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 Children and Adults With Ulcerative Colitis: A Nationwide Study From the epi-IIRN.

BACKGROUND: Data on predictors of complicated ulcerative colitis (UC) course from unselected populations cohorts are scarce. We aimed to utilize a nationwide cohort to explore predictors at diagnosis of disease course in children and adults with UC. METHODS: Data of patients diagnosed with UC since 2005 were retrieved from the nationwide epi-IIRN cohort. Complicated disease course was defined as colectomy, steroid-dependency, or the need for biologic drugs. Hierarchical clustering categorized disease severity at diagnosis based on complete blood count, albumin, C-reactive protein and erythrocyte sedimentation rate (ESR), analyzed together. RESULTS: A total of 13 471 patients with UC (1427 [11%] pediatric-onset) including 103 212 person-years of follow-up were included. Complicated disease course was recorded in 2829 (21%) patients: 1052 (7.9%) escalated to biologics, 1357 (10%) experienced steroid-dependency, and 420 (3.1%) underwent colectomy. Probabilities of complicated disease course at 1 and 5 years from diagnosis were higher in pediatric-onset (11% and 32%, respectively) than adult-onset disease (4% and 16%; P < .001). In a Cox multivariate model, complicated course was predicted by induction therapy with steroids (hazard ratio [HR], 1.5; 95% CI, 1.2-2.0), extraintestinal manifestations (HR, 1.3; 95% CI, 1.03-1.5) and the disease severity clusters of blood tests (HR, 1.8; 95% CI, 1.01-3.1), while induction therapy with enemas (HR, 0.6; 95% CI, 0.5-0.7) and older age (HR, 0.99; 95% CI, 0.98-0.99) were associated with noncomplicated course. CONCLUSION: In this nationwide cohort, the probability of complicated disease course during the first 5 years from diagnosis was 32% in pediatric-onset and 16% in adults with UC and was associated with more severe clusters of routinely collected laboratory tests, younger age at diagnosis, extraintestinal manifestations, and type of induction therapy.

Prognostic factors of complicated disease course are vital for clinical decision-making of early escalation to intensive treatment. In this nationwide cohort, one-third of children and one-fifth of adults with UC developed complicated disease course. Disease course was predicted particularly by routinely collected laboratory tests, age, extraintestinal manifestations, and type of induction therapy at diagnosis.

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.

Curcumin-QingDai Combination for Patients With Active Ulcerative Colitis: A Randomized, Double-Blinded, Placebo-Controlled Trial.

BACKGROUND & AIMS: We evaluated the efficacy of herbal combination of curcumin-QingDai (CurQD) in active ulcerative colitis (UC). METHODS: Part I was an open-label trial of CurQD in patients with active UC, defined by a Simple Clinical Colitis Activity Index score of 5 or higher and a Mayo endoscopic subscore of 2 or higher. Part II was a placebo-controlled trial conducted in Israel and Greece, randomizing active UC patients at a 2:1 ratio to enteric-coated CurQD 3 g/d or placebo for 8 weeks. The co-primary outcome was clinical response (reduction in the Simple Clinical Colitis Activity Index of ≥3 points) and an objective response (Mayo endoscopic subscore improvement of ≥1 or a 50% fecal calprotectin reduction). Responding patients continued either maintenance curcumin or placebo alone for an additional 8 weeks. Aryl-hydrocarbon receptor activation was assessed by cytochrome P450 1A1 (CYP1A1) mucosal expression. RESULTS: In part I, 7 of 10 patients responded and 3 of 10 achieved clinical remission. Of 42 patients in part II, the week 8 co-primary outcome was achieved in 43% and 8% of CurQD and placebo patients, respectively (P = .033). Clinical response was observed in 85.7% vs 30.7% (P < .001), clinical remission in 14 of 28 (50%) vs 1 of 13 (8%; P = .01), a 50% calprotectin reduction in 46.4% vs 15.4% (P = .08), and endoscopic improvement in 75% vs 20% (P = .036) in the CurQD and placebo groups, respectively. Adverse events were comparable between groups. By week 16, curcumin-maintained clinical response, clinical remission, and clinical biomarker response rates were 93%, 80%, and 40%, respectively. CurQD uniquely up-regulated mucosal CYP1A1 expression, which was not observed among patients receiving placebo, mesalamine, or biologics. CONCLUSIONS: In this placebo-controlled trial, CurQD was effective for inducing response and remission in active UC patients. The aryl-hydrocarbon receptor pathway may merit further study as a potential UC treatment target. CLINICALTRIALS: gov ID: NCT03720002.

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.

Real-world experience with Curcumin-QingDai combination for patients with active ulcerative colitis: A retrospective multicentre cohort study.

BACKGROUND: Curcumin and QingDai (QD, Indigo) have been shown to be effective for treating active ulcerative colitis (UC). AIM: To evaluate the real-world experience with the Curcumin-QingDai (CurQD) herbal combination to induce remission in active UC. METHODS: A retrospec-tive multicentre adult cohort study from five tertiary academic centres (2018-2022). Active UC was defined as a Simple Clinical Colitis Activity Index (SCCAI) ≥ 3. Patients were induced by CurQD. The primary outcome was clinical remission at weeks 8-12, defined as SCCAI ≤2 and a decrease ≥3 points from baseline. Secondary outcomes were clinical response (SCCAI decrease ≥3 points), corticosteroid-free remission, faecal calprotectin (FC) response (reduction ≥50%), FC normalisation (FC ≤100 µg/g for patients with FC ≥300 µg/g at baseline), and safety. All outcomes were analysed for patients who were maintaining stable treatment. RESULTS: Eighty-eight patients were included; 50% were biologics/small molecules experienced, and 36.5% received ≥2 biologics/small molecules. Clinical remission was achieved in 41 (46.5%), and clinical response in 53 (60.2%). Median SCCAI decreased from 7 (IQR:5-9) to 2 (IQR:1-3); p < 0.0001. Of the 26 patients on corticosteroids at baseline, seven achieved corticosteroid-free remission. Among 43 biologics/small molecules experienced patients, clinical remission was achieved in 39.5% and clinical response in 58.1%. FC normalisation and response were achieved in 17/29 and 27/33, respectively. Median FC decreased from 1000 µg/g (IQR:392-2772) at baseline to 75 µg/g (IQR:12-136) at the end of inductions (n = 30 patients with paired samples); p < 0.0001. No overt safety signals emerged. CONCLUSION: In this real-world cohort, CurQD effectively induced clinical and biomarker remission in patients with active UC, including patients who were biologics/small molecules experienced.

Comparison of Short- and Long-Term Effectiveness between Anti-TNF and Ustekinumab after Vedolizumab Failure as First-Line Therapy in Crohn's Disease: A Multi-Center Retrospective Cohort Study.

BACKGROUND: The effectiveness of anti-TNF or ustekinumab (UST) as a second-line biologic after vedolizumab (VDZ) failure has not yet been described. AIMS AND METHODS: In this retrospective multicenter cohort study, We aim to investigate the effectiveness of anti-TNF and UST as second-line therapy in patients with Crohn's disease (CD) who failed VDZ as a first-line treatment. The primary outcome was clinical response at week 16-22. Secondary outcomes included the rates of clinical remission, steroid-free clinical remission, CRP normalization, and adverse events. RESULTS: Fifty-nine patients who failed on VDZ as a first-line treatment for CD were included; 52.8% patients received anti-TNF and 47.2% UST as a second-line therapy. In initial period (Week 16-22), the clinical response and remission rate was similar between both groups: 61.2% vs. 68%, p = 0.8 and 48.3% vs. 56%, p = 0.8 on anti-TNF and UST therapy, respectively. Furthermore, in the maintenance period the rate was similar: 75% vs. 82.3%, p = 0.8 and 62.5% vs. 70.5%, p = 0.8, respectively. Of the patients, 12 out of the 59 stopped the therapy, without a significant difference between the two groups (p = 0.6). CONCLUSION: Second-line biological therapy after VDZ failure therapy was effective in >60% of the patients with CD. No differences in effectiveness were detected between the use of anti-TNF and UST as a second line.

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.

COVID-19 in Patients with Inflammatory Bowel Disease: The Israeli Experience.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are chronic, immune-mediated inflammatory bowel diseases (IBD) affecting millions of people worldwide. IBD therapies, designed for continuous immune suppression, often render patients more susceptible to infections. The effect of the immune suppression on the risk of coronavirus disease-19 (COVID-19) is not fully determined yet. OBJECTIVE: To describe COVID-19 characteristics and outcomes and to evaluate the association between IBD phenotypes, infection outcomes and immunomodulatory therapies. METHODS: In this multi-center study, we prospectively followed IBD patients with proven COVID-19. De-identified data from medical charts were collected including age, gender, IBD type, IBD clinical activity, IBD treatments, comorbidities, symptoms and outcomes of COVID-19. A multivariable regression model was used to examine the effect of immunosuppressant drugs on the risk of infection by COVID-19 and the outcomes. RESULTS: Of 144 IBD patients, 104 (72%) were CD and 40 (28%) were UC. Mean age was 32.2 ± 12.6 years. No mortalities were reported. In total, 94 patients (65.3%) received biologic therapy. Of them, 51 (54%) at escalated doses, 10 (11%) in combination with immunomodulators and 9 (10%) with concomitant corticosteroids. Disease location, behavior and activity did not correlate with the severity of COVID-19. Biologics as monotherapy or with immunomodulators or corticosteroids were not associated with more severe infection. On the contrary, patients receiving biologics had significantly milder infection course (p = 0.001) and were less likely to be hospitalized (p = 0.001). Treatment was postponed in 34.7% of patients until recovery from COVID-19, without consequent exacerbation. CONCLUSION: We did not witness aggravated COVID-19 outcomes in patients with IBD. Patients treated with biologics had a favorable outcome.

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.

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.

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.

Disease Activity in Inflammatory Bowel Disease Is Associated With Arterial Vascular Disease.

BACKGROUND AND AIMS: There is evidence that several inflammatory diseases are associated with increased cardiovascular risk. Whether this is true for inflammatory bowel diseases remains controversial. We aimed to assess this risk, corrected for the effects of conventional vascular risk factors and IBD disease activity. METHODS: We conducted a cohort study in British general practice and hospital records from the Clinical Practice Research Datalink. We extracted the records of subjects with IBD and matched controls from 1997 to 2017. We conducted Cox proportional hazards and self-controlled case series analyses to examine the associations of IBD, disease activity, and hospitalization with the risk of myocardial infarction, stroke, and cardiovascular death in a manner attempting to remove the effect of likely confounders. RESULTS: We identified 31,175 IBD patients (16,779 UC, 10,721 Crohn's disease, and 3675 unclassifiable cases) and 154,412 matched controls. Five hundred thirty-two myocardial infarctions, 555 strokes, and 469 cardiovascular deaths were observed in IBD cases. Our Cox regression models, adjusted for potential confounders, showed no significant excess of vascular events for IBD patients overall. There was, however, an increased hazard of myocardial infarction in ambulatory patients for acute disease (hazard ratio, 1.83 [1.28-2.62]) and chronic activity (hazard ratio, 1.69 [1.24-2.30]). This effect of disease activity was confirmed in our case series analysis. CONCLUSIONS: Though we have found no evidence of an overall excess of vascular events in IBD patients, our findings of increased risk with more active disease suggest the potential for anti-inflammatory therapies to reduce cardiovascular risk in this patient group.

The New Proactive Approach and Precision Medicine in Crohn's Disease.

The proactive approach to Crohn's disease (CD) management advocates moving toward algorithmic tight-control scenarios that are designed for each CD phenotype to guide remission induction, maintenance therapy, active monitoring, and multidisciplinary care to manage the complexities of each inflammatory bowel disease (IBD) patient. This requires accurate initial clinical, laboratory, radiological, endoscopic, and/or tissue diagnosis for proper phenotypic stratification of each CD patient. A substantial proportion of patients in symptomatic remission have been reported to demonstrate evidence of active disease, with elevated fecal calprotectin(FC) and C-reactive protein (CRP) levels as a hallmark for mucosal inflammation. Active mucosal inflammation, and elevated CRP and fecal calprotectin (FC) have been shown to be good predictors of clinical relapse, disease progression, and complications in IBD patients. The next frontier of treatment is personalized medicine or precision medicine to help solve the problem of IBD heterogeneity and variable responses to treatment. Personalized medicine has the potential to increase the efficacy and/or reduce potential adverse effects of treatment for each CD phenotype. However, there is currently an unmet need for better elucidation of the inflammatory biopathways and genetic signatures of each IBD phenotype, so personalized medicine can specifically target the underlying cause of the disease and provide maximal efficacy to each patient.