarriages, no congenital malformations and low risk of adverse pregnancy outcomes. Median infant:mother vedolizumab ratio at birth was 0.44 (95% confidence interval [CI], 0.32-0.56). The mean time to vedolizumab clearance in infants was 3.8 months (95% CI, 3.1-4.4). No infant had detectable levels of vedolizumab at 6 months of age. Developmental milestones at 12 months were normal or above average. Neither vedolizumab exposure in the third trimester (RR 0.54, 95% CI, 0.28-1.03) nor combination therapy with thiopurines (RR 1.29, 95% CI, 0.60-2.77) seemed to increase the risk of infections in the offspring. CONCLUSIONS: Neonatal vedolizumab clearance following intrauterine exposure is rapid. Infant vedolizumab levels did not correlate with the risk of infections during the first year of life. Continuation of vedolizumab throughout pregnancy is safe.

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.

Therapeutic thresholds and mechanisms for primary non-response to infliximab in inflammatory bowel disease.

BACKGROUND: Primary non-response to infliximab (IFX) inherits a poor prognosis in inflammatory bowel disease (IBD). We explored underlying mechanisms and therapeutic thresholds in an effort to provide basis for optimizing therapy. METHODS: A prospectively followed cohort of 166 IBD patients having received standard IFX induction therapy (5 mg/kg at weeks 2, 6, and 14) had trough IFX and anti-IFX antibodies (Abs) retrospectively assessed at weeks 2 (n = 148) and 6 (n = 108). Circulating TNFα was measured in matched primary non-responders (n = 29) and responders (n = 21) at baseline and weeks 6 and 14. Clinical outcome at week 14 was supported by disease activity scores in half of patients. RESULTS: In all, 18 patients (11%) had primary non-response. Infliximab was consistently lower throughout the induction phase in non-responders as compared to responders (Week 2: IFX median 18.9 µg/mL vs. 23.3, p < .05. Week 6: 8.4 vs. 17.0, p < .05). Optimal IFX thresholds associated with response was 22.9 µg/mL at week 2 (sensitivity 51%, specificity 80%, AUCROC 0.67, p < .05) and 11.8 at week 6 (72%, 77%, 0.71, p < .05). Anti-IFX Abs occurred in 28% of primary non-responders and associated with low IFX and treatment failure (OR 13.7 [2.8-67.5], p < .01). Markers of disease activity (disease activity scores, albumin, CRP) also associated with low IFX. Circulating TNFα was higher throughout induction in non-responders with ulcerative colitis but not Crohn's disease. CONCLUSION: IBD patients with primary IFX failure generally have lower IFX trough than responders during early induction phase. Pharmacokinetic failure seems common in ulcerative colits, whereas pharmacodynamic failure appears common in Crohn's disease.

Absence of Relationship Between Crohn's Disease Activity Index or C-Reactive Protein and Infliximab Exposure Calls for Objective Crohn's Disease Activity Measures for the Evaluation of Treatment Effects at Treatment Failure.

BACKGROUND: Circulating infliximab (IFX) concentrations correlate with clinical outcomes, forming the basis of the IFX concentration monitoring in patients with Crohn's disease. This study aims to investigate and refine the exposure-response relationship by linking the disease activity markers "Crohn's disease activity index" (CDAI) and C-reactive protein (CRP) to IFX exposure. In addition, we aim to explore the correlations between different disease markers and exposure metrics. METHODS: Data from 47 Crohn's disease patients of a randomized controlled trial were analyzed post hoc. All patients had secondary treatment failure at inclusion and had received intensified IFX of 5 mg/kg every 4 weeks for up to 20 weeks. Graphical analyses were performed to explore exposure-response relationships. Metrics of exposure included area under the concentration-time curve (AUC) and trough concentrations (Cmin). Disease activity was measured by CDAI and CRP values, their change from baseline/last visit, and response/remission outcomes at week 12. RESULTS: Although trends toward lower Cmin and lower AUC in nonresponders were observed, neither CDAI nor CRP showed consistent trends of lower disease activity with higher IFX exposure across the 30 evaluated relationships. As can be expected, Cmin and AUC were strongly correlated with each other. Contrarily, the disease activity markers were only weakly correlated with each other. CONCLUSIONS: No significant relationship between disease activity, as evaluated by CDAI or CRP, and IFX exposure was identified. AUC did not add benefit compared with Cmin. These findings support the continued use of Cmin and call for stringent objective disease activity (bio-)markers (eg, endoscopy) to form the basis of personalized IFX therapy for Crohn's disease patients with IFX treatment failure.

Disease-Specific Enteric Microbiome Dysbiosis in Inflammatory Bowel Disease.

Inflammatory Bowel disease (IBD) is traditionally divided into Crohn's disease (CD) and ulcerative colitis (UC). UC is a relapsing non-transmural inflammatory disease that is restricted to the colon and is characterized by flare-ups of bloody diarrhea. CD is a chronic, segmental localized granulomatous disease that can affect any part of the entire gastrointestinal tract. Ileo-anal pouch is a procedure restoring functionality of the rectum after a colectomy. IBD is a multifactorial disease and flares of IBD are probably triggered by changes in the intestinal microbiota followed by an abnormal immune response. In this study, we aim to analyze the intestinal bacterial diversity in IBD patients during various stages of disease compared with healthy controls. Permission for human experiments and recruitment of participants was obtained from the Ethic Committee for Copenhagen County hospitals (Permission no. KA-03019, Permission no. KA-20060159). Stools from 26 healthy controls, 42 CD, 38 UC and 18 pouch patients were collected. Stool DNA extraction was performed using Qiagen, DNA mini stool kit Denmark. DGGE-PCR amplifying the V2-V3 region of 16S-rDNA gene of the bacteria was amplified by universal primers HDA1 and HDA2. Analysis of DGGE was performed blinded using BioNumerics version 7.5. After normalization, a DGGE gel band matching was performed. The similarities between profiles were calculated with a ranked Pearson correlation coefficient based on the band matching results using band intensities. Simpson's index of diversity and Pielou's species evenness were calculated. Based on the Shannon Diversity Index, UC patients had lower species diversity and bacterial evenness in comparison to healthy persons, p < 0.05. However, only CD and disease pouch patients had lower species diversity compared to those with inactive disease and healthy controls. Well-functioning pouch patients had decreased species evenness in comparison to diseased pouch patients and control group. During the active disease stage in CD and pouch, the patients have a low bacterial diversity in their gut when compared to the inactive stage. In UC patients, a generally low diversity was observed at all stages of the disease compared to healthy controls.