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.

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.

Early Initiation of Adalimumab Significantly Diminishes Postoperative Crohn's Disease Endoscopic Recurrence and Is Superior to 6-Mercaptopurine Therapy: An Open-Label, Randomized Controlled Study.

Postoperative recurrence (POR) is the rule in patients with Crohn's disease (CD), mitigated with prophylactic therapy. The evidence for therapeutic choice and timing of intervention is lacking. We aimed to compare the rates of POR in patients treated early with prophylactic 6-mercaptopurine (6-MP) or adalimumab. We conducted a prospective single-center randomized open-label clinical study in which patients in surgical remission following their first ileocecectomy were randomized to receive early treatment with 6-MP or adalimumab. Patients were followed up clinically every 3 months and underwent endoscopy at weeks 32 and 58 postoperatively. The primary endpoint was endoscopic recurrence (ePOR) at 1 year (week 58), defined as a Rutgeerts score ≥ i2. We enrolled 35 patients (25 males, mean age 35 ± 1.4 years, median disease duration 5 ± 6.1 years) following ileocecectomy. Of these, seven (20%) were current smokers and nine (26%) biologics-experienced. Patients allocated to adalimumab had significantly less ePOR than patients treated with 6MP at week 32 (21% vs. 69%, p = 0.004) and 58 (47% vs. 75%), (p = 0.03, HR = 0.39, 95% CI = 0.16-0.93). POR was associated with an increased diameter of the resected small bowel surgical specimen, lower baseline body mass index (BMI), increased week 18 fecal calprotectin, increased week 18 serum alanine aminotransferase and decreased week 18 hemoglobin level. Adalimumab was more effective than 6-MP in preventing ePOR. Increased operative small bowel diameter and lower postoperative BMI were associated with ePOR. At eighteen weeks, serum hemoglobin, ALT and fecal calprotectin levels were predictive of endoscopic disease recurrence. (ClinicalTrials.gov ID NCT01629628).

The Crohn's Disease Exclusion Diet: A Comprehensive Review of Evidence, Implementation Strategies, Practical Guidance, and Future Directions.

Dietary therapy is increasingly recognized for the management of Crohn's disease (CD) over recent years, including the use of exclusive enteral nutrition (EEN) as first-line therapy for pediatric CD according to current guidelines. The Crohn's disease exclusion diet (CDED) is a whole-food diet designed to reduce exposure to dietary components that are potentially pro-inflammatory, mediated by negative effects on the gut microbiota, immune response, and the intestinal barrier. The CDED has emerged as a valid alternative to EEN with cumulative evidence, including randomized controlled trials, supporting use for induction of remission and possibly maintenance in children and adults. We gathered a group of multidisciplinary experts, including pediatric and adult gastroenterologists, inflammatory bowel diseases (IBD) expert dietitians, and a psychologist to discuss the evidence, identify gaps, and provide insights into improving the use of CDED based on a comprehensive review of CDED literature and professional experience. This article reviews the management of CDED in both children and adults, long-term aspects of CDED, indications and contraindications, selecting the best candidates, identifying challenges with CDED, globalization, the role of the multidisciplinary team, especially of dietitian, and future directions. We concluded that CDED is an established dietary therapy that could serve as an alternative to EEN in many pediatric and adult cases, especially with mild to moderate disease. In severe disease, complicated phenotypes, or with extraintestinal involvement, CDED should be considered on a case-by-case basis, according to physician and dietitians' discretion. More studies are warranted to assess the efficacy of CDED in different scenarios.

The Crohn's disease exclusion diet (CDED) has emerged as an alternative to exclusive enteral nutrition for the treatment of pediatric Crohn's disease. In this review, we summarize data on efficacy and challenges and identify research priorities, clinical gaps, and opportunities.

Real-Life Efficacy of Tofacitinib in Various Situations in Ulcerative Colitis: A Retrospective Worldwide Multicenter Collaborative Study.

BACKGROUND AND AIMS: Tofacitinib (TFB) appears to be effective in the treatment of ulcerative colitis (UC); however, available real-world studies are limited by cohort size. TFB could be an option in the treatment of acute severe ulcerative colitis (ASUC). We aimed to investigate efficacy and safety of TFB in moderate-to-severe colitis and ASUC. METHODS: This retrospective, international cohort study enrolling UC patients with ≥6-week follow-up period was conducted from February 1 to July 31, 2022. Indications were categorized as ASUC and chronic activity (CA). Baseline demographic and clinical data were obtained. Steroid-free remission (SFR), colectomy, and safety data were analyzed. RESULTS: A total of 391 UC patients (median age 38 [interquartile range, 28-47] years; follow-up period 26 [interquartile range, 14-52] weeks) were included. A total of 27.1% received TFB in ASUC. SFR rates were 23.7% (ASUC: 26.0%, CA: 22.8%) at week 12 and 41.1% (ASUC: 34.2%, CA: 43.5%) at week 52. The baseline partial Mayo score (odds ratio [OR], 0.850; P = .006) was negatively associated with week 12 SFR, while biologic-naïve patients (OR, 2.078; P = .04) more likely achieved week 52 SFR. The colectomy rate at week 52 was higher in ASUC group (17.6% vs 5.7%; P < .001) and decreased with age (OR, 0.94; P = .013). A total of 67 adverse events were reported, and 17.9% resulted in cessation of TFB. One case of thromboembolic event was reported. CONCLUSIONS: TFB is effective in both studied indications. TFB treatment resulted in high rates of SFR in the short and long terms. Higher baseline disease activity and previous biological therapies decreased efficacy. No new adverse event signals were found.

Crohn's Disease Exclusion Diet for the Treatment of Crohn's Disease: Real-World Experience from a Tertiary Center.

The Crohn's Disease (CD) exclusion diet (CDED) has been shown to induce remission in pediatric and adult patients with CD. In this retrospective cohort study, we describe our real-world experience with the CDED at the inflammatory bowel disease (IBD) unit of the Tel Aviv Medical Center between 2018-2021. CD patients with multiple clinical presentations and disease phenotypes who initiated the diet were included. Indications for treatment, medical and nutritional data were collected from dietician clinic visits and medical records. Clinical and biomarker responses were determined. The CDED was recommended to 220 CD patients. Seventy-two patients were included in the analysis for a clinically active disease (n = 48) or for remission maintenance (n = 24). Among patients with a clinically active disease, 62.5% of patients achieved clinical remission at week 6 and at week 12. A positive association between high adherence to the CDED and clinical remission at week 12 was observed (adjusted OR = 7.6, 95% CI 1.07-55.2, p = 0.043). Among patients treated for remission maintenance, remission at week 12 was maintained among 83.3% of patients. We conclude that the CDED may be a promising intervention for multiple CD presentations and indications. These findings should be further validated in larger, prospective, controlled studies.

Salvage Therapy in Acute Severe Ulcerative Colitis: Current Practice and a Look to the Future.

The risk of urgent bowel resection increases significantly among patients hospitalized with acute severe ulcerative colitis. In-hospital management requires quick diagnostic, therapeutic, and decision-making, combined with a multi-disciplinary approach and accessibility to multiple therapeutic options. However, the optimal strategy is still debatable. We performed a review of the current options for salvage therapy as well as novel therapy options emerging. We reviewed studies reporting outcomes of hospitalized steroid-refractory acute severe ulcerative colitis treated with salvage therapy (calcineurin inhibitors, infliximab) as well as studies using novel biologic, small molecules, antibiotics, and artificial intelligence to optimize therapy. We collected statistical data about patient factors that impact clinical management and how these can be applied to the real-life practice in order to prescribe a more personalized medicine. Several new drugs and approaches have shown benefits during the last decades for the management of acute severe ulcerative colitis. This effort is driven by the necessity of more effective, safe, and rapidly active therapeutic options with better convenient routes of administration, in order to improve therapeutic outcomes and quality of life for patients. The next step will be tailored medicine according to patients' profiles, taking into account disease characteristics, laboratory parameters, and patients' preferences.

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.

The Effect of the Crohn's Disease Exclusion Diet on Patients With Pouch Inflammation: An Interventional Pilot Study.

Restorative proctocolectomy with ileal pouch-anal anastomosis is the surgical treatment of choice for patients with ulcerative colitis.1 Unfortunately, pouch inflammation (ie, pouchitis) is reported in up to 72% of pouch patients.1,2.

Medical Cannabis Increases Appetite but Not Body Weight in Patients with Inflammatory Bowel Diseases.

We aimed to elucidate the effect of Medical Cannabis (MC) on appetite and nutritional status among patients with inflammatory bowel disease (IBD). A case series of patients with IBD were initiating treatment with MC for disease-related symptoms, at the IBD clinic of a tertiary referral medical center. Patients' demographics, anthropometrics, medical history and treatment and MC use were systematically recorded. An appetite and food frequency questionnaire (SNAQ and FFQ) were filled before, and at 3 and 6 months of treatment. Patients with IBD initiating MC were enrolled (n = 149, age 39.0 ± 14.1 years, 42.3% female), and 33.6% (n = 50) were treated for improvement of nutritional status. A modest increase in appetite after 3 months was detected among all patients enrolled (Pv = 0.08), but there were no significant differences in energy or macronutrient intake, and in patients' body mass index (BMI). A significant appetite improvement after 3 months was detected among 34.0% (n = 17) of patients, but this was not associated with increased caloric intake or BMI at 3 or 6 months. Among patients without increased appetite after 3 months of MC therapy, BMI decreased at 6 months (24.1 ± 3.7 vs. 23.4 ± 3.6, Pv = 0.010). MC may be a potential strategy to improve appetite among some patients with IBD, but not caloric intake or BMI.

Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation.

Human gut commensals are increasingly suggested to impact non-communicable diseases, such as inflammatory bowel diseases (IBD), yet their targeted suppression remains a daunting unmet challenge. In four geographically distinct IBD cohorts (n = 537), we identify a clade of Klebsiella pneumoniae (Kp) strains, featuring a unique antibiotics resistance and mobilome signature, to be strongly associated with disease exacerbation and severity. Transfer of clinical IBD-associated Kp strains into colitis-prone, germ-free, and colonized mice enhances intestinal inflammation. Stepwise generation of a lytic five-phage combination, targeting sensitive and resistant IBD-associated Kp clade members through distinct mechanisms, enables effective Kp suppression in colitis-prone mice, driving an attenuated inflammation and disease severity. Proof-of-concept assessment of Kp-targeting phages in an artificial human gut and in healthy volunteers demonstrates gastric acid-dependent phage resilience, safety, and viability in the lower gut. Collectively, we demonstrate the feasibility of orally administered combination phage therapy in avoiding resistance, while effectively inhibiting non-communicable disease-contributing pathobionts.

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.

Endoscopic Postoperative Recurrence in Crohn's Disease After Curative Ileocecal Resection with Early Prophylaxis by Anti-TNF, Vedolizumab or Ustekinumab: A Real-World Multicentre European Study.

BACKGROUND: Endoscopic-post-operative-recurrence [ePOR] in Crohn's disease [CD] after ileocecal resection [ICR] is a major concern. We aimed to evaluate the effectiveness of early prophylaxis with biologics and to compare anti-tumour necrosis factor [anti-TNF] therapy to vedolizumab [VDZ] and ustekinumab [UST] in a real-world setting. METHODS: A retrospective multicentre study of CD-adults after curative ICR on early prophylaxis was undertaken. ePOR was defined as a Rutgeerts score [RS] ≥ i2 or colonic-segmental-SES-CD ≥ 6. Multivariable logistic regression was used to evaluate risk factors, and inverse probability treatment weighting [IPTW] was applied to compare the effectiveness between agents. RESULTS: The study included 297 patients (53.9% males, age at diagnosis 24 years [19-32], age at ICR 34 years [26-43], 18.5% smokers, 27.6% biologic-naïve, 65.7% anti-TNF experienced, 28.6% two or more biologics and 17.2% previous surgery). Overall, 224, 39 and 34 patients received anti-TNF, VDZ or UST, respectively. Patients treated with VDZ and UST were more biologic experienced with higher rates of previous surgery. ePOR rates within 1 year were 41.8%. ePOR rates by treatment groups were: anti-TNF 40.2%, VDZ 33% and UST 61.8%. Risk factors for ePOR at 1 year were: past-infliximab (adjusted odds ratio [adj.OR] = 1.73 [95% confidence interval, CI: 1.01-2.97]), past-adalimumab [adj.OR = 2.32 [95% CI: 1.35-4.01] and surgical aspects. After IPTW, the risk of ePOR within 1 year of VDZ vs anti-TNF or UST vs anti-TNF was comparable (OR = 0.55 [95% CI: 0.25-1.19], OR = 1.86 [95% CI: 0.79-4.38]), respectively. CONCLUSION: Prevention of ePOR within 1 year after surgery was successful in ~60% of patients. Patients treated with VDZ or UST consisted of a more refractory group. After controlling for confounders, no differences in ePOR risk were seen between anti-TNF prophylaxis and other groups.

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.

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.

Long-term Antibiotic Treatment in Pouchitis-Patterns of Use and Safety.

INTRODUCTION: Pouchitis, often developing after colectomy and ileal pouch-anal anastomosis for ulcerative colitis, is highly responsive to antibiotics. Ciprofloxacin and/or metronidazole are commonly used, often for prolonged periods. We report patterns of antibiotic use, adverse events, and resistant infections in patients with pouchitis with long-term antibiotic treatment. METHODS: In a cohort of patients following pouch surgery, a retrospective nested case-control analysis was performed between 2010 and 2017. Ultra-long-term use, defined as the top 10% of users, was compared with the remaining users. Patterns of antibiotic use, adverse events, and resistant infections were analyzed. RESULTS: The cohort included 205 patients with UC, of whom 167 (81.5%) used antibiotics for pouchitis, predominantly ciprofloxacin. The long-term antibiotic use rate was 18% and 42% at 5 and 20 years postsurgery, respectively. Mean antibiotic use of at least 1, 3, and 6 months/year was noted in 54 (26.3%), 31 (15.1%), and 14 (6.8%) patients, respectively. Twenty-two (13.2%) and 4 (2.4%) patients reported mild and severe (transient) adverse events, respectively, without mortalities, tendinopathies or arrhythmias. Adverse event rates for ciprofloxacin and metronidazole were 1per 10,000 and 6 per 10,000 use-days, respectively. Longer, but not ultra-long antibiotic use, was associated with mild adverse events. There was no association between antibiotic use and resistant infections. Thirteen (6.3%) patients required ileostomy procedures-more commonly in the ultra-long-term antibiotic users. CONCLUSIONS: Patients with pouchitis may require prolonged antibiotic treatment, reflecting clinical benefit and favorable safety profile. Few adverse events and resistant infections were observed with long-term antibiotics use. However, resistant microbial strains selection, which are potentially transmittable, warrants consideration of different therapeutic alternatives.

Short-term effectiveness and safety of tofacitinib in ulcerative colitis - real world data from tertiary medical centers in Israel.

BACKGROUND: We sought to define the effectiveness and safety of tofacitinib in a real-world (RW) cohort of Israeli patients with moderate to severe ulcerative colitis (UC). METHODS: This was a multi-center retrospective observational cohort study (2019-2020) to assess the effectiveness and safety of tofacitinib induction and maintenance therapy up to 26 weeks. Clinical response and remission were defined as a reduction in Simple Clinical Colitis Activity Index (SCCAI) or partial Mayo score (PMS) of ≥3 points, and SCCAI ≤2 or a PMS ≤1, respectively. RESULTS: We included 73 patients, 47% male; median age 26 years [IQR: 19.5-39.5], disease duration 7 years [IQR: 2.5-14.5], follow-up 7.1 months [IQR: 3-12], 91% biologics-experienced, and 74% ≥ 2-biologics. Half of patients used concomitant corticosteroids (CS). Overall, 56.1% discontinued therapy due to either lack of response and/or adverse events (AEs), median time to discontinuation - 9.7 months [IQR 3.4-16]. Overall, response, remission, and CS-free-remission were achieved in 47.6%, 20.6%, and 17.5% of patients, respectively. At early maintenance (week 26), response, remission, and CS-free-remission were achieved in 65%, 22.5%, and 20% of patients, respectively. At week 26, tofacitinib 10 mg BID was still used in 43%. Seventeen patients (23.2%) had an adverse event including herpes zoster- 2.7%, hospitalization- 12.3%, and colectomy- 2.7%. CONCLUSIONS: Tofacitinib was effective in achieving CS-free-remission in about 1/5 of highly biologics -experienced patients with UC. Despite a considerable proportion of patients maintained on tofacitinib 10 mg bid, it was well tolerated and safe. Earlier positioning of tofacitinib in the therapeutic algorithm may result in improved outcomes.

Fecal Calprotectin Is Increased in Pouchitis and Progressively Increases With More Severe Endoscopic and Histologic Disease.

BACKGROUND & AIMS: Data regarding fecal calprotectin (FC), commonly used for noninvasive monitoring in inflammatory bowel diseases, are scarce in patients with ileal pouch-anal anastomosis (IPAA). We aimed to assess the association between FC levels and pouch inflammation in patients with ulcerative colitis who underwent IPAA. METHODS: A cross-sectional study of adults with ulcerative colitis who underwent IPAA with J-pouch formation prospectively followed in a dedicated pouch clinic. Patients had clinical, endoscopic, and histologic assessments within 90 days of FC sampling. Each patient encounter was evaluated separately. Pouchitis was defined as a Pouchitis Disease Activity Score of ≥7 (maximum score: 18). RESULTS: Overall, 156 patients had 296 encounters that met inclusion criteria. A total of 52% of patients were male, median age at evaluation was 43 (IQR, 35-58) years, and median pouch age was 10 (interquartile range [IQR], 2.5-15) years. Median FC values were significantly lower in patients without compared with those with pouchitis (208 [IQR, 96-478] µg/g vs 550 [IQR, 250-1051] µg/g; P < .0001). Mean FC values increased among patients with higher endoscopic and histologic scores. FC performed better than C-reactive protein as a predictor of pouchitis. FC of >460 µg/g had >80% specificity for predicting significant endoscopic disease (Pouchitis Disease Activity Score endoscopic subscore ≥5), while an FC of <125 µg/g had over 80% specificity in predicting endoscopic remission. CONCLUSIONS: FC levels are increased in patients with endoscopic and histologic inflammation of the pouch. FC may be a useful tool in the management of patients following IPAA.