Corticosteroid-free Clinical Remission Research Articles

Resolution of rectal bleeding by day 7 in acute severe ulcerative colitis is prognostic for post-discharge corticosteroid free clinical remission and endoscopic improvement

This study assesses two different disease activity measures, the MTWSI and the partial Mayo score, in hospitalized acute severe UC patients for prediction of post-discharge corticosteroid-free clinical remission and endoscopic improvement to help guide future considerations for disease activity assessment. In this post-hoc analysis from the TRIUMPH trial, these results suggest resolution of Mayo rectal bleeding sub-score may have high prognostic utility and could be considered as a primary endpoint for hospitalized UC trials. The study underscores the need for further research on patient-reported outcomes and endoscopic indices in larger populations for inpatient UC trials.

Effects of prednisolone tapering on effectiveness of infliximab in patients with ulcerative colitis: data from a retrospective cohort

Background and objectiveThe influence of concomitant prednisolone on clinical outcomes and safety in infliximab-treated ulcerative colitis (UC) patients is unknown.Design, setting, participants and outcome measuresA retrospective cohort study was performed,...

Long-term effectiveness and persistence rate of ustekinumab dose intensification in a South East Asian inflammatory bowel disease center.

Ustekinumab (UST) is an effective biologic for treatment of inflammatory bowel disease (IBD). However, some patients treated with UST have suboptimal clinical response with standard dosing. The aims of this study were to determine the effectiveness of UST dose intensification (DI), identify factors associated with DI, cumulative incidence of DI and persistence of UST among treated patients. Clinical data of patients with Crohn's disease (CD) and ulcerative colitis (UC) who received UST from September 2017 to October 2022 in Singapore General Hospital were collected. Primary outcome was defined as achieving corticosteroid-free clinical remission, biochemical remission, endoscopic healing and/or transmural healing (CD). Statistical analysis was performed to identify factors, which are predictive of UST DI and effectiveness of UST DI. Forty-two patients (34 CD and 8 UC) underwent UST DI to either 6-weekly (n=19, 45.2%) or 4-weekly (n=23, 35.9%) and the median time to intensification was 31.1weeks (17.8-65.7). Presence of perianal disease in CD (HR 4.9; 1.47-16.4) was associated with DI. After DI, 16 (38%) patients achieved primary outcome by week 52. The overall drug persistence rates at 1year and 2years were 75.7% (95% CI 62.9-84.6) and 63.5% (95% CI 49.9-74.3), respectively. Two third of IBD patients underwent DI while on UST treatment and the median time to DI was about 6months after induction. CD patients with perianal disease is more likely to undergo DI. More than one third of dose-intensified patients achieved remission by week 52.

Avoidant/restrictive food intake disorder symptoms are not as frequent as other eating disorder symptoms when ulcerative colitis is in remission.

Recent studies have shown that up to 53% of patients with inflammatory bowel disease (IBD) screen positive for avoidant/restrictive food intake disorder (ARFID). There is however concern that ARFID screening rates are over-inflated in patients with active disease. We aimed to evaluate the frequency and characteristics of ARFID symptoms using the Nine Item ARFID Screen (NIAS), and to use another eating disorder measure, the Eating Disorder Examination-Questionnaire 8 (EDE-Q8), to rule-out/characterize other eating disorder cognitive and behavioral symptoms. Participants included adults with UC who are enrolled in an in an ongoing cohort study with quiescent UC (SCCAI ≤2 or fecal calprotectin <150 µg/g with corticosteroid-free clinical remission for ≥ 3 months) at baseline. We used self-reported data on demographics, gastrointestinal medications, medical comorbidities, NIAS scores, and other eating disorder symptom scores (8-item Eating Disorder Examination-Questionnaire; EDE-Q-8). We included 101 participants who completed the NIAS at their baseline cohort assessment (age 49.9±16.5 years; 55% female). Eleven participants (11%) screened positively for ARFID on at least one NIAS subscale (n=8 male). Up to thirty participants (30%) screened positive for other eating disorder symptoms (EDE-Q-8 Global ≥2.3). Overall score distributions on the EDE-Q-8 showed that participants scored highest on the Weight Concern and Shape Concern subscales. Among adults with UC in remission, we found a low rate of ARFID symptoms by the NIAS but a high rate of positive screens for other eating disorder symptoms.

Application of clinical decision support tools for predicting outcomes with vedolizumab therapy in patients with inflammatory bowel disease: A KASID multicentre study.

We aimed to validate clinical decision support tools (CDSTs) to predict real-life effectiveness of vedolizumab (VDZ) in patients with inflammatory bowel disease. We retrospectively enrolled patients with Crohn's disease (CD) or ulcerative colitis (UC) treated with VDZ at 10 tertiary referral centres in Korea between January 2017 and November 2021. We assessed clinical remission (CREM) and response (CRES), corticosteroid-free clinical remission (CSF-CREM) and response (CSF-CRES), biochemical response based on C-reactive protein (BioRES[CRP]) and faecal calprotectin (BioRES[FC]), endoscopic healing (EH), and the need to optimise or switch drugs based on CDST-defined response groups. Additionally, the area under the receiver operating characteristics curve (AUC) for the CDSTs was calculated. We included 143 patients with CD and 219 with UC. We observed incremental trends on CSF-CRES at week 14 (W14) (ptrend = 0.004) and decreasing trends for the need to optimise or switch drugs (ptrend = 0.016) in CD from the low to high probability groups. Except for CSF-CREM at W54, we noticed incremental trends for all clinical responses at W14, W26 and W54 (ptrend <0.001) in UC. W26 and W54 BioRES[CRP] and W14 EH also showed increasing trends (ptrend <0.05) in UC. With increasing probabilities of response, drug optimisation or switching was less frequently required in UC (ptrend = 0.013). With 26 points cut-off, CDSTs effectively identified W14 CSF-CRES, W26 BioRES[CRP], BioRES[FC] and W54 BioRES[CRP] in UC, all with AUCs >0.600, whereas CDSTs showed poor accuracy in CD. CDSTs for VDZ had acceptable accuracy in predicting effectiveness outcomes including clinical and biochemical outcomes in UC. However, their utility in CD was limited.

Real-world effectiveness of upadacitinib in Crohn’s disease: a UK multicentre retrospective cohort study

BackgroundUpadacitinib is a Janus kinase inhibitor, which has recently been approved for treating Crohn’s disease. There are limited real-world studies on the outcomes of upadacitinib in Crohn’s disease.ObjectiveOur aim was...

Real-world effectiveness of ustekinumab and vedolizumab in TNF-exposed pediatric patients with ulcerative colitis.

Vedolizumab (VDZ) and ustekinumab (UST) are second-line treatments in pediatric patients with ulcerative colitis (UC) refractory to antitumor necrosis factor (anti-TNF) therapy. Pediatric studies comparing the effectiveness of these medications are lacking. Using a registry from ImproveCareNow (ICN), a global research network in pediatric inflammatory bowel disease, we compared the effectiveness of UST and VDZ in anti-TNF refractory UC. We performed a propensity-score weighted regression analysis to compare corticosteroid-free clinical remission (CFCR) at 6 months from starting second-line therapy. Sensitivity analyses tested the robustness of our findings to different ways of handling missing outcome data. Secondary analyses evaluated alternative proxies of response and infection risk. Our cohort included 262 patients on VDZ and 74 patients on UST. At baseline, the two groups differed on their mean pediatric UC activity index (PUCAI) (p = 0.03) but were otherwise similar. At Month 6, 28.3% of patients on VDZ and 25.8% of those on UST achieved CFCR (p = 0.76). Our primary model showed no difference in CFCR (odds ratio: 0.81; 95% confidence interval [CI]: 0.41-1.59) (p = 0.54). The time to biologic discontinuation was similar in both groups (hazard ratio: 1.26; 95% CI: 0.76-2.08) (p = 0.36), with the reference group being VDZ, and we found no differences in clinical response, growth parameters, hospitalizations, surgeries, infections, or malignancy risk. Sensitivity analyses supported these findings of similar effectiveness. UST and VDZ are similarly effective for inducing clinical remission in anti-TNF refractory UC in pediatric patients. Providers should consider safety, tolerability, cost, and comorbidities when deciding between these therapies.

Precise infliximab exposure and pharmacodynamic control to achieve deep remission in paediatric Crohn’s disease (REMODEL-CD): study protocol for a multicentre, open-label, pragmatic clinical trial in the USA

IntroductionThe only biologic therapy currently approved to treat moderate to severe Crohn’s disease in children (<18 years old) are those that antagonise tumour necrosis factor-alpha (anti-TNF). Therefore, it is critically...

Effectiveness of Tofacitinib in Ulcerative Proctitis Compared to Left Sided Colitis and Pancolitis.

Ulcerative proctitis (UP), though associated with high symptom burden and poor quality of life, is excluded from most of the randomized controlled trials in UC, including the OCTAVE trials. We aimed to analyse the effectiveness of tofacitinib in UP, and compare it to that in left sided colitis (LSC) and pancolitis (PC). This was a prospective cohort study. Patients with either steroid-dependent or refractory ulcerative colitis, who received tofacitinib, were divided into three groups based on the disease extent [UP, LSC and PC]. The primary outcome was comparison of proportion of patients in clinical remission in the three groups, at weeks 8, 16 and 48. Safety outcomes were reported using incidence rate per patient year of exposure. Clinical remission was achieved in 47%(15/32), 24%(23/94), and 43%(23/54) of patients at week 8, 56%(18/32), 37%(35/94), and 56%(30/54) of patients at week 16, and 59%(19/32), 38%(36/94), and 24%(13/54) of patients at week 48 in groups UP, LSC and PC, respectively. Corticosteroid-free clinical remission rates were significantly higher in patients in groups UP at week 48. Five (15%) patients with UP were primary non-responders to tofacitinib at week 16, while three (9%) patients had secondary loss of response at week 48. The probability of sustained clinical response was highest in patients with UP. Patients with UP had the lowest incidence of adverse effects. The effectiveness of tofacitinib in inducing and maintaining clinical remission is greater in patients with UP compared to LSC and PC.

P689 Adaptive steroid tapering impedes corticosteroid-free remissions compared to forced tapering in UC clinical trials

Abstract Background Protocols for managing steroids in clinical trials of ulcerative colitis (UC) vary. Most trials mandate steroid tapering at the beginning of maintenance phase. Adaptive steroid tapering allows for some discretion on whether to taper steroids for a patient. It remains unclear what impact steroid tapering protocols have on trial outcomes. Methods This post-hoc analysis from many clinical trials of advanced therapies in UC (VARSITY, ACT 1/2, PURSUIT, GEMINI1, OCTAVE and ULTRA2) was carried out under protocols with Vivli (00007656) and YODA (20224882). Responders to induction therapy with baseline corticosteroid use were considered as the primary population of interest. Adjustments were made to account for re-randomization designs and treatment exposure. Univariate analyses were conducted to identify baseline variables that had an association with the primary outcome of interest, one-year corticosteroid-free clinical remission (CR). All covariates with a significant univariate association (p &amp;lt; 0.05) were considered for inclusion in the multivariate model. Logistic regression was used to assess the impact of steroid-weaning regimen on the outcome of interest. Secondary outcome of interest was one-year CR. Results There was a total of 861 patients from the seven included trials who had achieved clinical response after induction and were using corticosteroids. Within multivariate analysis, patients using adaptive steroid weaning regimens were less likely to achieve one year corticosteroid-free CR (odds ratio (OR) 0.66 (95% CI 0.48-0.92), p=0.015). Patients with higher partial Mayo scores were also less likely to achieve one year corticosteroid-free CR (OR 0.88 (95% 0.8-0.97), p=0.012). Other variables found significant on univariate analysis were no longer significant once considered within the multivariate model (smoking, race, albumin, endoscopic Mayo score). For the secondary outcome of one year CR, patients using adaptive steroid weaning regimens had increased odds for achieving one year CR as compared to those using fixed regimens (OR 1.9 (95% 1.43-2.52), p&amp;lt;0.001). Several other variables were also found to have an association with one year CR within the multivariate model (Table 1). Conclusion Among patients with UC on corticosteroids at the time of study enrolment, adaptive steroid weaning regimens were less likely to achieve one-year corticosteroid-free CR but more likely to achieve one-year CR. This may help explain the findings within the VARSITY study, where patients treated with vedolizumab had increased odds for one-year CR but were less likely to achieve one-year corticosteroid-free CR. Consideration should be given to implementing mandatory steroid weaning protocols in future clinical trials of UC.

P1064 Upadacitinib is safe and effective in Ulcerative Colitis patients with prior exposure to Tofacitinib

Abstract Background Upadacitinib is a novel selective Janus Kinase (JAK) inhibitor which has recently been approved for use in ulcerative colitis. Clinical trials have rigorous criteria and excluded patients with prior exposure to JAK inhibitors. Given limited real-world effectiveness data we examined outcomes of patients treated with upadacitinib for ulcerative colitis in a real-world population, with a focus on prior tofacitinib exposure. Methods This retrospective, multi-centre study recruited patients commencing upadacitinib for moderate-to-severe ulcerative colitis from September 2022 until March 2023 from 13 Inflammatory Bowel Disease centres across Australia. Clinical, biochemical, endoscopic and intestinal ultrasound outcomes were recorded at baseline, week 8 and week 16. The primary outcome was a comparison between clinical remission using PRO2 definitions (STRIDE II guidelines) in those with prior Tofacitinib exposure compared with Tofacitinib-naïve. Secondary endpoints included clinical response, corticosteroid free clinical remission (CFCR), biochemical response and transmural remission assessed by intestinal ultrasound (IUS). Adverse events in both cohorts were also recorded. Results 152 patients were identified and included (Table 1) – 42 tofacitinib-exposed and 110 tofacitinib-naïve. Complete clinical data was available for all patients at baseline, week 8, and week 16. For the overall cohort, the rate of clinical remission was 20% (30/152) at baseline, 78% (119/152) at week 8 and 85% (129/152) at week 16. In patients with prior tofacitinib exposure, the rate of clinical remission was 23% (10/42) at baseline, 72% (30/42) at week 8 and 86% (36/42) at week 16. In tofacitinib-naïve patients, the rate of clinical remission was 19% (21/110) at baseline, 78% (86/110) at week 8 and 84% (92/110) at week 16 (Figure 1). There was no statistically significant difference in rate of clinical remission at baseline (p=0.23), week 8 (p=0.13) or week 16 (p=0.67). There was no statistically significant difference in clinical response, CFCR, biochemical response or transmural remission by IUS between the cohorts. Adverse events were seen in 40 (26%) patients over the course of 16 weeks follow-up. Most common were acne (12%), rash (4%) and nasopharyngitis (4%). No venous thromboembolism, systemic infection or cardiovascular events were observed. These events were spread evenly among both groups (p=0.37). Conclusion This is the largest real-world study to show that upadacitinib is effective and safe for patients with moderate to severe ulcerative colitis and prior tofacitinib exposure.

P659 Prognostic markers in Treat-to-Target for Crohn’s Disease- an Asian institution’s experience

Abstract Background Endoscopic healing (EH) is a long-term treatment target in the Treat-to-Target approach for Crohn’s Disease (CD). However, not all patients with CD will achieve this treatment target due to a combination of factors. This study aims to evaluate the proportions of patients with CD who achieve EH at 24 months from diagnosis. Secondary aims include proportion of patients who achieve corticosteroid free clinical remission (CSFR), biomarker (BM) normalization and predictors of failure to achieve EH. Methods This is a retrospective study of all patients with Crohn’s disease seen at a tertiary hospital in Singapore from January 2010 to December 2021. Patients with a confirmed diagnosis of CD based on endoscopic, clinical and histological findings were identified from existing IBD registry. Those with a follow-up period of less than 12 months, no repeat endoscopy and missing data were excluded from analysis. We collected data on baseline demographics, disease characteristics and treatment received. Treatment targets were assessed in terms of CSFR, biomarkers normalization, EH and transmural healing (when available). We defined these targets as outlined in the selecting therapeutic Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) II initiative. Statistical analysis was performed in Python using statsmodels 0.14.0. Results We identified a total of 86 CD patients. After excluding 29 patients, 59 patients were included in the final analysis.Mean age at diagnosis was 33 years old, and 69.5% were males. Table 1 demonstrates the baseline demographics and disease characteristics of all patients. The median follow-up period was 101 months. Out of 59 patients, 88% (n=52) and 80% (n=47) achieved CSFR and biomarker normalization respectively at 12 months. At 24 months of follow up, EH was achieved in 54% (n =32) of all patients. Of those who achieved EH, 22 had repeat imaging and transmural healing was documented in 14 patients. On multivariate logistic regression, Montreal B3 (penetrating type) disease was predictive of failure to achieve EH (OR 9.8, p= 0.036). Use of biologics also showed a trend for failing to achieve EH though this was not statistically significant (OR 3.5, p = 0.075). Conclusion A vast majority of CD patients were able to achieve corticosteroid free clinical remission and biomarker normalization. Penetrating disease was predictive of failure to achieve EH at 24 months. This study provides additional evidence in determining treatment targets for CD patients based on their disease phenotypes. These findings could be further validated in larger cohort, prospective studies.

DOP46 Tofacitinib for hospitalized acute severe Ulcerative Colitis – the TRIUMPH study

Abstract Background Tofacitinib is a rapidly acting Janus kinase (JAK) inhibitor with several case series reporting effectiveness in patients with acute severe ulcerative colitis (ASUC). However, there remains a paucity of prospective data evaluating its efficacy and rapidity of onset in ASUC. Methods The TRIUMPH study is a phase 4 prospective interventional trial of tofacitinib in ASUC conducted in five hospitals across Canada (Clinicaltrials.gov: NCT04925973). Patients with ASUC (biologic naïve and experienced) refractory to three days of intravenous corticosteroids (Modified Truelove-Witts Severity Index [MTWSI] &amp;gt; 10 despite steroids) were eligible for enrollment. Patients were treated with tofacitinib 10mg bid and assessed daily while in hospital. The primary outcome was day 7 clinical response (MTWSI reduction of &amp;gt; 3 from baseline and &amp;lt; 10). Secondary outcomes included rapidity of clinical and biomarker improvements over the first 7 days, colectomy over the course of one year, and corticosteroid-free clinical remission (total Mayo score &amp;lt; 2), endoscopic improvement (endoscopic Mayo score 0 or 1), and adverse events at 3, 6, and 12 months. Results This is an interim analysis as the study has been fully recruited with six-month follow-up available for all participants. 24 patients with ASUC were recruited and received tofacitinib 10mg bid. The mean total baseline Mayo score was 10.1 (SD 1.4) and all patients had a baseline Mayo endoscopic subscore of 2 (25%, 6/24) or 3 (75%, 18/24). One third of the patients (8/24) had previous anti-TNF failure. Day 7 clinical response was achieved in 58.3% (14/24) patients. The mean number of days to achieve clinical response was 2.4 days (SD 1.3). Marked reduction in C-reactive protein was observed in responders as soon as one day after tofacitinib initiation compared to non-responders (Figure 1). Colectomy occurred in 16.7% (4/24) patients by day 7 and 25% (6/24) by six months. At six months, 45.8% (11/24) patients remained on tofacitinib (including 78.6% (11/14) of day 7 responders), with 33.3% (8/24) having achieved endoscopic improvement and corticosteroid-free clinical remission. A total of six patients reported adverse events, one of which was considered severe (stroke at day 3 after initiation of tofacitinib). Conclusion Tofacitinib may be an effective induction strategy in patients hospitalized with steroid-refractory ASUC. Randomized controlled trials are needed to compare JAK inhibitors with infliximab for steroid refractory ASUC.

P1003 Dietary pattern can influence the level of fatigue in patients with Inflammatory Bowel Disease in remission

Abstract Background It is well known that dietary pattern can play an important role in the onset of inflammatory bowel diseases (IBD). In patients with established disease, they can influence the risk of relapse and the disease course. The aim of the study is to explore the impact of dietary patterns on health-related quality of life (HR-QoL), fatigue, anxiety and depression in patients with IBD in corticosteroid-free clinical remission. Methods A total of 96 consecutive patients diagnosed with IBD that were in corticosteroid-free remission for at least 12 weeks were enrolled in this observational, cross-sectional study. During an interview, patients were asked about their dietary patterns. Twelve categories of foods were identified, 6 of them being considered "healthy" (vegetables and fruits &amp;gt;4 portions/day, cereals &amp;gt;3 portions/day, seeds &amp;gt;4 portions/week, cheese &amp;gt;1 portion/day, yoghurt &amp;gt;1 portion/day, fish &amp;gt;2 portions/week) and the other 6 "unhealthy" (fatty red meat &amp;gt;1 portion/day, sweetened beverages &amp;gt;1L/day, cured meat &amp;gt;2 portions/day, fried food &amp;gt;1 portion/day, chips &amp;gt;1 portion/day, mayonnaise &amp;gt;1 portion/day) (see Figure 1). An "unhealthy" dietary pattern was considered if the proportion of "unhealthy" food categories from the total food categories consumed by the patient exceeded 50%. HR-QoL, fatigue, anxiety and depression were evaluated using the following self-administered questionnaires: IBDQ-32, FACIT-Fatigue and HADS. Results Out of the 96 patients included, 60 (62.5%) were men. The median patient age was 38 years (IQR 31.5 – 45.5). Sixty patients (62.5%) were diagnosed with CD, and 36 (37.5%) with UC. Most of the patients were treated with biologics (93.8%). An unhealthy dietary pattern was identified in 58 (60.4%) patients. Patients with an "unhealthy" dietary pattern experienced significantly more fatigue compared to patients with a "healthy" dietary pattern (mean FACIT-F score 40.3 vs. 44.4 points, p=0.02). Even though not statistically significant, patients with "unhealthy" dietary pattern had a trend towards a lower HR-QoL (mean IBDQ score 187.3 vs. 192.8, p=0.24). Anxiety and depression were less frequent among patients with "unhealthy" dietary pattern, but the differences were not statistically significant (anxiety: 24.1% vs. 31.6%, p=0.57; depression: 13.8% vs. 21.2%, p=0.51). Conclusion Patients with an "unhealthy" dietary pattern experience significantly higher levels of fatigue compared to patients that are eating "healthier" food. There is also a trend towards lower HR-QoL in this category of patients.

P1232 Alterations in microbial composition in patients with newly diagnosed Crohn's disease over a course of one year: data from a prospective longitudinal real-world study

Abstract Background Gut microbial composition in Crohn's disease (CD) is variable, changing with specific interventions. We aimed to explore the dynamics in microbial alterations in a cohort of patients with newly diagnosed Crohn's disease (ndCD) over one year. Methods This was a prospective longitudinal real-world study of patients with ndCD1 naïve to therapy who were treated at the physician's discretion. Clinical outcomes at one year were corticosteroid-free clinical remission (CSFR) and biochemical remission ([BR], CRP&amp;lt;1mg/dL and FC&amp;lt;150ug/g). We sequenced paired stool samples from diagnosis and after one year using 16S rRNA gene (V4) and analyzed changes in diversity and dysbiosis indices. A linear mixed-effect model was constructed to identify factors associated with microbial alterations and to identify specific genera that drove the alterations while controlling for confounders. Results Seventy-five patients completed one-year follow-up (49.3% female, median age 27 years [IQR 22-38.5], therapeutic interventions: 45 patients on biological therapies [43 anti-TNF], 26 antibiotics, 10 corticosteroids, 5 underwent surgery, and 59 various nutritional interventions). Rates of CSFR, BR, and conjoined CSFR-BR at one-year post-diagnosis were 64%, 56%, and 45.3%, respectively. We observed an overall significant increase in microbial Shannon diversity (H index), p&amp;lt;0.001, and decreased microbial dysbiosis index (MDI), p=0.007, from baseline to one year. On subgroup analysis, these alterations were significant among patients who achieved the clinical outcomes (all p&amp;lt;0.05) and even more prominent among patients who were on biological therapies (both indices p&amp;lt;0.001). Notably, in the biological therapy subgroup, the microbial composition at diagnosis was less diverse and more dysbiotic than in the non-biological subgroup. In the latter, microbial composition at diagnosis was less disrupted and remained relatively stable over time. Linear mixed model analysis corroborated a positive association between biological therapy and the positive dynamics in microbial indices (H-index, p=0.020 and MDI, p=0.040). Fifteen specific genera drove the microbial alterations over time (Table 1), while alterations in the relative abundance of some genera correlated with changes in clinical biomarkers and clinical indices (Figure 1). Conclusion The microbial composition of this real-world cohort of patients with ndCD improved over the course of one year, which was significant for patients who achieved clinical outcomes and was more prominent for patients requiring biological therapy. In this subgroup, the microbial signature was less diverse and more dysbiotic when diagnosed; this likely led the significant improvement over time. 1 Yanai H,et al. Crohns Colitis 360 2023;5:otad064

OP35 Efficacy of mirikizumab in comparison to ustekinumab in patients with moderate to severe Crohn’s disease: Results from the phase 3 VIVID 1 study

Abstract Background The primary objective of the VIVID-1 trial (NCT03926130) was to demonstrate efficacy and safety of mirikizumab (miri), a p19-directed anti-IL-23 antibody, compared to placebo (PBO) in patients (pts) with moderate-to-severe Crohn’s disease. Miri demonstrated statistically significant improvements in co-primary and all key secondary endpoints versus (vs) PBO1. Here we present the results of secondary endpoints on the comparisons of miri to ustekinumab (uste), a p40 directed anti-IL-12/IL-23 inhibitor from the Phase 3, randomised, double-blind, double-dummy, active- and PBO-controlled, treat-through (TT) study, VIVID-1 (NCT03926130). Methods Adult pts (N=1065) were randomised 6:3:2 to miri (N=579) 900mg intravenously (IV) every 4 weeks (Q4W) to W12, then 300mg subcutaneously (SC) Q4W to W52, uste (N=287) one ~6 mg/kg IV dose, then 90mg SC Q8W to W52 or PBO (N=199). At W12 PBO responders continued PBO to W52; PBO non-responders received the same blinded miri regimen as described above (IV then SC). Efficacy of miri vs uste was assessed by the proportion of pts achieving endoscopic response and by the proportion of pts achieving clinical remission by Crohn’s Disease Activity Index (CDAI) at W52 (both gated). Additional non-multiplicity-adjusted endpoints included endoscopic remission, corticosteroid-free clinical remission by CDAI, and the composite of CDAI clinical remission and endoscopic response at W52. (Figure 1 for definitions). Results Baseline characteristics were overall balanced across the three treatment groups (table 1). Pts treated with miri achieved all key major secondary endpoints (p&amp;lt;.000001) compared to PBO (Figure 1). Miri achieved non-inferiority to uste for clinical remission by CDAI (p=0.113117) (Figure 1C). Although superiority to uste in endoscopic response was not achieved (p=0.51) (Figure 1A), in biologic failed pts miri demonstrated a numerical trend towards greater response rates compared to uste for endoscopic response and clinical remission by CDAI (Figure 1 B &amp; D). The overall safety profile was consistent with the known safety profile of miri. The proportion of treatment emergent adverse events (TEAE) were similar for miri (78.6%) and uste (77.3%); most common TEAEs were COVID-19, anaemia, arthralgia, headache, upper respiratory tract infection, nasopharyngitis and injection site reaction. Instances of serious adverse events were comparable for miri (10.3%) and uste (10.7%). Conclusion In this phase 3 TT design study, miri achieved non-inferiority to uste for clinical remission by CDAI. In biologic failed pts miri had a numerical trend towards greater response compared to uste in clinical and endoscopic endpoints, with an acceptable safety profile. 1Ferrante et al., submitted to ECCO 2024

P964 Vedolizumab trough concentrations during subcutaneous treatment in patients with inflammatory bowel diseases

Abstract Background An exposure-response relationship has been described for intravenous (IV) vedolizumab (VDZ), but little is known about through levels and real life outcomes of subcutaneous (SC) VDZ treatment. We aimed to study the effect of SC VDZ in a prospective real life cohort and assessed what clinical variables are associated with vedolizumab trough concentrations. Methods IBD patients initiating VDZ SC treatment were included in our nationwide, prospective Initiative on Crohn and Colitis (ICC) registry. Adult IBD patients were included if a known trough level during IV and SC therapy was available. Two different assays were used for trough levels measurements : i.e. an enzyme linked immunosorbent assay (ELISA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The primary outcome measure was the mean VDZ trough concentration during maintenance treatment (after at least four SC injections). In addition, associations between VDZ serum trough concentrations and corticosteroid-free clinical remission were assessed. A Receiver Operating Characteristic (ROC) analysis was performed to determine the concentration threshold that was associated with corticosteroid free clinical remission after 4 SC VDZ injections (i.e. defined as a Harvey Bradshaw Index (HBI) score ≤ 4 for CD and a Short Clinical Colitis Activity Index (SCCAI) score ≤ 2 for UC). Results In total, 24 with Crohn’s disease (CD) and 32 with ulcerative colitis (UC) patients were included. Twelve patients started SC VDZ after a maximum of three VDZ infusions and 44 patients switched to VDZ SC after at least four VDZ infusions. The mean VDZ trough concentration was 34.4 µg/mL (SD 12.9) after 13 (IQR 11-20) weeks of SC treatment. The mean VDZ trough concentration increased from 20.5 µg/mL to 35.2 µg/mL (P &amp;lt; 0.001) in patients who switched from IV to SC VDZ. Biochemical remission (defined as a C-reactive protein (CRP) ≤ 5 µg/mL with a faecal calprotectin (FC) ≤ 250 µg/g) prior to the switch, VDZ measurements using LC-MS/MS and higher VDZ levels during IV therapy were associated with higher VDZ serum levels during SC therapy. Active smoking and prior use of &amp;gt;1 biologic and/or tofacitinib were associated with lower VDZ levels during SC therapy (table 1). A VDZ trough concentration of ≥ 34.5 µg/mL during SC maintenance therapy predicted corticosteroid free clinical remission with a sensitivity, specificity, positive predictive value and negative predictive value of 60%, 75%, 86% and 43%, respectively. Conclusion VDZ serum concentrations were significantly higher during SC therapy versus IV treatment. A VDZ trough concentrations ≥ 34.5 µg/mL was associated with corticosteroid free remission.

P909 Proactive therapeutic drug monitoring and pharmacogenomics in mercaptopurine therapy for ulcerative colitis

Abstract Background OPTIC was a prospective placebo-controlled trial investigating therapeutic drug monitoring (TDM)-based mercaptopurine (MP) therapy in ulcerative colitis (UC). Although the primary endpoint (corticosteroid-free clinical remission and endoscopic improvement at week 52) favoured patients with TDM-based MP therapy over placebo, drug-related adverse events were frequent and drop-out rates high. This post-hoc analysis was carried out to show the therapeutic implications of proactive TDM of MP. Methods UC patients with active disease, despite ≥2 g/day mesalamine, underwent remission induction treatment with corticosteroids and initiated weight-based MP therapy (1-1.5 mg/kg). TDM based optimisations were performed at week 6, 12, 18, 24, 36 and 52 using the Dervieux method, unblinded non-including thiopurine expert physicians (DA, MD and AB) provided dosing advice according to a predefined algorithm, aiming for 6-TGN levels of 600-1200 pmol/8×108 RBC and 6-MMP of &amp;lt;5700 pmol/8×108 RBC. Associations between 6-TGN and 6-MMP levels, MP dose and thiopurine S-methyltransferase (TPMT) polymorphisms were explored. Results In total, 29 patients initiated MP treatment (41% female, median age 46 yrs [IQR 26-58], median disease duration 6 yrs [IQR 1-14]). TPMT heterozygosity was found in 4/29 patients (3/4 TPMT*3A, 1/4 TPMT*3C). TDM dose adjustments were required in 22/29 patients: 14/29 started allopurinol and decreased MP dose, 5/29 discontinued MP before the first TDM assessment, 2/29 continued MP at the initial dose up until week 52 and the remaining underwent MP dose adjustments. Most adjustments (71%) were made at week 6, thereafter 6-MMP levels stabilised, while 6-TGN concentrations remained stable (Figure 1). TPMT variant carriers had a higher median 6-TGN concentration compared to non-carriers (1700 [IQR 1625-1850] vs 539 pmol/8×108 RBC [IQR 355-953], P&amp;lt;0.001) and more likely to have leukopenia (P=0.025). Two TPMT heterozygous patients achieved the primary endpoint with dose reductions, two discontinued due to myelotoxicity or hepatotoxicity. Until week 52, 16/29 patients completed the trial, 14/29 reached the endpoint with a median 6-TGN of 585 pmol/8×108 RBC (IQR 428-745) and 6-MMP of 268 pmol/8×108 RBC (IQR 110-1257). MP dose correlated with 6-MMP but not with 6-TGN levels. Independently of allopurinol co-prescription, the initial median weight-based MP dose of 100 mg (IQR 75-125) decreased significantly to 50 mg (IQR 25-100, P=0.041). Conclusion Most patients underwent TDM optimisation of MP, half of the patients initiated allopurinol with decreased MP dose. TPMT heterozygosity led to supratherapeutic 6-TGN concentrations and adverse events. Weight-based initial MP dose may need reconsideration.

P542 Clinical decision support tool guided selective intensive induction strategy of ustekinumab in patients with Crohn’s disease: real-world evidence

Abstract Background Clinical decision support tool (CDST) of ustekinumab (UST) can predict the possibility of drug response1. However, the potential benefits of initial intensification induction therapy (IIT) to improve clinical outcomes for different responders has not been explored2. We aimed to evaluate the effectiveness and safety of the strategy of initial IIT for Crohn’s disease patients who exhibit varying responses based on UST-CDST. Methods This is a multicenter retrospective study included active Crohn’s disease patients who were low, intermediate and high probability responders according to UST-CDST (Figure 1). IIT was defined as intensive induction by 2 or 3 initial doses of a weight-based intravenous UST. The patients treated with standard therapy (ST) were identified as controls. The primary endpoint was corticosteroid-free clinical remission (CFCR) at week 24. The secondary endpoint was clinical remission, clinical response, endoscopic remission, endoscopic response, and CRP normalization at week 24. Propensity-matched analyses were applied to ensure comparability. Results A total of 296 patients were included, with 69 patients receiving IIT and 227 patients receiving ST. At week 24, in low-intermediate probability responders, IIT group was associated with higher rates of CFCR (72.3% vs 43.0%, OR 3.47 [95%CI 2.15-5.68], clinical remission (77.3% vs 47.1%, OR 3.82 [95%CI 2.33-6.37]), clinical response (78.1% vs 60.1%, OR 2.37 [95%CI 1.43-3.97]), endoscopic remission (50.6% vs 22.4%, OR 3.55 [95%CI 1.65-7.92]) and endoscopic response (83.1% vs 44.1%, OR 6.23 [95%CI 2.75-15.26]). CRP normalization were comparable. In high probability responders, all end points did not demonstrate statistically significant differences (Table 1). The cut-off UST trough concentration for predicting corticosteroid-free clinical remission was determined to be 1.43µg/mL, with an area under the curve (AUC) of 0.612, a sensitivity of 55.0%, and a specificity of 70.0%. No serious adverse events occurred. Conclusion Initial dose intensification induction in low-intermediate responders based on UST-CDST was superior to the ST in both clinical and endoscopic remission at week 24, which provide a novel strategy for stratifying patients at baseline. 1. Park J, Chun J, Yoon H, Cheon JH. Feasibility of a Clinical Decision Support Tool for Ustekinumab to Predict Clinical Remission and Relapse in Patients With Crohn's Disease: A Multicenter Observational Study. Inflamm Bowel Dis. 2023;29(4):548-554. 2. Ren H, Kang J, Wang J, et al. Efficacy of Ustekinumab Optimization by 2 Initial Intravenous Doses in Adult Patients With Severe Crohn's Disease [published online ahead of print, 2023 Aug 24]. Inflamm Bowel Dis. 2023; izad184.

P823 Real-world effectiveness of upadacitinib in Crohn's disease; a UK multicentre retrospective cohort study

Abstract Background Upadacitinib is a Janus kinase inhibitor which has recently been approved for the treatment of Crohn’s disease. There are limited real-world studies on the outcomes of upadacitinib in Crohn’s disease. Our aim was to evaluate the outcomes of upadacitinib in a real-world cohort. Methods We conducted a retrospective, multicentre, cohort study. Our primary outcome was treatment persistence at week 24. Our secondary endpoints were corticosteroid-free clinical remission (Harvey-Bradshaw Index ≤4), and biomarker remission (CRP ≤5 mg/L and FCAL &amp;lt;250 µg/g). We measured outcomes at 12 weeks, 24 weeks and at last observation. We recorded adverse events. Results We included 74 patients who commenced upadacitinib over a two-year period for analysis, with a median follow-up time of 23 weeks (IQR, 15-39 weeks). All patients had failed anti-TNF therapy, with 78% and 58% additionally failing prior IL12/23 and vedolizumab (Table 1). Treatment persistence was 83.6% at week 12, and 76.6% at week 24 (Figure 1). Reasons for treatment cessation included primary non-response 15% (11/74), secondary loss of response 1% (1/74), and adverse events 12% (9/74). Rates of clinical remission were 58% (32/55) at week 12, 43% (16/37) at week 24, and 52% (35/67) at last observation. CRP remission rates were 45% (27/60) at week 12, 35% (12/34) at week 24, and 44% (30/69) at last observation. FCAL remission rates were 40% (17/42) at week 12, 31% (9/29) at week 24, and 36% (19/53), at last observation. There was a significant reduction in HBI, CRP and FCAL during follow-up (Figure 1). During the maintenance period, 11% (7/61) of the cohort who continued therapy were prescribed corticosteroids. Ten patients (19%) had a hospitalisation due to a Crohn’s flare. Five patients (7%) underwent Crohn’s disease related resectional surgery during the study period. Two were emergency surgeries (3%), and three (4%) were elective surgeries for symptomatic fibrotic strictures, which were present prior to commencing upadacitinib. Thirty-four adverse events were recorded across 29 patients (39%). Serious adverse events occurred in 9 patients (12%), three of which (4%) led to hospitalisation. Conclusion Upadacitinib was effective in a real-world, medically refractory, moderate to severe Crohn’s disease cohort with good persistence.