Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and inter-leukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn’s Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P = 0.005 and P = 0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohn’s disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355.

P726 Fecal calprotectin and quality of life questionnaires are responsive to change in pouch disease activity following antibiotic therapy—results from a prospective clinical trial

Abstract Background Whether fecal calprotectin (FC) and quality of life (QoL) questionnaires reflect change in disease activity in patients with a J-pouch is unknown. Methods Patients with UC following ileal pouch-anal anastomosis developing acute pouchitis were prospectively recruited to a clinical trial at the Rabin Medical Center in Israel, a major referral center for patients with a J-pouch. Consecutive patients with acute pouchitis were diagnosed clinically by the treating physician in a patient with compatible clinical symptoms. Patients were treated with a 2-week course of antibiotics – either metronidazole and ciprofloxacin or metronidazole and doxycycline. Full PDAI, including clinical, endoscopic, and histologic evaluation, was performed at baseline and following 2 weeks of antibiotic therapy. Patients had comprehensive laboratory tests, including fecal calprotectin (FC) measurements at both time points. Patients also filled out QoL questionnaires (short inflammatory bowel disease questionnaire - SIBDQ, inflammatory bowel disease [IBD] disk) at both time points. Outcomes of interest included the responsiveness of FC and QoL questionnaires to change in pouch disease activity according to the PDAI. Paired analyses were performed to compare results between the 2-time points. Results Twenty patients were enrolled in a prospective clinical trial. At enrollment, the median age was 36 years IQR [27-56], females 12 (60%). The median interval from the ileostomy closure was 7 years IQR [2-17]. Median PDAI score: 9 IQR [8-11.5], median FC: 661 ug/g IQR [425-1261], median C-reactive protein: 1.1 mg/dl IQR [0.5-1.8] and median hemoglobin: 13.2 g/dl IQR [12.1-14.1]. Following 14 days of antibiotic treatment, there was a significant decrease in the total PDAI, which decreased from a median of 9 IQR[8-11.5] to 6 IQR[2.5-7],(p=0.007). This difference was mainly related to a significant reduction in both the clinical (p=0.01) and endoscopic subscores (p=0.001) but not the histologic subscore (p=0.1). FC was responsive to this change in PDAI and correlated with the change in endoscopic findings; it decreased significantly between the 2-time points from a median of 661 ug/g IQR[425-1261] to 294 ug/g IQR[113-418] (p=0.02). Both quality of life questionnaires (SIBDQ, IBD disk) improved significantly following antibiotic therapy: The median SIBDQ increased from 44 to 50 (p=0.02), and the median IBD disk score decreased from 59 to 31 (p=0.01) Figure 2 Panel B and C respectively. Conclusion FC is a sensitive and rapidly responsive biomarker of pouch disease activity, and we encourage its use when managing patients with pouchitis. Likewise, the SIBDQ and IBD disk accurately reflect change in QoL associated with change in disease state in patients with a pouch </jats:sec

P506 Increased risk of anti-drug antibodies to a second anti-TNF in patients who developed antibodies to the first anti-TNF

Abstract Background Evidence regarding predisposition to develop anti-drug antibodies to a second anti-TNF in patients with inflammatory bowel diseases (IBD) who previously developed antibodies to a first anti-TNF (either infliximab or adalimumab) is conflicting. We aimed to assess the rates of such consecutive immunogenicity. Methods The medical records of all patients with IBD followed at the Rabin and Schneider Medical Centers (all ages) from 2014 to 2019, who were treated with an anti-TNF agent were reviewed. Clinical data including age at diagnosis, gender, disease type, concomitant use of immunomodulators, as well as drug trough levels (TLs) and anti-drug antibodies (ADAs) for both agents were registered. Patients who switched from one anti-TNF to another and had comprehensive clinical and pharmacokinetic data were assessed for consecutive immunogenicity. Results Overall, 1570 patients were tested for TLs and ADAs (infliximab, n = 702, 45%). Rates of positive infliximab ADAs were 31%, and positive adalimumab ADAs were 13%. We identified 55 eligible patients (Crohn’s disease = 52, ulcerative colitis = 2, IBD unclassified = 1; females = 26 [47%]; mean age at diagnosis 26.5 ± 13 years). Of 29 patients with infliximab as the first anti-TNF, 25 (86%) had positive ADAs. None of the 4 patients without ADAs against infliximab developed ADAs against consequent adalimumab, whereas 7/25 (28%) of patients with positive ADAs against infliximab developed ADAs against adalimumab, significantly higher than the overall immunogenicity rate of adalimumab (28% vs. 13%, p = 0.03). Of the 26 patients who were switched from adalimumab to infliximab, 10 (38%) had positive ADAs. Out of 16 patients with negative ADAs against adalimumab, 5 (31%) developed ADAs against consequent infliximab whereas 7/10 (70%) of patients with positive ADAs against adalimumab developed ADAs against infliximab, significantly higher than the overall immunogenicity rate of infliximab (70% vs. 31%, p = 0.008). The overall rate of immunogenicity against the second anti TNF following a switch due to immunogenic failure was 39%. Only 33% of patients were treated with concomitant immunomodulators after an immunogenicity driven switch. Clinical data, as well as TLs and ADA, were comparable in children and adults. Conclusion The rate of consecutive immunogenicity in anti-TNF treated patients is significantly higher than the overall immunogenicity against the first anti-TNF. This higher rate of consecutive immunogenicity may be associated with a predisposition to developing anti-drug antibodies to anti-TNF agents. It may also be a consequence of the relatively low rates of combination therapy following an immunogenic failure. </jats:sec

Supplementary Material for: Video-capsule endoscopy after bariatric surgery: a tertiary referral center experience

Background and aim: Minimal data is available regarding the performance of video capsule endoscopy (VCE) in patients that underwent bariatric surgery. We aim to report indications, feasibility and safety of VCE performed after bariatric surgery, specifically focusing on diagnosis rates of Crohn’s disease (CD) in this population. Methods: A retrospective analysis of all VCE procedures performed between January 2015 to December 2019. All patients that underwent bariatric surgery prior to VCE were included. Indication for VCE, Ingestion methods, completion rates, retention rates, and endoscopic findings were recorded. Results: A total of 1255 patients underwent VCE examination during the study period, of which 31 (2.5%) underwent bariatric surgery prior to VCE. The most common bariatric surgery was laparoscopic sleeve gastrectomy (16 patients, 51.6%) and the most common indication for VCE was evaluation of iron deficiency anemia (14 patients, 45.1%). The majority of patient ingested the capsule independently, without endoscopic assistance (20, 64.5%). Although patency capsule was not used in our cohort, no events of capsule retention were documented. Mean transit time was 4.32 hours. Only 4 events of incomplete examination were recorded. Over a median follow up of 27.5 months (IQR 13.0-34.2) 10 patients (31.2%) had a final diagnosis of CD with a median Lewis score of 225 (IQR 135-900). Conclusion: VCE is a feasible and safe procedure after bariatric surgery. Oral ingestion does not carry risk of retention. It is an effective means of diagnosis of small bowel CD in this population

P412 Drug persistence and endoscopic, histologic and biochemical remission rates among patients following ileal pouch-anal anastomosis treated with biologic therapy: Results from a prospective patient cohort

Abstract Background Patients with ulcerative colitis (UC) after total proctocolectomy and ileal pouch-anal anastomosis (IPAA) may develop chronic pouchitis or Crohn’s like disease of the pouch (CLDP). These patients may need treatment with biologic therapies. Data regarding treatment persistence as well as clinical, biochemical, endoscopic, and histologic remission rates are lacking Methods Patients after IPAA were followed prospectively at a dedicated pouch clinic. Patients with CP or CLDP who were antibiotic/steroid-refractory or dependent, had antibiotics/steroids side effects or had extraintestinal manifestations were treated with biologics. Clinical, endoscopic, histologic, and laboratory data were extracted from medical records at the last follow-up. Patient’s quality of life (QoL) was assessed by visual analog scale (VAS), with scores of, 0–100 (higher=better QoL). Time to biologic therapy discontinuation was measured for all patients; patients were censored if still on biologic therapy at the time of the last follow-up. Biochemical remission was defined as C-reactive protein (CRP)&amp;lt;, 0.5 mg/dl and a fecal calprotectin (FC)&amp;lt;, 150 ug/dl with a normal albumin level. Endoscopic and histologic remission was defined by the pouchitis disease activity index (PDAI) as an endoscopic subscore ≤2 and a histologic subscore, 0 or, 1, respectively. Results The prospective cohort constituted, 130 patients. Females:, 73 (56%). Before IPAA, most (70%) patients had pancolitis, 95% received steroids and mesalamine, and, 37% - biologic therapies. Median follow-up after ileostomy closure:, 16 years. Biologic therapy was started in, 28 patients (22%) due to CP or CLDP. The first line biologic for all, 28 patients was anti-TNF’s and, 9 patients received more than one line of biologics. Median time to commencing biologics:, 130 months. Median first-line biologic drug persistence:, 222 weeks. Among patients treated with biologic therapy, at the last clinic visit, median CRP was, 0.58 mg/dl, median FC:, 255ug/g, median HB:, 12.46 mg/dl, and median albumin was, 4.5 mg/dl.Median PDAI endoscopic and histologic scores were, 2; median VAS rating was, 80. Biologic remission criteria were fulfilled by, 43% of patients (N-12). An additional, 43% (N-12) were also in endoscopic remission with an endoscopic PDAI subscore of, 2 or below, and an additional, 29% of patients (N-8) were in histologic remission with a histologic PDAI score of, 0 or 1. Conclusion Biologics reintroduction after IPAA was relatively common, albeit after a very long interval. Biologic therapy was effective, with a sizable proportion of patients in biochemical, endoscopic, and histologic remission. Likewise, drug persistence was long. We suggest that early initiation of biologic therapy in certain patients may be prudent. </jats:sec

P501 Vedolizumab is associated with longer drug sustainability compared to infliximab in moderate-to-severe Ulcerative Colitis: a real-world cohort study

Abstract Background Data regarding sustainability of biologics in ulcerative colitis (UC) are limited. We aimed to assess sustainability of intravenous biologics used to treat UC, infliximab (IFX) and vedolizumab (VDZ), in biologic-naïve and biologic-experienced patients, specifically focusing on their sustainability over time. Methods This retrospective cohort study was conducted at the Rabin Medical Center (RMC), a tertiary referral center for patients with inflammatory bowel diseases. We included patients ≥ 18 years, treated at the RMC IV infusion center between Dec 1st 2017 and May 1st 2021. An extensive medical chart review was performed. Patients’ data were collected from the first to last documentation of treatment or end of follow-up. Drug sustainability was defined as long as cortico-steroid-free, surgical-free treatment was documented. Data collected, included sex, age at UC diagnosis, age at biologic treatment commencement and the interval UC-diagnosis-first biologic, disease extent (proctitis, left-sided or extensive colitis), previous treatment with biologics, and clinical laboratory data. Concomitant therapy was documented as well, specifically immunomodulatory drugs. Results were adjusted to factors associated with disease severity (based on factors including hemoglobin, hematocrit, neutrophil-to-lymphocyte ratio, albumin, C-reactive protein, and total protein), combination therapy and age. Results A total of 217 patients with UC treated with IFX or VDZ were included. Of those, 186 were treatment-(biologic)-naïve. First biologic was IFX in 77 (41.3%) patients and VDZ-in 109 (58.6%). Follow-up continued for up to 300 weeks. Median survival time was 106.5 (82.9–135) weeks for IFX and 265.6 weeks (121.3–273.1) for VDZ (p=0.002, KM survival curve shown in Figure 1). Median survival time was longer for vedolizumab even when adjusting for factors associated with disease severity, combination therapy and age (HR 0.55 95 CI 0.3–0.98, p=0.042). In treatment-experienced patients, IFX and VDZ sustainability was comparable (p=0.593). Conclusion In this -real world, tertiary referral center study, VDZ had significantly longer drug sustainability in treatment-naïve patients with UC compared to IFX. This held true when adjusted for disease severity. Drug sustainability in treatment-experienced patients with UC was comparable. The data support VDZ as the first-line biologic in moderate-to-severe UC. </jats:sec

P627 Acute severe ulcerative colitis in pregnancy: A retrospective cohort study

Abstract Background Ulcerative colitis is a chronic inflammatory condition of the colon with peak incidence rates between the ages of 15 and 35 years. Consequently, women with ulcerative colitis are often diagnosed during childbearing years, which makes the effect of the disease on pregnant patients an important clinical question. Acute severe ulcerative colitis will affect up to 25% of patients. There are limited studies that describe the medical treatment, colectomy rates, and birth outcomes of women hospitalised with acute severe ulcerative colitis during pregnancy. Methods We performed a retrospective observational study of pregnant ulcerative colitis patients hospitalised at two large tertiary medical centres between January 2003 and December 2018. The primary endpoint was colectomy-free survival. Secondary endpoints included details of disease management and fetal outcomes. Results Twenty patients met the inclusion criteria. At admission, the median age was 30.3 years (IQR 23.4–32), and the median gestational age was 21 weeks (IQR 14–28). All patients met Truelove and Witts criteria for acute severe ulcerative colitis. The median follow-up time was 48 months (IQR 20.7–80). Colectomy free survival rates from admission were 90% at six months, 84% at one year, and 64% at four years (Figure 1). Only one patient (5%) underwent colectomy at her index admission. All patients were treated with intravenous steroids, and half received anti-tumour necrosis factor agents as inpatients (7 received infliximab and 3 received adalimumab). Following discharge, seven (35%) patients were maintained on infliximab, four (20%) were maintained on adalimumab, vedolizumab and azathioprine were used as the maintenance drug in one patient each, and another seven (35%) patients were transitioned to mesalamine preparations. Live birth occurred in 18 patients (90%), and the median gestational age at birth was 37 weeks (IQR 34.5–38). Adverse pregnancy outcomes included two spontaneous abortions (10%), six premature births (30%), and four low birth weight infants (20%). There were no stillbirths, and no major congenital abnormalities were noted. Conclusion We report on the largest cohort of pregnant patients hospitalised for acute severe ulcerative colitis and have shown that these patients have good response rates to standard treatments and comparable colectomy rates to studies of non-pregnant patients. In our cohort, there were relatively high rates of preterm and low weight births. </jats:sec

P661 Post-operative prophylaxis with anti-TNF in patients with Crohn’s disease who are anti-TNF experienced is associated with higher rates of prophylaxis failure

Abstract Background Anti-TNF therapy is the most effective strategy for post-operative prophylaxis in patients with Crohn’s disease (CD) who are considered to be at high risk for recurrence. However, some patients fail to maintain long-term remission under these therapies. We aimed to assess predictors for the efficacy of post-operative anti-TNF therapy. Methods Patients with CD who underwent a curative bowel resection and were given post-operative anti-TNF prophylaxis between 2010 and 2019 were identified, and their data analysed retrospectively. Patients were assessed for disease recurrence at their first post-operative colonoscopy, a Rutgeerts score of &amp;gt;2a or clinically active disease that required a change in treatment was considered prophylaxis failure. Results Overall, 51 patients were included in our analysis. Male: 23 (45%); most of them had a penetrating complication (n = 23, 63%) that required surgery. Median age at surgery: 32 years (IQR 26–46). Anti-TNF therapy was started within a median of 9 weeks (IQR 6–14) post-surgery. Anti-TNF naïve: 14/51; 37/51 were anti-TNF experienced; of whom, 23 (62%) were treated with the same anti-TNF given before surgery. Disease recurrence occurred in 23 patients (45%) within a median follow-up of 13 months (IQR 8–26). Of the patients with disease recurrence, 10 (43%) were male, the median age of CD diagnosis was 26 years (IQR 15–49), 15 (65%) had penetrating disease, 5 (21%) had previous surgery, and 5 (21%) were active smokers. Disease recurrence was more common among patients operated at an older age (43 vs 33 years, p &amp;lt; 0.05) and in patients who had previous exposure to anti-TNF agents (56% vs. 14%, p = 0.01). In a multivariate Cox regression analysis, previous anti-TNF exposure was predictive of disease recurrence after surgery (HR 5.5, 95% CI 1.3–24, p &amp;lt; 0.05). Conclusion Post-operative prophylaxis using anti-TNF therapy in patients with CD who are anti-TNF experienced is associated with high rates of disease recurrence. This failure might be attributed to immunogenicity or pharmacodynamic failure. Closer monitoring and early treatment modifications should be considered in anti-TNF experienced patients. </jats:sec

P807 Pregnancy and maternal outcomes in a cohort of patients with Inflammatory bowel disease: Encouraging data from a multi-disciplinary clinic in a tertiary center

Abstract Background Pregnant women with inflammatory bowel diseases (IBD) are prone to adverse pregnancy outcomes. This study aimed to assess pregnancy outcomes and disease management for pregnant patients with IBD treated at a multi-disciplinary IBD- maternal-fetal medicine (MFM) clinic. Methods This retrospective cohort study included consecutive pregnant patients with IBD having a singleton gestation who attended the IBD-MFM clinic at the Rabin Medical Center between 2012 and 2019. We assessed disease activity and flare management at conception and through pregnancy for the IBD cohort. Pregnancy outcomes of interest included: adverse neonatal and obstetrical outcome and mode of delivery. We also assessed three integrative outcomes: a favorable and a poor pregnancy outcome and an unfavorable maternal outcome. The IBD pregnant cohort was compared with a cohort of non-IBD pregnant women who gave birth at the same shift (1:5-10 control). Multivariable logistic regression was used for risk assessment. Results 141 IBD pregnant patients and 1119 non-IBD pregnant women were included. Mean maternal age 32[±4] years. IBD patients had a higher rate of nulliparity (70% [50/141] vs. 30% [340/1119], p&amp;lt;0.001) and had a lower BMI (21.42 kg/m2 [19.18-23.44] vs. 22.48 [20.31-25.59], p=0.002). All other baseline characteristics were comparable. Among the IBD patients, 60% (85/141) were diagnosed with Crohn’s disease (CD), and the rest with ulcerative colitis (UC). At conception, 88% (124/141) were in clinical remission, 83% (117/141) were on maintenance therapy, and 30.5% (43/141) were on biologics. Through pregnancy, 36.2% (51/141) flared, 14% (20/141) received systemic steroids, and 3% (2/141) initiated a new biologic. Flares were significantly more frequent among patients with UC vs. CD (48.2%, [27/56] vs. 28.2%, [24/85], p=0.015). The majority of neonatal and obstetrical outcomes and all three composite outcomes were comparable between the IBD pregnant and the non-IBD cohorts, table 1. Cesarean delivery was more frequent among the IBD pregnant patients compared with the non-IBD pregnant women (34.8%, [49/141] vs. 24.1%, [270/141], p=0.021). Risk analysis revealed that a diagnosis of IBD was not associated with either a favorable or a poor pregnancy outcome, nor an unfavorable maternal outcome, see table 2. Conclusion In this IBD-pregnant cohort followed at a multi-disciplinary IBD- MFM clinic, outcomes were encouraging and comparable with the non-IBD cohort. A diagnosis of IBD was not associated with pregnancy or maternal outcomes. </jats:sec