bluuebunny/crossref_metadata_2025 huggingface dataset:
P824 Association between visceral adipose tissue and disease duration, clinical activity, and response to various biological agents in inflammatory bowel disease
Authors: Karakan T , Coşkun M , Bilican G , Demir B , Karataş A , Ekmen N , Moral K , Karakoç A , Cindoruk M
Published: January 2024

Background

The relationship between body fat composition and inflammatory bowel disease (IBD) progression, medical response, and prognosis is widely acknowledged. Visceral adipose tissue (VAT) has been shown to be profoundly responsible of most of the obesity-associated metabolic derangements, however it is also related to severity of inflammation. Although VAT can be estimated using computerized tomography, abdominal bioimpedance is a new and reliable technique without expense and radiation exposure. We investigated whether VAT is linked to the disease activity in severe IBD and the short-term response to biological therapies.

Methods

We prospectively evaluated 65 IBD patients, (n=26 with ulcerative colitis (UC) and n=39 with Crohn’s disease (CD) who had moderate-severe disease activity) at baseline before the initiation of biological therapy. We quantified VAT using abdominal bioimpedance (ViScan). VAT and other body fat metric measures (BMI, total and free fat mass, abdominal fat mass) were also analyzed. The response to biological agents was assessed by clinical (Mayo and CDAI) and endoscopical (mucosal healing) scores at 3 months.

Results

Out of the 65 patients, 22 individuals (33.8%) exhibited clinical and/or endoscopic response after 3 months. Among responders and non-responders, there was a comparable approximation of disease location (p=0.321) and behavior (p=0.239). Patients with CD had slightly lower levels of VAT, BMI, and free fat mass compared to those with UC. In non-responders with UC, VAT levels were lower than in responders, whereas in non-responders with CD, VAT levels were higher than in responders. No distinction was observed in the VAT response among other classes of biologics, including anti-TNF, ustekinumab, and vedolizumab.

Conclusion

In summary, VAT parameters using bioimpedance (ViScan) were found to be correlated with the disease activity and reliably identified IBD patients who responded well to various biological treatment in the short-term. Therefore, human fat indices might be novel biomarkers for disease severity and response to therapy.
P827 Has opioid use increased among adults with Crohn’s disease? A Swedish Nationwide cohort Study 2008-2020
Authors: Osooli M , Bruze G , Bryder N , Nordenvall C , Myrelid P , Åsa Hallqvist E , Olén O
Published: January 2024

Background

Chronic opioid use has turned into a global health challenge. Crohn’s disease (CD) patients may experience severe pain requiring opioids which could exacerbate CD symptoms and pose a risk of chronic use. The use of opioids among CD patients has not been explored on a national level. We compared the secular trends of opioid use among prevalent CD patients and matched reference individuals in Sweden.

Methods

This nationwide cohort study included adults with a prevalent CD diagnosis who lived in Sweden for at least 12 consecutive months at some point between 1 January 2008 and 31 December 2020. For each patient, up to 10 reference individuals from the general population were matched on birth year, sex, calendar year, and place of residence. We retrieved the data on dispensed opioid prescriptions (opioid use) from the National Prescribed Drug Register. We defined opioid use as ≥1 filled prescription per calendar year. We also estimated the annual prevalence of ≥1 dispensation of weak (codeine combinations, tramadol, and Dextropropoxifen) and/or strong opioids (Oxycodone, Morphine, Hydromorphone, Fentanyl, Buprenorphine, Tapentadol, and Petidin).

Results

We identified 43,155 adult CD patients and 418,218 reference individuals (Table 1). The prevalence of opioid use was stable from 2008-2016. However, between 2017 and 2020 it decreased from 19.7% (95% CI: 19.2, 20.2) to 16.9% (95% CI: 16.2, 17.7) and from 8.5% (95% CI: 8.4, 8.7) to 6.9% (95% CI: 6.7, 7.1) among CD patients and reference individuals, respectively (Figure 1a). However, between 2008 and 2020, the prescription of strong opioids more than doubled among both CD patients (increasing from 4.3% [95% CI: 4.1, 4.6] to 11.5% [95% CI: 11.1, 11.8]), and reference individuals (increasing from 1.3% [95% CI: 1.3, 1.4] to 5.4% [95% CI: 5.3, 5.5]) (Figure 1b). In 2020, the last year of the observation, compared with males, both female CD patients (20.3% [19.7, 20.8] vs 9.3% [9.2, 9.5]) and their matched reference individuals (15.3% [14.8, 15.9] vs 7.1% [6.9, 7.2]) had a higher prevalence of annual opioid use. The secular trends of overall opioid use and increasing use of strong opioids were similar for males and females (data not shown).

Conclusion

Annual opioid use among prevalent CD patients in Sweden, a country with publicly-funded healthcare and access to modern CD treatment, was two-fold higher than in the general population in the last 13 years. The annual opioid use remained stable from 2008-2016 and slightly decreased from 2017-2020 for CD patients and reference individuals. During the same period, the use of strong opioids more than doubled for CD patients and the general population.
P843 Effectiveness and tolerability of methotrexate combined with biologics in patients with Crohn’s disease: A multicenter observational study
Authors: Park J , Jaeyoung C , Soo Jung P , Jae Jun P , Tae Il K , Hyuk Y , Jae Hee C
Published: January 2024

Background

Methotrexate (MTX) combination therapy with biological agents has gained increasing interest. Here, we assessed the efficacy and tolerability of the MTX combination therapy in patients with Crohn’s disease (CD).

Methods

We performed a multicenter observational study with 185 patients with CD with MTX and biologics combination therapy; the patients were recruited from three IBD Clinics in Korea. We evaluated the outcomes of the MTX combination therapy and examined the predictive factors of clinical and endoscopic remission.

Results

MTX was administered orally to 62.7% of patients; the mean dose was 15.5 mg per week, and the mean treatment duration was 36 months. Of the 169 patients treated with MTX combination therapy for over 6 months, the steroid-free clinical remission rates were 34.3%, 26.0%, 29.8%, and 32.7% at 4, 12, 18, and 24 months, respectively. Previous thiopurine use was a significant negatively associated independent factor (p < 0.001), and a higher dose of MTX (≥15 mg/week) was a positively associated independent factor of steroid-free clinical remission (p = 0.035). Ninety-six patients underwent follow-up endoscopy after 28 months, and 36 (37.5%) achieved endoscopic remission. Longer disease duration (p = 0.006), ileocolonic type of Montreal location (p = 0.036), and baseline C-reactive protein (CRP) level of more than 5 mg/L (p = 0.035) were significant negatively associated independent factors and a higher dose of MTX (≥15 mg/week) was a positively associated independent factor of endoscopic remission (p = 0.037).

Conclusion

MTX combination therapy with biologics was effective and tolerable in patients with CD.
P862 Effects of induction and maintenance therapy with risankizumab on health-related quality of life outcomes in patients with moderately to severely active ulcerative colitis: A post-hoc analysis of Phase 2b/3 trials
Authors: Panés J , Loftus Jr. E V , Armuzzi A , Siegmund B , Sands B E , Boland B S , Kalabic J , Lai J H , Sharma D , Remple V , Sanchez Gonzalez Y , Lindsay J O
Published: January 2024

Background

Ulcerative colitis (UC) has a detrimental impact on patients’ health-related quality of life (HRQoL).1 Long-term treatment goals for patients with moderately to severely active UC include restoration of HRQoL. This post-hoc analysis evaluated the effect of induction and maintenance treatment with risankizumab (RZB) on HRQoL outcomes.

Methods

Data from two Phase 2b/3 clinical trials (INSPIRE induction: NCT03398148 and COMMAND maintenance: NCT03398135) were evaluated. Patients received RZB 1200 mg intravenous (IV) or placebo (PBO) induction treatment at weeks 0, 4, and 8. Patients with a clinical response per Adapted Mayo score to RZB IV were randomised 1:1:1 to subcutaneous (SC) RZB 180 or 360 mg, or placebo (PBO [RZB withdrawal] SC) every 8 weeks for 52 weeks of maintenance. The proportion of patients achieving a meaningful within-person change (MWPC) for each HRQoL outcome was reported. HRQoL outcomes included Functional Assessment of Chronic Illness Therapy-Fatigue, disease-specific instruments such as Inflammatory Bowel Disease Questionnaire (IBDQ) and Ulcerative Colitis Symptom Questionnaire (UCSQ), as well as generic quality-of-life questionnaires like Work Productivity and Activity Index-Ulcerative Colitis (WPAI-UC), 36-Item Short-Form Survey (SF-36), and EuroQoL 5 Dimensions 5 Levels. MWPCs were measured from baseline to induction Week 12 and to maintenance Week 52. Estimated differences in proportions with 95% confidence intervals and p-values between RZB and PBO were compared using the Cochran-Mantel-Haenszel test adjusting for baseline strata.

Results

For RZB 1200 mg IV (n=650) versus PBO IV-treated (n=325) patients, a greater proportion of patients achieved MWPC across all HRQoL outcomes at Week 12 of induction (p<0.01; Table). At Week 52 of maintenance, a greater proportion of patients treated with RZB 180 mg SC (N=179) versus PBO (withdrawal) SC (N=183) achieved MWPC across all HRQoL outcomes (p<0.05), except for absenteeism from WPAI-UC (p=0.33). For RZB 360 mg SC (N=186) versus PBO (withdrawal) SC, a greater proportion of patients achieved MWPC for UCSQ, IBDQ, and SF-36 physical component summary (all p<0.05).

Conclusion

In this analysis, a greater proportion of patients treated with RZB versus PBO achieved MWPC on various HRQoL outcomes after completing 12-week induction IV therapy. HRQoL improvements were sustained up to Week 52 of treatment. This suggests RZB has the potential to help patients achieve restoration of HRQoL as a long-term goal of treatment in patients with moderately to severely active UC.

1. Mavroudis G. Therap Adv Gastroenterol. 2022;15:17562848211062406.
P871 A modified Crohn’s disease exclusion diet in a multi-ethnic Asian setting
Authors: Tan C K , Wong A , Huang Y , Ling K L , Wang L M , Ang T L , Ong J
Published: January 2024

Background

Crohn’s disease exclusion diet (CDED) has been shown to be well-tolerated and effective in adults with active Crohn’s disease (CD). There is limited data on using CDED in Asian setting. We performed this study to evaluate the feasibility and tolerability of using CDED as a nutritional intervention in Asian adults with CD.

Methods

We performed a prospective single centre observational study using 12-weeks of CDED as a nutritional intervention in adults with CD. The original CDED was adapted to foods commonly eaten in Asia. Patients with active CD were offered CDED as monotherapy or as an adjunct treatment to drug therapy. Dietary counselling was done by a dietitian and all food was prepared by individual participants or their family members. Participants were seen at baseline, week 6 and week 12. Dietary compliance was monitored by physician using direct questioning and, modified Medication Adherence Rating Scale (MARS) questionnaire. In addition, dietitian monitored compliance using 24-hour dietary recall and 3-day food journal. We monitor the disease activity using Harvey Bradshaw Index (HBI), C-reactive protein (CRP) and faecal calprotectin (FC). (Figure 1) The primary endpoint was tolerance to CDED; secondary endpoints were compliance to CDED and biomarker normalization. Intolerance was defined as refusal to continue with CDED and withdrawal from study. This study was approved by Singhealth Institutional review Board. Informed consent was obtained from all participants.

Results

A total of 6 participants were recruited from November 2022 to May 2023. Most participants were young. Four patients were on biologics (1 infliximab, 1 adalimumab, 1 vedolizumab, 1 ustekinumab). Two patients had CDED as monotherapy. (Table 1). All participants were able to tolerate 12 weeks of CDED and were mostly compliant to CDED. (Table 1) 5 of 6 patients had downward trend of CRP at week 12 compared to baseline and 4 of 6 had Two patients who received CDED as monotherapy had biomarker normalization at week 12. All patients were continued on CDED for another 12 weeks (maintenance phase).

Conclusion

Dietary intervention using CDED is well-tolerated among Asian adults with CD. More data is required to confirm the efficacy of CDED, both as monotherapy and in combination with drug therapy.
P879 Comparative Efficacy of Biologics and Small Molecule Therapies for the Induction and Maintenance of Endoscopic and Histological Remission in Ulcerative Colitis: A Systematic Review and Network Meta-analysis
Authors: Shehab M , Alrashed F , Alsayegh A , Aldallal U , Ma C , Narula N , Jairath V , Singh S , Bessissow T
Published: January 2024

Background

Treatment options for moderate to severe ulcerative colitis (UC) are increasing rapidly, but lack of comparative efficacy trials make treatment choices a clinical challenge. We aimed to compare the relative efficacy of biologics and small molecules in achieving endoscopic and histological remission in patients with moderate to severe UC.

Methods

The literature was searched between January 1990 and July 2023. Phase 3 placebo or active comparator randomized controlled trials (RCTs) were included to assess the efficacy of biologics or small molecule drugs as induction or maintenance therapies for patients with UC. The primary outcome was induction and maintenance of endoscopic improvement (Mayo endoscopic score ≤1), whereas secondary outcomes were the induction and maintenance of endoscopic (Mayo endoscopic score = 0) and histological remission. Sub-analysis was performed based on previous exposure to biologic therapy. We used a random effects model and reported data as odd ratio (OR) with 95% confidence intervals (CIs).

Results

We identified 34 studies that met our inclusion criteria, with a total of 12,227 patients with UC. Upadacitinib was superior to most biologics in inducing endoscopic improvement and remission as well as maintaining endoscopic improvement and histological remission. Etrasimod ranked second, after upadacitinib, in maintenance of endoscopic improvement in both biologic naive (80.4%) and experienced (78.9%) patients. Infliximab was superior to adalimumab (OR 1.88, 95% CI, 1.07; 3.29) and vedolizumab (OR1.85, 95% CI, 1.13; 3.03) in inducing endoscopic improvement in overall UC patients. Filgotinib 200 mg (OR 4.76, 95% CI, 1.89; 5.88) and vedolizumab (OR 4.16, 95% CI, 2.94; 6.25) were superior to adalimumab in maintaining histological remission. In biologic naive patients, infliximab was found to be superior to adalimumab (OR 1.80, 95% CI, 1.05;3.07), vedolizumab (OR 5.20, 95% CI, 2.04;7.69), and golimumab (OR 6.30, 95% CI, 3.39;9.71) in inducing endoscopic improvement

Conclusion

Upadacitinib appears to be superior to other therapies in achieving both endoscopic improvement and remission as well as maintaining histological remission. Furthermore, etrasimod, filgotinib and tofacitinib ranked high in achieving these outcomes. This study highlights the role of small molecules drugs as effective alternatives to biologics.
P888 Effectiveness and safety of Adalimumab Biosimilars in Bio-naive patients with Inflammatory Bowel Disease: The Galician experience
Authors: Vega Villaamil P , Vázquez Rey M T , Bastón Rey I , Ayude Galego M , Carmona Campos A , Baz López A M , Molina Arriero G , Ruiz Barcia M J , Regueiro Expósito C
Published: January 2024

Background

Biological drugs has revolutionized the management of inflammatory bowel disease (IBD). However, its use has led to a significant increase in cost that has strained health systems. Biosimilars will reduce cost related to treatment, allowing access to a greater proportion of patients. However, data on the efficacy and safety of the various ADA biosimilars in IBD patients "naive" to biologics remains scarce.

Methods

We performed an observational cohort study in 9 hospitals in Galicia. All patients with IBD naïve to biologics who started ADA biosimilar between November 2018 and January 2022 for control of their disease were enrolled. The primary endpoints were efficacy defined as clinical remission at week 8 and long term efficacy defined as persistence on drug treatment at the end of follow-up. The other co-primary endpoint was to determine the incidence of adverse events that lead to suspension or discontinuation of the drug or hospitalization of the patient

Results

384 patients (95 CU; 283 CD) with a median age of 47 (34-60) years and a median disease duration of 3.4 (0.8-10.0) years before starting treatment were included. After induction (at 8 weeks) 63.7 % of patients were in clinical remission and 85.0 % achieved clinical response. At this time of follow-up, 14 patients (4.9 %) discontinued treatment mainly due to primary non-response (PNR) (57.1 %) and adverse events (42.9 %). In total, 112 patients discontinued treatment during follow-up (Figure 1). The main reasons for stopping therapy were adverse events (32.1 %), PNR (30.4 %) and secondary loss of response (37.5 %). Clinical remission was maintained in 60.9 % of patients, after a median follow-up of 18 (12-24) months. Drug persistence shown by Kaplan-Meier survival curves were significantly higher in CD patients (p = 0.007) and in the group of patients treated with immunomodulators (IMM) (p = 0.001). Additionally, the rates of clinical remission and clinical response were higher in CD patients and in IMM-treated patients (Table 1). Adalimumab levels were also measured during follow-up, showing a median of 11 (6.8-14) μg/mL. Significantly, drug persistence was higher in patients with adalimumab levels ≥ 7 μg/mL at week 4 (p < 0.001). Regarding treatment safety in this population, adverse events that required treatment suspension or discontinuation were reported in 36 patients.

Conclusion

Adalimumab biosimilars in usual clinical practice are safe and effective in inducing and maintaining remission in Galician patients with IBD. Drug persistence was significantly higher in patients with CD, treated with IMM and with post-induction ADA levels ≥ 7 μg/mL.
P891 Comparative Effectiveness and Safety of Infliximab and Tacrolimus in the Treatment of Acute Severe Ulcerative Colitis
Authors: Cohen N A , Tamir-Degabli N , Rozenfeld A , Hirsch A , Thurm T , Ron Y , Fishman S , Leibovitzh H , Maharshak N
Published: January 2024

Background

Acute severe ulcerative colitis (ASUC) affects approximately 20% of patients with ulcerative colitis (UC). Patients failing initial corticosteroid therapy receive salvage therapy with either infliximab (IFX) or calcineurin inhibitors, cyclosporine (CYS) or tacrolimus (TAC). We aimed to compare the effectiveness and safety of IFX and the oral calcineurin inhibitor, TAC, in this setting.

Methods

This retrospective cohort study included consecutive patients with ASUC, based on the Truelove and Witts criteria, admitted to Tel Aviv Medical Center between 2017 and 2022 and treated with salvage therapy. Demographic, clinical, and laboratory data were retrieved. The primary endpoint was successful salvage therapy defined as clinical response resulting in discharge without colectomy. Secondary endpoints included the colectomy rates at 90 days and the safety profile of the treatments.

Results

During the study period 96 patients with ASUC were admitted to our center. Of these, 40 patients received salvage therapy – 21 patients received IFX and 16 received TAC and were included in the analysis; 3 patients received CYS and were excluded from the study. Demographic data are detailed in Table 1. Disease duration was significantly longer in patients receiving TAC (mean (±SD) 9.7 years (±7.1) vs 4.5 (±5.9), p=0.04). In addition, patients receiving TAC had significantly greater prior exposure to advanced therapies (14 (87.5%) vs 6 (28.6%), p<0.001) and 12 (75%) patients had previous exposure to IFX. Baseline markers of disease severity including disease extent, hemoglobin, C-reactive protein (CRP), albumin and body mass index (BMI) were similar between the treatment groups (Table 1). Therapeutic success was similar between treatment groups (IFX: 18 (86%) vs TAC: 15 (94%), p=0.62). The 90-day colectomy rate (IFX: 4 (19%) vs TAC: 2 (12.5%), p=0.68), CRP upon discharge (median (IQR) IFX: 15 mg/L (3.3-27) vs TAC: 11 mg/L (5.4-25, p=0.64) and length of hospitalization (mean (±SD) IFX: 23.5 days (±19.46) vs TAC: 17.56 days (±5), p=0.19) were similar between the groups. Safety profiles were similar between the treatment groups with mild electrolyte disturbances treated conservatively in both groups and no observed infections, deaths or other adverse events.

Conclusion

This real world, retrospective study shows that IFX and TAC have similar effectiveness and safety in the setting of ASUC. In this study, patients receiving TAC had significantly longer disease duration and advanced therapy exposure than those receiving IFX and still maintained excellent effectiveness highlighting TAC’s value in this setting.
P902 Subcutaneous infliximab (CT-P13 SC) as maintenance therapy for Crohn’s disease: 2 years results of the LIBERTY-CD study
Authors: Colombel J F , Hanauer S B , Sandborn W J , Sands B E , Schreiber S , Danese S , Kierkus J , Kulynych R , Klopocka M , Lahat A , Gonciarz M , Osipenko M , Borzan V , Kowalski M , Saenko D , Sardinov R , Lee S J , Kim S , Bae Y , Lee S , Lee S G , Yang S , Lee J , Park G
Published: January 2024

Background

CT-P13 subcutaneous (SC) infliximab formulation showed superiority over placebo as maintenance therapy at Week 54 in Crohn’s disease (CD)1 and ulcerative colitis2. The LIBERTY-CD study1 included an extension phase up to Week 102, the results, of which, are reported.

Methods

Patients who completed the maintenance phase up to Week 54 and, in the opinion of the investigator, would benefit from continued treatment could continue the open-label extension phase from Week 56 to Week 102 and received CT P13 SC 120 mg regardless of the previous assigned arm of maintenance phase. Patients who had received the adjusted dose of CT-P13 SC 240 mg during the maintenance phase continued receiving the same doses in the extension phase. At Week 54 and Week 102, clinical remission, clinical response, endoscopic remission, endoscopic response, clinical remission (alternative definition) and corticosteroid-free remission were assessed for patients who were treated CT-P13 SC during the extension phase (Figure 1.A) or who were treated CT-P13 SC during the extension phase and had valid efficacy results at the visit of interest (Figure 1.B). Patients with dose adjustment to CT-P13 SC 240 mg prior to Week 54 were considered as non-remitter/non-responder. Safety was evaluated through the extension phase.

Results

A total of 180 patients in the CT-P13 SC arm (assigned arm at the maintenance phase) entered into the extension phase. Overall, 85.6% (154/180) completed extension phase. Compared to the Week 54 results, efficacy results in the CT-P13 SC arm based on the non-responder imputation for missing or invalid data (i.e., patients who had missing or invalid data were considered as non-remitter/non-responder) were generally maintained in clinical remission, clinical response, endoscopic remission, endoscopic response, clinical remission (alternative definition), and corticosteroid-free remission at Week 102 (Figure 1.A). The efficacy results based on the no imputation for missing or invalid data (i.e., observed data) at Week 54 and Week 102 were similar (Figure 1.B). There was no new safety issue reported during the extension phase (Table 1). No death was reported during the extension phase.

Conclusion

Efficacy of CT-P13 SC was maintained through the extension phase. No new safety concerns were observed during the extension phase. These results show that CT-P13 SC provides both a long-term clinical benefit and safety with the convenience of SC administration for moderately to severely active CD patients.

[1] Colombel et al., Journal of Crohn's and Colitis, 2023.

[2] Sands et al., Journal of Crohn's and Colitis, 2023.
P904 Appendectomy for refractory ulcerative colitis: results of prospective observational study
Authors: Adamou A , Bercher M , Iesalnieks I , Streetz K , Morgenstern J , Dinter J , Bästlein C , Weingärtner J H
Published: January 2024

Background

Appendectomy is suggested to improve the course of the disease in many patients with refractory ulcerative colitis (UC). The present prospective observational study demonstrates middle-term outcomes after an appendectomy in 26 patients with refractory UC.

Methods

Between 5/2022 and 2/2023, 26 selected patients underwent appendectomy for refractory UC. Refractory UC was defined as a failure of at least one biologic therapy. Patients with Dysplasia or Cancer were excluded. The appendectomy was performed without the removal of the cecal base. Primary Endpoint of the study was the Mayo clinical score (MCS) at 6 months after the appendectomy. Secondary Endpoint was the “Treatment failure” which was defined as occurrence of one of the following events during the first 6 months after appendectomy: 1) high-dosed steroid treatment, 2) change of biologic treatment, 3) colectomy.

Results

Mean age was 35 years (18 to 59 years) and there were 11 female patients. 15 had a pancolitis (58%). Twelve were taking steroids (46%). Median number of biologic therapies taken by patients prior to surgery was 3 (range, 1-5). One patient underwent surgery for sever acute UC. The appendix appeared to be inflamed histologically in 16 patients (62%). Hospital stay was median 2 days, there was one wound infection at the port site and one postoperative hematoma. A significant improvement of disease symptoms was reported by 21 patients during the first 4 weeks (81%). At 6 months, MCS improved from mean 6.4 to 4.5 (p=0.057). Therapy failure was observed in 15 patients (58%) – two underwent colectomy, 11 needed at least one high-dose steroid treatment and biologic therapy was changed due to refractory symptoms in 9 patients. Intake of JAK-inhibitors at the time of appendectomy was the only factor to be associated with lower probability of treatment failure (30% vs. 75%, p=0.043). The only patient undergoing appendectomy for severe acute UC was free of symptoms 14 months after surgery.

Conclusion

The majority of patients with refractory UC demonstrated rapid clinical response to the appendectomy. After 6 months, more than 40% of patients did not experience disease flares necessitating intensification of treatment.
P909 Proactive therapeutic drug monitoring and pharmacogenomics in mercaptopurine therapy for ulcerative colitis
Authors: Anjie S , Derijks L J , Volkers A G , van Gennep S , Clasquin E , Duijvestein M , van Bodegraven A A , Rietdijk S , van Asseldonk D P , van der Zanden E P , Hettinga J , West R L , D'Haens G R A M , Löwenberg M , Schwab M , de Boer N K
Published: January 2024

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 <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<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.
P911 Development and Characterization of SPY002, a Novel Extended Half-life Monoclonal Antibody Drug Candidate Targeting TL1A for the Treatment of IBD
Authors: Zhu E , Rios D , Milligan J , Ministro J , Friedman J , Nguyen D , Spencer A , Oh J , Shaheen H
Published: January 2024

Background

Tumor necrosis factor (TNF)-like ligand 1A (TL1A) mediates a broad spectrum of pro-inflammatory and fibrotic effects and is implicated in the pathogenesis of several immunologic disorders. Blockade of the interaction of TL1A with its cognate receptor, DR3, has been shown to ameliorate disease activity patients with Crohn’s disease (CD) and ulcerative colitis (UC). SPY002 is a novel, extended half-life fully human IgG1 monoclonal antibody (mAb) that binds soluble TL1A with high affinity and specificity, and potently inhibits TL1A-mediated signaling.

Methods

SPY002 was evaluated in multiple in vitro and ex vivo assays compared to other clinical anti-TL1A mAbs (PRA023/MK-7240, RVT-3101, and TEV-48574). Binding affinity to soluble TL1A was determined by surface plasmon resonance (SPR) and binding to membrane-bound TL1A was confirmed by flow cytometry (FACS). Competitive blockade of TL1A binding to cell-surface DR3 was determined by FACS, and competition against the decoy receptor, DcR3, was evaluated by ELISA. The binding epitope of SPY002 was determined using cryogenic electron microscopy. TF-1 cell apoptosis and a primary human whole blood-based assay measuring IFNg secretion were used to assess functional blockade of exogenously added TL1A. Half-life extension was measured via pharmacokinetic analysis in both Tg276 transgenic mice (hemizygous for human FcRn) and cynomolgus monkeys given a single bolus of SPY002 by intravenous and/or subcutaneous administration.

Results

SPY002 binds specifically to monomeric and trimeric TL1A and not to related TNF super family proteins TNF, FasL, TRAIL, or LIGHT. SPY002 demonstrates sub-nanomolar affinity for soluble TL1A and binds to TL1A over-expressed on the surface of human embryonic kidney (HEK) cells. SPY002 potently inhibits both TL1A-induced apoptosis of TF-1 cells and TL1A-induced secretion of IFNg in human whole blood, with IC50 values comparable to those of RVT-3101 and TEV-48574, and a substantially lower IC50 than that of PRA023/MK-7240. The half-life of SPY002 is significantly extended in Tg276 mice compared to RVT-3101. In cynomolgus monkeys, the half-life of SPY002 is at least 18 days, compared to an observed half-life of 9-12 days for RVT-3101 and PRA023/MK-7240.

Conclusion

SPY002 exhibits high selectivity and affinity for TL1A, demonstrates effective blockade of the TL1A interaction with DR3, and potently inhibits downstream cellular signaling. With an extended half-life in NHP, SPY002 demonstrates therapeutic potential for effective and safe treatment of CD and UC with the advantage of infrequent SC dosing. Further preclinical and clinical studies are warranted to demonstrate this potential.
P930 Rapid symptomatic improvement with subcutaneous infliximab induction treatment for patients with moderate-to-severe Crohn’s disease: first results from the DIRECT-CD study
Authors: Anjie S , Jharap B , Jansen J M , Mares W G , Duijvestein M , Maljaars J P W , Oldenburg B , D'Haens G R A M , Gecse K B
Published: January 2024

Background

Subcutaneous (SC) formulation of infliximab (IFX) received regulatory approval for the maintenance treatment of Crohn’s disease (CD) in 2020. DIRECT-CD is an ongoing multicentre trial to evaluate the efficacy of SC IFX induction and maintenance treatment in monotherapy versus combination therapy in CD (EUDRACT 2021-000469-33). Here we aimed to determine the rapidity of symptom improvement during this SC IFX induction regimen.

Methods

Patients with moderate-to-severe CD (Crohn’s disease activity index [CDAI]) >220 and endoscopic ulceration) received fixed SC IFX induction doses of 240 mg at Week 0 and 2, followed by maintenance treatment (120 mg every other week). We analysed diary PRO-2 entries (stool frequency and abdominal pain) through 14 days from the first injections of SC IFX. CDAI was assessed at Week 0, 2, 4 and 8. Changes in biochemical parameters were assessed (C-reactive protein [CRP]: Week 4 and 8; faecal calprotectin [FC] at Week 8). Combined corticosteroid-free remission (CSFR) was defined as CDAI<150 and CRP≤5 mg/L or FC≤250 mg/kg and complete tapering of corticosteroids.

Results

Twenty-five patients completed 8 weeks of treatment (60% female, median age 30 years [IQR 24-45], median weight 66.6 kg [IQR 64.0-89.5], median disease duration 4 years [IQR 1-8], 64% had ileocolonic disease [L3] and 76% exhibited an inflammatory phenotype [B1], 52% were using concomitant immunomodulators, and 28% were on stable dose of steroids). On the first day after the initial dose of SC IFX (240 mg), a significant decrease in PRO-2 was observed compared to baseline (5 [IQR 3-9] vs 8 [IQR 7-10], P<0.001) and this response was sustained throughout day 14 (P<0.001, Figure 1). At all measured time points, CDAI decreased significantly compared to baseline (Week 0: 313 [IQR 271-402]; Week 2: 245 [IQR 140-296], P<0.001; Week 4: 218 [101-258], P<0.001; Week 8: 172 [127-260], P<0.001). Combined CSFR was reached in 30% and 57% of all patients at Week 4 and 8, respectively. Median CRP was lower at Week 4 compared to baseline CRP (2.8 mg/L [IQR 0.7-4.9] vs 7.1 mg/L [IQR 2.1-26.3], P=0.001), a significant drop of FC was observed at Week 8 compared to baseline (77 mg/kg [IQR 37-847] vs 1385 mg/kg [IQR 219-3093], P<0.001).

Conclusion

Induction treatment with SC IFX provided a rapid decrease of abdominal pain and diarrhoea as early as day one. CDAI, CRP and FC decreased significantly at the earliest time point of evaluation (Week 2-8). DIRECT-CD is an ongoing clinical trial.
P932 Corticosteroid-sparing effect of mirikizumab for the treatment of moderately-to-severely active Ulcerative Colitis: Extended induction subgroup analysis from Phase 3 trial
Authors: Laharie D , Siegel C , Dulai P , Matsuoka K , Gisbert J , Samaan K , Redondo I , Baygani S , Paulissen J , Jairath V
Published: January 2024

Background

Mirikizumab, an anti-IL-23p19 antibody, has demonstrated efficacy and safety in moderately-to-severely active ulcerative colitis (UC) Phase 3 trials (LUCENT-1 and -2; NCT03518086, NCT03524092).1 A treatment goal for patients with UC is corticosteroid (CS)-free remission. We assessed the CS-sparing effect of mirikizumab among the extended induction patient population receiving CS at induction baseline.

Methods

In LUCENT-1, patients in the modified intention to treat mirikizumab group (n=868) received mirikizumab 300 mg intravenously (IV) at Week (W)0, W4, and W8. Patients receiving mirikizumab on CS at baseline (n=351) remained on their stable baseline dose (prednisone ≤20 mg/day or equivalent, budesonide MMX 9 mg/day, or beclomethasone 5 mg/day) during induction (W0 to W12). Patients not achieving clinical response (≥2-point and ≥30% decrease in Modified Mayo Score from baseline; and rectal bleeding=0 or 1, or ≥1-point decrease from baseline) at W12 (n=272) entered LUCENT-2 open label (OL) extended induction and received 300 mg mirikizumab IV at W12, W16, and W20. Extended induction responders at W24 (n=144) entered OL maintenance and received 200mg mirikizumab subcutaneously (SC) Q4W until W52. CS taper was initiated if clinical response was achieved at W24 or earlier based on investigator discretion if symptomatic improvement was evident. Patients who discontinued CS and remained off throughout the study were considered "discontinued." Descriptive statistics for efficacy outcomes were summarized. Missing data were imputed as non-response.

Results

Of the 272 mirikizumab patients in the extended induction population, 118 received CS at induction baseline. The mean prednisone equivalent dose was 15mg. At W24, among the 62/118 (52.5%) who achieved clinical response and continued with maintenance, 8 (12.9%) discontinued CS, 2 (3.2%) achieved clinical remission off CS, and 8 (12.9%) achieved symptomatic remission off CS. At W52, 43/62 (69.4%) of the extended induction responders discontinued CS, 18 (29.0%) achieved clinical remission off CS, and 37 (59.7%) achieved symptomatic remission off CS. Among patients with non-missing data who completed W52 of mirikizumab treatment, 89.6% had discontinued CS (Table).

Conclusion

Nearly 70% of extended induction responders discontinued CS by W52. CS-sparing effect of mirikizumab in patients with moderately-to-severely active UC is clinically meaningful and aligns with the treatment goal of CS discontinuation.

References:

1. D’Haens G, et al. N Engl J Med 2023;388(26):2444-2455.
P936 Ultrasound Transmural Remission in Crohn's disease: Different Rate between First and Second Line of Biological Therapy
Authors: De Sire R , Rispo A , Caiazzo A , Cantisani N , Calabrese G , Guarino A , Testa A , Nardone O M , Castiglione F
Published: January 2024

Background

Ultrasound transmural remission in Crohn’s disease (CD) has been associated with improved long-term clinical outcomes including reduced hospitalization, surgery, escalation of treatment, and a decrease in clinical relapse over endoscopic remission alone. Albeit transmural remission rate (TRR) in CD patients treated with anti-TNF drugs in first line has been well explored, data on TRR using vedolizumab (VDZ) or ustekinumab (UST) as second-line therapy for CD are still limited. The aim of this study was to evaluate the TRR in CD patients in maintenance treatment, comparing adalimumab (ADA) in first line with VDZ/UST in second line.

Methods

From 2018 to 2022 we performed a real world observational longitudinal study evaluating the TRR in all consecutive CD patients in a 2-years maintenance treatment with ADA in first line compared with those treated by VDZ or UST in second line. HBI, fecal calprotectin (FC), SES-CD, and bowel wall thickness (BWT) at ultrasound were analyzed in all patients at the baseline (T0) and after 2 years of maintenance treatment (T1). Clinical remission was defined when HBI was <4. Endoscopic remission was defined when SES-CD was <2. Transmural remission was defined when BWT was <3 mm at a "per-patient" analysis. In accordance with recent literature, laboratory remission was defined when FC was <94 ug/gr.

Results

One hundred and sixty-one CD patients (78 ADA, 41 VDZ, 42 UST) were included in the study. At T1, TRR was recorded in 39.7% of CD patients treated in first line with ADA, and in 17.1% and 21.4% for VDZ and UST, respectively, in second line (ADA vs VDZ/UST: p<0.05; VDZ vs UST: p 0.6). Endoscopic remission rate was 50% for patients treated in first line with ADA, and 31.7% and 35.7% for second line VDZ and UST, respectively (ADA vs VDZ/UST: p<0.05; VDZ vs UST: p 0.7). Laboratory remission rate was 53.8% for patients treated in first line with ADA, and 29.3% and 35.7% for VDZ and UST in second line, respectively (ADA vs VDZ/UST: p<0.05; VDZ vs UST: p=0.5). Clinical remission rate was 58.9% for patients treated in first line with ADA, and 43.9% and 47.6% for second line VDZ and UST, respectively (ADA vs VDZ/UST: p=0.09; VDZ vs UST: p=0.2).

Conclusion

Our findings showed that in CD patients in maintenance treatment with biologics, ADA in first line showed a higher TRR compared with VDZ/UST in second line. Moreover, VDZ and UST showed similar TRR and other outcomes when used in second line.
P940 A glance into paediatric Inflammatory Bowel Disease in Australasia – Crohn’s Colitis Cure (CCC) data insights program
Authors: Pipicella J L , Dutt S , Giles E , Day A S , Wright R , Goodfellow T , William W , Andrews J M , Connor S J
Published: January 2024

Background

Around 10% of people with inflammatory bowel diseases (IBD) are diagnosed in childhood1. Clinical manifestations are known to differ in children compared to adults2,3. This study aims to describe the real-world characteristics of children with IBD.

Methods

Crohn’s Colitis Care (CCCare) is an IBD-specific electronic medical record (EMR) used at IBD centres across Australasia. Data feed into a de-identified clinical quality registry (CQR), which was interrogated in November 2023. All children (<18 years at time of extract) under active care (encounter within 14 months) were included.

Results

Clinical data from 162 children across 14 centres were available for analysis. Of these, 64.8% (n=105) had Crohn’s disease (CD), 31.5% (n=51) ulcerative colitis (UC) and 3.7% (n=6) IBD-unclassified. There was a roughly equal split in gender (male=55.0%), with a minority aged <10 years (9.9%, n=16). The mean recorded body mass index was 20.5kg/m2 (n=101 with BMI data), with 78.2% in the ‘normal’ range (18.5-24.9kg/m2). Five patients (5.0%) were ‘underweight’ (<18kg/m2), and 16.8% (n=17) were overweight or obese (>25kg/m2).

Only 7.4% (n=12) were currently receiving steroids, and over half (55.6%, n=90) had received an advanced therapy (biologic or small molecule). Few reported incontinence (n=5, 3.1%), and 6% (n=9) had an IBD-related surgery recorded. Around 20% (11/56) had current or previous fistulising CD. On most recent data, the mean faecal calprotectin was 637μg/g, C-reactive protein 6.1mg/L and ESR 9.4mm/hr. In those with UC, 43.7% had either moderate (S2) or severe (S3) disease activity at last assessment (Figure 1). In those with CD, 31.1% had either stricturing (B2, 21.5%) or penetrating intra-abdominal disease (abscess/perforation/phlegmon, B3, 10.6%).

Conclusion

This study provides a detailed real-world overview of IBD in children in Australasia, demonstrating the ability of CCCare to help collate data at scale across a large geography. Data show clear changes in phenotype over time. Such data allow for the tracking and benchmarking of outcomes over time across centres, thus promoting evidence-based care improvements. Ongoing real-world data collection is crucial in optimising management strategies and improving care outcomes.

1 - Burgess CJ et al. Paediatric Patients (Less Than Age of 17 Years) Account for Less Than 1.5% of All Prevalent Inflammatory Bowel Disease Cases. J Pediatr Gastroenterol Nutr. doi: 10.1097/MPG.0000000000002842.

2 - Seyedian SS et al. A review of the diagnosis, prevention, and treatment methods of inflammatory bowel disease. J Med Life. doi:10.25122/jml-2018-0075

3 - Moon JS. Clinical Aspects and Treatments for Pediatric Inflammatory Bowel Diseases. Pediatr Gastroenterol Hepatol Nutr. doi:10.5223/pghn.2019.22.1.50
P967 Allogeneic bone marrow-derived mesenchymal stromal cell therapy for complex perianal and rectovaginal fistulas in Crohn´s disease: a retrospective single-centre study
Authors: Husman J , Wardenga M , Kirk S H , Matthes K , Naumann B , Dobroschke J , Nebelung H , Plodeck V , Krech M , Bornhäuser M , Hampe J , Zeissig S , Schmelz R
Published: January 2024

Background

Perianal fistulising Crohn´s disease (CD) is associated with a high burden of disease and treatment of fistulas remains challenging. Promising data on short-term efficacy of bone marrow-derived mesenchymal stromal cell (bmMSC) treatment emerged in the recent past, but there is limited data regarding long-term efficacy and safety.

Methods

Between February 2013 and January 2016, patients with non-active CD (Harvey-Bradshaw Index < 5) and draining complex, treatment-refractory perianal or rectovaginal fistulas underwent local bmMSC therapy as compassionate use. After curettage of the fistula tract, patients received three local bmMSC injections biweekly with 20 million cells each. In case of incomplete clinical and radiological healing 3 to 12 months after the first treatment, up to six additional injections with 40 million cells each were administrated, resulting in a maximal cumulative dose of 300 million bmMSC (table 1). We retrospectively analysed patient records for disease course and documentation of adverse events. Clinical remission was defined by closure of external fistula openings without discharge at digital pressure. The modified Van Assche index was assessed before bmMSC treatment as well as in short- and long-term MRI follow-up.

Results

Six female patients (median age 35 years, range 19 – 46 years) with two or three complex fistulas each were included. In total, 13 fistulas (9 transsphincteric, 2 extrasphincteric and 2 rectovaginal) underwent local bmMSC application (table 1). Median radiological and clinical follow up was 80 months (range, 44 – 98 months) after first local bmMSC injection. 8 of 13 fistulas (62%) exhibited complete closure at last observation. For rectovaginal fistulas, long-term remission was 50 % (1 of 2). Excluding rectovaginal fistulas, 4 of 6 patients (67%) showed long-term closure of all other fistulas. Pelvic MRI showed a decrease in modified Van Assche index from baseline (median score 7.8, range 6.2-9.7) to long-term follow up (median score 2.1, range 1.5-11.7). No immediate adverse events related to bmMSC injections were observed. One patient (p1) was diagnosed with a local adenocarcinoma of the rectum (pT1, pN0, R0) 106 months after first bmMSC injection. MRI control 11 months prior showed complete fistula remission. The tumor exhibited a female karyotype, while bmMSC had been derived from a male volunteer.

Conclusion

More than 60% of all treatment-refractory CD perianal fistulas showed long-term remission up to 8 years after local allogenic bmMSC therapy.