Refractory Ulcerative Colitis Patients Research Articles

Comparison between tofacitinib and ustekinumab as a third-line therapy in refractory ulcerative colitis: A multicenter international study.

Ustekinumab and tofacitinib have recently been approved for the management of moderate to severe ulcerative colitis (UC). However, there is no evidence on how they should be positioned in the therapeutic algorithm. The aim of this study was to compare tofacitinib and ustekinumab as third-line therapies in UC patients in whom anti-TNF and vedolizumab had failed. This was a multicenter retrospective observational study. The primary outcome was disease progression, defined as the need for steroids, therapy escalation, UC-related hospitalization and/or surgery. Secondary outcomes were clinical remission, normalization of C-reactive protein, endoscopic remission, treatment withdrawal, and adverse events. One-hundred seventeen UC patients were included in the study and followed for a median time of 11.6months (q1-q3, 5.5-18.7). Overall, 65% of patients were treated with tofacitinib and 35% with ustekinumab. In the entire study cohort, 63 patients (54%) had disease progression during the follow-up period. Treatment with ustekinumab predicted increased risk of disease progression compared to treatment with tofacitinib in Cox regression analysis (HR: 1.93 [95% CI: 1.06-3.50] p=0.030). Twenty-eight (68%) patients in the ustekinumab group and 35 (46%) in the tofacitinib group had disease progression over the follow-up period (log-rank test, p<0.054). No significant differences were observed for the secondary outcomes. Six and 22 adverse events occurred in the ustekinumab and tofacitinib groups, respectively (15% vs. 31%, p=0.11). Tofacitinib was more efficacious in reducing disease progression than ustekinumab in this cohort of refractory UC patients. However, prospective head-to-head clinical trials are needed as to confirm these data.

P1218 Non-invasive point-of-care stool sample for detection of Cytomegalovirus infection in patients with Active or Refractory Ulcerative Colitis using multiplex polymerase chain reaction (mPCR): a pilot feasibility study

Abstract Background Cytomegalovirus (CMV) infection is associated with more flare-ups and deteriorates the prognosis of active inflammatory bowel disease (IBD). Patients with refractory IBD should be tested for CMV colitis, especially if they are not responding to immunosuppressive therapy. The prevalence of CMV co-infection ranges from 10% to 30% in steroid-refractory acute colitis. Concurrent CMV-colitis is associated with an increased risk of worse therapeutic outcomes, resistance to corticosteroids, and need for salvage therapy. One of the two gold standards of diagnosis of CMV colitis in IBD patients with active disease requires the analysis of tissue biopsies using PCR. The aim of our pilot study was to evaluate the diagnostic accuracy of non-invasive point-of-care faecal samples using mPCR for detecting CMV in patients with ulcerative colitis compared to standard practice biopsies PCR. Methods We performed a prospective, observational, feasibility study including 62 consecutive patients with active ulcerative colitis (UC) requiring intravenous steroids or steroid-refractory UC in the Department of Gastroenterology of University Hospital „Tsaritsa Yoanna – ISUL", from April 2022 to October 2023. In all UC patients, colonic tissue biopsies were performed and analyzed by qualitative CMV PCR. Faecal sample mPCR CMV was performed on the positive patient cohort to compare the feasibility of (ME) Panel IVD using FilmArray mPCR (Biofire, bioMerieux, France). All the tested patients had undergone immunosuppressive therapy and initial stool specimen cultures were obtained to exclude infection with C. difficile and other pathogen flora. Results Out of 62 active UC patients with colonic tissue samples qualitative CMV PCR, n=5 (8%) were positive. Of these n=5 UC patients, n=4 (80%) were positive from the Fecal sample mPCR CMV, resulting in a compatibility of 80% for diagnosing CMV in these patients by the two DNA extraction methods. Calculated Sensitivity and diagnostic accuracy was 80% (95% CI) for the mPCR CMV. The patient cohort predominantly comprised males (75%) with a median age of 45 years (range: 30–72 years). Three patients (75%) out of this cohort group were treated with peroral antiviral agent Valganciclovir, one (25%) of them went into clinical and endoscopic remission after the treatment and two patients (50%) received colectomy. The median time performing the Faecal sample mPCR CMV was approx. 1 hour. Conclusion This novel faecal mPCR point-of-care test is a promising, fast and easy non-invasive tool for detection CMV in active or refractory UC patients, comparable with the colonic tissue CMV-DNA PCR.

P944 Ustekinumab in refractory Ulcerative Colitis: single-center, real-world experience

Abstract Background Ustekinumab, an anti-interleukin 12/23 agent, was approved by the European Medicines Agency in 2019 as a treatment for moderate-to-severe ulcerative colitis (UC). Limited real-world data is available regarding the utilization of ustekinumab in UC, particularly medication persistence and escalation, which are indicators of medication performance in real-world settings. Our aim was to describe our experience with ustekinumab in refractory UC patients. Methods This was an observational single-center study on UC patients who received at least one intravenous dose of ustekinumab 16 weeks before data analysis due to active UC (Simple clinical colitis activity index (SCCAI)&amp;gt;5). Data regarding disease activity prior to and post-induction were analyzed. Patients were followed up until the last ustekinumab administration. Clinical response to therapy was assessed at 16, 24,52 weeks, and the end of follow-up. Response was defined as SCCAI&amp;lt;4, and remission as SCCAI≤2. Dose adjustment or IV maintenance was considered part of the treatment regimen. Patients who discontinued ustekinumab due to lack of therapeutic effect or worsening of UC were considered failures. When available, colonoscopy data was analyzed. Results Forty-seven patients who received ustekinumab for refractory UC were included. Thirty-eight percent were female, and 34% were former smokers. Median age was 46 [37.5-61.5]; 62% had extensive disease, and 15% had perianal disease. Ninety-three percent received at least one biologic before ustekinumab, and 24% had received a JAK inhibitor. Thirty-eight patients required dose escalation, and 11 were on maintenance IV. Clinical response at week 16 was achieved in 74% and remission in 46%. At 24 and 52 weeks, 65% and 61% were in remission, respectively. At the end of follow-up, 59% of patients had endoscopic remission (Endoscopic Mayo score ≤ 1). Sixty percent continued treatment during a mean follow-up of 12 months [6-21]. No variable was associated with risk of discontinuation. No serious adverse events were reported. Discontinuation of treatment was due to treatment failure in all cases. Conclusion Ustekinumab was effective for induction and maintenance in our cohort of UC patients, although a significant proportion required dose escalation. Drug persistence was higher than 50% during the follow-up. The safety profile of ustekinumab was similar to that in controlled studies and other real-world studies.

P941 Observational study of tofacitinib in ulcerative colitis in Sweden (ODEN) – Interim analysis of clinical and biomarker data

Abstract Background Tofacitinib is a Janus kinase (JAK) inhibitor for the treatment of moderate to severe ulcerative colitis (UC). ODEN is an ongoing Swedish multicentre prospective observational study regarding effectiveness of tofacitinib in UC. In this interim analysis, we aimed to assess the clinical outcomes during the first 16 weeks. Methods Patients with active UC were enrolled 2020-2023 when starting tofacitinib as per clinical indication. Inclusion criteria were fecal (F) calprotectin &amp;gt;250 mg/kg or Mayo endoscopic score ≥2. Data were collected using an electronic case report form linked to the Swedish National Quality Registry for Inflammatory Bowel Disease (SWIBREG). Data concerning inflammatory markers, endoscopic activity, partial (p) Mayo, extra intestinal manifestations, health-related quality of life measures, corticosteroid use, and colectomy rates were collected regardless of tofacitinib discontinuation. Information collected at week 8 and 16 is presented here. Intention-to-treat (ITT) analysis was applied and tofacitinib discontinuation was considered as treatment failure (i.e., no tofacitinib-induced clinical or laboratory response or remission). McNemar’s test was used for proportion differences. Results The proportion of patients who previously had failed at least one biologic was 95% and at least two biologics, 62%. At inclusion, median p-Mayo was 5 and 39% of patients were on corticosteroids (Table 1a). Patients’ survival on drug is shown in Figure 1a. At week 8 and 16, 42% and 43%, respectively, achieved corticosteroid free clinical remission, Figure 1b. A 50% reduction in F-calprotectin was seen in 54% and 49% at week 8 and 16, respectively. The endpoint of Mayo endoscopic score 0 and/or F-calprotectin &amp;lt;100 mg/kg was achieved by 30% and 38% at week 8 and 16, respectively. Arthralgia frequency decreased significantly from baseline from 29% at inclusion to 13% and 11% at week 8 and 16 respectively. Three patients underwent colectomy the first 16 weeks (Table 1b). Conclusion After 16 weeks of treatment with tofacitinib, a substantial proportion of previously treatment refractory UC patients were in clinical and endoscopic corticosteroid-free remission, and a distinct improvement in F-calprotectin levels was observed. In addition, a significant reduction in arthralgia was noted.

DOP74 Short and long-term effectiveness and safety of ustekinumab in Ulcerative Colitis in real life: the ULISES study

Abstract Background Primary aim: To assess the durability of ustekinumab treatment in patients with ulcerative colitis (UC). Secondary aims: To assess the short-term effectiveness, the durability of response, and the tolerability of ustekinumab in clinical practice. Methods Retrospective, multicenter study including UC patients who had received the 1st ustekinumab dose at least 16 weeks before inclusion. Patients were followed-up from the 1st ustekinumab dose to treatment discontinuation or last visit. Only patients with active disease [Partial Mayo Score (PMS)&amp;gt;2] at ustekinumab start were considered in the effectiveness analysis. Clinical effectiveness was based on PMS. Patients who stopped ustekinumab before their last visit were considered not in remission at subsequent time points (negative imputation). Results 620 patients were included (table 1). 78% of patients who started ustekinumab maintenance treatment, did it with 90 mg every-8-weeks dose. 155 patients (25%) withdrew ustekinumab during follow-up [median=12 months (m)]. Incidence rate of ustekinumab discontinuation was 20% per patient-year of follow-up. The probability of maintaining ustekinumab is shown in figure 1A. Among patients who withdrew ustekinumab, the main reasons were primary non-response (39%) and loss of response (35%). Anaemia at baseline (HR=1.5, 95%CI=1.1-2.1), steroids at baseline (HR=1.5; 95%CI=1.06-2.08), and more severe clinical activity at baseline (HR=1.5; 95%CI=1.09-2.06) were associated with higher risk of ustekinumab discontinuation. Short and long-term effectiveness of ustekinumab is shown on figure 1B. Moderate-severe vs. mild disease activity at baseline (OR=0.3, 95%CI=0.2-0.5), male sex (OR=0.5; 95%CI=0.4-0.8), and increased number of previous biologics (OR=0.6, 95%CI=0.6-0.8) were associated with lower likelihood of steroid-free remission at week 16. A total of 57 (25%) patients among those with active disease at baseline and with steroid-free remission at week 16, lost response during a median follow-up of 8 m (IQR=3-16 m) (figure 1C). The dose was escalated in 72% of patients with loss of response, and 80% improved (67% remission); an intravenous reinduction was given in 3 patients, and none of them improved. A total of 176 patients (28%) had at least one adverse event, with infections being the most frequent (11%). No negative impact on extraintestinal manifestations and/or immunomediated diseases was seen. Conclusion Ustekinumab was effective in inducing remission even in highly refractory UC patients. A proportion of patients discontinue the treatment, mostly due to primary failure and loss of response. Dose escalation may be effective to regain response after loss of effectiveness. The safety profile was similar to previously reported.

Real-world long-term effectiveness of ustekinumab in ulcerative colitis: results from a spanish open-label cohort

Objective Ustekinumab was recently approved for the treatment of moderate-to-severe ulcerative colitis (UC). Although data from the UNIFI clinical trial are encouraging, real-world data assessing effectiveness and safety are scarce. The aim of this study was to assess the effectiveness, safety and pharmacokinetics of ustekinumab in a large cohort of refractory UC patients. Methods Multicenter observational study of UC patients who received ustekinumab for active disease. The Partial Mayo Score (PMS), endoscopic activity, C-reactive protein (CRP) and faecal calprotectin (FC) were recorded at baseline and at different time points. Demographic and clinical data, adverse events (AEs) and surgeries were documented. Results A total of 108 patients were analyzed from 4 referral Spanish hospitals. The clinical remission rates were 59%, 56.5%, 57% and 69% of patients at weeks 8, 16, 24 and 52, respectively. Normalization of FC was achieved in 39.6%, 41% and 51% at weeks 8, 24 and 52, respectively. CRP normalization was observed in 79%, 75% and 76.5% of patients at weeks 8, 24 and 52, respectively. Fewer previous anti-TNF agents and loss of response to anti-TNF were associated with clinical response and normalization of FC, respectively. AEs were observed in 5 patients, and 9 underwent colectomy. Ustekinumab persistence rates were 91%, 83% and 81% at 24, 48 and 96 weeks, respectively. Conclusions Ustekinumab demonstrated, in the real-world setting, long-term effectiveness and a favorable safety profile in a cohort of refractory UC patients.

Single-incision laparoscopic clockwise continuous total abdominal colectomy with end ileostomy in ulcerative colitis; surgical technique and results of a 7-year experience

Total abdominal colectomy with end ileostomy is the first stage of the three-stage surgical treatment of medically refractory ulcerative colitis. Laparoscopic surgery is a safe approach offering several benefits. Single-incision laparoscopic surgery is an alternative minimally invasive approach providing excellent cosmetic results. Literature on single-incision laparoscopic clockwise continuous total abdominal colectomy in the treatment of ulcerative colitis is limited. Aim of the study is to describe our surgical technique and report the outcomes. Medically refractory ulcerative colitis patients who underwent single-incision laparoscopic clockwise continuous total abdominal colectomy with end ileostomy by a single surgeon between January 2013 and December 2020 at our tertiary care center are included. Patient charts were reviewed retrospectively. 52 patients were included in the final analysis. 51.9% patients were male with the median age of 31.5years and body mass index of 22.2kg/m2. Median duration of operation was 100min with estimated blood loss of 50ml. There were no intraoperative complications, conversions to conventional laparoscopy or open surgery. Postoperative complications were reported in 13 (25%) patients with most common being ileus (17.3%). 3 patients had surgical site infections. 2 patients had postoperative bleeding requiring blood transfusion. 2 patients had reoperation within postoperative 30days. Median length of hospital stay was 2days. No mortalities were reported. Single-incision laparoscopic clockwise continuous approach is safe and effective in ulcerative colitis patients undergoing total abdominal colectomy with end ileostomy. Further prospective randomized studies are warranted.

P408 Dual therapy with vedolizumab and tofacitinib in refractory ulcerative colitis patients – single centre experience

Abstract Background Despite significant impact biological treatment had on prospects of patients with ulcerative colitis, there is still a substantial proportion of patients with non-response to multiple drugs. Beside dose optimization and selection of agents with different mechanism of action, combination of two different targeted molecules has recently been proposed in cases where inflammatory activity cannot get under control. This case series provide promising results of vedolizumab in combination with tofacitinib in treatment resistent UC patients. Methods Patients with complicated refractory or acute severe colitis, in whom combined treatment with vedolizumab and tofacitinib based on shared clinical decision was started, were included. Data on demographics, treatment details, persistence and disease activity including laboratory markers, clinical activity index (partial Mayo score) during regular visits every 2 months up to one year after treatment initiation were collected. Currently available data were analyzed at 6 months. Endoscopic disease activity before and 2-6 months after dual therapy start was evaluated. Results In total, 21 UC patients who were started on vedolizumab and tofacitinib dual therapy between Oct 2020 and Sep 2022 were included. Tofacitinib dose was 10mg bid in all patients and all patients on vedolizumab maintenance treatment had intensified dosing regimen. Mean patients age was 36.4±8.1 years, 47.6% were males and 52.4% females. Mean disease duration at baseline was 7.5±5.8 years. All patients had advanced disease including 61.9% with extensive colitis and 38.1% with left-sided colitis. At least 2 previous biologics in monotherapy were used in 85.7% of patients. Mean pMayo score at baseline was 5.6±1.9 and decreased to 0.5±0.9 at 6 months (p=0.0020). Initial fecal calprotectin in the cohort was 1829±2520µg/g vs. 225±257µg/g at 6 months (p=0.0068) and mean CRP changed from 11.4±17.1 to 5.4±7.2mg/l (p=ns). Endoscopic Mayo score before dual treatment initiation averaged 2.8±0.5 indicating mostly severe disease activity and decreased to 1.4±1.2 during follow-up endoscopy (p=0.0005) with half of the patients having only no to mild activity (eMayo 0-1). Up to now, dual therapy had to be terminated in 7 patients – 4 patients failed on the treatment, 1 refused to continue with dual therapy, 1 patient experienced adverse event (liver lesion) and 1 was discontinued for reimbursement reasons. Conclusion In the presented small cohort of patients with refractory ulcerative colitis, in whom other modalities were depleted or colectomy was considered, combined vedolizumab and tofacitinib treatment has proven to be efficient with half of the patients reaching mucosal healing after 6 months and without raising significant safety concerns.

P500 Real life 2 year experience with ustekinumab in a Spanish open-label cohort of ulcerative colitis patients.

Abstract Background Ustekinumab has been recently approved for the treatment of moderately to severe ulcerative colitis (UC). Data from the UNIFI clinical trial are encouraging; nevertheless, real-world assessment is needed. We assess the effectiveness, safety and pharmacokinetics of ustekinumab in a cohort of refractory UC patients. Methods Multicentre and observational study of UC patients who received ustekinumab for active disease. Values for Partial Mayo Score (PMS), endoscopic activity, C reactive protein (CRP) and faecal calprotectin (FC) were recorded at baseline and at weeks 8, 24 and 52 weeks and at 18 and 24 months when was possible. Demographic and clinical data, previous treatments, adverse events (AEs), surgeries and hospitalizations were documented. Possible predictors of response were examined. Results One hundred and eight patients were analyzed (Table 1). Two patients only received the first IV dose. During follow-up, 58 patients (54%) required interval reduction (every 4 weeks (76%) and every 6 weeks (24%)) after a median of 22.3 weeks [11.6, 41.2]. Intravenous reinduction doses were administered to 20 (18.5%) after 27.7 weeks [6.64, 56.3]. Three patients required a maintenance therapy with IV administration. The clinical remission (PMS≤ 2) rates were 39.6%, 41%, 51% at 8, 24 and 52 weeks, respectively, and 61%, and 57.7% at 18 and 24 months, respectively. FC levels returned to normal (&amp;lt;250 μg/g) in the 39.6%, 41%, 51%, 61%, 58% of the patients at weeks 8, 24 and 52 and at 18 and 24 months respectively. CRP returned to normal (&amp;lt;3 mg/L) in the 79%, 75%, 76.5%, 71% and 70% of the patients at weeks 8, 24 and 52 and at 18 and 24 months respectively. PMS, FC and CRP values and ustekinumab through levels over time are shown in Figure. Fewer previous anti-TNF agents and the loss of response to anti-TNF were associated with clinical response and with normalization of FC respectively. No variables at baseline (body mass index, serum albumin, and lymphocytes count) were associated with ustekinumab through levels. Of the 17 patients with endoscopy before and after treatment, 6 were in remission and 3 with mild activity. The AEs were recorded in 5 (4.6%) patients, 12 (11%) were hospitalized and 9 (8.3%) had surgery. A total of 23 patients (21%) discontinued ustekinumab over time, the persistence rates were 98%, 91%, 83% and 81% at 8, 24, 48 and 96 weeks respectively. Conclusion This is the first study to show the real-world long-term effectiveness, persistence, endoscopic improvement and safety of ustekinumab in a cohort of highly refractory UC patients. The clinical remission preceded the FC normalization. Ustekinumab through levels and their pharmacokinetic require further investigations.

P675 Real world evidence of tofacinitib in ulcerative colitis: short and long-term effectiveness, safety and impact of extraintestinal manifestations and immunomediated diseases

Abstract Background Main aim: To assess the durability of tofacitinib treatment in patients with ulcerative colitis (UC). Secondary aims: To assess the short and long-term effectiveness; the tolerability of tofacitinib in clinical practice; and to evaluate the evolution of extraintestinal manifestations (EIMs) and immunomediated inflammatory diseases (IMIDs). Methods Retrospective, multicenter study including UC patients who had received the first tofacitinib dose at least 8 weeks before the inclusion. Patients were followed-up from the first tofacitinib dose to treatment discontinuation or last visit, whichever came first. Only patients with active disease [Partial Mayo Score (PMS)&amp;gt;2] at tofacitinib start were considered in the effectiveness analysis. Clinical effectiveness was based on PMS. In patients who stopped tofacitinib before their last visit, the last observation carried forward method was used to impute missing values at subsequent time points. Results 408 patients were included (figure 1). Incidence rate of tofacitinib discontinuation was 41% per patient-year of follow-up. The probability of maintaining tofacitinib is shown in figure 2a. Main reasons for tofacitinib withdrawal were primary non-response (44%) and loss of response (26%). Age at the start of tofacitinib (older) (HR=0.98, 95%CI=0.97-0.99) and the severity of clinical activity were associated with tofacitinib withdrawal (mild vs. remission: HR=1.5, 95%CI=0.5-4; and moderate-severe vs. remission: HR=3.0, 95%CI=1.2-7.4). Short-term effectiveness is shown in figure 3a. To have moderate-severe vs. mild disease activity at baseline (OR=0.2, 95%CI=0.1-0.4) and age at tofacitinib start (older) (OR=1.01, 95%CI=1.002-1.03) were associated with clinical remission at week 8. The probability of maintaining response in shown in figure 2b. Tofacitinib dose was escalated in 55 patients (66%) of those who had lost response, and 82% of them improved (60% regained remission). The proportion of patients on 10 mg b.i.d was over 40% in all timepoints during follow-up. The proportion of patients in clinical remission during follow-up in shown in figure 3b. Adverse events during tofacitinib treatment are summarized in figure 4. There was not any signal of negative impact of tofacitinib on EIM o IMIDs. Conclusion Tofacitinib is effective in inducing remission even in highly refractory UC patients. A relevant proportion of patients discontinue the treatment, mostly due to primary failure. Dose escalation is effective to regain response after loss of efficacy. The safety profile is similar to that previously reported

Longitudinal monitoring of STAT3 phosphorylation and histologic outcome of tofacitinib therapy in patients with ulcerative colitis.

Tofacitinib is the first in class, pan-JAK inhibitor approved for ulcerative colitis (UC). Clinical efficacy has been shown, but long-term real-life endoscopic and histologic data are lacking. To investigate the effects of tofacitinib in patients with refractory UC focussing on endoscopic, histologic and molecular outcomes, including STAT3 phosphorylation (pSTAT3) detection in the spatial context of mucosal inflammation METHODS: We prospectively monitored 59 highly refractory patients (96.7% anti-TNF exposure, 91.7% vedolizumab exposure) initiating tofacitinib at two IBD referral centres and assessed outcome at the end of induction and after 48 weeks of therapy. Endoscopic improvement was defined as a Mayo endoscopic subscore ≤1, endoscopic and histologic remission as Mayo endoscopic subscore 0 and Nancy histologic score 0. Multiplex immunohistochemistry with multispectral imaging was used to assess pSTAT3. Endoscopic improvement was achieved by 24.4% and 30.5% of patients at weeks 8 and 48, respectively. Endoscopic and histologic remission rates were 11.1%, 23.7 and 16.7%, 21.4%, respectively. Endoscopic improvement at week 8 was significantly associated with treatment continuation in the long-term (72.7% vs 20.6%, p= 0.003). Although we observed a gradual decrease of mucosal pSTAT3 levels in both remitters and non-remitters (p< 0.05), no association with treatment outcome could be demonstrated. However, lamina propria pSTAT3 was significantly associated with the Nancy Histologic index (p= 0.004). Tofacitinib can induce and maintain endoscopic and histologic remission in up to one-quarter of highly refractory UC patients. Longitudinal monitoring of nuclear pSTAT3 in mucosal tissue compartments reflects distinctive on-target effects, independently of long-term treatment outcomes.

P430 Longer-term tofacitinib effectiveness for the treatment of ulcerative colitis: Two-year outcomes from a UK observational cohort study

Abstract Background Tofacitinib is an oral small molecule inhibitor licensed for the treatment of ulcerative colitis (UC). Whilst real world data has been presented, outcomes beyond, 26 weeks are limited. The objective of this study was to assess the persistence and long-term effectiveness of tofacitinib. Methods We conducted a retrospective observational cohort study, using a prospectively maintained database, at a large UK IBD tertiary referral centre. The primary objective was to assess the proportion of patients in deep remission at one year. Deep remission was defined as corticosteroid free clinical remission (CSFR) and endoscopic remission (Mayo Endoscopic Subscore (MES) of, 0 or, 1). All adult patients receiving tofacitinib for moderate to severe UC were included from October, 2018 to October, 2021. Disease activity was assessed using the Simple Clinical Colitis Activity Index (SCCAI); clinical response and remission were defined as a reduction of SCCAI ≥3 and a SCCAI ≤2, respectively. All analyses were based on an intention-to-treat principle, and we used non-responder imputation in cases of missingness. Results In total, 103 patients were included with a median follow up duration of, 53 weeks (range, 1–156). Prior to treatment, patients had active disease clinically (median SCCAI, 7 (range, 0–15) and endoscopically (median MES, 3) with, 54% on corticosteroids. The cohort had refractory disease;, 90% were anti-TNF-experienced and, 48% had prior exposure to at least two different biologic classes. Table, 1 shows the baseline characteristics of the cohort and figure 1 shows patient disposition in the study. Median treatment duration on, 10mg bd was, 18 weeks (range, 1–135);, 27% (n=15) were on, 10mg BD at one year and, 11% (n=3) at two years. At, 52 weeks, 61% were in CSFR, 38% in endoscopic remission, and, 36% in deep remission (figure 2). Deep remission was not associated with baseline variables, including prior biologic exposure or disease severity on univariate analyses. Faecal calprotectin fell from median, 451ug/g [range, 5-6020] at baseline to, 86ug/g [range, 5-2360] at week, 52 (n=41, p&amp;lt;0.001), but CRP change was not significant. Three-quarters of those remaining on tofacitinib at, 104 weeks (n=27) were in deep remission. The Kaplan Meier estimated probability of remaining on tofacitinib was, 62% (95% CI, 51–71%) at week, 52 and, 44% (CI, 95%, 32–54%) at week, 104 (figure 3). Conclusion Longer term effectiveness and treatment persistence data in a cohort of highly refractory UC patients is reassuring.

P373 Real world evidence of tofacinitib in ulcerative colitis: short and long-term effectiveness, impact of extraintestinal manifestations and immunomediated diseases and safety

Abstract Background Main aim: To assess the retention rate of tofacitinib treatment in patients with ulcerative colitis (UC). Secondary aims: To assess the short-term effectiveness and the durability of response; to evaluate the evolution of extraintestinal manifestations (EIMs) and immunomediated inflammatory diseases (IMIDs); to assess the tolerability of tofacitinib in clinical practice. Methods Retrospective, multicenter study. UC patients who had received the first tofacitinib dose at least, 8 weeks before the start date of recruitment. Patients were followed-up from the first tofacitinib dose to treatment discontinuation or last visit, whichever came first. Only patients with active disease [Partial Mayo Score (PMS)&amp;gt;2] were considered in the short-term effectiveness analysis. Clinical response was based on the PMS. Variables associated with short-term remission were identified by logistic regression analysis. Kaplan-Meier curves and Cox-regression analysis were used to evaluate the long-term effectiveness and durability of tofacitinib treatment. Results 335 patients have been included so far (recruitment still ongoing) (Table 1). A total of, 70 patients (21%) would have met the criteria for entering A3921133 trial. A total of, 155 patients interrupted tofacitinib during follow-up (Figure 1a), mainly due to primary non-response (46%) and loss of response (25%); predictive factors of tofacitinib discontinuation are shown in figure 1b. Short-term effectiveness and predictive factors of remission are shown on figure 2;, 16% of non-responders and, 35% with partial response at week, 4 reached remission at week, 8, and, 19% of non-responders and, 37% of partial responders at week, 8 reached remission at week, 16. Of, 151 patients in remission at week, 8, 68 (45%) lost response (Figure 3); tofacitinib dose was increased in, 27%, and, 71% of them reached remission again. Obvious blood with stool most of the time or blood alone passed at baseline was the only variable associated with losing response over time. There were, 86 adverse events related to tofacitinib treatment (Table 2). Fifty-seven patients (17%) had EIMs or IMIDs non-active at tofacitinib start; only, 2 out of, 12 patients with peripheral arthropathy worsened., 53 patients (16%) had active EIMs or IMIDs at the start of tofacitinib and some of them improved. A total of, 17 EIMs or IMIDs occurred after starting tofacitinib but only, 1 (vasculitis) caused tofacitinib withdrawal. Conclusion Tofacitinib is effective in inducing remission even in highly refractory UC patients. A relevant proportion of patients discontinue the treatment, mainly during the first months due to primary failure. The safety profile is similar to that previously reported for tofacitinib

P383 Ustekinumab as an opportunity for refractory Ulcerative Colitis patients

Abstract Background There are limited data in real-life of ustekinumab (USK) used in ulcerative colitis (UC). The aim of this study was to assess the effectiveness and safety in clinical practice of USK in UC in the medium and long-term. Methods Observational study in UC patients who received USK at the recommended dose based on weight ~6 mg/kg IV week, 0.90 mg SC week, 8 and maintenance, 90 mg SC every, 8 or, 12 weeks and with, 1 year of follow-up. The partial Mayo score (PMS) was used to assess clinical remission (PMS≤, 2). The PMS, C-reactive protein (CRP) and faecal calprotectin (FC) values ​​were recorded at baseline and after, 8, 16, 24 and, 52 weeks. Dose adjustment was performed by the measure of UST trough levels by ELISA, when patient lost clinical and/or biochemical response and the levels were low (&amp;lt;1.3 µg/ml). Demographic, clinical, biochemical and endoscopic data, previous treatments, adverse events (AEs), surgeries and hospitalizations, were documented. Results Twenty-three patients with UC were analysed. (Table, 1). All patients had received previous biological treatment:, 52% ≥2 anti-TNF, 65% vedolizumab and, 30% JAK inhibitors. Treatment discontinuation occurred in, 3 patients (13%). The persistence was, 83% and, 79% at, 6 and, 12 months (Figure, 1). During follow-up, 12 patients (52%) maintained standard dose of USK. Dose adjustment was performed in, 13 patients (56%):, 3 (13%) required intravenous UST reinduction and, 10 (43%) required dose escalation (8 by shortening the interval between doses and, 2 by switching to intravenous USK administration). Clinical remission was reached in, 61%, 58%, 56%, 79% of the patients after, 8, 16, 24, 52 weeks, respectively. Normal CRP (&amp;lt;5mg/L) and FC (&amp;lt;150 µg/g) levels were achieved in, 76%, 93% and, 80% and in, 35%, 31% and, 40% of patients after, 8, 24, 52 weeks, respectively. Five of, 6 patients who had endoscopy before and after treatment showed endoscopic Mayo subscore ≤1. There were, 2 AEs, 1 hospitalization, and, 1 colectomy during follow-up. Conclusion This study demonstrates the safety as well as the clinical, biological and endoscopic effectiveness of USK adjusted by levels in real life in a highly refractory UC cohort.

Medical Therapy in Chronic Refractory Ulcerative Colitis: When Enough Is Enough.

Despite significant improvements in the management of ulcerative colitis (UC) in parallel with the evolution of therapeutic targets and novel biologics and small molecules, a subset of medically refractory patients still requires colectomy. Recent population-based studies demonstrate a trend toward a decrease in the rates of surgery for UC patients in the biological era, although the potential of disease modification with these agents is still debated. As the concept of irreversible bowel damage is underexplored in UC, refractory patients can be exposed to multiple treatments losing optimal timing for surgery and further developing complications such as dysplasia/cancer, dysmotility, microcolon, and other functional abnormalities. This review aims to discuss the concept of disease progression in UC, explore the limitations of medical treatment in refractory UC patients, and propose the application of a three-step algorithm that allows timely indication for surgery in clinical practice.

S710 Efficacy of High Dose Tofacitinib in Refractory Ulcerative Colitis Patients

Introduction: Tofacitinib is an oral small molecule Janus kinase inhibitor approved for the treatment of adults with moderate to severe ulcerative colitis (UC) who have failed or are intolerant to anti-TNF agent-based therapy. However, many patients fail to fully respond to standard dose of therapy. In some cases increasing the therapy dose may help however there is concern of potential side effects. Our study assessed the safety and efficacy of UC patients to tofacitinib with standard dose (SD) and high dose (HD) treatment. HD was defined as immediate release dosing more than 10 mg twice daily or extended release dosing more than 22 mg daily. Methods: This is a retrospective single-center study of all UC patients who were treated with tofacitinib. Clinical response was evaluated using the Mayo score and Ulcerative Colitis Activity Index (UCAI) and endoscopic activity was assessed with endoscopic Mayo scoring. Documentation of tofacitinib doses as well as combined biologic therapy was made. Any adverse events were documented. Results: Seventy UC patients had been treated with tofacitinib, with 21 on HD therapy. Both populations were predominantly female (approximately 60%) with mean age of 41 and 35.6, and predominant left-sided colon disease activity 25(51%) and 15(71%), in the SD and HD groups, respectively. All had previously failed treatment with at least one biologic, with approximately 70% in each group failing 2 or more. Approximately 50% of patients in both groups were treated with tofacitinib monotherapy. Vedolizumab and infliximab were the most common combination biologic agents. All the HD and SD patients who improved achieved clinical remission. The average time to clinical remission was longer in the HD group, which was expected due to the highly refractory nature of their disease. An important consideration is that 15(45%) SD patients and 1(4.8%) HD patient in the clinically improved groups were de-escalated to maintenance dosing or completely off tofacitinib therapy. Adverse events in the study were reported in 3(4%) patients, all occurring in the SD group and included lower extremity DVT formation (with uncontrolled disease activity accompanied by hospitalization), skin rash (face and trunk), and excessive bloating. No adverse events were reported in the HD group. Conclusion: The findings from this study suggest that tofacitinib can benefit UC patients who have failed multiple prior biologics with HD dosing as a potential short term option with low risk of adverse events.Figure 1.: Graphical representation of temporal trends of biologics utilization as a first line therapy in patients with IBD.Table 1.: Adjusted odds ratio and adjusted means for selected variables in patients with IBD and chronic depression compared to patients with IBD and no chronic depression.

One-year effectiveness and safety of ustekinumab in ulcerative colitis: a multicenter real-world study from Italy

ABSTRACT Background Efficacy and safety of ustekinumab for the treatment of ulcerative colitis (UC) has been demonstrated in clinical trials, but few real-world data are available so far. The aim of this study was to assess effectiveness and safety of ustekinumab in a cohort of refractory UC patients. Methods Data of patients with moderate to severe UC treated with ustekinumab were retrospectively collected. Primary endpoint was steroid-free clinical remission at weeks 24 and 52 of therapy. Secondary endpoints were treatment response, endoscopic remission, treatment persistence at 12 months and safety. Results A total of 68 patients [males 63%; median (range) age 42 (16–72) years] were included. Almost all patients (97%) were biologics experienced. At weeks 24 and 52, 31% and 50% of patients achieved steroid-free clinical remission, 84% and 82% had clinical response, respectively. At the end of follow-up, there was a significant reduction of pMS from baseline (p < 0.001) and of steroid use (p < 0.001). At week 52, 22% of the available endoscopies (18/38) showed mucosal healing. The probability to persist in therapy at week 52 was 87%. Only one adverse event occurred. Conclusions Data from our real-life cohort of refractory UC patients suggest satisfactory effectiveness and a good safety of ustekinumab.

Impact of the Concomitant Use of Immunomodulator and a Lower Week 8 Partial Mayo Score on the Persistence of Adalimumab in Refractory Ulcerative Colitis.

Objective Real-world data of adalimumab (ADA) in the treatment of ulcerative colitis (UC) are scarce. We aimed to study the ADA response rates and predictors of response in UC treatment. Methods This observational, prospective and multi-center study assessed the clinical outcome of refractory UC patients treated with ADA who previously had an inadequate response to either conventional therapies or other anti-TNF antibodies or tacrolimus. The primary endpoint was the proportion of UC patients achieving a clinical response and remission at 8 and 52 weeks. We also evaluated the parameters which were associated with a clinical response at 8 and 52 weeks. Results A total of 35 patients were enrolled from 11 centers. The clinical responses at 8 and 52 weeks were 60.0% and 51.4%, respectively. The clinical remission rates at 8 and 52 weeks were 45.7% and 48.6%, respectively. Positive predictors for week 52 response were combination of ADA with immunomodulator (IM) (OR: 27.229; 95% CI; 1.897-390.76; p=0.015) and a week 8 lower partial Mayo score (OR: 0.406; 95% CI; 0.204-0.809; p=0.010). A receiver operation characteristic curve analysis revealed the optimal week 8 partial Mayo score to be 2.5, therefore a partial Mayo score of ≤2 was a positive predictor for the continuation of ADA. No malignancy or death occurred during this study. Conclusion ADA was effective for inducing and maintaining both a clinical response and remission in patients with refractory UC. It remains possible that the concomitant use of IM and a week 8 partial Mayo score of ≤2 may predict the long-term response of ADA.

P465 One year endoscopic and histologic outcomes to tofacitinib therapy in refractory ulcerative colitis

Abstract Background Long-term real-life data on the efficacy of the Janus kinase inhibitor tofacitinib in moderate-to-severe ulcerative colitis (UC) are limited. We here report efficacy of tofacitinib in refractory UC patients with an emphasis on endoscopic and histologic outcome. Methods Fifty-four consecutive UC patients (Mayo endoscopic sub-score ≥2) initiating tofacitinib in 2 tertiary IBD referral centres were prospectively included (Table 1). Almost all were refractory to both anti-TNF (96.4%) and vedolizumab (92.7%) and received tofacitinib in standard dosage. Steroid-free clinical remission was defined as partial Mayo score of ≤2 with no single sub-score &amp;gt;1 and without any steroid exposure at assessment. Biological remission was defined as faecal calprotectin &amp;lt;250mcg/g, endoscopic remission as Mayo endoscopic sub-score of 0, endoscopic improvement as Mayo endoscopic sub-score of ≤1, and histologic remission as Nancy histology index of 0. A combination of endoscopic and histologic remission was referred as mucosal healing. All outcomes were assessed at year 1. Non-responder imputation and last observation carried forward analysis were applied. Results Patients were followed for a median [IQR] of 91.7 [67.2–102.4] weeks, with an exposure to tofacitinib of 23.9 [14.6–51.6] weeks. By year one, 31.5% of patients were in steroid-free clinical remission (Figure 1). Biological remission was observed in 26.9% of patients. Endoscopic improvement, endoscopic remission, histologic remission and mucosal healing, were observed in 31.5%, 24.1%, 22.0% and 18.0% of patients, respectively. Multivariate analysis identified baseline Mayo endoscopic sub score (OR 0.03, p=0.03); endoscopic improvement by week 16 (OR 36.5, p=0.008) and disease extent (OR 0.11, p=0.05) as independent predictors for endoscopic remission at year 1. Patients with left-sided colitis or proctitis experienced higher endoscopic remission rates (33.3% and 25.0%) then patients with extensive colitis (10.5%, p=0.09; p=0.6). Ultimately, 61.1% of all patients discontinued tofacitinib therapy after a median of 15.9 [9.2–24.5] weeks, due to primary non-response (n=25), loss-of-response (n=6) or (serious) adverse events (n=2). Thirteen patients (24.1%) required colectomy. During follow-up, no venous thrombo-embolisms or cancers were observed. One patient had to be admitted at ICU due to several life-threatening opportunistic infections. Conclusion In this highly refractory cohort of UC patients, tofacitinib induced and maintained endoscopic and histologic remission in up to one quarter of patients. UC patients with moderate left-sided colitis and proctitis had a numeric higher likelihood for a sustained effect than patients with extensive colitis.

Cytapheresis re-induces high-rate steroid-free remission in patients with steroid-dependent and steroid-refractory ulcerative colitis.

BACKGROUNDIt is a crucial issue for patients with refractory ulcerative colitis (UC), including steroid-dependent and steroid-refractory patients, to achieve and maintain steroid-free remission. However, clinical studies focused on the achievement of steroid-free remission in refractory UC patients are insufficient. Cytapheresis (CAP) is a non-pharmacological extracorporeal therapy that is effective for active UC with fewer adverse effects. This study comprised UC patients treated with CAP and suggested the efficacy of CAP for refractory UC patients.AIMTo clarify the efficacy of CAP in achieving steroid-free remission in refractory UC patients.METHODSWe retrospectively reviewed the collected data from 55 patients with refractory UC treated with CAP. We analyzed the following points: (1) Efficacy of the first course of CAP; (2) Efficacy of the second, third, and fourth courses of CAP in patients who experienced relapses during the observation period; (3) Efficacy of CAP in colonic mucosa; and (4) Long-term efficacy of CAP. Clinical efficacy was evaluated using Lichtiger’s clinical activity index or Sutherland index (disease activity index). Mucosal healing was evaluated using Mayo endoscopic subscore. The primary and secondary endpoints were the rate of achievement of steroid-free remission and the rate of sustained steroid-free remission, respectively. Statistical analysis was performed using the paired t-test and chi-squared test.RESULTSThe rates of clinical remission, steroid-free remission, and poor effectiveness after CAP were 69.1%, 45.5%, and 30.9%, respectively. There were no significant differences in rate of steroid-free remission between patients with steroid-dependent and steroid-refractory UC. The mean disease activity index and Lichtiger’s clinical activity index scores were significantly decreased after CAP (P < 0.0001). The rates of steroid-free remission after the second, third, and fourth courses of CAP in patients who achieved steroid-free remission after the first course of CAP were 83.3%, 83.3%, and 60%, respectively. Mucosal healing was observed in all patients who achieved steroid-free remission after the first course of CAP. The rates of sustained steroid-free remission were 68.0%, 60.0%, and 56.0% at 12, 24, and 36 mo after the CAP. Nine patients (36%) had maintained steroid-free remission throughout the observation period.CONCLUSIONOur results suggest that CAP effectively induces and maintains steroid-free remission in refractory UC and re-induces steroid-free remission in patients achieving steroid-free remission after the first course of CAP.