Severe Ulcerative Colitis Patients Research Articles

Efficacy and safety of etrolizumab in treatment of moderate to severe ulcerative colitis: A systematic review and meta-analysis.

Etrolizumab is a promising drug for treating moderate to severe ulcerative colitis. The aim of this study was to assess the efficacy and safety of etrolizumab for induction and maintenance of remission in moderate to severe ulcerative colitis. We searched the following databases: PUBMED, Web of Science, OVID, and SCOPUS from inception to January 15. Inclusion criteria were any phase 2 and 3 clinical trials that compared etrolizumab with a placebo in treating moderate to severe ulcerative colitis, excluding case reports, animal studies, phase 1 trials, and conference abstracts due to duplication. We used RevMan software (5.4) for the meta-analysis. Five clinical trials were included in our meta-analysis. The total number of patients included in the study is 1248 patients, 860 patients in the etrolizumab group and 388 patients in the placebo group. In the induction phase, the pooled analyses showed a statistically significant association between etrolizumab and increased clinical remission, and endoscopic remission compared with placebo (risk ratio [RR] = 2.66, 95% confidence interval [CI] = 1.69-4.19, p < 0.0001), and (RR = 2.35, 95% CI = 1.52-3.65, p = 0.0001), respectively. In the maintenance phase, the pooled analyses showed a statistically significant association between etrolizumab and increased histologic remission and endoscopic remission (RR = 2.04, 95% CI = 1.40-2.98, p = 0.0002) and (RR = 1.92, 95% CI = 1.29-2.85, p = 0.001), respectively. No statistically significant difference was observed in adverse events between etrolizumab and placebo in the induction and maintenance phases. Our results show that etrolizumab is an effective and safe drug for the induction and maintenance of clinical remission in moderate to severe ulcerative colitis patients, as proved by histologic and endoscopic findings. Future randomized trials are still needed to compare etrolizumab to the other agents and further establish its value for the practice.

P228 Predictors of steroid therapy refractoriness in admitted Acute Severe Ulcerative Colitis patients

Abstract Background One third of acute severe ulcerative colitis (ASUC) patients are steroid refractory and require colectomy or rescue therapy. Risk stratifying ASUC patients who are steroid non responders to facilitate early initiation of rescue therapy or consideration of colectomy remains an unmet needs in the management of ASUC. Methods Records of admitted patients with ASUC over a 5-year period were included. Clinical (diagnosis history, previous medications, disease extent) laboratory (FBC, CRP and albumin at admission and day 3, CRP/albumin ratio) and endoscopic scores (Mayo and UCEIS) at admission were recorded. The primary outcome was response to IV steroids. Secondary outcomes were the proportion of patients requiring re admission or initiation of advanced therapy (biologics or small molecules) within 1 year. Results Our study included 103 ASUC patients (44/103 male, median age: 41 years(Min:18, Max:84, range:66, IQR:27). 53 patients were steroid responders, 50 patients were non responders. Among non responders 48 had rescue therapy and 5 had colectomy at index admission (3 after rescue therapy and 2 without rescue therapy). There was no statistical significant difference between both groups in age, gender, disease extent and duration, haemoglobin level, platelets, CRP level, Mayo score of sigmoid, UCEIS score of rectum and sigmoid. There was statistically significant difference between both groups in being on oral steroids at entry, duration of hospital stay, albumin at admission, day 3 albumin, CRP/Albumin ratio at day 3 and Mayo score of rectum. On univariate analysis, albumin at admission and at day 3, CRP/Albumin ratio at day 3 and being on oral steroids at entry predicted non response to steroids while on multivariate analysis, being on steroids at admission was the only factor independently associated with steroid non-response(OR= 4.695, 95% CI: 1.79-12.34, P=0.002). Among steroid responders, 13(24.5%) required readmission within 1 year while only 3(6.7%) of the steroid non responders who received rescue therapy required readmission. Twenty five(47.2%) of steroid responders required initiation of advanced therapies within 1 year of index admission while 28 didn’t. Patients who required initiation of advanced therapy have statistically significant lower hemoglobin and higher platelets than who didn’t. Hemoglobin was the only factor to predict initiation of advanced therapy in multivariate regression analysis(-0.043, P=0.029) Conclusion Being on oral steroids at admission for ASUC can predict non response to IV steroids with majority may benefit from upfront advanced therapies at Day 1 of admission. Nearly half of the admitted ASUC patients who respond to steroids require treatment escalation to advanced therapies at 1 year.

P572 Evaluation of safety, pharmacokinetics and efficacy of oral treatment with OST-122 in patients with moderate to severe ulcerative colitis: A Phase Ib/IIa, randomized, double blind, placebo controlled clinical trial

Abstract Background OST-122 is an orally administered, GI-targeted and non-systemic JAK3/TYK2 inhibitor. In preclinical models and in healthy volunteers, OST-122 has demonstrated excellent safety and tolerability with minimal systemic exposure, thereby reducing the risk of causing serious systemic toxicities associated with current JAK inhibitors. The aim of this study was to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of OST-122 in moderate to severe ulcerative colitis (UC) patients. Methods This randomized, double blind, placebo controlled, multicenter proof of concept trial enrolled patients aged 18 to 75 years with moderate to severe UC (Total Mayo score 5-10, Endoscopic score ≥2) and with inadequate/loss of response, or intolerance to conventional (steroids and immunomodulators) and/or advanced therapy (ie. anti-TNFα, anti-integrin, anti-interleukin 12/23) in a 3:1 ratio to receive oral OST-122 400 mg (n=28) or placebo (n=9) for 28 days. The main objective of this study was to evaluate the safety and tolerability of OST-122 in patients with moderate to severe UC over 28 days by assessing the number, severity and type of adverse events. The pharmacokinetic profile was determined to confirm the compound’s low exposure in plasma (Cmax, AUC) previously observed in healthy volunteers and preclinical model. Another objective was to explore preliminary efficacy by assessing clinical parameters including rectal bleeding score and clinical response. Results A total of thirty-seven patients, 59.5% males, mean age of 44.8 years were included. The patients in the OST-122 group (n=28) had a mean Total Mayo Score at baseline of 8.1 compared to TMS = 6.7 in the placebo group (n=9). Safety analysis revealed no significant differences in the number of reported adverse events between the two treatment groups, nor did serious adverse events occur (Table 1). There were no clinically relevant changes in vital signs, laboratory values or ECG parameters which raise any safety concerns. After 28 days of treatment, 63% of patients taking OST-122 showed an improvement in rectal bleeding (vs 33% in the placebo group), 44% achieved a clinical response (vs 11% on placebo) and 22% reached clinical remission (Figure 1). Statistical significance was not achieved due to the small study size and patient variability. Pharmacokinetic data indicated minimal plasma concentrations (Cmax,ave. Day28 0.92 ng/mL) and therapeutically relevant levels in colon tissue (Cave.,Day28 15.5 ug/g tissue). Conclusion GI-restricted OST-122 was well tolerated during the 4-week treatment. Its excellent safety profile, limited systemic absorption and promising trends of clinical activity may provide a safer therapeutic option for patients with moderate to severe UC.

P782 Comparison of accelerated and standard infliximab induction regimens in Acute Severe Ulcerative Colitis using propensity score: A retrospective multicenter study in a Chinese cohort

Abstract Background The optimal regimen of infliximab salvage in acute severe ulcerative colitis (ASUC) patients remains controversial. This retrospective multicenter study aimed to compare accelerated and standard infliximab induction in a Chinese cohort of ASUC patients, and to explore risk factors associated with poor prognosis. Methods Data were collected retrospectively from steroid-refractory ASUC patients who received infliximab induction as rescue therapy at seven tertiary centers across China. Accelerated infliximab induction was defined as receiving two doses of infliximab on or before day 13 and/or receiving intensified doses of ≥ 7.5 mg/kg. Outcomes including colectomy and clinical remission (Mayo score ≤ 2 and every subscore ≤ 1 at day 14) rates were compared using propensity score adjustment for potential confounders. The variables in propensity score model was determined by logistic regression analysis for accelerated induction. Results A total of 76 patients were included: 29 received standard induction and 47 received accelerated induction. The overall disease severity was significantly higher in patients of accelerated group (Table). The 30-day colectomy rates did not differ between two groups (4.3% vs. 0%, P=0.522). However, the accelerated group had a higher 90-day colectomy rate (17.8% vs. 0%, P=0.019) and lower clinical remission rate (27.7% vs. 65.5%, P=0.001). (Figure. A) After adjusting with propensity score and institution, there was no significant difference in colectomy (P=0.20) or no clinical remission (P=0.48) hazards. Dose-effect curves plotted by restricted cubic splines (adjusted for propensity score and institution) showed decreased colectomy hazard with higher cumulative infliximab dosage within 5 days, while no improvement was observed for increasing cumulative infliximab dosage within 28 days. (Figure. B) Multivariate logistic regression analyses revealed female gender (OR=7.69, 95%CI: 1.96-33.33) and C-reactive protein (CRP) &amp;gt;10 mg/L at infliximab initiation (OR=5.00, 95%CI: 1.27-24.34) as independent risk factors for no clinical remission. (Figure. C) Conclusion After adjusting for confounders, there were no significant differences in colectomy or clinical remission rates between accelerated and standard infliximab induction among steroid-refractory ASUC patients. Elevated CRP at infliximab initiation indicated more intensive treatment or earlier surgery to be considered. And it would be better to give early intensified dosage within 5 days if needed.

P711 Outcomes of Outpatient Biologic Exposed Patients Hospitalized with Severe Ulcerative Colitis

Abstract Background Up to 20% of patients with ulcerative colitis (UC) will require hospitalization for an acute severe flare. It is unclear whether outpatient exposure to biologics alters the outcomes of inpatient severe UC. We aimed to assess the outcomes of hospitalized severe UC patients exposed to biologics in the outpatient setting. Methods This was a multicenter, retrospective study of adult patients hospitalized with severe UC at University of Cambridge, Cambridge, St. Mark’s Hospital, London and Yale University, Connecticut (from 1/1/2012-11/1/2021). We included adult patients (age ≥ 18 years) who were hospitalized for a severe UC flare as determined by the treating clinician. The primary outcome was need for colectomy among outpatient biologic exposed vs biologic naïve patients. Secondary outcomes stratified by outpatient biologic exposure included length of hospitalization and need for rescue medical therapy. Results A total of 382 patients (53.2% male) with a median age of 35 years [interquartile range (IQR) 25-53] were reviewed. Outpatient biologic exposure was noted in 23.2% (n=86, 52 exposed to infliximab) while 76.8% (n=284) were naïve to biologics. Median disease duration was longer in the biologic exposed group at 6 years (IQR 2-11) compared to 2 years (IQR 1-8) in the biologic naïve group (p &amp;lt; 0.001). Biologic exposed group was more likely to have pancolitis (70.2% vs. 54.7%; p=0.04). The C-reactive protein (CRP) to albumin ratio was higher in the biologic naïve group was higher at 12.8 (IQR: 3.2-35) vs. 8 (IQR: 1-21.5) (p=0.004). The biologic exposed group was more likely to undergo colectomy at 25% (n=21) vs. 9.3% (n=26) in the biologic naïve group (p&amp;lt;0.001). The median hospital length of stay was 6 days (IQR: 4-9) in both groups (p=0.96). Need for rescue medical therapy 37.7% (n=107) in the biologic naïve group vs. 41.9% (n=36) in the biologic exposed group (p=0.49). Colectomy was associated with outpatient biologic exposure (44.7% vs. 19.9%, p=0.0002), Mayo UC endoscopic sub-score of 3 (81.6% vs. 55.1%, p=0.002), higher median CRP [70.6 (IQR:26.8-126.3) vs. 38.8 mg/dL (IQR: 9.7-94.7), p=0.04], lower median albumin [3 (IQR: 2.7-3.6) vs. 3.5 (IQR: 3-4) g/dL, p=0.0002], and female sex (61.2% vs. 44.8%, p=0.03). On multivariable analysis, only low albumin was independently associated with risk of colectomy (odds ratio: 3.31, 95% confidence interval 1.59-6.87, p=0.0005) Conclusion In our multicenter cohort, outpatient biologic exposure was associated with increased risk of colectomy among hospitalized patients with severe UC but on multivariable analysis only low albumin was independently associated with risk of colectomy. Further study of larger cohorts is warranted.

P703 Comparison of infliximab and adalimumab therapies Persistence in patients with Ulcerative Colitis: Results from a Single Tertiary Turkish IBD Center Cohort

Abstract Background In the last 25 years, the introduction of biological therapies has been a significant milestone in the management of inflammatory bowel diseases. Despite the recent emergence of new biological therapies and small molecules, Anti-TNF agents still play a crucial role in treatment. In a number of countries, anti-TNF agents are still reimbursed as a first line treatment following either a failure or intolerance to conventional therapies such as thiopurines and aminosalycilates. Many studies have been conducted previously to compare the efficacy of these drugs, but a clear conclusion could not be reached. In this study, we aimed to compare the persistence of infliximab (IFX) to adalimumab (ADA) in the treatment of ulcerative colitis at a tertiary IBD center in Turkey. Methods This was a retrospective cohort analysis of patients with ulcerative colitis either received adalimumab or infliximab as a first line biologic treatment. A total of 234 patients were included to this analysis. Demographic information such as gender, age, montreal classification, smoking and prior medications were noted from patients electronic medical records. Weighted Kaplan-Meier and Cox models were used to assess the outcomes. Results Out of the 234 patients included in the study, 116 had used infliximab, and 118 had used adalimumab as a first-line treatment. Age and gender of the patients in both groups did not differ from each other statistically. 88% of the patients treated with adalimumab and 84% of the patients treated with infliximab were thiopurine experienced. Montreal classification did not differ between two groups (in IFX group, 73% of the patients had Montreal E3 involvement where as in ADA group, 66% of the patients had Montreal E3 involvement, p&amp;gt;0.05). Primary non-response rates were not different between IFX and ADA group, 13.6% vs 13.4% respectively. In addition, clinical response rates after first year were 60% and 53% respectively. Drug persistency rates of adalimumab and infliximab in moderate to severe ulcerative colitis patients were not statistically different from each other (Figure 1). Conclusion Neither clinical efficacy rates nor drug persistency rates of adalimumab and infliximab in ulcerative colitis treatment were not different from each other. Factors such as age, gender, location of involvement, concomitant therapies, and smoking did not alter the outcome.

P706 Tofacitinib in Moderate to Severe Ulcerative Colitis patients naïve to biological therapy: A prospective real world analysis of efficacy and safety

Abstract Background Tofacitinib is an oral non-selective Janus Kinase inhibitor approved for Ulcerative colitis (UC) after the failure of biological therapy. Tofacitinib as first line therapy in biologic naive patients has not been evaluated. Methods We conducted a prospective study to assess the safety and efficacy of Tofacitinib as first line therapy in biologic naive moderate to severe UC. Tofacitinib was given at a dose of 10mg BD for 8 weeks followed by de-escalation to 5mg BD maintenance in responders. Dose escalation was done for relapses. Demographics, disease characteristics, concomitant medication, adverse events, severity and time to relapse were recorded. Clinical response and remission (defined as partial Mayo score: PMS decrease ≥2 and PMS ≤1 respectively) were measured at 4 weeks, 8 weeks, 24 weeks and 52 weeks. Endoscopic response (UCEIS score decrease ≥2) and remission (UCEIS 0-1) were assessed at 1 year. Time to event analysis was done to evaluate the cumulative rate of clinical response. Results 176 patients (136 biologic naive, 58% male; median age 40y [IQR:31-48y]) were included. Median baseline PMS and UCEIS score were 5 (IQR: 5-7 and 4-6 respectively) (Table 1). Of the biologic naïve cohort, clinical response was achieved in 68.4% and 79.4% at 4 and 8 weeks respectively. Clinical remission was achieved in 45.6%(4-weeks) and 55% (8-weeks). Maintenance of remission was seen in 44.1% and 32.4% in 24 and 52 weeks respectively (Fig1A). There was a significant reduction in PMS from baseline to end of 8-weeks (p&amp;lt;0.001) (Fig 1B). Corticosteroid-free clinical remission was achieved in 64.8% at 24-weeks. 106 patients (77.9%) maintained response till last follow-up. 11 relapsed after dose de-escalation (median time of 5m [range 3-22m]. 7/11 responded to dose escalation to 10mg. Endoscopic response was noted in 62.5% and remission in 33.9% with significant reduction in UCEIS from baseline to 52-weeks(p&amp;lt;0.001) (Fig 1B). Severe and minor adverse events were noted in 4 and 3 patients respectively (Table 1). Overall 1/3 of patients discontinued therapy at 24-weeks (14%) and 52 weeks (10%). No significant difference in proportion of clinical or endoscopic remission was observed between the biologic naïve and those with history of prior biologic usage (n=31, median time from withdrawal of biologics to Tofacitnib initiation=9 months). Conclusion Tofacitinib was effective in induction of clinical remission in more than half of biologic naive, moderate to severe UC . Three-fourth of these patients continued to be in remission at one year with few serious adverse events. Tofacitinib can be considered as upfront oral therapy after failure of conventional management.

Lung Involvement in Patients with Ulcerative Colitis: Relationship between Exhaled Nitric Oxide and Lung Function.

Ulcerative colitis (UC) is characterized by immune system dysregulation with frequent extraintestinal manifestations, including airway involvement. A reduction in CO diffusing capacity and functional alterations in small airways have been described. An extended analysis of fractional exhaled nitric oxide (FeNO) may distinguish the sites of production, and the presence of small airway inflammation may be a useful, non-invasive marker for patient follow-up. The aim of our study was to compare the PFTs as well as FeNO and CANO values of UC patients with different clinical disease activities and healthy subjects to reveal lung function abnormalities and the presence of subclinical airway inflammation. We enrolled 42 adult outpatients at different clinical activity stages of UC (39 ± 13 years) and a healthy control group of 41 subjects (29 ± 3 years). C-reactive protein (CRP) and FeNO values at different flows (50,100, and 200 mL/s) were collected. All patients performed pulmonary function tests (PFTs) with static volumes and diffusing capacity (DLCO). FeNO and CANO values were significantly increased in UC patients when compared with controls (p = 0.0008 and p < 0.0001, respectively) and were proportional to disease activity (FeNO class 3: 28.1 ppb vs. classes 1-2: 7.7 ppb; CANO values class 3: 8.6 ppb vs. classes 1-2: 2.7 ppb (p < 0.0001)). TLC and DLCO were significantly reduced in severe (Mayo 3) UC patients (p = 0.010 and p = 0.003, respectively). The results of this study show significant lung functional abnormalities in UC patients and suggest the presence of airway inflammation directly correlated with disease activity, suggesting the need for an integrated approach in routine assessment.

In Acute Severe Ulcerative Colitis Patients Who Receive Rescue Therapy, Prior Maintenance Therapy and Day 3 C-Reactive Protein After Rescue Therapy Are Associated With 12-Month Colectomy Risk.

Lay Summary In steroid-refractory patients with acute severe ulcerative colitis, the number of advanced therapies prior to admission and day 3 C-reactive protein post–rescue therapy is associated with a higher risk of colectomy within 12 months.

Tofacitinib in Steroid-Refractory Acute Severe Ulcerative Colitis: A Retrospective Analysis.

Steroid-refractory acute severe ulcerative colitis (ASUC) patients are at the highest risk of colectomy. Among the available options, cyclosporine and infliximab have similar efficacy but infliximab is a costly drug and cyclosporine has multiple side effects like kidney injury, neurotoxicity, and dyselectrolytemia.Surgical management is often associated with higher morbidity. Newer oral small molecules like Janus kinase inhibitors are the ideal molecules to bridge the gap. Tofacitinib has already been extensively evaluated in patients with moderate to severe UC; however, data on ASUC treated by tofacitinib are limited. We retrospectively analyzed the data of patients with ASUC who were admitted to our hospital's luminal gastroenterology unit between January 2021 and July 2023. Patients with ASUC who were managed with tofacitinib were included in the study. Eight patients with ASUC were identified who did not respond to intravenous hydrocortisone and were treated with tofacitinib.The mean age was 39 ± 15 years and 87.5% were female. The median duration of illness was 24 months (interquartile range (IQR): 12-120 months).Seven of eight patients (87.5%) responded to oral tofacitinib 10 mg twice a day by the fifth day of treatment. The median follow-up period was six months (IQR: 1-12 months). One patient required colectomy and one patient had varicella zoster reactivation requiring treatment discontinuation. Tofacitinib is an attractive alternative to the currently available salvage therapy for steroid-refractory ASUC;however, long-term efficacy and risk remain to be explored.

Predictive Factors for Efficacy of Oral Tacrolimus Induction Therapy in Moderate to Severe Ulcerative Colitis Patients: Large Multicenter Retrospective Cohort Study.

Tacrolimus (TAC), a calcineurin inhibitor, is used for remission induction therapy in patients with moderate to severe ulcerative colitis (UC), with short-term efficacy and related predictive factors shown in previous cohort studies. However, most studies reported data for only a limited number of patients enrolled from a single center. We performed a large multicenter retrospective cohort study to identify factors related to prediction of clinical remission in UC patients treated with oral TAC. The medical records of patients with moderate to severe UC treated with oral TAC as induction therapy at 7 institutions between April 2009 and March 2017 were retrospectively reviewed. A total of 216 patients who received TAC for induction were analyzed, of whom 123 (56.9%) showed clinical remission at week 12. Logistic regression analysis indicated that previous or current use of antitumor necrosis factor (TNF)-α antibodies (odds ratio [OR], 0.259; P = .006), and concomitant treatment with 5-aminosalicylate (5-ASA) at the baseline (OR, 0.268; P = .005) were independent predictive factors correlated with failure of clinical remission, whereas higher levels of C-reactive protein (OR, 1.124; P = .014) predicted achievement of clinical remission. Results of this multicenter study clearly indicate the efficacy of TAC induction therapy for patients with moderate to severe UC. Notably, previous or current use of anti-TNF-α antibodies was associated with poor achievement of clinical remission by week 12.

The significance of PD-1/PD-L1 imbalance in ulcerative colitis.

To investigate the expression and significance of programmed cell death protein 1 (PD-1) and programmed cell death ligand-1 (PD-L1) in the mucosal tissues and peripheral blood of patients with ulcerative colitis (UC). Eighty patients with UC were recruited from January 2021 to August 2022 from the Shanxi Province People's Hospital. PD-1 and PD-L1 expression was assessed by immunohistochemistry in mucosal tissues. An enzyme-linked immunosorbent assay was used to measure soluble PD-1 and PD-L1 levels in peripheral blood serum, and the membrane-bound forms of PD-1 (mPD-1), (T-helper cell) Th1 and Th17, in peripheral blood were determined by flow cytometry. PD-1 expression was observed only in the monocytes of the mucosal lamina propria of UC patients, while PD-L1 was mainly located in both epithelial cells and monocytes on the cell membrane. The expression level of PD-1/PD-L1 in the monocytes and epithelial cells of mucosal lamina propria increased with disease activity (P < 0.05). The percentages of PD-1/T and PD-1/CD4+T in the peripheral blood of moderate UC patients (PD-1/T 12.83 ± 6.15% and PD-1/CD4+T 19.67 ± 9.95%) and severe UC patients (PD-1/T 14.29 ± 5.71% and PD-1/CD4+T 21.63 ± 11.44%) were higher than in mild UC patients (PD-1/T 8.17 ± 2.80% and PD-1/CD4+T 12.44 ± 4.73%; P < 0.05). There were no significant differences in PD-1/CD8+T cells between mild and severe UC patients (P > 0.05). There was a statistically significant difference in the expression level of sPD-L1 between the UC groups and healthy controls, and the expression level of sPD-L1 increased with disease severity (P < 0.05); however, there was no statistically significant difference in sPD-1 expression levels between the UC groups and healthy controls (P > 0.05). The correlation coefficients between Th1 and sPD-L1, PD-1/T, PD-1/CD4+T and PD-1/CD8+T were 0.427, 0.589, 0.486, and 0.329, respectively (P < 0.001). The correlation coefficients between Th17 and sPD-L1, PD-1/T, PD-1/CD4+T and PD-1/CD8+T were 0.323, 0.452, 0.320, and 0.250, respectively (P < 0.05). The expression level of PD-1/PD-L1 was correlated with UC disease activity, and two forms of PD-1 and PD-L1 may be used as a potential marker for predicting UC and assessing disease progression in UC patients. PD-1/PD-L1 imbalance was a significant phenomenon of UC immune dysfunction. Future research should focus on two forms of PD-1/PD-L1 signaling molecules to better understand the pathogenesis of UC and to identify potential drug therapies.

Gut Microbiome and Metabonomic Profile Predict Early Remission to Anti-Integrin Therapy in Patients with Moderate to Severe Ulcerative Colitis.

Patients with ulcerative colitis (UC) have low response rates to anti-integrin medications, necessitating the identification of noninvasive biomarkers for predicting remission to anti-integrin therapy. In this study, patients with moderate to severe UC commencing anti-integrin therapy (n = 29), inactive to mild UC patients (n = 13), and healthy controls (n = 11) were selected. Besides clinical evaluation, fecal samples were collected at baseline and week 14 from moderate to severe UC patients. The clinical remission was defined based on the Mayo score. Fecal samples were assessed with 16S rRNA gene sequencing, liquid chromatography-tandem mass spectrometry, and gas chromatography-mass spectrometry (GC-MS). We identified that Verrucomicrobiota was significantly more abundant in the remission group (P < 0.001) than that of nonremission group at phylum level for patients commencing vedolizumab. GC-MS analysis revealed that the concentrations of butyric acid (P = 0.024) and isobutyric acid (P = 0.042) were significantly higher in the remission group compared to the nonremission group at baseline. Finally, the combination of Verrucomicrobiota, butyric acid, and isobutyric acid improved the diagnosis of early remission to anti-integrin therapy (area under the concentration-time curve = 0.961). We identified significantly higher phylum level diversity of Verrucomicrobiota in remission than the nonremission groups at baseline. Notably, the combination of gut microbiome and metabonomic profiles improved the diagnosis of early remission to anti-integrin therapy. IMPORTANCE It is reported that patients with ulcerative colitis (UC) have low response rates to anti-integrin medications in the latest VARSITY study. Therefore, our primary goals were to discover differences in the gut microbiome and metabonomics patterns between early remission and nonremission patients and to explore the diagnostic value in predicting clinical remission to anti-integrin therapy accurately. In this study, we found that Verrucomicrobiota was significantly more abundant in the remission group (P < 0.001) than that of nonremission group at phylum level for patients commencing vedolizumab. Gas chromatography-mass spectrometry analysis revealed that the concentrations of butyric acid (P = 0.024) and isobutyric acid (P = 0.042) were significantly higher in the remission group compared with the nonremission group at baseline. Notably, the combination of Verrucomicrobiota, butyric acid, and isobutyric acid improved the diagnosis of early remission to anti-integrin therapy (area under the concentration-time curve = 0.961).

P783 Symptom Improvement of ulceRative colitis after an Injection dose of Ustekinumab in Japanese clinical practice, measured using patient-reported outcomes (SIRIUS) study, Interim Analysis

Abstract Background Ustekinumab (UST) is treated to moderate to severe adult ulcerative colitis (UC) patients. We conducted the SIRIUS study (Symptom Improvement of ulceRative colitis after an Injection dose of UStekinumab in Japanese clinical practice, measured using patient-reported outcomes (PRO)) to record daily symptoms for 8 weeks after the introduction of intravenous ustekinumab in moderate to severe UC patients, which aimed to reveal early response patterns of symptoms during the induction of remission period with ustekinumab, and to explore symptoms suitable for monitoring and predicting treatment effect. This interim analysis focuses on stool frequency (SF) and rectal bleeding (RB) scores in the PRO-2 during the 8-week induction period. Methods This single-arm prospective observational study conducted in 23 centers in Japan aimed to recruit 140 patients with moderate-to-severe UC between July 2021 and July 2022. RB score, SF score, abdominal pain, nocturnal diarrhea, tenesmus, and patient perception of improvement were recorded daily using a smartphone app. To be eligible for the study, participants must have a documented diagnosis of UC, be ≥16 years of age, have UC (partial Mayo score of 5~9), have had an inadequate response or intolerance to prior UC therapies, and be able to understand and complete PRO instruments using a smartphone. Patients who had prior exposure to UST, history of extensive colectomy, or were hospitalized when UST was started were excluded. Results In this analysis,137 patients were included. Seventy-four (54.4%) patients were male and the median age was 35 years. Seventy-six (55.9%) patients were Bio-naïve. This high proportion of Bio-naïve patients reflects the fact that UST can be used for Bio-naive patients without restrictions in the Japanese health insurance. At weeks 2 and 4, 56 (41.2%) and 57 (41.9%) patients attended outpatient clinics, respectively. The data collection rate of the PROs was 95%. Mean SF and RB scores were demonstrated stratified by prior treatment with Bio (Figure 1&amp;3). Significant decreases in mean SF and RB scores were observed within 1 week in both Bio-naïve and -experienced patients. the time-course change in SF was similar between Bio-naïve and -experienced patients, but the decrease in RB scores was greater in the Bio-naïve patients than the Bio-experienced patients. Conclusion A daily PRO-based analysis was conducted in the Sirius study to monitor symptoms during the first 8 weeks after the introduction of UST in patients with moderate-to-severe UC. This interim analysis revealed that SF and RB scores started to decrease within 1 week, demonstrating a rapid symptomatic response to UST. The analysis of the other PROs and predictors of efficacy will be performed in further studies.

P922 Gut microbiome and mycobiome in inflammatory bowel disease patients with Clostridium difficile infection

Abstract Background Clostridium difficile infection (CDI) is common in patients with inflammatory bowel disease (IBD) and has been reported as a risk factor for poor outcome. However, gut microbiome and mycobiome of IBD patients with CDI have been barely investigated. This study aimed to assess the gut microbiome and mycobiome in IBD patients with CDI. Methods We collected fecal samples from patients with IBD and concomitant CDI (IBD-CDI group, n=38), patients with IBD and no CDI (IBD-only group, n=91), and healthy subjects (HC, n=40). Patients characteristics including demographic data, disease severity, and medication history were collected. 16S rRNA sequencing, metagenomic sequencing, and untargeted metabolomic analysis were carried out in the samples. Results We found that the bacterial alpha diversity of the IBD-CDI group was lower than the IBD-only group and HC. And the bacterial and fungal beta diversity variations between IBD patients and HC were significant, regardless of CDI status. But the IBD-CDI group did not significantly cluster separately from the IBD-only group. Several bacterial taxa, including Ruminococcus gnavus, Clostridium innocuum, and Veillonella were overrepresented in the IBD-CDI group compared with IBD-only group and HC. Furthermore, IBD patients with CDI were distinguished from the IBD-only group and HC by several fungal taxa, including underrepresentation of Candida albicans, and overrepresentation of Saccharomyces cerevisiae, Eremothecium sinecaudum, Torulaspora delbrueckii, Grosmannia clavigera, and Eremothecium gossypii. The fungal-bacterial transkingdom network was altered in the IBD patients with CDI with a decreased network density. Notably, the relative abundance of Grosmannia clavigera was markedly higher in severe ulcerative colitis patients (defined by Truelove and Witts criteria and Mayo score). Besides, prior antibiotic exposure was associated with decreased biodiversity and increased dysbiosis. Functional differences in IBD patients with CDI include enrichment of branched-chain fatty acid biosynthesis, succinate fermentation to butanoate, peptidoglycan biosynthesis, and tetrahydrofolate biosynthesis. The metabolomic data indicated that the differential metabolites were predominantly involved in amino sugar and nucleotide sugar metabolism, fatty acid metabolism, porphyrin and chlorophyll metabolism, and neomycin, kanamycin and gentamicin biosynthesis. Conclusion IBD patients with CDI had pronounced microbial dysbiosis. Gut micro-ecological changes and interkingdom crosstalk in IBD patients with CDI might provide insight into the pathological process and potential strategies for diagnosis and treatment in this subset of patients.

P262 Development and validation of a score predicting non-response to intravenous corticosteroids in patients with Acute Severe Ulcerative Colitis on day 3 of admission

Abstract Background Colectomy rates in acute severe ulcerative colitis (ASUC) patients have declined over the last 25 years. Objective predictors of non-response to IV corticosteroids (IVCS) in ASUC can further improve outcomes. Our aim was to develop and validate predictors of IVCS non-response in ASUC patients in the biologic era. Methods Consecutive patients with ASUC satisfying Truelove and Witts’ criteria hospitalised at two tertiary IBD centres in Australia between 2013-2020 were included. Primary outcome was steroid non-response requiring medical or surgical rescue therapy. UCEIS was scored on flexible sigmoidoscopy performed within 24-48 hours of admission. Development cohort comprised 112 episodes of ASUC between 2013 and 2017, and the validation cohort comprised 114 episodes of ASUC between 2018-2020. Results In the development cohort, 52 (46.4%) episodes were steroid non-responders and 18 (16%) episodes underwent colectomy during the same admission. On multi-variable analysis, predictors of non-response to IVCS were UCEIS score [OR 2.45 (1.65-3.63, p &amp;lt;0.001)] and serum albumin day 3 after admission [OR 0.83 (0.76-0.90), p &amp;lt;0.001]. A score was developed allocating 1 point to each variable (UCEIS ≥ 7 and day 3 serum albumin ≤ 25 mg/L) For predicting steroid non-response, the score had OR 6.31 (3.11- 12.79), p &amp;lt;0.001, AUROC 0.763 (0.676-0.849), score of 2 points had a sensitivity of 26%, specificity 100%, PPV 100, NPV 59.5%; for same admission colectomy OR 20.58 (6.16-68.6), p &amp;lt;0.001, AUROC 0.905 (0.846-0.964). In the validation cohort, 52 (45.6%) episodes were steroid non-responders and 7 (6.1%) episodes underwent colectomy during the same admission. For predicting steroid non-response, the score had OR 4.26 (2.07-8.76), p &amp;lt;0.001, AUROC 0.684 (0.593-0.776), score of 2 points had sensitivity 13%, specificity 100%, PPV 100%, NPV 57%; for same admission colectomy OR 5.42 (2.44-12.05), p &amp;lt;0.001, AUROC 0.83 (0.753-0.907). Conclusion In the biologic era, UCEIS score and serum albumin on day 3 of admission are predictors of steroid non-response in patients with ASUC. We have developed and validated a score comprising UCEIS ≥ 7 and day 3 serum albumin ≤ 25mg/L. A score of 2 has a specificity of 100% and PPV 100% for predicting non-response to IVCS.

Ulcerative Colitis and Acute Severe Ulcerative Colitis Patients Are Overlooked in Infliximab Population Pharmacokinetic Models: Results from a Comprehensive Review.

Ulcerative colitis (UC) is part of the inflammatory bowels diseases, and moderate to severe UC patients can be treated with anti-tumour necrosis α monoclonal antibodies, including infliximab (IFX). Even though treatment of UC patients by IFX has been in place for over a decade, many gaps in modelling of IFX PK in this population remain. This is even more true for acute severe UC (ASUC) patients for which early prediction of IFX pharmacokinetic (PK) could highly improve treatment outcome. Thus, this review aims to compile and analyse published population PK models of IFX in UC and ASUC patients, and to assess the current knowledge on disease activity impact on IFX PK. For this, a semi-systematic literature search was conducted, from which 26 publications including a population PK model analysis of UC patients receiving IFX therapy were selected. Amongst those, only four developed a model specifically for UC patients, and only three populations included severe UC patients. Investigations of disease activity impact on PK were reported in only 4 of the 14 models selected. In addition, the lack of reported model codes and assessment of predictive performance make the use of published models in a clinical setting challenging. Thus, more comprehensive investigation of PK in UC and ASUC is needed as well as more adequate reports on developed models and their evaluation in order to apply them in a clinical setting.

Adalimumab Efficacy for Management of Inflammatory Bowel Disease in Southwest Region of Iran

Background: In recent years, biological drugs, including antitumor necrosis factors, have revolutionized the treatment of inflammatory bowel disease (IBD); however, there is no consensus about the superiority of adalimumab over infliximab. Objectives: This study was designed to evaluate the efficacy of adalimumab for the management of IBD in the southwest region of Iran. Methods: During this prospective observational study, the patients with active IBD and a history of no response to previous treatments that referred to an IBD clinic were included. Moreover, this study evaluated and compared the effectiveness of treatment, including clinical remission rate, disease activity index (the Mayo score in ulcerative colitis (UC) patients and the Crohn’s disease activity index (CDAI) in Crohn’s disease (CD) patients), clinical response, and side effects related to adalimumab injection in 0, 12th, 24th, and 52nd weeks after treatment. Results: A total of 71 patients, including 42 male and 29 female, with a mean age of 29 years, were included. In this study, 37 and 34 patients were diagnosed with UC (52.1%, 20 male and 17 female) and CD (47.8%, 22 male and 12 female), respectively. The time to remission in the UC group was significantly longer than in the CD group (10.05 and 1.71 months; P &lt; 0.0001). Clinical remission rate (≥ 2 points reduction in the Mayo score) in the 12th week among UC patients after treatment with adalimumab was 67.5% and raised to 100% (all the UC patients) in the 24th and 52nd weeks after treatment. None of the UC patients experienced disease recurrence. In CD patients, the CDAI significantly decreased during the treatment time (P &lt; 0.0001); however, all CD patients (100%) experienced disease recurrence after a mean time of 2.59 ± 0.55 months (within 2 - 4 months) (P &lt; 0.0001). Failure of treatment was observed in 94.1% of CD patients (n = 32); nevertheless, none of the UC patients had treatment failure (P &lt; 0.0001). There were no complications related to adalimumab, and no patients needed colectomy during the study period. Conclusions: Adalimumab has a positive effect on the improvement of clinical symptoms, reduction of disease activity, prevention of disease recurrence, and need for colectomy in moderate to severe UC patients. However, adalimumab has no efficacy in the improvement of CD patients, and failure of treatment was observed in most of these patients. Adalimumab could be a therapeutic option for the management of UC with prior failure of treatment.

Update on ozanimod for ulcerative colitis.

Treating moderate to severe ulcerative colitis (UC) has been enriched by the increasing number of drugs available for this disease. However, failure of conventional therapies, an incomplete response, or loss of response to biologics is experienced in many UC patients. Thus, there is still a growing need for new drugs in the therapeutic arsenal for UC. Ozanimod is a sphingosine-1-phosphate (S1P) receptor modulator which has been recently approved for UC therapy. In this review, we focus on the mechanism of action of ozanimod hydrochloride in preclinical studies of intestinal inflammation as well as its clinical effectiveness and safety in moderate to severe UC patients. In this population, ozanimod was shown to be significantly more effective than placebo to induce clinical remission. Additionally, in terms of clinical response, corticosteroid-free remission, endoscopic improvement and mucosal healing, ozanimod performed significantly better than placebo in this population. No significant safety concerns about ozanimod emerged from clinical trials in UC.

Cyclosporine Therapy as a Rescue Treatment in Steroid Refractory Acute Severe Ulcerative Colitis: A Real Life Data From a Tertiary Center.

Cyclosporine is a rescue treatment alternative to avoid colectomy in corticosteroid refractory acute severe ulcerative colitis. In this study, we aimed to evaluate the long-term efficacy and safety of cyclosporine therapy in acute severe ulcerative colitis patients. Acute severe ulcerative colitis (basal Lichtiger score > 10) patients who did not respond to 40 mg intravenous methylpredniso- lone therapy after 3-5 days were included in the study. The presence of clinical response and remission was assessed at 1st week, 1st, 6th, and 12th month according to the Lichtiger index. In this study, 40 patients, whose steroid refractory acute severe ulcerative colitis and basal Lichtiger score > 10 points were enrolled. The median disease duration was 49.3 months (2-204). All patients received cyclosporine for 132 ± 78 days (7-270). Clinical response was obtained on seventh day in 82.5%. The clinical response rates of the first and sixth months were 72.5% and 62.5%, respectively. A total of 17/40 (42.5%) patients underwent colectomy within 1 year. In the patients who underwent colectomy, the basal LS (14.2 ± 1.9 vs 12.3 ± 1.7) (P = .002) was higher and the basal hemoglobin value (11.8 ± 2.3 vs 10.1 ± 1.5) (P = .037) was lower than those who did not undergo colectomy. Our findings suggest that cyclosporine treatment may be successfully and safely used in steroid refractory acute severe ulcerative colitis patients. Cyclosporine is a drug that has recently started to come up again with the introduction of new maintenance treatments. Especially in patients who develop a loss of response to infliximab therapy, or where infliximab therapy is contraindicated, or who have azathioprine intolerance, or are unresponsive.