Fecal transplantation for ulcerative colitis from diet conditioned donors followed by dietary intervention results in favorable gut microbial profile compared to fecal transplantation alone.

BACKGROUND AND AIMS: Several fecal microbial transplantation (FMT) approaches for ulcerative colitis (UC) have been investigated with conflicting results. We have recently published the clinical outcomes from the CRAFT-UC Trial using FMT with the UC Exclusion Diet (UCED), compared with FMT alone. Here we aimed to compare the two FMT strategies in terms of microbial profile and function. METHODS: Subjects recruited to the CRAFT-UC study with available pre- and post-intervention fecal samples were included. Donors received diet conditioning for 14 days based on the UCED principles. Group-1 received single FMT by colonoscopy (Day 1) and enemas (Days 2 and 14) without donors' dietary conditioning (N=11). Group-2 received FMT but with donors' dietary pre-conditioning and UCED for the patients (N=10). Fecal samples were assessed by DNA shotgun metagenomic sequencing. RESULTS: Following diet conditioning, donors had depletion in metabolic pathways involved in sulfur-containing amino acids biosynthesis. Only Group-2 showed significant shifts towards the donors' microbial composition (ADONIS: R2=0.15, p=0.008) and significant increased Eubacterium_sp_AF228LB post-intervention (ß-coefficient 2.66, 95%CI 2.1-3.3, q<0.05) which was inversely correlated with fecal calprotectin (rho=-0.52, p=0.035). Moreover, pathways involved in gut inflammation and barrier function including branched chain amino acids were enriched post intervention in Group-2 and were significantly inversely correlated with fecal calprotectin. CONCLUSION: FMT from diet conditioned donors followed by the UCED led to microbial alterations associated with favorable microbial profile which correlated with decreased fecal calprotectin. Our findings support further exploration of additive benefit of dietary intervention for both donors and patients undergoing FMT as a potential treatment of UC.

Predictors of Complicated Disease Course in Adults and Children With Crohn's Disease: A Nationwide Study from the epi-IIRN.

BACKGROUND: Since data on predictors of complicated Crohn's disease (CD) from unselected populations are scarce, we aimed to utilize a large nationwide cohort, the epi-IIRN, to explore predictors of disease course in children and adults with CD. METHODS: Data of patients with CD were retrieved from Israel's 4 health maintenance organizations, whose records cover 98% of the population (2005-2020). Time-to-event modeled a complicated disease course, defined as CD-related surgery, steroid-dependency, or the need for >1 class of biologics. Hierarchical clustering categorized disease severity at diagnosis based on available laboratory results. RESULTS: A total of 16 659 patients (2999 [18%] pediatric-onset) with 121 695 person-years of follow-up were included; 3761 (23%) had a complicated course (750 [4.5%] switched to a second biologic class, 1547 [9.3%] steroid-dependency, 1463 [8.8%] CD-related surgery). Complicated disease was more common in pediatric- than adult-onset disease (26% vs 22%, odds ratio, 1.3; 95% confidence interval [CI], 1.2-1.4). In a Cox multivariate model, complicated disease was predicted by induction therapy with biologics (hazard ratio [HR], 2.1; 95% CI, 1.2-3.6) and severity of laboratory tests at diagnosis (HR, 1.7; 95% CI, 1.2-2.2), while high socioeconomic status was protective (HR, 0.94; 95% CI, 0.91-0.96). In children, laboratory tests predicted disease course (HR, 1.8; 95% CI, 1.2-2.5), as well as malnutrition (median BMI Z score -0.41; 95% CI, -1.42 to 0.43 in complicated disease vs -0.24; 95% CI, -1.23 to 0.63] in favorable disease; P < .001). CONCLUSIONS: In this nationwide cohort, CD course was complicated in one-fourth of patients, predicted by laboratory tests, type of induction therapy, socioeconomic status, in addition to malnutrition in children.

Prognostic factors of complicated disease course are vital for considering early escalation to biologics. In this nationwide cohort, complicated disease course was apparent in approximately one-fourth of patients and was predicted particularly by routinely collected laboratory tests, age, and type of induction therapy at diagnosis.

Adherence to ECCO Guidelines for Management of Iron Deficiency and Anemia in Inflammatory Bowel Diseases Among Israeli Adult and Pediatric Gastroenterologists.

OBJECTIVES: The consensus guidelines of the European Crohn's and Colitis Organization (ECCO) for the diagnosis and treatment of iron deficiency anemia (IDA) were published in 2015. We examined the management practices of both adult gastroenterologists (AGs) and pediatric gastroenterologists (PGs) in Israel in treating ID among patients with inflammatory bowel disease (IBD). METHODS: An 18-question multiple-choice anonymous questionnaire was electronically delivered to AGs and PGs. Questions explored 3 areas of interest: physician demographics, adherence to ECCO guidelines, and management practices of IDA in patients with IBD. RESULTS: Completed questionnaires were returned by 72 AGs and 89 PGs. Practice setting and years of practice were similar. A large majority of AGs and PGs (89% and 92%, respectively) measure complete blood count (CBC) and serum ferritin (S-Fr) at least every 3 months in outpatients with active IBD, as recommended by the ECCO guidelines. In contrast, in IBD patients in remission, only 53% and 26% of AGs and PGs, respectively ( P < 0.001), reported adherence to ECCO guidelines, measuring CBC and S-Fr every 6 months. The ECCO treatment guidelines recommend that intravenous (IV) iron should be considered the first-line treatment in patients with clinically active IBD, with previous oral iron intolerance and those with a hemoglobin level <10 g/dL. Study results indicate that only 43% of AGs recommend IV iron for these indications, compared to 54% of PGs ( P > 0.1). CONCLUSIONS: In this study we have demonstrated a relatively low level of adherence to ECCO guideline recommendations among both AGs and PGs, regarding the management of IDA in patients with IBD.

Serologic Response and Safety after a Third Dose of the COVID-19 BNT162b2 Vaccine in Patients with Inflammatory Bowel Diseases.

Vaccines are pivotal for control of the coronavirus disease (COVID-19) pandemic. Patients with inflammatory bowel diseases (IBDs) treated with antitumor necrosis factor (TNF)-α have lower serologic response after two COVID-19 vaccine doses. Data regarding a third vaccine dose are scarce. An Israeli multicenter prospective observational study recruited 319 subjects: 220 with IBD (79 treated with anti-TNFα) and 99 healthy control (HC) participants. All patients received two mRNA-BNT162b2 vaccines (Pfizer/BioNTech), 80% of whom received a third vaccine dose. Evaluation included disease activity, anti-spike (S) and nucleocapsid (N) antibody levels, anti-TNFα drug levels, and adverse events (AEs). All participants showed significant serologic response one month after receiving a third dose. However, three months later, the anti-S levels decreased significantly in patients treated with anti-TNFα compared with the non-anti-TNFα and HC groups. A correlation between serologic response to the third vaccine dose and anti-TNF drug levels was not found. No significant AE or IBD exacerbation was observed. Importantly, lower serologic response after the third vaccine dose predicted infection. A third dose of BNT162b2 is effective and safe in patients with IBD. Lower serologic response predicted infection, even in seropositive subjects. Lower serologic responses and their rapid decline suggest a fourth vaccine dose in this patient population.

Autoimmune Pancreatitis in Patients with Inflammatory Bowel Disease: A Real-World Multicentre Collaborative ECCO CONFER Study.

BACKGROUND: Autoimmune pancreatitis [AIP] is rarely associated with inflammatory bowel disease [IBD]. The long-term outcomes of AIP and IBD in patients with coexisting AIP-IBD and predictors of complicated AIP course have rarely been reported. METHODS: An ECCO COllaborative Network For Exceptionally Rare case reports project [ECCO-CONFER] collected cases of AIP diagnosed in patients with IBD. Complicated AIP was defined as a composite of endocrine and/or exocrine pancreatic insufficiency, and/or pancreatic cancer. We explored factors associated with complicated AIP in IBD. RESULTS: We included 96 patients [53% males, 79% ulcerative colitis, 72% type 2 AIP, age at AIP diagnosis 35 ±â€…16 years]. The majority of Crohn's disease [CD] cases [78%] had colonic/ileocolonic involvement. In 59%, IBD preceded AIP diagnosis, whereas 18% were diagnosed simultaneously. Advanced therapy to control IBD was used in 61% and 17% underwent IBD-related surgery. In total, 82% of patients were treated with steroids for AIP, the majority of whom [91%] responded to a single course of treatment. During a mean follow-up of 7 years, AIP complications occurred in 25/96 [26%] individuals. In a multivariate model, older age at AIP diagnosis was associated with a complicated AIP course (odds ratio [OR] = 1.05, p = 0.008), whereas family history of IBD [OR = 0.1, p = 0.03], and CD diagnosis [OR = 0.2, p = 0.04] decreased the risk of AIP complications. No IBD- or AIP-related deaths occurred. CONCLUSIONS: In this large international cohort of patients with concomitant AIP-IBD, most patients have type 2 AIP and colonic IBD. AIP course is relatively benign and long-term outcomes are favourable, but one-quarter develop pancreatic complications. Age, familial history of IBD, and CD may predict uncomplicated AIP course.

Ustekinumab during pregnancy in patients with inflammatory bowel disease: a prospective multicentre cohort study.

BACKGROUND: Women with inflammatory bowel diseases (IBD) often receive biologics to maintain remission during pregnancy. AIMS: To assess maternal and neonatal outcomes in patients with IBD treated with ustekinumab (UST) during pregnancy METHODS: In a multicentre, prospective cohort study, we recruited women with IBD treated with UST during pregnancy between 2019 and 2021. Outcomes were compared among patients treated with UST, anti-tumour necrosis factor α, (anti-TNF) and non-UST, non-anti-TNF therapies. UST-treated patients were matched 1:2 to controls according to age, body mass index and parity. Newborns were followed up to 12 months. RESULTS: We recruited 129 pregnant patients: UST 27; anti-TNF 52; non-UST, non-anti-TNF 50 (thiopurine or mesalazine 30, no therapy 20); Crohn's disease 25 (96.9%). Overall, pregnancy, neonatal and newborn outcomes were satisfactory, with no significant differences among patients treated with UST, anti-TNF and non-UST non-anti-TNF agents for obstetrical maternal complications [UST 3 (11.5%), anti TNF 12 (23.1%), non UST, non-anti-TNF 4 (8.2%), p = 0.095], pre-term delivery [1 (4.3%), 9 (18.4%), 4 (5.7%), p = 0.133], low birth weight [1 (4.2%), 5 (10.2%), 4 (8.3%), p = 0.679], or first year newborn hospitalisation [2 (9.1%), 4 (8.2%), 3 (6.1%), p = 0.885]. CONCLUSION: Pregnant patients with IBD treated with UST demonstrated favourable pregnancy and neonatal outcomes that were comparable with those in patients treated with anti-TNF or other therapy. Data are reassuring for patients with IBD and their physicians when considering UST during pregnancy.

Anti-TNFα Treatment Impairs Long-Term Immune Responses to COVID-19 mRNA Vaccine in Patients with Inflammatory Bowel Diseases.

Patients with inflammatory bowel disease (IBD) treated with anti-tumor-necrosis factor-alpha (TNFα) exhibited lower serologic responses one-month following the second dose of the COVID-19 BNT162b2 vaccine compared to those not treated with anti-TNFα (non-anti-TNFα) or to healthy controls (HCs). We comprehensively analyzed long-term humoral responses, including anti-spike (S) antibodies, serum inhibition, neutralization, cross-reactivity and circulating B cell six months post BNT162b2, in patients with IBD stratified by therapy compared to HCs. Subjects enrolled in a prospective, controlled, multi-center Israeli study received two BNT162b2 doses. Anti-S levels, functional activity, specific B cells, antigen cross-reactivity, anti-nucleocapsid levels, adverse events and IBD disease score were detected longitudinally. In total, 240 subjects, 151 with IBD (94 not treated with anti-TNFα and 57 treated with anti-TNFα) and 89 HCs participated. Six months after vaccination, patients with IBD treated with anti-TNFα had significantly impaired BNT162b2 responses, specifically, more seronegativity, decreased specific circulating B cells and cross-reactivity compared to patients untreated with anti-TNFα. Importantly, all seronegative subjects were patients with IBD; of those, >90% were treated with anti-TNFα. Finally, IBD activity was unaffected by BNT162b2. Altogether these data support the earlier booster dose administration in these patients.

Colectomy Rates did not Decrease in Paediatric- and Adult-Onset Ulcerative Colitis During the Biologics Era: A Nationwide Study From the epi-IIRN.

BACKGROUND: It is still of debate whether the advent of biologics has been associated with a change in the natural history of ulcerative colitis [UC]. In this nationwide study we evaluated trends of long-term outcomes in all patients diagnosed with UC in Israel during the biologic era. METHODS: Data in the epi-IIRN cohort were retrieved from the four Israeli Health Maintenance Organizations covering 98% of the population, and linked to the Ministry of Health prospective registry on surgeries and hospitalizations. Joinpoint Regression and Kaplan-Meier survival analyses were used, reporting annual average percentage change [AAPC] for each outcome. RESULTS: A total of 13 231 patients were diagnosed with UC since 2005 (1426 [11%] paediatric-onset, 10 310 [78%] adults, 1495 [11%] elderly) with 93 675 person-years of follow-up. The probabilities of surgery after 1, 3 and 5 years from diagnosis were 1.1, 2.3 and 4.1%, respectively, and the corresponding rates of hospitalizations were 22, 33 and 41%. The overall utilization of biologics in UC increased from 0.1% in 2005 to 9.6% in 2019 [AAPC 22.1%] and they were prescribed earlier during the disease course (median of 5.6 years [interquartile range 2.8-9.1] in 2005-2008 vs 0.8 years [0.4-1.5] in 2015-2018; p < 0.001]. Annual rates of surgeries [AAPC -1.3; p = 0.6] and steroid-dependency [AAPC -1.2; p = 0.3] remained unchanged, while rates of hospitalizations slightly decreased [AAPC -1.2; p < 0.001]. Outcomes were consistently worse in paediatric-onset disease than in adults, despite higher utilization of biologics [28% vs 12%, respectively; p < 0.001]. CONCLUSION: During the biologic era rates of surgeries and steroid-dependency have remained unchanged in patients with UC, while rates of hospitalizations have slightly decreased.

Lower Serologic Response to COVID-19 mRNA Vaccine in Patients With Inflammatory Bowel Diseases Treated With Anti-TNFα.

BACKGROUND & AIM: Patients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor necrosis factor (TNF)α biologics, are at high risk for vaccine-preventable infections. Their ability to mount adequate vaccine responses is unclear. The aim of the study was to assess serologic responses to messenger RNA-Coronavirus Disease 2019 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared with healthy controls (HCs). METHODS: Prospective, controlled, multicenter Israeli study. Subjects enrolled received 2 BNT162b2 (Pfizer/BioNTech) doses. Anti-spike antibody levels and functional activity, anti-TNFα levels and adverse events (AEs) were detected longitudinally. RESULTS: Overall, 258 subjects: 185 IBD (67 treated with anti-TNFα, 118 non-anti-TNFα), and 73 HCs. After the first vaccine dose, all HCs were seropositive, whereas ∼7% of patients with IBD, regardless of treatment, remained seronegative. After the second dose, all subjects were seropositive, however anti-spike levels were significantly lower in anti-TNFα treated compared with non-anti-TNFα treated patients, and HCs (both P < .001). Neutralizing and inhibitory functions were both lower in anti-TNFα treated compared with non-anti-TNFα treated patients, and HCs (P < .03; P < .0001, respectively). Anti-TNFα drug levels and vaccine responses did not affect anti-spike levels. Infection rate (∼2%) and AEs were comparable in all groups. IBD activity was unaffected by BNT162b2. CONCLUSIONS: In this prospective study in patients with IBD stratified according to treatment, all patients mounted serologic response to 2 doses of BNT162b2; however, its magnitude was significantly lower in patients treated with anti-TNFα, regardless of administration timing and drug levels. Vaccine was safe. As vaccine serologic response longevity in this group may be limited, vaccine booster dose should be considered.

The Crohn's disease exclusion diet for induction and maintenance of remission in adults with mild-to-moderate Crohn's disease (CDED-AD): an open-label, pilot, randomised trial.

BACKGROUND: The Crohn's disease exclusion diet (CDED) with partial enteral nutrition is effective for induction of remission in children with mild-to-moderate Crohn's disease. We aimed to assess the CDED in adults with Crohn's disease. METHODS: We did an open-label, pilot randomised trial at three medical centres in Israel. Eligible patients were biologic naive adults aged 18-55 years with mild-to-moderate Crohn's disease (defined by a Harvey-Bradshaw Index score of 5-14 points), a maximal disease duration of 5 years, with active disease on colonoscopy, or imaging with elevated inflammatory markers (C-reactive protein >5 mg/L or faecal calprotectin concentration >200 µ/g). Patients were randomly assigned (1:1) to CDED plus partial enteral nutrition or CDED alone for 24 weeks. Randomisation was via block randomisation (block sizes of six) using sealed, numbered, and opaque envelopes. Patients and investigators were aware of which group patients were assigned to due to the nature of the different interventions. The primary endpoint was clinical remission, defined as a Harvey-Bradshaw Index score of less than 5 at week 6. The primary endpoint was assessed in the intention-to-treat (ITT) population, which included all patients who used the dietary therapy for at least 48 h. We report results of the final analysis. This trial is registered with ClinicalTrials.gov, NCT02231814. FINDINGS: Between Jan 12, 2017, and May 11, 2020, 91 patients were screened, of whom 44 were randomly assigned to the CDED plus partial enteral nutrition group (n=20) or CDED alone group (n=24). 19 patients in the CDED plus partial enteral nutrition group and 21 patients in the CDED alone group received the allocated intervention for at least 48 h and thus were included in the ITT analysis. At week 6, 13 (68%) of 19 patients in the CDED plus partial enteral nutrition group and 12 (57%) of 21 patients in the CDED group had achieved clinical remission (p=0·4618). Among the 25 patients in remission at week 6, 20 (80%) were in sustained remission at week 24 (12 patients in the CDED plus partial enteral nutrition group and eight in the CDED alone group). 14 (35%) of 40 patients were in endoscopic remission at week 24 (eight patients in the CDED plus partial enteral nutrition group and six in the CDED alone group). No serious adverse events or treatment-related adverse events were reported in either group. INTERPRETATION: CDED with or without partial enteral nutrition was effective for induction and maintenance of remission in adults with mild-to-moderate biologic naive Crohn's disease and might lead to endoscopic remission. These data suggest that CDED could be used for mild-to-moderate active Crohn's disease and should be assessed in a powered randomised controlled trial. FUNDING: Azrieli Foundation and Nestle Health Science.

Use of Faecal Transplantation with a Novel Diet for Mild to Moderate Active Ulcerative Colitis: The CRAFT UC Randomised Controlled Trial.

BACKGROUND: We evaluated whether integration of novel diets for donors and patients, in addition to faecal transplantation [FT], could increase FT remission rate in refractory ulcerative colitis [UC]. METHODS: This was a blinded, randomised, controlled trial in adults with active UC, defined by a simple clinical colitis activity index [SCCAI] of ≥5 and ≤11 and endoscopic Mayo score 2-3, refractory to medication. Group 1 received free diet and single donor standard FT by colonoscopy on Day 1and rectal enemas on Days 2 and 14 without dietary conditioning of the donor. Group 2 received FT as above but with dietary pre-conditioning of the donor for 14 days and a UC Exclusion Diet [UCED] for the patients. Group 3 received the UCED alone. The primary endpoint was Week 8 clinical steroid-free remission, defined as SCCAI <3. RESULTS: Of 96 planned patients, 62 were enrolled. Remission Week 8 Group 1 was 2/17 [11.8%], Group 2 was 4/19 [21.1%], Group 3 was 6/15 [40%] [non-significant]. Endoscopic remission Group 1 was 2/17 [12%], Group 2 was 3/19 [16%], Group 3 was 4/15 [27%] [Group 1 vs 3 p = 0.38]. Mucosal healing [Mayo 0] was achieved only in Group 3 [3/15, 20%] vs 0/36 FT patients [p = 0.022]. Exacerbation of disease occurred in 3/17 [17.6%] of Group 1, 4/19 [21.1%] of Group 2, and 1/15 [6.7%] of Group 3 [Group 2 vs 3, p = 0.35]. CONCLUSIONS: UCED alone appeared to achieve higher clinical remission and mucosal healing than single donor FT with or without diet. The study was stopped for futility by a safety monitoring board.

Post-Induction High Adalimumab Drug Levels Predict Biological Remission at Week 24 in Patients With Crohn's Disease.

INTRODUCTION: We investigated whether early adalimumab drug levels (ADL) at week 4 predicted biological remission at week 24. METHODS: In a prospective study, we assessed clinical and biological remission at weeks 0, 4, 12, and 24 after induction of adalimumab in 33 patients with Crohn's disease. Disease activity was determined by the Harvey-Bradshaw Index, ileocolonoscopy reports, cross-sectional imaging, C-reactive protein (CRP), and fecal calprotectin (FC) levels. Clinical remission was defined as Harvey-Bradshaw Index <5. Biological remission was defined as a combination of FC < 200 µg/g and CRP <5 µg/mL. ADL trough levels were tested using a liquid phase, mobility shift assay. RESULTS: At 24 weeks, 18/33 (55%) of the patients were with biological remission. Ten (30%) patients required dose escalation or withdrawal from adalimumab by week 24 because of lack of response and exhibited significantly higher FC (P = 0.003) and CRP (P = 0.002). ADL levels at week 4 (19.8 µg/mL vs 10.2 µg/mL, P = 0.001) were significantly higher in patients with biological remission vs nonresponders at week 24. ADL levels at week 4 were a good predictor of biological remission at week 24, with area under the curve 0.86, 95% confidence interval (1.1; 1.67) and for combined biological and clinical remission, with area under the curve 0.8. The best ADL cutoff at week 4 that predicted biological remission at week 24 was 13.9 µg/mL (sensitivity 94.4% and specificity 73.3%). DISCUSSION: In individuals with Crohn's disease, higher adalimumab drug levels at week 4 (>13.9 µg/mL) were significantly associated with biological remission at week 24.

Effectiveness of ustekinumab dose escalation in Crohn's disease patients with insufficient response to standard-dose subcutaneous maintenance therapy.

BACKGROUND: Ustekinumab is effective in Crohn's disease. However, a substantial proportion of patients will not respond or lose response to ustekinumab. The current evidence to support the effectiveness of dose-optimisation for ustekinumab nonresponse is limited. AIM: To assess the effectiveness of dose escalation of ustekinumab. METHODS: This was a multicentre retrospective cohort study. We included active Crohn's disease patients who received a standard-dose intravenous induction and at least one subcutaneous ustekinumab 90 mg dose. All enrolled patients received dose escalation by either shortening the interval between the doses to every 4 or 6 weeks, intravenous reinduction or a combination of strategies. The primary outcome of the study was clinical response at week 16 after dose escalation. RESULTS: A total of 142 patients (22 centres/14 countries) were included. The patients were dose-escalated after a median treatment duration of 30 weeks. At week 16 from escalation, 73/142 (51.4%) responded to treatment, including 55/142 (38.7%) in clinical remission. Corticosteroid-free remission was achieved in 6/34 (17.6%) patients on corticosteroids at the time of escalation; 118/142 (83%) continued treatment beyond week 16. Follow-up data beyond week 16 were available for 74/118 (62.7%) patients. On the last follow-up, 51/98 (52%) patients with available data responded to treatment, including 41/98 (42%) in clinical remission. CONCLUSIONS: Intensification of ustekinumab maintenance dosage was effective in over 50% of the patients. This strategy should be considered in patients who are nonresponsive to every 8 weeks ustekinumab maintenance dosing.

Preoperative Exclusive Total Parental Nutrition is Associated with Clinical and Laboratory Remission in Severe Active Crohn's Disease-A Pilot Study.

BACKGROUND: The effect of 1-3 months of preoperative exclusive total parental nutrition (TPN) in active Crohn's disease (CD) patients is not well established. We investigated the efficacy of exclusive TPN in active CD patients. METHODS: In a retrospective multi-visit study with data according to our standard care therapy, we assessed clinical and laboratory remission to refractory CD with exclusive preoperative TPN. Inclusion required exclusive preoperative home TPN without additional oral intake for 1-3 months prior to planning surgery. RESULTS: Twenty preoperative CD patients (65% male; 35% female) were on exclusive TPN. The mean age of the cohort was 30.8 ± 11.6 years. Mean duration of preoperative TPN treatment was 73 days (range: 24-142 days). Most patients had terminal ileal (35%) or ileocolonic CD (30%), and with stricturing (B2) phenotype. All 20 patients had significant clinical improvement in all disease activity indices at the end of preoperative TPN (baseline vs. post TPN): HBI 14.5 vs. 4.0 (p = 0.001); BMI 19.2 vs. 19.7 kg/m2 (p = 0.017); CRP 57.2 vs. 10.3 mg/L (p = 0.001); Fecal calprotectin (FC) 672 vs. 200 (µg/g); albumin 2.7 vs. 3.6 g/dL (p = 0.001). Two patients (10%) no longer required surgery after completion of exclusive TPN. CONCLUSION: Exclusive preoperative TPN was found to provide significant improvement in nutritional status, and clinical and laboratory remission in severe active Crohn's patients.

Safety and effectiveness of ustekinumab for induction of remission in patients with Crohn's disease: A multicenter Israeli study.

INTRODUCTION: Ustekinumab is an effective treatment of Crohn's disease (CD). Real-world data addressing the efficacy and safety of ustekinumab are scarce. AIM: Our aim was to assess the safety and efficacy of ustekinumab in a large national patient cohort. METHODS: A prospective multicenter study, in which we followed patients with active CD treated with ustekinumab for 24 weeks. Induction dose was intravenous ranging from 260 to 520 mg, according to body weight, followed by 90 mg doses given subcutaneously every 8 weeks. Clinical response was defined as a reduction of at least 1 severity category, as defined by Harvey-Bradshaw index (HBI). Patients with HBI < 5 were considered to be in clinical remission. Patients who stopped needing steroids at week 24 were defined as being in steroid-free clinical remission. RESULTS: A total of 106 CD patients from eight Israeli centers were included. All patients were previously exposed to at least one biological agent. Our cohort consisted of 65 (61.3%) females. Mean age was 41 ± 14 years with an average disease duration of 12.2 ± 8 years. A total of 96 (90.5%) patients continued treatment throughout week 24. Clinical response was observed in 52% of these patients with mean HBI reduction from 8.34 ± 3.8 to 6.8 ± 4.4 at week 24 (p = 0.001). Clinical remission was achieved in 33 patients (31.1%). Moreover, the number of patients requiring steroid treatment was reduced by 66% at week 24. Out of 106 patients, 11 patients (10.4%) discontinued treatment: 3 due to adverse events (2.8%), 7 due to a lack of response, and 1 who was lost to follow-up. Following 24 weeks of treatment, 15 patients reported minor adverse events. CONCLUSIONS: In a large real-world Israeli cohort of non-naïve-to-biological-treatment CD patients, ustekinumab was effective and safe in induction of clinical remission with a significant reduction in the number of patients requiring steroid treatment.

Associations between quantitative evaluation of bowel wall microvascular flow by contrast-enhanced ultrasound and indices of disease activity in Crohn's disease patients using both bolus and infusion techniques.

PURPOSE: The aim is to investigate whether baseline contrast-enhanced ultrasound (CEUS) correlates with indices of activity in Crohn's disease (CD) and can predict response to medical treatment. METHODS: In this prospective study, symptomatic CD patients underwent baseline CEUS performed with Definity using both bolus and infusion methods. Time-intensity curves (TIC), peak intensity (PI), and area under curve (AUC) from a region of interest over the diseased bowel were calculated for both bolus and infusion acquisitions. We used Mann-Whitney U test for continuous and chi-square/two-tailed Fisher's exact test for categorical variable comparison and Spearman's correlation coefficient to correlate clinical score and CEUS kinetic parameters. RESULTS: Twenty-one patients (9 men, 12 women, median age 32 years) were accrued. Fifteen patients had clinically active disease defined as Harvey-Bradshaw Index (HBI) score ≥5. Median values of baseline CEUS parameters PI (bolus: 26 vs 8.86; P = .023 and perfusion: 7.6 vs 3.2; P = .009) and AUC (bolus: 769 vs 248.8; P = .036 and perfusion: 188.9 vs 73.9; P = .012) differed significantly in patients with active vs inactive disease. Nine patients with active disease underwent escalated or new treatment. Five were nonresponders. Responders had higher median values of baseline parameters (PI, bolus: 35 vs 18.8; P = .556, and perfusion: 7.6 vs 3.9; P = 190), (AUC, bolus: 1473.9 vs 314; P = .111, and perfusion: 154.7 vs 74.4, P = .286). CONCLUSIONS: CEUS kinetic parameters correlate with clinical and laboratory indices and are significantly higher in patients with active disease. The responders had higher CEUS kinetic parameters than nonresponders that did not reach statistical significance in our small cohort.

Preoperative exposure to anti-tumor necrosis factor therapy in ulcerative colitis patients undergoing ileal pouch-anal anastomosis (IPAA) is not associated with histological fibrosis: A case control study.

BACKGROUND: We sought to determine whether preoperative exposure to anti-TNF therapy affects objective histological measures of fibrosis in the colorectum. METHODS: Ulcerative colitis (UC) patients who received infliximab as maintenance therapy pre IPAA surgery were identified and compared to anti-TNF-naïve matched controls by age, sex, BMI, disease duration, albumin levels, and post-operative leak outcome. Hematoxylin and eosin- (H&E) and trichrome-stained slides from the most distal, well-oriented, full-thickness section of colorectum from each patient's total colectomy specimen were evaluated. Blinded histopathological assessment of the degree of fibrosis was performed using a semi-quantitative pictorial scale. RESULTS: Histological fibrosis in 65 patients from the therapy group was compared to 65 patients from the matched control group. There were no statistically significant differences in the degree of fibrosis observed in any of the bowel layers. In the lamina propria, 29% of the control group and 28% of the treatment group had fibrosis scores ≥3. Fibrosis scores were higher in the submucosa, with both groups having 66% of patients showing scores ≥3. Similarly, in the region above the muscularis propria, 77% of the control group and 80% of the treatment group had fibrosis scores ≥3. In the subserosa, fibrosis scores were lower, with 25% of the control group and 32% of the treatment group having fibrosis scores ≥3. CONCLUSION: Resection specimens from UC patients treated with maintenance anti-TNF therapy who underwent IPAA surgery showed no significant differences in the degree of histologic fibrosis in any of the bowel layers compared to a matched control group.

Development of the Harvey-Bradshaw Index-pro (HBI-PRO) Score to Assess Endoscopic Disease Activity in Crohn's Disease.

BACKGROUND: There is a need for better, less-invasive disease activity indices that provide a representative assessment of endoscopic disease activity. We developed a new clinical score that incorporates the Harvey-Bradshaw index [HBI] with modified patient-reported outcomes [PROp] and physician [clinician]-reported outcomes [PROc] and assessed its ability to measure endosopic disease activity in ileocolonic Crohn's disease [CD]. METHODS: A cohort of 88 CD patients undergoing colonoscopy was accrued in a prospective fashion. In total, 48 of the subjects were CD cases and 40 had already undergone a post-operative ileocolonic resection [post-op CD]. Each patient underwent multiple, endoscopist-blinded assessments including: HBI score, a PROp question asking for patient perception of disease activity status, a PROc question for clinician perception of disease activity status and C-reactive protein [CRP]. Active endoscopic disease was defined as Simple Endoscopic Score for CD [SES-CD] ≥ 3 for CD subjects and Rutgeerts score > i1 for post-op CD subjects. RESULTS: Clinical remission as defined by the HBI did not accurately reflect endoscopic remission as defined by the SES-CD (area under the curve [AUC] = 0.54). Combining the HBI with PROp and PROc scores and then further adding CRP significantly improved the correlation with SES-CD [AUC = 0.78 and AUC = 0.88, respectively, p < 0.00001]. In post-op CD, HBI-defined remission also performed poorly against endoscopic remission defined by the Rutgeerts score [AUC = 0.52]. Combining HBI with PROp and the PROc scores and then further adding CRP did not significantly improve the model [AUC = 0.65 and AUC = 0.61, respectively, p = NS]. CONCLUSION: In CD, the HBI correlates poorly with endoscopic disease activity. However, the HBI-PRO score, which incorporated PROp, PROc, CRP and HBI, significantly improved its ability to predict endoscopic activity in ileocolonic CD without prior surgery.

Efficacy and Safety of Vedolizumab for Induction of Remission in Inflammatory Bowel Disease-the Israeli Real-World Experience.

BACKGROUND: Vedolizumab (VDZ) is an anti-integrin monoclonal antibody effective in ulcerative colitis (UC) and Crohn's disease (CD). The aim of this study was to examine the "real world" efficacy and safety of VDZ in a large national patient cohort. METHODS: Patients with inflammatory bowel disease treated with VDZ were prospectively followed for 14 weeks. Patients who completed the induction protocol (week 0/2/6/14) or discontinued the treatment before week 14 for adverse events (AEs) or primary nonresponse were included. The primary outcome was induction of clinical remission at week 14; secondary outcomes included clinical response and corticosteroid-free clinical remission. RESULTS: A total of 204 patients (CD-130, UC-69, inflammatory bowel disease-unclassified-5) from 8 centers in Israel were included. Fifteen (7.4%) of the patients were anti-tumor necrosis factor naive and 46 (35.4%) had a previous surgery. For patients with CD, 69/130 (53.1%) responded to treatment; 45 (34.6%) achieved clinical remission; and 38 (29.2%) achieved corticosteroid-free remission at week 14. Fourteen (10.7%) patients discontinued VDZ before week 14 due to primary nonresponse or AEs. For UC, 32/74 (43.2%) responded to treatment; 20 (28.4%) achieved clinical remission, and 18 (24.3%) achieved corticosteroid-free remission at week 14. Fifteen (20.3%) patients with UC did not complete the induction due to primary nonresponse or AEs. AEs were reported by 29 (14.2%) patients (CD and UC combined), most common being nasopharyngitis and skin eruptions. CONCLUSIONS: In a large real-world Israeli cohort of anti-tumor necrosis factor-experienced patients with inflammatory bowel disease, VDZ was effective and safe in induction of clinical remission and steroid-free clinical remission.

Preoperative Anti-tumor Necrosis Factor Therapy in Patients with Ulcerative Colitis Is Not Associated with an Increased Risk of Infectious and Noninfectious Complications After Ileal Pouch-anal Anastomosis.

BACKGROUND: There are conflicting data regarding the effect of previous exposure to anti-tumor necrosis factor (anti-TNF) therapy on complication rates after pelvic pouch surgery for patients with ulcerative colitis (UC). In particular, there is concern surrounding the rates of pouch leaks and infectious complications, including pelvic abscesses, in anti-TNF-treated subjects who require ileal pouch-anal anastomosis (IPAA) surgery. METHODS: A retrospective study was performed in UC subjects who underwent IPAA between 2002 and 2013. Demographic data, clinical data, use of anti-TNF therapy, steroids, immunosuppressants, and surgical outcomes were assessed. RESULTS: Seven hundred seventy-three patients with UC/IPAA were reviewed. Fifteen patients were excluded from the analysis because of missing data. There were 196 patients who were exposed to anti-TNF therapy and 562 patients who were not exposed to anti-TNF therapy preoperatively. There were no significant differences in the postoperative IPAA leak rate between those exposed to anti-TNF therapy and the control group (n = 26 [13.2%] versus 66 [11.7%], respectively, P = 0.44). In addition, there were no significant differences in the postoperative 2-stage IPAA leak rate in those who had been operated on within 15 days from the last anti-TNF dose (n = 10), within 15 to 30 days (n = 17), or 31 to 180 days (n = 54) (10%, 5.9%, and 14.8% respectively, P = 0.43) nor were there differences based on the presence of detectable infliximab serum levels. CONCLUSIONS: Preoperative anti-TNF therapy in patients with UC is not associated with an increased risk of infectious and noninfectious complications after IPAA including pelvic abscesses, leaks, and wound infections.