bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract

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

Abstract

Background
OPTIC was a prospective placebo-controlled trial investigating therapeutic drug monitoring (TDM)-based mercaptopurine (MP) therapy in ulcerative colitis (UC). Although the primary endpoint (corticosteroid-free clinical remission and endoscopic improvement at week 52) favoured patients with TDM-based MP therapy over placebo, drug-related adverse events were frequent and drop-out rates high. This post-hoc analysis was carried out to show the therapeutic implications of proactive TDM of MP.

Methods
UC patients with active disease, despite ≥2 g/day mesalamine, underwent remission induction treatment with corticosteroids and initiated weight-based MP therapy (1-1.5 mg/kg). TDM based optimisations were performed at week 6, 12, 18, 24, 36 and 52 using the Dervieux method, unblinded non-including thiopurine expert physicians (DA, MD and AB) provided dosing advice according to a predefined algorithm, aiming for 6-TGN levels of 600-1200 pmol/8×108 RBC and 6-MMP of &lt;5700 pmol/8×108 RBC. Associations between 6-TGN and 6-MMP levels, MP dose and thiopurine S-methyltransferase (TPMT) polymorphisms were explored.

Results
In total, 29 patients initiated MP treatment (41% female, median age 46 yrs [IQR 26-58], median disease duration 6 yrs [IQR 1-14]). TPMT heterozygosity was found in 4/29 patients (3/4 TPMT*3A, 1/4 TPMT*3C). TDM dose adjustments were required in 22/29 patients: 14/29 started allopurinol and decreased MP dose, 5/29 discontinued MP before the first TDM assessment, 2/29 continued MP at the initial dose up until week 52 and the remaining underwent MP dose adjustments. Most adjustments (71%) were made at week 6, thereafter 6-MMP levels stabilised, while 6-TGN concentrations remained stable (Figure 1). TPMT variant carriers had a higher median 6-TGN concentration compared to non-carriers (1700 [IQR 1625-1850] vs 539 pmol/8×108 RBC [IQR 355-953], P&lt;0.001) and more likely to have leukopenia (P=0.025). Two TPMT heterozygous patients achieved the primary endpoint with dose reductions, two discontinued due to myelotoxicity or hepatotoxicity. Until week 52, 16/29 patients completed the trial, 14/29 reached the endpoint with a median 6-TGN of 585 pmol/8×108 RBC (IQR 428-745) and 6-MMP of 268 pmol/8×108 RBC (IQR 110-1257). MP dose correlated with 6-MMP but not with 6-TGN levels. Independently of allopurinol co-prescription, the initial median weight-based MP dose of 100 mg (IQR 75-125) decreased significantly to 50 mg (IQR 25-100, P=0.041).

Conclusion
Most patients underwent TDM optimisation of MP, half of the patients initiated allopurinol with decreased MP dose. TPMT heterozygosity led to supratherapeutic 6-TGN concentrations and adverse events. Weight-based initial MP dose may need reconsideration.
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

Abstract

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

Abstract

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]) &gt;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&lt;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&lt;0.001) and this response was sustained throughout day 14 (P&lt;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&lt;0.001; Week 4: 218 [101-258], P&lt;0.001; Week 8: 172 [127-260], P&lt;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&lt;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

Abstract

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

Abstract

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 &lt;4. Endoscopic remission was defined when SES-CD was &lt;2. Transmural remission was defined when BWT was &lt;3 mm at a "per-patient" analysis. In accordance with recent literature, laboratory remission was defined when FC was &lt;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&lt;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&lt;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&lt;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

Abstract

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 (&lt;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 &lt;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’ (&lt;18kg/m2), and 16.8% (n=17) were overweight or obese (&gt;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

Abstract

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 &lt; 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.