Induction Of Remission In Patients Research Articles

Probiotics for inflammatory bowel disease: Is there sufficient evidence?

Inflammatory bowel disease (IBD) refers to chronic inflammatory disorders of the gut. Ulcerative colitis (UC) and Crohn's disease (CD) are two subtypes of IBD. Evidence suggests that the intestinal microbiota plays a role in the pathogenesis of IBD, so probiotics have garnered a lot of interest as a potential treatment or prevention for IBD. However, clinical evidence of the efficacy of probiotics is still debatable. We performed a literature review. An advanced search considered clinical studies on probiotic for IBD from inception to 2023 in PubMed, Embase, Cochrane Library, and Web of Science. In the treatment of UC with probiotics, only Escherichia coli Nissle 1917 for maintenance treatment of UC in remission, and Bifidobacterium and VSL#3 for induction of remission in patients with mild to moderately active UC have shown strong evidence. Currently, there are no definitive conclusions regarding the effectiveness of probiotics in CD. The mechanism of probiotic treatment for IBD may be related to reducing oxidative stress, repairing the intestinal barrier, regulating intestinal flora balance, and modulating intestinal immune response. Differences in the benefits of probiotics between CD and UC may be attributable to the different lesion extent and immune-mediated pathophysiology. More robust randomized clinical trials are required to validate the efficacy and safety of diverse probiotic strains in IBD.

Immunoregulatory Effects of Elemental Diet and Its Ingredient, Tryptophan, via Activation of the Aryl Hydrocarbon Receptor in Mice.

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation and its treatment varies widely; however, when inflammation is high, a complete nutrient containing pre-digested elemental diet (ED) is used to preserve the intestinal tract. In this study, we investigated the mechanisms underlying the effectiveness of EDs for IBD using mice. C57BL/6 mice were orally treated with the ED (5 mL/day) and its ingredient L-tryptophan (Trp) (1-100 mg/kg), respectively. Flow cytometry analysis revealed that treatment with the ED and Trp (10 and 100 mg/kg) significantly increased the percentage of splenic CD4+-/CD25+-/Foxp3+ regulatory T cells (Tregs). In the 2% DSS-induced colitis-mouse model, Trp administration (100 mg/kg) led to a significant decrease in TNF-α and increase in IL-10 in the serum as well as a significant decrease in the inflammation score. Furthermore, the aryl hydrocarbon receptor (AhR) agonistic activity, which is a key function of Treg induction, of Trp and 15 Trp metabolites was characterized using a highly sensitive DR-EcoScreen cell assay. Five Trp metabolites, including L-kynurenine, acted as AhR agonists, while Trp did not. Taken together, these results suggest that the ED treatment has a Trp-dependent immunoregulatory effect, and several Trp metabolites that activate the AhR might contribute to induction of remission in patients with IBD.

P1031 Intestinal ultrasound for monitoring therapeutic response in patients with ulcerative colitis treated with upadacytynib

Abstract Background Intestinal ultrasound (IUS) is a noninvasive method to assess disease activity in inflammatory bowel disease (IBD) although there are still limited data of usefulness of IUS in ulcerative colitis (UC) compared to Crohn’s disease (CD). The aim of the study was to evaluate usefulness of intestinal ultrasound in comparison to endoscopy in assessment of the efficacy of upadacytynib (UPA) in induction of remission in patients with UC. Methods This was a prospective, two-centers study in which we enrolled 27 patients with a flare of UC (total Mayo score>7) treated with UPA (8 weeks of induction period). IUS, calprotectin level and laboratory tests were conducted in week 0, 4 and 8. Milano ultrasound criteria (MUC) were used to assess the IUS disease activity. Results Among 27 patients 34% achieved clinical remission and 40,6% endoscopic remission already in week 4. After 8 weeks of treatment with UPA clinical remission in 53,1% and endoscopic remission in 56,2% of UC patients were achieved. In IUS the most affected parts of the colon were rectum and sigmoid colon. 100% of the patients had an increased bowel wall thickness (BWT)>3mm in the sigmoid colon and rectum at baseline. In the first 4 weeks of the study, the percentage of patients with an increased BWT in the sigmoid colon and rectum decreased significantly and remained low at week 8. 78% of patients with normalized BWT had endoscopic remission vs 22% without endoscopic remission (p<0.001). There was 74% correlation between MUC and total Mayo score (p=0,013). Conclusion Upadacitinib has demonstrated a positive efficacy during induction of remission in UC patients, shown as improvement in IUS parameters as well as in endoscopy improvement. Our data showed a strong correlation between normalization of BWT and endoscopic remission in patients with UC treated with upadacytynib. IUS seems to be a useful and non-invasive method for monitoring disease course and for assessing treatment response in UC patients.

P876 Efficacy and safety of microencapsulated butyrate add-on therapy in induction of remission in patients with mild-to-moderate Ulcerative Colitis - results from multi-center, double-blind, randomized, placebo-controlled clinical study

Abstract Background Butyrate is the most beneficial among short-chain fatty acids (SCFA’s) that plays a key role in intestinal homeostasis by modifying: gut microbiome, gut barrier integrity, and reducing inflammation. There are some evidence of its usefulness in the treatment of Ulcerative Colitis (UC), however the data are not clear. The aim of our study was to assess the efficacy and safety of oral microencapsulated sodium butyrate (MSB) as add-on treatment in induction of remission in active UC. Methods 100 patients with mild to moderate UC were enrolled in the study and randomized to MSB group treated with 2x300 mg/d of butyrate or placebo group (C); 96 of those patients completed all study protocol. Total Mayo Score (TMS), endoscopic images and fecal calprotectin were investigated to estimate the effect of MSB administration in induction remission, as well as relation between fecal butyrate concentrations (C4) and effectiveness of treatment. Results Clinical and endoscopic improvement (p < 0.001 and p = 0.042) and clinical remission (p < 0.001) was observed in MSB group. Accordingly, an improvement in the endoscopic image(defined as Mayo Score (MS) difference ≥ 1) at 8 weeks of follow up was achieved in 26patients (55.3%) in the study group and 16 (32.7%) in placebo group (p=0.042). Clinical improvement (defined as TMS difference ≥ 3) was observed in 39 (83%) study group patients and 15 (30.6%) in placebo group (p < 0.001). Clinical remission (TMS at visit 2 ≤ 2) was obtained in 30 (63.84%) MSB group patients and 11 (22.4%) in control group (p < 0.001). Significant improvement was also expressed as reduction of calprotectin level. In MSB group significant increase of C4 was observed in the group with clinical improvement, clinical remission and endoscopic improvement, and it was significantly higher than among non-responders. (MD =1.35 CI 95 [0.51;3.56], p < 0.001), clinical remission (MD = 1.69 CI 95 [0.44;3.45], p = 0.001) and endoscopic improvement (MD = 1.99 CI 95 [0.84;2.82], (p < 0.001)). In C group the level of C4 was significantly lower, regardless of clinical response. No side effects was observed during treatment. Conclusion MSB supplementation increases the fecal butyrate concentration and results in clinical remission and endoscopic improvement in mild to moderate UC. Our study clearly showed that MSB appears to be a beneficial and safe add-on treatment of those patients.

Budesonide Extended Release for Ulcerative Colitis


 In 2017, the CADTH Canadian Drug Expert Committee recommended that budesonide extended release (with multi-matrix system) not be reimbursed for the induction of remission in patients with active mild to moderate ulcerative colitis based on limitations in the evidence at that time.
 The limited primary clinical evidence (i.e., 1 randomized controlled trial) published since the literature searches conducted for the previous CADTH Reimbursement Review corroborates the clinical findings of that report. The evidence demonstrates that budesonide extended release is more effective for inducing remission in patients with mild to moderate ulcerative colitis compared to placebo.
 No new clinical evidence was identified describing head-to-head comparisons of budesonide extended release with active therapies. Indirect comparative evidence between budesonide extended release and other active therapies suggests minimal or no difference in remission, clinical response, or adverse events.
 Cost-effectiveness evidence from 1 study conducted in the Netherlands indicates that budesonide extended release is a more effective and less costly second-line therapy versus aggregated comparators for patients with mild to moderate ulcerative colitis.
 Evidence-based recommendations support the use of budesonide extended release for patients with mild to moderate ulcerative colitis who have not responded to 5-ASAs.
 No clinical or cost-effectiveness evidence or evidence-based recommendations were found describing the use of budesonide extended release in patients with moderate to severe ulcerative colitis.

An Overview of Emerging Trends and Technologies in Ulcerative Colitis


 This report provides an overview of the evolving therapeutic landscape for moderate to severe ulcerative colitis (UC), including recent changes to clinical practice guidelines, key trends in therapeutic strategies, and new or emerging treatment options, with a focus on biologics and small-molecule therapies.
 Recent guidelines on the medical management of patients with UC include those of the American Gastroenterological Association (AGA), American College of Gastroenterology (ACG), and European Crohn’s and Colitis Organisation (ECCO), which were published in 2019, 2020, and 2022, respectively. These guidelines provide an accurate reflection of how clinical practice has changed to incorporate newer therapies that have entered the market and newer evidence that has been published since the release of the Canadian guidelines in 2015. The ACG, AGA, and ECCO guidelines all recommend use of a tumour necrosis factor (TNF) antagonist, vedolizumab, or tofacitinib for induction of remission in patients with moderate to severe UC; the AGA and ECCO guidelines also recommend ustekinumab as an option and recommend vedolizumab over adalimumab, whereas the AGA guidelines recommend early use of biologic drugs over a step-up approach after failure of 5-aminosalicylates.
 Two important trends in therapeutic strategies for UC include changes in the use and definition of treatment targets and recommendations regarding therapeutic drug monitoring (TDM).
 
 The 2021 Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) guidelines provide contemporary consensus recommendations for using new and updated targets throughout an individualized treatment timeline in patients with inflammatory bowel disease (IBD). Although histologic remission is not considered a formal UC treatment target in STRIDE-II, it is acknowledged as an adjunctive measure to endoscopic remission to represent a deeper level of healing and is the focus of many current studies.
 The use of TDM emerged from challenges associated with the use of older biologics (primarily TNF antagonists), which posed difficulties related to immunogenicity and dosing. The relevance of TDM for newer biologics with different mechanisms of action, reduced immunogenicity, and fixed dosing (e.g., vedolizumab and ustekinumab) is a topic of ongoing debate. Although AGA guidelines on TDM in IBD and expert consensus statements support the use of reactive TDM for patients with UC who lose response to a TNF antagonist, evidence gaps remain regarding appropriate use of proactive TDM, utility of TDM for small molecules and biologics outside of the TNF antagonist class, and consistent target concentration thresholds to guide dose changes.
 
 
 There is a substantial pipeline of new and emerging drugs for the treatment of adults with moderate to severe UC, with many in phase IIb or III of clinical development; several notable trends of emerging pharmacotherapies exist, including an increasing number of Janus kinase inhibitors, several therapies with biologic targets that are new in UC (e.g., interleukin-23 antibodies, TNF-like ligand 1A inhibitors), an increasing number of oral therapies, and the first combination of 2 biologic therapies in UC.
 The Canadian health care system should be prepared to adapt to the rapidly evolving treatment landscape and potential clinical practice changes in moderate to severe UC. Drugs with new mechanisms of action in the treatment area and the new paradigm of combination therapy with multiple biologics of different classes may lead to improved patient outcomes but can also further complicate the treatment decision-making process. Therefore, it is important for health care providers to stay up to date on new and upcoming treatment options, which may require educational initiatives for both providers and patients as well as updates to the Canadian treatment guidelines. Overall, potential changes on the horizon may have substantial implications for the health care system given the prevalence of UC in Canada, the costs of advanced therapies, and the increasing number of available treatment options.

Capsulized Fecal Microbiota Transplantation Induces Remission in Patients with Ulcerative Colitis by Gut Microbial Colonization and Metabolite Regulation.

Fecal microbiota transplantation (FMT) can induce clinical remission in ulcerative colitis (UC) patients. Enemas, nasoduodenal tubes, and colonoscopies are the most common routes for FMT administration. However, there is a lack of definitive evidence regarding the effectiveness of capsulized FMT treatment in UC patients. In this study, we administered capsulized FMT to 22 patients with active UC to assess the efficiency of capsulized FMT and determine the specific bacteria and metabolite factors associated with the response to clinical remission. Our results showed that the use of capsulized FMT was successful in the treatment of UC patients. Capsulized FMT induced clinical remission and clinical response in 57.1% (12 of 21) and 76.2% (16 of 21) of UC patients, respectively. Gut bacterial richness was increased after FMT in patients who achieved remission. Patients in remission after FMT exhibited enrichment of Alistipes sp. and Odoribacter splanchnicus, along with increased levels of indolelactic acid. Patients who did not achieve remission exhibited enrichment of Escherichia coli and Klebsiella and increased levels of biosynthesis of 12,13-DiHOME (12,13-dihydroxy-9Z-octadecenoic acid) and lipopolysaccharides. Furthermore, we identified a relationship between specific bacteria and metabolites and the induction of remission in patients. These findings may provide new insights into FMT in UC treatment and provide reference information about therapeutic microbial manipulation of FMT to enhance its effects. (This study has been registered at ClinicalTrails.gov under registration no. NCT03426683). IMPORTANCE Fecal microbiota transplantation has been successfully used in patients. Recently, capsulized FMT was reported to induce a response in patients with UC. However, limited patients were enrolled in such studies, and the functional factors of capsulized FMT have not been reported in the remission of patients with UC. In this study, we prospectively recruited patients with UC to receive capsulized FMT. First, we found that capsulized FMT could induce clinical remission in 57.1% of patients and clinical response in 76.2% after 12 weeks, which was more acceptable. Second, we found a relationship between the decrease of opportunistic pathogen and lipopolysaccharide synthesis in patients in remission after capsulized FMT. We also identified an association between specific bacteria and metabolites and remission induction in patients after capsulized FMT. These findings put forward a possibility for patients to receive FMT at home and provide reference information about therapeutic microbial manipulation of FMT to enhance its effects.

DOP44 Tofacitinib versus corticosteroids for induction of remission in moderately active ulcerative colitis (ORCHID): A prospective randomized open-label pilot study

Abstract Background The exact positioning of tofacitinib in the therapeutic algorithm is still unclear. We evaluated the efficacy of tofacitinib in comparison to corticosteroids for induction of remission in patients with moderately active UC. Methods This was a randomized, parallel-group active-controlled pilot study comparing the efficacy and safety of corticosteroids and tofacitinib in inducing remission in adults with moderately active UC (defined as total Mayo clinic score 6-9). Patients were randomly assigned to receive corticosteroids (prednisolone, starting 40 mg daily and tapered by 5 mg every week over 8 weeks) or tofacitinib (10 mg twice daily) for 8 weeks. The primary endpoint was composite remission (defined as total Mayo clinic score≤2, with an endoscopic subscore of 0 and fecal calprotectin<100 mcg/g) at 8 weeks. Clinical remission (defined as Mayo clinic score ≤2) and clinical response (defined as a decrease of 30% in the Mayo clinic score from baseline or more and 3 or more points, along with either a rectal bleeding subscore of 0 or 1 or a decrease in the rectal bleeding subscore of 1 point or more) at week 8 were also evaluated. Follow-up assessments for efficacy and safety were done at weeks 2, 4, and 8. Results Seventy-eight patients (mean age 37.78±13.94 years, 42[53.84%] males; 43 assigned to tofacitinib and 35 to corticosteroids group) were enrolled. At week 8, there was no significant difference in the proportion of patients achieving composite remission in the two treatment groups (7 of 43, 16.28% in the tofacitinib group versus 3 of 35, 8.57% in the corticosteroid group; p=0.31). Clinical remission at week 8 was achieved in 18 of 43(41.86%) patients receiving tofacitinib and 13 of 35 (37.14%) patients receiving corticosteroids (p=0.67). Clinical response was seen in 28 of 43(65.12%) and 25 of 35(71.42%) patients in the tofacitinib and corticosteroid groups, respectively(p=0.55). No difference was observed in the median number of days required to achieve symptomatic remission between the two groups (10[IQR 7-18.75] and 10[IQR 5-12.5] days for tofacitinib and corticosteroids, respectively;p=0.25). One patient in the tofacitinib and corticosteroid group discontinued treatment due to the development of pulmonary tuberculosis and pustular acne, respectively. Another patient receiving tofacitinib developed herpes zoster. No serious adverse events or major adverse cardiovascular events were observed. Conclusion In patients with moderately active ulcerative colitis, there is no difference between the efficacy and safety of tofacitinib and corticosteroids for induction of remission. Tofacitinib can be used as a first-line therapy for inducing remission in moderately active UC. (CTRI Registration number: CTRI/2021/10/037641)

Enteral Nutrition Prescription in Children and Adults with Inflammatory Bowel Diseases: Gaps in Current Gastroenterology Practice in Saudi Arabia.

Background: Evidence for the effectiveness of enteral nutrition (EN) for the management of patients with inflammatory bowel disease (IBD) is well-established. However, there is considerable global variation in EN practices. This study aimed to characterize the practices and perceptions of gastroenterologists regarding the use of EN in patients with IBD in one of the largest countries in the Gulf region. Methods: A cross-sectional study was conducted on pediatric and adult gastroenterologists working in Saudi Arabia who are involved in IBD management. A self-administered web-based survey was distributed via social media platforms and mailing lists of national gastroenterology societies. Results: A total of 80 gastroenterologists completed the survey. However, only 55 reported that they were currently practicing EN in any form. EN was mostly indicated by gastroenterologists who “sometimes” recommend EN for: the prevention and correction of undernutrition (50.9%), preoperative optimization (50.9%), and the induction of remission in patients with active and long-standing CD (36.4%), at initial diagnosis (34.5%), during the management of complications (61.8%), and after failing to respond to pharmacological therapy (58.2%). Exclusive enteral nutrition (EEN) is regularly recommended by 14.5% of gastroenterologists. The prescription of EEN was significantly associated with the pediatric profession (p < 0.01), IBD specialty (p < 0.05), level of nutrition education during training (p < 0.01), and previous training in a unit with regular EN use (p < 0.01). The most reported barriers to using EN were patients’ lack of acceptance (73.8%) and poor adherence (65%). A lack of dietitian support and a lack of standardized protocols were also reported as barriers by many physicians. Pediatric gastroenterologists were more likely to use at least one assessment method to evaluate EN success. Conclusion: EN practices differ between gastroenterologists working in Saudi Arabia. Future EN protocols should be optimized to support both children and adults with IBD. Gastroenterology training programs should offer nutrition support-focused training to help physicians better utilize EN.

Adalimumab for induction of remission in patients with Crohn's disease: a systematic review and meta-analysis

PurposeA large number of people with Crohn's disease (CD) fail to recover from conventional therapy or biological therapy. Some studies showed that adalimumab (ADA) may be an effective alternative therapy for these patients. The aim of this study was to evaluate the efficacy and safety of ADA in inducing CD remission.MethodsWe performed search of Pubmed/MEDLINE, Embase, CENTRAL, the Cochrane IBD Group Specialized Register, and several other databases. Randomized controlled trials (RCTs) comparing any dose of ADA with controls (placebo or active) in participants with active CD were included. The primary outcome was the failure to achieve clinical response/remission at 4 weeks. Several subgroup and sensitivity analyses were performed. Review Manager Software v5.3 was used.ResultsFour RCTs were included (n = 919), in which 553 participants received ADA and 366 participants received placebo. A meta-analysis of four studies showed that at 4 weeks, there were more people in the ADA group with clinical response/remission or symptom improvement compared with the placebo group. The rates of side effects, serious side effects, and study withdrawals due to side effects were lower in ADA participants than placebo ones.ConclusionThis meta-analysis shows that ADA is superior to placebo in induction of clinical response/remission of CD patients, but no firm conclusions can be drawn on the safety of ADA in CD due to the low number of events.Graphical

Технология построения функции эффективности преднизолона на клинической модели лечения воспалительных заболеваний кишечника

To determine the effective doses of prednisone for induction of remission in patients with ulcerative colitis (UC) and Crohn's disease (CD) based on the “dose-effect” relationship.

Low-dose naltrexone for the induction of remission in patients with mild to moderate Crohn’s disease: protocol for the randomised, double-blinded, placebo-controlled, multicentre LDN Crohn study

IntroductionCrohn’s disease (CD) is an inflammatory bowel disease (IBD). Several drugs exist to induce and maintain remission, but a significant part of the patients is refractory to current IBD drugs...

Budesonide orodispersible tablets for induction of remission in patients with active eosinophilic oesophagitis: A 6-week open-label trial of the EOS-2 Programme.

BackgroundA novel budesonide orodispersible tablet (BOT) has been proven effective in adult patients with active eosinophilic oesophagitis (EoE) in a 6‐week placebo‐controlled trial (EOS‐1).AimsTo report the efficacy of an open‐label induction treatment with BOT in a large prospective cohort of EoE patients within the EOS‐2 study.MethodsPatients with clinico‐histological active EoE were treated with BOT 1 mg BID for 6 weeks. The primary endpoint was clinico‐histological remission (≤2 points on numerical rating scales [0–10] each for dysphagia and odynophagia, and peak eosinophil count <16 eos/mm2 hpf (corresponds to <5 eos/hpf)). Further study endpoints included clinical and histological remission rates, change in the EEsAI‐PRO score, change in peak eosinophil counts, and deep endoscopic remission using a modified Endoscopic Reference Score.ResultsAmong 181 patients enrolled, 126 (69.6%) achieved clinico‐histological remission (histological remission 90.1%, clinical remission 75.1%). The mean peak eosinophil counts decreased by 283 eos/mm2 hpf (i.e., by 89.0%). Mean EEsAI‐PRO score decreased from baseline by 29 points and deep endoscopic remission was achieved in 97 (53.6%) patients. The majority of patients judged tolerability as good or very good (85.6%) and compliance was high (96.5%). Local candidiasis was suspected in 8.3% of patients; all were of mild severity, resolved with treatment and none led to premature withdrawal from the study.ConclusionsIn this large prospective trial, a 6‐week open‐label treatment with BOT 1 mg BID was highly effective and safe in achieving clinico‐histological remission of active EoE and confirmed the results of the placebo‐controlled EOS‐1 trial.

A145 EFFICACY AND SAFETY OF UPADACITINIB MAINTENANCE THERAPY IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS: RESULTS FROM A RANDOMIZED PHASE 3 STUDY

BackgroundUpadacitinib (UPA), an oral selective and reversible JAK inhibitor, demonstrated significantly greater efficacy compared with placebo (PBO) for induction of remission in patients with moderately to severely active ulcerative colitis (UC) in two phase 3 induction trials.AimsEvaluate safety and efficacy of 52 weeks of UPA 15 mg QD (UPA15) and 30mg QD (UPA30) compared to placebo in patients achieving clinical response following UPA 45 mg treatment in the induction trials.MethodsThe primary analysis (n=451) evaluated efficacy and safety of UPA15 and UPA30 compared to PBO as maintenance therapy. The primary endpoint was clinical remission via adapted Mayo score at wk 52. Ranked secondary endpoints included endoscopic improvement, maintenance of clinical remission, corticosteroid-free clinical remission, maintenance of endoscopic improvement, endoscopic remission, maintenance of clinical response and Histologic-endoscopic mucosal improvement (HEMI).ResultsBaseline characteristics were similar between all treatment groups. Both UPA15 and UPA30 met the primary endpoint, and all secondary endpoints. Significantly greater percentages of patients receiving UPA15 and UPA30 vs. PBO achieved clinical remission (42.3% and 51.7%, vs. 12.1%), endoscopic improvement (48.7% and 61.6%, vs. 14.5%), maintenance of clinical remission (59.2% and 69.7%, vs. 22.2%), corticosteroid-free clinical remission (57.1% and 68.0%, vs. 22.2%), maintenance of endoscopic improvement (61.6% and 69.5%, vs. 18.9%), endoscopic remission, (24.2% and 25.9%, vs. 5.6%) and HEMI (34.8% and 49.3%, vs. 11.8%) (p<0.001 for all endpoints). UPA15 and UPA30 were both well-tolerated and no new safety signals were observed. Rates for serious adverse events (AEs) and AEs leading to treatment discontinuation were similar between UPA15 and UPA30 groups and lower compared to the PBO group. Most common AEs were nasopharyngitis and creatine phosphokinase elevation among UPA groups and UC exacerbation within the PBO group (30.2%). Herpes zoster was only reported in UPA groups (3.9%-4.1%). Similar rates of malignancy excluding NMSC were seen within all groups (0.7%-1.3%). MACE were only reported among patients receiving PBO (0.7%), while VTE were only found with UPA30 (1.3%).ConclusionsIn patients responding to UPA induction therapy, both UPA15 and UPA30 were safe and effective as maintenance treatment at 52 wk for all primary and secondary endpoints. Patients receiving UPA30 responded approximately 10% better for most endpoints compared to those receiving UPA15. Both doses were well-tolerated, with no new safety signals observed.Funding AgenciesAbbVie

EARLY VERSUS DELAYED INITIATION OF VEDOLIZUMAB IN ULCERATIVE COLITIS: TREATMENT RESPONSE IN THE REAL WORLD (RALEE)

Abstract BACKGROUND Pivotal trials in ulcerative colitis (UC) have indicated that earlier intervention with a biologic is associated with greater likelihood of treatment response. However, in real-world clinical practice, patients with newly diagnosed UC are often prescribed conventional therapies, such as immunomodulators (IM), corticosteroids (CS), and/or 5-aminosalicylates (5-ASA) before biologic treatment, which may result in suboptimal clinical outcomes and high costs. RALEE is an observational study investigating the impact of early versus delayed initiation of vedolizumab (VDZ) on clinical and economic outcomes in patients with inflammatory bowel disease, using administrative data sets. Here, we report the impact on treatment response in patients with UC. METHODS Using the MarketScan Commercial Claims and Encounters database and the MarketScan Medicare Supplemental database, we identified adult patients diagnosed with UC between 2017 and 2018 who had ≥ 1 claim for VDZ and continuous enrollment for ≥ 12 months before and after their initial UC diagnosis. Patients were excluded if they received VDZ, anti-tumor necrosis factor therapy, or other biologic therapy in the 12 months before their initial UC diagnosis. Five post-diagnosis treatment pathways were predefined: (1) EARLY VDZ, VDZ within 30 days of initial UC diagnosis; (2) DELAYED VDZ 1, IM (not 5-ASA) before VDZ; (3) DELAYED VDZ 2, CS with IM before VDZ; (4) DELAYED VDZ 3, 5-ASA with CS before VDZ; or (5) DELAYED VDZ 4, 5-ASA with CS and IM before VDZ. Response was defined as no occurrence of the following events within 60 days after VDZ initiation: new concomitant use of CS, inflammatory bowel disease-related surgery, increased administration of VDZ, VDZ treatment discontinuation, or treatment switch. Response was evaluated with logistic regression (backwards selection) with EARLY VDZ as the reference group. RESULTS We identified 136,315 patients with UC, of whom 1,342 received VDZ and met the selection criteria. The median age of patients was 43 years; 51.0% of patients were male and 96.4% were commercially insured. The proportion of patients with response to VDZ was higher for EARLY VDZ (88.8%) than any of the DELAYED VDZ treatment pathways (70.1–79.8%) (Figure 1). Delayed initiation of VDZ (DELAYED VDZ 1, 2, and 4) was associated with a significantly lower likelihood of response than EARLY VDZ (Figure 2). CONCLUSION This analysis demonstrates that patients with UC are more likely to respond to therapy if initiated on VDZ within 30 days of diagnosis than if initiation is delayed by use of IM, CS, and/or 5-ASA. These findings are consistent with clinical guidelines that recommend use of VDZ for induction of remission in patients with moderately to severely active UC. Further analyses of remission, healthcare resource utilization, and associated direct medical costs are underway.

DOP38 Upadacitinib Therapy Reduces Ulcerative Colitis Symptoms as Early as Day 1

Abstract Background Upadacitinib (UPA), an oral, reversible JAK inhibitor engineered for increased selectivity for JAK1 over JAK2, JAK3, or tyrosine kinase 2 (TYK2), demonstrated significantly greater efficacy compared with placebo (PBO) for induction of remission in patients with moderately to severely active ulcerative colitis (UC) in two phase 3 trials, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026). This analysis evaluated the efficacy of UPA on early symptomatic improvement for the first 14 days, using pooled data from U-ACHIEVE Induction and U-ACCOMPLISH. Methods U-ACHIEVE and U-ACCOMPLISH were multicentre, double-blind, PBO-controlled trials that enrolled patients who have had moderately to severely UC with an Adapted Mayo Score of 5 to 9 points and centrally reviewed endoscopy subscore of 2 to 3. A total of 998 patients were randomized to receive UPA 45mg once daily (QD) (n=658) or PBO (n=328) for 8 weeks (wks) in a 2:1 ratio. First dose of study drug was administered on Day 0. Improvement in symptoms including stool frequency subscore (SFS), rectal bleeding subscore (RBS), abdominal pain, and bowel urgency were analysed from daily symptom diary data. Multivariate regression analysis was used to determine if early changes in UC symptoms could be used to evaluate a potential correlation with patients’ likelihood of achieving clinical response or clinical remission per Adapted Mayo score at the end of induction. Results Baseline characteristics were similar between both treatment groups. Patients treated with UPA 45 mg QD experienced significant improvement in daily symptoms, with significantly more subjects achieving SFS≤1 (p&amp;lt;0.001), RBS of 0 (p&amp;lt;0.05), and SFS of 0 (p&amp;lt;0.05) as early as day 1 and maintained through day 14 (Figure 1). A significantly higher percentage of patients who received UPA 45 mg QD compared to PBO, achieved abdominal pain=0 and the absence of bowel urgency within 3 days of beginning treatment through day 14 (p&amp;lt;0.05). Multivariate analysis revealed that patients who achieved day 7 SFS≤1 (OR 2.42, 95% CI, 1.53–3.82) were more likely to attain clinical response (Table). Patients who attained day 7 SFS≤1 (OR 2.53, 95% CI 1.59–4.00) or day 7 bowel urgency absent (OR 2.40, 95% CI 1.52–3.79) were more likely to achieve clinical remission at week 8. Conclusion UPA 45 mg QD significantly improved UC symptoms as early as day 1, providing patients with rapid symptom relief. Patients who achieved early symptom improvement were more likely to attain clinical remission or clinical response at week 8. [Clinicaltrials.gov, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026)]

P702 Faecal Microbiota Transplantation Sculpts the faecal and mucosal microbial and metabolomic profiles in patients with Ulcerative Colitis

Abstract Background Gut microbiota modulation via faecal microbiota transplantation (FMT)is known to induce long lasting clinical as well as endoscopic remission in patients with UC. The present study aims to identify microbial and metabolomic changes in the faecal as well mucosal niches, in response to FMT in patients with UC. Methods 28 patients with mild-moderate UC and 16 non-IBD controls were enrolled. Patients were given a weekly infusion of pooled-multidonor-FMT, for 8 weeks, while maintaining a uniform dietary pattern. We collected paired stool and recto-sigmoidal biopsysamples from patients with UC pre-FMT (n=28), post-FMT (n=10) and controls (n=16). 16S (V3-V4) rRNA sequencing and LC-MS based untargeted metabolomics was performed. α and β diversity analysis and differential abundance (DA) analysis of microbiota was performed using DeSeq2 R package. Differential metabolite peaks between the three groups were identified via volcano plot and annotated using LipidMaps, HMDB, Kegg and Metlin databases. (Fig.1) Results α-diversity of patients with UC was not significantly different from that of controls, in both sample matrices. Post-FMT α-diversity of faecal samples differed significantly from the Pre-FMT group, however in mucosal tissue, the difference was non-significant. β-diversity indices were significant in UC pre-FMT vs post-FMT populations for both matrices (Fig.2A and B). DA analysis identified faecal and mucosal controls and UC post-FMT samples to be significantly similar [ANOSIM R=0.07; p=0.1 (faecal) and R=0.02; p=0.315 (mucosal)]. Analysis of core microbiota revealed diminished faecal microbial core in UC, with no major UC-associated loss of mucosal core members, showing relatively conserved nature of mucosal microbiota. FMT restored microbial core along both niches. UC pre-FMT samples displayed increased abundance of Firmicutes (Limosilactobacillus, Lactobacillus, Streptococcus, Veilonella and Sphingomonas) and Proteobacteria (Methylobacterium) in faecal samples, while mucosa-associated microbiota displayed increased abundances of Firmicutes (Streptococcus, Limosilactobacillus, Ligilactobacillus, Eubacterium, Enterococcus, etc), Bacteroidetes (Parabacteroides and Alistipes) and Proteobacteria (Burkholderia)(Fig.3). Distinct functional classes of metabolites, including bacterial cell wall and QS molecules, membrane lipids, metabolism of vitamins, long and medium chain fatty acids, bile acids, and tryptophan etc, were also found to be altered between the three groups in both sample matrices(Fig.4) Conclusion FMT efficiently restores beneficial bacterial populations and related metabolic pathways in faecal as well the relatively reserved mucosal microbial niches, which may pave way for induction of remission in patients with UC.

Lyophilised oral faecal microbiota transplantation for ulcerative colitis (LOTUS): a randomised, double-blind, placebo-controlled trial

Faecal microbiota transplantation (FMT) delivered via colonoscopic infusion or enemas have been shown to induce remission in a proportion of patients with active ulcerative colitis. Whether orally administered FMT is effective in ulcerative colitis is unknown. We aimed to assess the efficacy of oral lyophilised FMT for the treatment of active ulcerative colitis. A double-blind, randomised, placebo-controlled trial was conducted at two centres in Australia. Eligible patients were aged 18-75 years with active ulcerative colitis (defined as clinical and endoscopic active ulcerative colitis, with a total Mayo score of 4-10, and a Mayo endoscopic subscore ≥1). After 2 weeks of amoxicillin, metronidazole, and doxycycline, patients were randomly assigned in a 1:1 ratio to receive either oral lyophilised FMT or placebo capsules for 8 weeks, using a prespecified computer-generated randomisation list with a permuted block size of 8. The primary outcome was corticosteroid-free clinical remission with endoscopic remission or response (total Mayo score ≤2, all subscores ≤1, and ≥1 point reduction in endoscopic subscore) at week 8. At week 8, FMT responders were randomly assigned (in a 1:1 ratio, permuted block size of 8) to either continue or withdraw FMT for a further 48 weeks. Analyses were done by modified intention-to-treat, including all patients who received at least one study dose. This trial is registered with Australian New Zealand Trial Registry, number ACTRN 12619000611123; this is the final report of the trial. Between May 20, 2019, and March 24, 2020, 35 patients were randomly assigned: 15 to receive FMT and 20 to receive placebo. Recruitment was terminated early due to the COVID-19 pandemic. At week 8, eight (53%) of 15 patients in the FMT group were in corticosteroid-free clinical remission with endoscopic remission or response, as were three (15%) of 20 patients in the placebo group (difference 38·3%, 95% CI 8·6-68·0; p=0·027; odds ratio 5·0, 95% CI 1·8-14·1). Adverse events occurred in 10 (67%) patients in the FMT group and 17 (85%) of those in the placebo group during the 8-week induction period, and were generally mild and self-limiting gastrointestinal complaints. Serious adverse events included worsening ulcerative colitis (two in the FMT group, one in the placebo group) and per-rectal bleeding (one in the placebo group). Ten patients in the FMT group who achieved a clinical or endoscopic response entered the maintenance phase and were randomly assigned to continue open-label FMT (n=4) or withdraw therapy (n=6). All four (100%) patients who continued FMT were in clinical, endoscopic, and histologic remission at week 56 compared with none of the patients who had FMT withdrawn. Antibiotics followed by orally administered FMT was associated with the induction of remission in patients with active ulcerative colitis. Continuing FMT was well tolerated and appeared to demonstrate clinical, endoscopic, and histological efficacy. Oral FMT could be a promising and feasible treatment option for patients with ulcerative colitis. St Vincent's Clinic Foundation, Gastroenterological Society of Australia, Gutsy Group.

Etrolizumab versus adalimumab or placebo as induction therapy for moderately to severely active ulcerative colitis (HIBISCUS): two phase 3 randomised, controlled trials

Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission relative to placebo in patients with moderately to severely active ulcerative colitis. The HIBISCUS studies aimed to compare the efficacy and safety of etrolizumab to adalimumab and placebo for induction of remission in patients with moderately to severely active ulcerative colitis. HIBISCUS I and HIBISCUS II were identically designed, multicentre, phase 3, randomised, double-blind, placebo-controlled and active-controlled studies of etrolizumab, adalimumab, and placebo in adult (18-80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. All patients had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In both studies, patients were randomly assigned (2:2:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks; subcutaneous adalimumab 160 mg on day 1, 80 mg at week 2, and 40 mg at weeks 4, 6, and 8; or placebo. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All patients and study site personnel were masked to treatment assignment. The primary endpoint was induction of remission at week 10 (defined as MCS of 2 or lower, with individual subscores of 1 or lower, and rectal bleeding subscore of 0) with etrolizumab compared with placebo. Pooled analyses of both studies comparing etrolizumab and adalimumab were examined for several clinical and endoscopic endpoints. Efficacy was analysed using a modified intent-to-treat population, defined as all randomly assigned patients who received at least one dose of study drug. These trials are registered with ClinicalTrials.gov, NCT02163759 (HIBISCUS I), NCT02171429 (HIBISCUS II). Between Nov 4, 2014, and May 25, 2020, each study screened 652 patients (HIBISCUS I) and 613 patients (HIBISCUS II). Each study enrolled and randomly assigned 358 patients (HIBISCUS I etrolizumab n=144, adalimumab n=142, placebo n=72; HIBISCUS II etrolizumab n=143; adalimumab n=143; placebo n=72). In HIBISCUS I, 28 (19·4%) of 144 patients in the etrolizumab group and five (6·9%) of 72 patients in the placebo group were in remission at week 10, with an adjusted treatment difference of 12·3% (95% CI 1·6 to 20·6; p=0·017) in favour of etrolizumab. In HIBISCUS II, 26 (18·2%) of 143 patients in the etrolizumab group and eight (11·1%) of 72 patients in the placebo group were in remission at week 10, with an adjusted treatment difference of 7·2% (95% CI -3·8 to 16·1; p=0·17). In the pooled analysis, etrolizumab was not superior to adalimumab for induction of remission, endoscopic improvement, clinical response, histological remission, or endoscopic remission; however, similar numerical results were observed in both groups. In HIBISCUS I, 50 (35%) of 144 patients in the etrolizumab group reported any adverse event, compared with 61 (43%) of 142 in the adalimumab group and 26 (36%) of 72 in the placebo group. In HIBISCUS II, 63 (44%) of 143 patients in the etrolizumab group reported any adverse event, as did 62 (43%) of 143 in the adalimumab group and 33 (46%) in the placebo group. The most common adverse event in all groups was ulcerative colitis flare. The incidence of serious adverse events in the pooled patient population was similar for etrolizumab (15 [5%] of 287) and placebo (seven [5%] of 144) and lower for adalimumab (six [2%] of 285). Two patients in the etrolizumab group died; neither death was deemed to be treatment related. Etrolizumab was superior to placebo for induction of remission in HIBISCUS I, but not in HIBISCUS II. Etrolizumab was well tolerated in both studies. F Hoffmann-La Roche.

Efficacy of Biologic Drugs in Short-Duration Versus Long-Duration Inflammatory Bowel Disease: A Systematic Review and an Individual-Patient Data Meta-Analysis of Randomized Controlled Trials

Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may be associated with higher efficacy, especially in Crohn's disease (CD). This was a systematic review and individual-patient data meta-analysis of all placebo-controlled trials of biologics approved for IBD at study inception (October 2015), using Vivli data-sharing platform. The primary outcome was the proportional biologic/placebo treatment effect on induction of remission in patients with short-duration (≤18 months) vs long-duration disease (>18 months) analyzed separately for CD and ulcerative colitis (UC). We used meta-regression to examine the impact of patients' characteristics on the primary outcome. We included 25 trials, testing infliximab, adalimumab, certolizumab, golimumab, natalizumab, or vedolizumab (6168 patients with CD and 3227 patients with UC). In CD, remission induction rates were higher in pooled placebo and patients in active arms with short-duration disease of ≤18 months (41.4% [244 of 589]) compared with disease duration of >18 months (29.8% [852 of 2857], meta-analytically estimated odds ratio, 1.33; 95% confidence interval, 1.09-1.64). The primary outcome, proportional biologic/placebo treatment effect on induction of remission, was not different in short-duration disease of ≤18 months (n= 589, odds ratio, 1.47; 95% confidence interval, 1.01-2.15) compared with longer disease duration (n= 2857, odds ratio, 1.43; 95% confidence interval, 1.19-1.72). In UC trials, both the proportional biologic/placebo remission-induction effect and the pooled biologic-placebo effect were stable, regardless of disease duration. Primary outcome results remained unchanged when tested using alternative temporal cutoffs and when modeled for individual patient's covariates, including prior anti-tumor necrosis factor exposure. There are higher rates of induction of remission with biologics and with placebo in early CD, resulting in a treatment to placebo effect ratio that is similar across disease durations. No such relationships between disease duration and outcomes was found in UC. PROSPERO registration: CRD42018041961.