Biologics In Ulcerative Colitis Research Articles

PERSISTENCE WHILE ON LABELED MAINTENANCE DOSE AMONG ADVANCED THERAPY-EXPERIENCED PATIENTS WITH ULCERATIVE COLITIS INITIATED ON USTEKINUMAB OR ADALIMUMAB

Abstract BACKGROUND Persistence on biologics in ulcerative colitis (UC) is a useful real-world treatment performance measure particularly important in advanced therapy (ADT)-experienced patients. Dose escalation on biologics is an indicator of suboptimal treatment response associated with higher biologic costs. This study compared persistence while on labeled maintenance dose among ADT-experienced patients with UC initiated on ustekinumab or adalimumab. METHODS Adults with UC initiated on ustekinumab or adalimumab (index date: 10/21/2019-03/02/2022) were selected from the IQVIA PharMetrics® Plus database. Patients were ADT-experienced (i.e., ≥1 claim for a non-index UC-indicated ADT agent) and without other auto-immune diseases in the 12-month baseline period. Cohorts were balanced on baseline characteristics using inverse probability of treatment weights. Persistence while on the labeled maintenance dose was defined as (1) no gaps between days of therapy supply (ustekinumab, >120 days; adalimumab, >60 days); (2) absence of any dose change relative to the maintenance dose per US label. Composite endpoints of being persistent while corticosteroid-free (<14 consecutive days of corticosteroid supply after day 90 post-index) and persistent while on monotherapy (no immunomodulators or non-index ADT) were also assessed. Endpoints were assessed from the maintenance phase start until the earliest of discontinuation (event), corticosteroid use (event), immunomodulator, non-index advanced therapy use (event), dose change (censored), 12 months follow-up or data end (censored) using weighted Kaplan-Meier analyses and Cox proportional hazards models. RESULTS Weighted cohorts included 693 ustekinumab and 294 adalimumab patients (Fig. 1). At 12 months after the maintenance phase start, 88.7% and 65.8% of the ustekinumab versus adalimumab cohort were persistent while on the labeled maintenance dose with persistence 4.77 times higher in the ustekinumab cohort (p-value:<0.001; Fig. 2a). Further, 55.7% and 44.6% of the ustekinumab versus adalimumab cohort were persistent and corticosteroid-free while on the labeled maintenance dose; persistence was 1.48 times higher in the ustekinumab cohort (p-value:0.002; Fig. 2b). Finally, 77.2% and 47.3% of the ustekinumab versus adalimumab cohort were persistent and on monotherapy while on the labeled maintenance dose; persistence was 3.29 times higher in the ustekinumab cohort (p-value:<0.001; Fig. 2c). CONCLUSIONS ADT-experienced patients with UC treated with ustekinumab were significantly more persistent while on the labeled maintenance dose, including persistent while corticosteroid-free and while on monotherapy versus patients treated with adalimumab. Findings may help inform treatment strategies for ADT-experienced patients with UC. Figure 1 Selected baseline characteristics in weighted ustekinumab and adalimumab cohorts Figure 2 Persistence while on US labelled dose among weighted ustekinumab and adalimumab cohorts: a) persistent on index biologic, b) persistent and corticosteroid-free, c) persistent and on monotherapy

REAL-WORLD RATE AND MAGNITUDE OF DOSE ESCALATION WITH BIOLOGICS IN PATIENTS WITH ULCERATIVE COLITIS

Abstract INTRODUCTION Advanced therapies (ATs), such as adalimumab (ADA), infliximab (INF), golimumab (GOL), vedolizumab (VED), and ustekinumab (UST), referred to as biologics, are regularly used to treat moderate-to-severe ulcerative colitis (UC). Loss of response is a common problem with biologics in UC and one solution is to increase dose of biologics, affecting the cost of UC management. Assessing real-world dosing with biologics is important to inform the estimated treatment cost. The objective of this study was to assess the rate and magnitude of dose escalation with biologics in treatment of UC. METHODS This retrospective cohort study identified adult American patients in the IQVIA PharMetrics® Plus database who were diagnosed with UC and started an AT for UC between 01 Jan 2015 and 31 May 2021. Index date was the start date of a qualifying AT. Patients had ≥12 months of continuous pre- and post-index enrollment in a health plan, no claims for AT during the pre-index period, and no autoimmune diseases or indeterminate colitis. Rate and magnitude of dose escalation were assessed from the start of maintenance phase with AT until the end of follow-up period. Dose escalation was measured in first-line (1L) and second-line (2L) settings and defined as an increase in average dose ≥20% than expected dosing per FDA label during follow-up period after maintenance dose was reached. Dose escalations of ≥50% and ≥100% were also measured. RESULTS The study identified 5,997 UC patients starting an AT (1L setting) (median age, 40 years; 55.5% male; median follow-up, 27.5 [18.5-41.8] months), and 1,896 (31.6%) patients who received treatment with AT in a 2L setting. More patients reached maintenance dose in a 1L setting (86.6% [INF] to 92.7% [ADA]) than in a 2L setting (82.0% [INF] to 87.4% [ADA]). The rate of dose escalation in patients who reached maintenance dose for ADA, IFX, GOL, VED, UST was 22.0%, 17.9%, 7.0%, 28.8%, 50.6%, respectively, in a 1L setting, vs 21.9%, 19.2%, 7.7%, 25.9%, 55.1%, respectively, in a 2L setting (Figure 1). The frequency of dose escalation ≥50% varied for different therapies, 15.0% [ADA], 5.7% [IFX], 4.3% [GOL], 21.0% [VED], and 44.6% [UST] in a 1L setting vs 16.4% [ADA], 8.4% [IFX], 1.9% [GOL], 19.2% [VED], and 46.5% [UST] in a 2L setting (Figure 2). Dose escalation ≥100% was uncommon with both 1L therapies (0.4% [ADA] to 10.0% [VED]) and 2L therapies (0% [GOL] to 7.0% [VED]). CONCLUSIONS A meaningful percentage of ulcerative colitis patients treated with adalimumab, infliximab, vedolizumab, or ustekinumab had dose escalation regardless of line of treatment. Understanding the impact of these utilization patterns may inform real-world cost management. Figure 1 Rate of dose escalation with advanced therapies in ulcerative colitis Figure 2 Magnitude of dose escalation with advanced therapies in ulcerative colitis

P1000 A meta-analysis and systematic review of 5-aminosalicylates withdrawal in Inflammatory Bowel Disease

Abstract Background 5-aminosalicylic acids (5-ASA) are the first-line agents in mild-to-moderate ulcerative colitis (UC). They are not recommended for Crohn’s disease (CD) or moderate-to-severe UC. 5-ASAs are the most prescribed medication for all patients with inflammatory bowel diseases (IBD). Its continuous use is associated with significant cost, adverse effects, and delay in treatment escalation. Recent analyses suggest no benefit of 5-ASA use in patients escalated to more advanced therapies. Hence, 5-ASA withdrawal was suggested, but the outcomes remain unclear. We aimed to perform a meta-analysis of 5-ASA withdrawal in patients with IBD and compare the risk of disease relapse in different cohorts of patients. Methods A search for articles was conducted in five medical databases, studies were selected, and their quality was assessed. Studies were divided into six clinically relevant cohorts depending on the type of IBD and other treatments used; the relative risk of relapse for individual studies in each cohort was analysed. Results 1714 studies were identified; 27 were included in the meta-analysis. Withdrawal of oral 5-ASA monotherapy was associated with a 60% increased risk of relapse. Similarly, withdrawal of rectal 5-ASA had a relative risk of relapse of 2.03. When combined with immunomodulators and/or biologics in UC or CD, oral 5-ASA withdrawal was not associated with an increased risk of relapse. Patients on combined oral 5-ASA and immunomodulators had a higher risk of relapse in the 5-ASA continuation group across three studies; this can be attributed to the persistence of oral 5-ASA use in patients with more severe disease, delaying the appropriate escalation to advanced therapies. Two studies reported no increased risk of colorectal cancer when 5-ASA was withdrawn either as monotherapy or when combined with other treatments. Conclusion Oral or rectal 5-ASA monotherapy in UC should not be discontinued. 5-ASA withdrawal does not increase relapse in patients with UC or CD escalated to immunomodulator and/or biological treatment. Oral 5-ASA continuation combined with immunomodulators delays escalation to advanced therapy. Available data suggest that 5-ASA withdrawal does not increase the risk of colorectal cancer; however, this must be considered carefully in patients with unmodifiable risk factors.

P1038 Does combination immunomodulator therapy impact real-world biologic effectiveness in Inflammatory Bowel Diseases?A propensity score analysis in patients treated with anti-TNF and non-anti-TNF biologics in the UK IBD BioResource

Abstract Background Randomised controlled trials have demonstrated that the combination of infliximab and azathioprine is superior to either drug as monotherapy both in patients with Crohn’s Disease (CD) and ulcerative colitis (UC). Data on the combination of other biological agents -including other anti-TNFs, vedolizumab and ustekinumab- and immunomodulators (IMMs) is lacking or shows conflicting results. Given the risks of combination therapy, physicians are often hesitant on whether to combine IMMs with biologic therapies. Methods We measured the effectivenessof biologic therapies [infliximab (IFX), adalimumab (ADA), golimumab (GLM), vedolizumab (VDZ) and ustekinumab (UST)] in patients with UC and CD with and without IMM use enrolled in the UK Inflammatory Bowel Disease (IBD) BioResource over long durations of followup.Demographic, disease, treatment and outcome data were retrieved. Inverse probability of treatment weighting (IPTW) was used to balance groups of those receiving vs those not receiving IMM using a propensity score-weighting approach accounting for baseline patient or disease related clinical characteristics. Effectiveness of treatment was based on persistence free of treatment discontinuation or treatment failure. Failure was defined as occurring if any of the following occurred: (a) clinician-recorded treatment failure (b) start of treatment with a different advanced therapy (c) occurrence of resectional or defunctioning bowel surgery. We compared Kaplan Meier curves for treatment failure-free survival after IPTW and used a log rank test for differences between the groups. Results In UC, we included 2479 patients receiving IFX (1173 on IMM), 1117 ADA (401 on IMM), 188 GLM (77 on IMM) and 1256 VDZ (392 on IMM). In CD, we included 5956 patients receiving IFX (3062 on IMM), 4524 ADA (1898 on IMM), 1067 VDZ (340 on IMM) and 627 UST (198 on IMM).As expected, combination IMM therapy was associated with increased drug effectiveness for IFX in both UC and CD. Combination IMM therapy was also associated with increased effectiveness of ADA in CD. For all other drugs, there was no significant benefit for combination IMM. Hazard ratios(HRs) for the effect of IMM of each drug effectiveness in UC and CD are summarised (Figure 1). Conclusion We confirm prior results indicated that IFX effectiveness is improved by concomitant use of an IMM in both UC and CD.In contrast to RCT data but in accordance to other robust real-world studies, we find evidence that for ADA in CD concomitant IMM can increase drug effectiveness. We find no evidence of benefit for concomitant IMM for other biologics in UC or CD.

P792 Real-world evidence comparison of the effectiveness of ustekinumab with anti-TNF or vedolizumab in ulcerative colitis: 1-year maintenance therapy results from the prospective, observational RUN-UC study

Abstract Background Observational real-world evidence (RWE) studies on the effectiveness of ustekinumab (UST) in ulcerative colitis (UC) are needed in addition to RCTs, which may not represent everyday clinical practice. For this reason, the prospective, controlled, propensity score (PS)-adjusted RUN-UC study was conducted on UC patients starting a new biologic therapy with a follow-up period of up to 3 years. The aim of the present analysis was to evaluate the 1-year maintenance therapy effectiveness of UST vs. anti-TNF or vedolizumab (VDZ). Methods Between 2020-2022, 507 UC patients starting a new therapy with UST or other biologics were enrolled in 34 IBD-experienced centres in Germany. After the exclusion of patients with a stoma, small molecules and missing outcomes, the final sample consisted of 476 patients. Response modified (reduction in partial Mayo score (pMayo) by ≥3 points from baseline to month 12 and a reduction of at least 30% or achievement of remission at month 12), clinical remission (CR) (pMayo ≤ 1 plus a bleeding subscore=0) and steroid-free remission (pMayo ≤ 1, bleeding subscore=0 and no systemic use of steroids or oral budesonide use in the previous 8 weeks) were considered as outcomes. To reduce the effect of confounders, PS adjustment with inverse probability of treatment weighting (IPTW) was implemented. Health-related QoL was assessed by using the visual analogue scale (EQ-VAS) of the EQ-5D. Results A total of 476 UC-patients [147 UST (bio-naïve: 12), 168 anti-TNF (ADA: 32.7%, IFX: 59.5%, GOL: 7.7%) (bio-naïve: 114) and 161 VDZ (bio-naïve: 105)] were included in the analysis. The PS-adjustment eliminated systemic differences in the baseline parameters (UST/anti-TNF/VEDO: 42.2/47.0/50.3% males, 25.2/25.0/19.9% EIMs), in particular, the "bio-experienced" characteristic was also equalised, between the groups. Treatment persistence over 12 months was different between UST (93.9%), VDZ (87.0%) and anti-TNF (75.0%) (Fig. 1). The PS-weighted effectiveness of UST (mITT analysis) in terms of response, clinical and steroid-free remission at month 12 (Tab. 1) was comparable to that of anti-TNF and VDZ, as was also the case without PS-weighting (CR: UST 33.1%, anti-TNF 38.5%, VDZ 38.1%). Patients of all treatment groups showed significant improvements in QoL measured as the EQ-VAS after 12 months of treatment. Conclusion In this prospective RUN-UC study with PS-weighted groups, UST showed similar maintenance effectiveness compared to established biologics in UC (anti-TNF and VDZ) with a relatively higher treatment persistence of UST, probably serving as a proxy for effectiveness, suggesting that additional criteria, such as safety and patients´ profile, may play an important role in the selection of biologics.

Network meta-analysis on efficacy and safety of different biologics for ulcerative colitis

BackgroundTherapeutic options for ulcerative colitis (UC) have increased since the introduction of biologics a few decades ago. Due to the wide range of biologics available, physicians have difficulty in selecting biologics and do not know how to balance the best drug between clinical efficacy and safety. This study aimed to compare the efficacy and safety of biologics in treating ulcerative colitis.MethodsIn this study, eight electronic databases (PubMed, Web of Science, Cochrane, Embase, Sinomed, China National Knowledge Infrastructure, Chongqing VIP Information, and WanFang Data) were searched to collect eligible studies without language restrictions. Retrieved 1 June 2023, from inception. All articles included in the mesh analysis are randomised controlled trials (RCTs). The inclusion of drugs for each outcome was ranked using a curved surface under cumulative ranking (SUCRA). Higher SUCRA scores were associated with better outcomes, whereas lower SUCRA scores were associated with better safety. This study has registered with PROSPERO, CRD42023389483.ResultsInduction Therapy: Among the biologic therapies evaluated for induction therapy, vedolizumab demonstrated the highest efficacy in achieving clinical remission (OR vs daclizumab, 9.09; 95% CI, 1.01–81.61; SUCRA 94.1) and clinical response. Guselkumab showed the lowest risk of recurrence of UC (SUCRA 94.9%), adverse events resulting in treatment discontinuation (SUCRA 94.8%), and serious infections (SUCRA 78.0%). Maintenance Therapy: For maintenance therapy, vedolizumab ranked highest in maintaining clinical remission (OR vs mesalazine 4.36; 95% CI, 1.65–11.49; SUCRA 89.7) and endoscopic improvement (SUCRA 92.6). Infliximab demonstrated the highest efficacy in endoscopic improvement (SUCRA 92.6%). Ustekinumab had the lowest risk of infections (SUCRA 92.9%), serious adverse events (SUCRA 91.3%), and serious infections (SUCRA 67.6%).ConclusionOur network meta-analysis suggests that vedolizumab is the most effective biologic therapy for inducing and maintaining clinical remission in UC patients. Guselkumab shows promise in reducing the risk of recurrence and adverse events during induction therapy. Infliximab is effective in improving endoscopic outcomes during maintenance therapy. Ustekinumab appears to have a favorable safety profile. These findings provide valuable insights for clinicians in selecting the most appropriate biologic therapy for UC patients.

Upadacitinib (Rinvoq)


 CADTH recommends that Rinvoq be reimbursed by public drug plans for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have demonstrated prior treatment failure (i.e., an inadequate response to, loss of response to, or intolerance to at least 1 of conventional therapy and/or biologic therapy), if certain conditions are met.
 Rinvoq should be covered for a similar patient population and in a similar way to other drugs currently reimbursed by public drug plans for the treatment of moderately to severely active UC.
 Rinvoq should only be reimbursed if it is prescribed by a physician experienced in treating UC, the dosage does not exceed the product monograph’s recommended dosage, and it is not used in combination with biologics for UC. It should not cost more than other biologics or targeted synthetic drugs covered by the public drug plans for the treatment of moderately to severely active UC.

Early Intestinal Ultrasound Predicts Long-Term Endoscopic Response to Biologics in Ulcerative Colitis.

The Milan ultrasound criteria [MUC] is a validated score to assess endoscopic activity in ulcerative colitis [UC]. MUC > 6.2 detects Mayo endoscopic score [MES] > 1. In this study we evaluated the predictive value of MUC for biologic treatment response, using colonoscopy [CS] as a reference standard. Consecutive UC patients starting biologic therapy were included, and underwent CS, IUS, clinical assessment and faecal calprotectin [FC] measurement at baseline and within 1 year. In addition, IUS, clinical and FC assessments were performed at week 12. The primary objective was to evaluate whether ultrasound improvement [MUC ≤ 6.2] at week 12 predicted endoscopic improvement at reassessment [MES ≤ 1]. Endoscopic remission was defined as MES = 0. Forty-nine patients were included [59% under infliximab, 29% under vedolizumab, 8% under adalimumab, 4% under ustekinumab]. MUC ≤ 6.2 at week 12 was the only independent predictor for MES ≤ 1 and MES = 0 at reassessment (odds ratio [OR] 5.80, p = 0.010; OR 10.41, p = 0.041; respectively). MUC ≤ 6.2 at week 12 showed a negative predictive value of 96% for detecting MES = 0. A ≥2 reduction of the MUC predicted MES = 0 (area under the curve [AUC] 0.816). MUC ≤ 4.3 was the most accurate cut-off value for MES = 0 [AUC 0.876]. Guyatt's responsiveness ratio for the MUC was 1.73 [>0.8]. MUC ≤ 6.2 at week 12 predicts long-term endoscopic response. MUC is accurate in monitoring treatment response and may be used in both clinical trials and routine practice.

P410 Long-term persistence and safety of biological drugs in patients with Inflammatory Bowel Disease. Differences between women and men: SEXEII study of ENEIDA

Abstract Background Female sex has been associated with a worse response to anti-TNF drugs and with discontinuation of these drugs in immune-mediated diseases. Data in Inflammatory Bowel Disease (IBD) are unclear. The aims of study are to assess possible differences in long-term treatment persistence and safety of biological drugs between women and men with IBD. Methods Multicenter observational study carried out with data from the ENEIDA registry. Patients diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) who receive or have received biological drugs, and have had a minimum treatment follow-up of 6 months, were included. We evaluated the first biological treatment used in the patient. Statistic analysis; Regression logistic models were used for safety evaluation. Kaplan-Meier curves, Log-Rank test and COX regression were used to treatment persistance. Results A total of 51,595 patients with IBD were evaluated [ 25,947 with CD (13238 men and 12709 women) and 25,648 with UC (13596 men and 12052 women)]. Mean follow up of 13 years. Biologic use: 28.7% of the evaluated patients had been treated with at least one biologic drug. Biologics use in UC was less common in women than in men (15.5% vs. 17.2%, OR (95%CI): 0.88 (0.81-0.94), p= 0.001) and there were no differences between sexes in CD ( 45.7% in men, 44.7% in women). Infliximab (IFX) and adalimumab (ADA) were the most used drugs (in 8914 and 5269 patients, respectively). Safety evaluation. Women suffered more frequently adverse effects to IFX and ADA than men, being the withdrawal of IFX and ADA due to adverse effects also significantly more frequent in women than in men. Biological treatment persistence in patients with IBD was longer in men than in women [median 3.1 years vs. 2.3 years, p < 0.001]. Female sex was a risk factor of biologic discontinuation [adjusted hazard ratio [aHR] (95%CI): 1.20 (1.14-1.25), p<0.001]. Combotherapy with thiopurines and CD were protective factors for discontinuation [ combotherapy; aHR (95%CI): 0.46 ( 0.44-0.48), p<0.001; CD aHR (95%CI): 0.78 (0.74-0.82), p < 0.001]. In the analysis of each specific biological drug, female sex was identified as independent predictor for discontinuation of IFX [aHR (95%CI) 1.21; 1.13-1.30, p<0.001] and ADA [aHR (95%CI) 1.24; 1.14-1.35, p<0.001] in patients with CD and of IFX in patients with UC [aHR (95%CI): 1.16; 1.05-1.28, p=0.004]. Figure 1. Conclusion 1.The use of biologics in ulcerative colitis seems to be higher in men than in women. 2. Female sex is an independent risk factor for the development of adverse effects to IFX and ADA and for the discontinuation of these drugs. 3. The long-term persistence of IFX and ADA (as first biological treatments) is low, being higher in men compared to women.

P631 Long-term safety of vedolizumab versus other biologic agents in ulcerative colitis (UC) and Crohn’s Disease (CD): Results from a large multinational prospective observational study

Abstract Background Vedolizumab (VDZ) is a gut-selective humanised monoclonal anti-α4β7 integrin antibody for treatment of UC and CD. This post-authorization safety study (PASS) compared long-term safety in patients (pts) treated with VDZ or other biologics for UC or CD. Methods This was a prospective, observational, multicentre, cohort study in pts with UC or CD starting treatment with VDZ or other biologics (NCT02674308, EUPAS6469). Pts were biologic naïve (VDZ=35%, Other biologic=65%) or had prior exposure to biologics other than VDZ and were followed for up to 7 yrs. Pts were treated under usual standard of care as directed by their physician with no discontinuation from the study due to physician-directed treatment changes. The primary safety outcome was serious infections and was compared between cohorts using a Cox proportional hazards model adjusted by propensity score (with other biologics as reference). Secondary safety outcomes were adverse events (AE) of special interest (AESI) as listed in Tables 2 and 3. Results In total, 5208 patients were enrolled across 21 countries between Mar 2015 and Jul 2019. The full analysis set comprised 5008 pts (VDZ=2502; other biologic=2506) and mean (SD) study duration was 37.4 (14.1) months. Consistent with the observational nature of the study and the current standard of care, the baseline characteristics in the two cohorts were imbalanced (Table 1). The overall treatment-emergent Adverse Event (AE) rate was 61.3% (VDZ) and 59.5% (other biologic), with serious AEs in 27.5% (VDZ) and 25.7% (other biologic), respectively. In UC pts, the incidence rate (IR) of serious infections were: 0.014 (95% CI: 0.010, 0.019) [VDZ] and 0.015 (0.010, 0.023) [other biologic], with a hazard ratio (HR) of 1.018 (0.931, 1.114), p=0.70 (Table 2). In CD pts, corresponding findings were 0.012 (95% CI: 0.008, 0.017) [VDZ] and 0.006 (95% CI: 0.004, 0.009) [other biologic] with HR of 1.035 (0.959, 1.117), p=0.38 (Table 3). The incidence of primary and secondary safety outcomes is reported in Table 2 for UC and Table 3 for CD. There were no safety issues relating to pregnancy and no cases of PML observed. There were 19 deaths in the VDZ cohort (1 case of pneumonia deemed as treatment-related); and 13 deaths in the other biologic cohort, 2 cases deemed treatment-related (one case septic shock and pneumonia; one case non-small cell lung cancer). Clinical outcomes and quality of life (QoL) measures were comparable between cohorts. Conclusion In this long-term, prospective, real-world observational study of a large multinational population under routine standard of care there was no new safety signal identified in relation to VDZ. Results are consistent with the known safety profile of VDZ.

P129 Intestinal ultrasound at week 12 predicts long-term endoscopic response to biologics in ulcerative colitis

Abstract Background Intestinal ultrasound (IUS) is accurate to assess endoscopic activity in ulcerative colitis (UC). The Milan ultrasound criteria (MUC) is a validated scoring system to assess and grade endoscopic activity in UC. The most accurate cutoff value for MUC was > 6.2 for endoscopic activity (defined as a Mayo endoscopic score, MES ≥ 2). The aim of this study was to assess the predictive value of IUS and MUC for treatment response in a longitudinal cohort, using colonoscopy (CS) as reference standard. Methods Consecutive active UC patients starting biologic therapy were included. All patients underwent CS, IUS, clinical and faecal calprotectin (FC) evaluations prior commencing a biological therapy, and within one year (mean 9.4 months). In addition, patients were evaluated by IUS, clinical and FC assessments at week 12. The primary objective was to evaluate whether ultrasound improvement (defined as MUC ≤ 6.2) at week 12 predicted endoscopic improvement at reassessment (defined as MES ≤ 1). Endoscopic remission was defined as MES = 0. Results Forty-nine patients were included (59% under infliximab, 29% under vedolizumab, 8% under adalimumab, 4% under ustekinumab). MUC and MES correlated at reassessment (r= 0.767, p < 0.001). Ultrasound improvement at week 12 was the only independent predictor for MES ≤ 1 and MES = 0 at reassessment (OR 5.80, p = 0.010; OR 10.41, p = 0.041; respectively). Ultrasound improvement at week 12 showed NPV of 96% for detecting MES = 0. A ≥ 2 reduction of the MUC score predicted MES=0 (area under the curve, AUC 0.816). MUC ≤ 4.3 was the most accurate cut-off value for MES = 0 (AUC 0.876). The responsiveness ratio of Guyatt for the MUC was 1.73 and the standardized effect size ratio was 1.6. Both these values > 0.8 indicate a large effect of responsiveness for the MUC. Conclusion MUC is highly accurate to monitor treatment response. Ultrasound improvement after the induction period may predict long-term endoscopic response. The MUC may be used both in clinical trials and routine practice.

P682 Predictors of response to biologics in Ulcerative Colitis: A population-based study from the epi-IIRN

Abstract Background Identifying prognostic factors of therapeutic failure, may facilitate balancing the risks and benefits of biologic treatment. In this population-based study, we aimed to explore predictors of therapeutic failure of biologics in Ulcerative Colitis (UC). Methods We retrieved data from two of four Health Maintenance Organizations in Israel, covering 38% of the population and part of the validated epi-IIRN IBD cohort. We included an inception cohort of UC patients, diagnosed since 2005, who were commenced on biologics. Those who underwent colectomy within 90 days from diagnosis were excluded. The primary outcome was therapeutic failure (i.e. discontinuation of treatment or need for colectomy or >1 short steroid courses). The secondary outcome was primary non-response (PNR; i.e. therapeutic failure within 4 months of initiation). Predictors were sought through Cox proportional hazard model. Results A total of 910 patients were included (246 [27%] pediatric-onset, 664 [73%] adults) with a median follow-up of 7.9 years (IQR 4.9–12.0). The probability of PNR was 16% and of therapeutic failure 35%, 55% and 63% after one, three and five years after commencing biologics, respectively. Older age at diagnosis (HR 1.01 [95%CI 1.005–1.01]), number of flares prior to initiation of biologics (HR 1.1 [95%CI 1.05–1.2]) and steroid use prior to biologics (HR 1.3 [95%CI 1.1–1.6]) were associated with therapeutic failure. PNR was associated with use of steroids prior to initiation of biologics (HR 2.1 [95%CI 1.4–3.3]). Laboratory blood work, including CRP, ESR, albumin, leukocytes, hemoglobin and platelets did not predict therapeutic failure, whether at diagnosis (HR 1.1 [95%CI 0.6–2.0]) or at initiation of biologics (HR 1.2 [95%CI 0.7–2.1]). Conclusion One third of UC patients failed to response to biologic treatment within one year. Older age at diagnosis and disease severity prior to biologic treatment, reflected by number of flares and steroid use, predicted therapeutic failure.

P501 Vedolizumab is associated with longer drug sustainability compared to infliximab in moderate-to-severe Ulcerative Colitis: a real-world cohort study

Abstract Background Data regarding sustainability of biologics in ulcerative colitis (UC) are limited. We aimed to assess sustainability of intravenous biologics used to treat UC, infliximab (IFX) and vedolizumab (VDZ), in biologic-naïve and biologic-experienced patients, specifically focusing on their sustainability over time. Methods This retrospective cohort study was conducted at the Rabin Medical Center (RMC), a tertiary referral center for patients with inflammatory bowel diseases. We included patients ≥ 18 years, treated at the RMC IV infusion center between Dec 1st 2017 and May 1st 2021. An extensive medical chart review was performed. Patients’ data were collected from the first to last documentation of treatment or end of follow-up. Drug sustainability was defined as long as cortico-steroid-free, surgical-free treatment was documented. Data collected, included sex, age at UC diagnosis, age at biologic treatment commencement and the interval UC-diagnosis-first biologic, disease extent (proctitis, left-sided or extensive colitis), previous treatment with biologics, and clinical laboratory data. Concomitant therapy was documented as well, specifically immunomodulatory drugs. Results were adjusted to factors associated with disease severity (based on factors including hemoglobin, hematocrit, neutrophil-to-lymphocyte ratio, albumin, C-reactive protein, and total protein), combination therapy and age. Results A total of 217 patients with UC treated with IFX or VDZ were included. Of those, 186 were treatment-(biologic)-naïve. First biologic was IFX in 77 (41.3%) patients and VDZ-in 109 (58.6%). Follow-up continued for up to 300 weeks. Median survival time was 106.5 (82.9–135) weeks for IFX and 265.6 weeks (121.3–273.1) for VDZ (p=0.002, KM survival curve shown in Figure 1). Median survival time was longer for vedolizumab even when adjusting for factors associated with disease severity, combination therapy and age (HR 0.55 95 CI 0.3–0.98, p=0.042). In treatment-experienced patients, IFX and VDZ sustainability was comparable (p=0.593). Conclusion In this -real world, tertiary referral center study, VDZ had significantly longer drug sustainability in treatment-naïve patients with UC compared to IFX. This held true when adjusted for disease severity. Drug sustainability in treatment-experienced patients with UC was comparable. The data support VDZ as the first-line biologic in moderate-to-severe UC.

S732 Comparative Long-Term Drug Survival of First-Line Biologic Agents for Ulcerative Colitis

Introduction: Real-world data comparing long-term survival of first-line biologics for ulcerative colitis (UC) is limited. We sought to compare long-term drug survival related to non-response (NR) and adverse effects (AEs) among biologic-naïve UC patients initiating infliximab (IFX), adalimumab (ADA), or vedolizumab (VDZ). Methods: Retrospective cohort study of adult, biologic-naïve UC patients initiating IFX, ADA, or VDZ 6/1/14-11/30/20 at a large academic center. Electronic health records were reviewed for clinical data. The primary outcome was time to biologic discontinuation for primary/secondary NR (including colectomy), confirmed by documentation of inadequate therapeutic effect. The secondary outcome was time to discontinuation for AEs. Kaplan-Meier analysis (KMA) and Cox regression were used to compare outcomes. Patients were censored at loss of follow-up, discontinuation for reasons unrelated to outcome, colectomy for dysplasia, or death, whichever occurred first. Confounders for Cox analyses were chosen a priori from the literature; p< 0.025 was considered significant. The proportional hazards assumption was tested using Shoenfeld residuals. Results: 503 UC patients initiated IFX (n=194), ADA (n=169), or VDZ (n=140) 6/1/14-11/30/20. Baseline characteristics compared by biologic are presented in Table 1. Biologic discontinuation for NR occurred in 52/194 (26.7%) for IFX, 77/169 (45.6%) ADA, and 30/140 (21.4%) VDZ (p< 0.01). Discontinuation for AEs occurred in 41/194 (21.1%) for IFX, 22/169 (13.0%) ADA, and 7/140 (5.0%) VDZ (p< 0.01). KMA demonstrated separation in drug survival curves for NR (Fig 1A) and AEs (Fig 1C). For the NR Cox model (Fig 1B), ADA but not VDZ was associated with greater hazard for discontinuation vs IFX (HR 2.4, 95% CI 1.5-3.6); higher serum albumin was associated with lower hazard for discontinuation (HR 0.7, 95% CI 0.5-0.9). For the AE Cox model (Fig 1D), VDZ but not ADA was associated with lower hazard for discontinuation vs IFX (HR 0.2, 95% CI 0.1-0.5); dose escalation was associated with lower hazard (HR 0.4, 95% CI 0.2-0.6) and female sex was associated with greater hazard for discontinuation (HR 2.0, 95% CI 1.1-3.7). Common AEs involved joints, rashes, infections, and infusion reactions (Fig 1E). Conclusion: After adjusting for confounders, ADA but not VDZ had a higher rate of NR compared to IFX. VDZ but not ADA had a lower rate of AEs compared to IFX. Prospective studies comparing long-term outcomes of biologics in UC are needed to personalize treatment decisions.Table 1.: Disease characteristics of the patient cohort.Figure 1.: Modified pouchitis disease activity index (mPDAI) among pouch phenotypes.

Patient access to biological medications for ulcerative colitis

This article considers the evidence for using different biologics in ulcerative colitis (UC), in particular the landmark head-to-head VARSITY trial. It reviews and addresses questions about VARSITY and its study design, including potential underdosing of adalimumab and lack of steroid tapering. It weighs up the implications of the evidence for clinical practice, as well as how this evidence supports increasing patient access to vedolizumab. It also assesses how the COVID-19 pandemic has changed the prescribing of biologics in ulcerative colitis, with a focus on subcutaneous adalimumab as the most commonly prescribed first biologic in UC. Declaration of interest This article was commissioned and funded by Takeda UK Ltd, who suggested the author and topic. Takeda UK Ltd also reviewed and approved the content. Prescribing information for vedolizumab (Entyvio) can be found at the end of the article.

Early Change in Epithelial Neutrophilic Infiltrate Predicts Long-Term Response to Biologics in Ulcerative Colitis

The prognostic value of histologic scores, grades, and individual histologic subcomponents, alone or in combination with endoscopy, for predicting endoscopic improvement (EI) and histoendoscopic mucosal improvement (HEMI) during maintenance therapy in ulcerative colitis remains uncertain.We performed a post hoc analysis of participants from the VARSITY trial (n = 734 with histology). Receiver operating characteristic and multivariate logistic regression analyses were performed to assess whether baseline and/or week 14 assessments for the Robarts Histopathology Index, Geboes score, individual histologic subcomponents, and baseline disease characteristics, including endoscopic severity and biomarkers, could predict the achievement of EI and HEMI at week 52.Changes in epithelial neutrophil involvement from baseline to week 14 had the best performance for predicting week 52 EI (area under the curve, 0.83; 95 % confidence interval [CI], 0.74-0.91) and HEMI (area under the curve, 0.85; 95 % CI, 0.76-0.94). On multivariate analyses, improvement of neutrophils in the epithelium was the only histologic parameter associated with increased odds of week 52 EI (odds ratio, 3.63; 95 % CI, 1.45-9.08; P = .0059) and HEMI (odds ratio, 6.88; 95 % CI, 3.29-14.36; P < .0001). Patients with more than 50 % of crypts involved with neutrophils at week 14 were significantly less likely to achieve week 52 HEMI irrespective of week 14 Mayo endoscopic scores (week 14 Mayo endoscopic score of 2-3: 9.9 % vs 22.4 %; P = .001; week 14 Mayo endoscopic score of 0-1: 33 % vs 62.4 %; P = .044).Our results on epithelial neutrophilic infiltrate after induction therapy as the only independent predictor for achievement of maintenance EI or HEMI helps clarify the clinical relevance of measuring histologic disease activity in ulcerative colitis. Epithelial neutrophilic infiltrate poses a means to stratify patients according to their likelihood of response to biologic treatment.

DOP03 Early change in epithelial neutrophilic infiltrate predicts long-term response to biologics in Ulcerative Colitis

Abstract Background The prognostic value of histologic scores, grades, and individual histologic sub-components, alone or in combination with endoscopy, for predicting endoscopic improvement (EI) and histo-endoscopic mucosal improvement (HEMI) during maintenance therapy in ulcerative colitis (UC) remains uncertain. Methods Post-hoc analysis of participants from the VARSITY trial (n=734 with histology). Receiver operating characteristic and multi-variate logistic regression analyses were performed to assess whether baseline and/or week 14 assessments for the Robarts Histopathology Index (RHI), Geboes score, or individual histologic sub-components, could predict the achievement of EI and HEMI at week 52. Results RHI and Geboes scores at baseline, and changes in scores at week 14, had fair to poor accuracy for predicting week 52 EI or HEMI (Area Under the Curve [AUC] 0.58–0.67). Among individual sub-components, changes in epithelial neutrophil involvement from baseline to week 14 had the best performance for predicting week 52 EI (AUC 0.83, 95% confidence interval (CI) 0.74–0.91) and HEMI (AUC 0.85, 95% CI 0.76–0.94). On multivariate analyses, improvement of neutrophils in the epithelium was associated with increased odds of week 52 EI (Odds Ratio [OR] 3.63, 95% CI 1.45–9.08, p=0.0059) and HEMI (OR 6.88, 95% CI 3.29–14.36, p&amp;lt;0.0001), and lack of improvement of neutrophils in the epithelium was associated with lack of week 52 EI (OR 0.24, 95% CI 0.12–0.48, p&amp;lt;0.0001) and lack of HEMI (OR 0.03, 95% CI 0.01–0.014, p&amp;lt;0.0001). No other parameters significant on univariate analysis were significant within the multivariate model. Among patients with endoscopic Mayo scores of 2 or 3 at week 14, those who had &amp;gt;50% crypts involved with neutrophils at week 14 were significantly less likely to achieve week 52 EI (18.0%; 31/172 vs. 34.3%; 72/210, p&amp;lt;0.001), HEMI (9.9%; 17/172 vs. 22.4%; 47/210, p=0.001) (Figure 1) and clinical remission (11.0%; 19/172 vs. 23.3%; 49/210, p=0.002). Among patients with endoscopic Mayo scores of 0 or 1 at week 14, those who had &amp;gt;50% crypts involved with neutrophils were significantly less likely to achieve HEMI at week 52 (33%; 4/12 vs. 62.4%; 141/226, p=0.044) (Figure 1). Conclusion Our results on epithelial neutrophilic infiltrate following induction therapy as the only independent predictor for achievement of maintenance EI or HEMI helps clarify the clinical relevance of measuring histologic disease activity in UC. Epithelial neutrophilic infiltrate poses a means to stratify patients according to their likelihood of response to biologic treatment.

A Machine Learning Model Accurately Predicts Ulcerative Colitis Activity at One Year in Patients Treated with Anti-Tumour Necrosis Factor α Agents.

Background and objectives: The biological treatment is a promising therapeutic option for ulcerative colitis (UC) patients, being able to induce subclinical and long-term remission. However, the relatively high costs and the potential toxicity have led to intense debates over the most appropriate criteria for starting, stopping, and managing biologics in UC. Our aim was to build a machine learning (ML) model for predicting disease activity at one year in UC patients treated with anti-Tumour necrosis factor α agents as a useful tool to assist the clinician in the therapeutic decisions. Materials and Methods: Clinical and biological parameters and the endoscopic Mayo score were collected from 55 UC patients at the baseline and one year follow-up. A neural network model was built using the baseline endoscopic activity and four selected variables as inputs to predict whether a UC patient will have an active or inactive endoscopic disease at one year, under the same therapeutic regimen. Results: The classifier achieved an excellent performance predicting the disease activity at one year with an accuracy of 90% and area under curve (AUC) of 0.92 on the test set and an accuracy of 100% and an AUC of 1 on the validation set. Conclusions: Our proposed ML solution may prove to be a useful tool in assisting the clinicians’ decisions to increase the dose or switch to other biologic agents after the model’s validation on independent, external cohorts of patients.

Treatment patterns for biologics in ulcerative colitis and Crohn’s disease: a Danish Nationwide Register Study from 2003 to 2015

Background: The choice of treatment for Crohn’s disease (CD) and ulcerative colitis (UC) depends among other factors, disease severity. Patients with moderate-to-severe disease should be prescribed biologic response modifiers (biologics), according to guidelines. This study aims to explore the treatment patterns of patients diagnosed with CD and UC between 2003 and 2015 that were treated with biologics in Denmark between the years 2003 and 2016.Methods: This national register study included patients diagnosed between 2003 and 2015, identified in the Danish National Patient Registry. Biologic therapies available during the study period were infliximab, adalimumab, vedolizumab and golimumab. The share of patients initiating and receiving biologic treatment in each year was estimated. Additionally, the time from IBD diagnosis to first biologic treatment and time between treatments was calculated.Results: Among 10,302 CD patients and 22,144 UC patients, 28.5% of CD patients and 11.3% of UC patients received treatment with biologics during the study period, with an increasing trend in the number of patients initiating treatment with biologics each year. About 46% of CD patients and 45% of UC patients received their first biologic treatment within the first year after IBD diagnosis. About 57–68% of CD and UC patients received treatment with their second line biologic within 2 months of the last treatment of their first line.Conclusions: The number of patients initiating biologic treatments after diagnosis increased throughout the study period. Most patients diagnosed with CD and UC are receiving biologic treatments relatively soon after their diagnosis.

Aminosalicylate withdrawal following escalation to immunomodulators or biologics in ulcerative colitis: cost saving, convenient and does not compromise efficacy

Aminosalicylate withdrawal following escalation to immunomodulators or biologics in ulcerative colitis: cost saving, convenient and does not compromise efficacy