Refractory Crohn's Disease Research Articles

839 Refractory Crohn's disease in a pediatric patient with xiap deficiency: a case highlighting the intersection of ibd and immune dysregulation

839 Refractory Crohn's disease in a pediatric patient with xiap deficiency: a case highlighting the intersection of ibd and immune dysregulation

Combination vedolizumab and ustekinumab for refractory Crohn's disease after immune checkpoint inhibitors.

Combination vedolizumab and ustekinumab for refractory Crohn's disease after immune checkpoint inhibitors.

Circulating and Magnetic Resonance Imaging Biomarkers of Intestinal Fibrosis in Small Bowel Crohn's Disease.

We previously identified circulating and MRI biomarkers associated with the surgical management of Crohn's disease (CD). Here we tested associations between these biomarkers and ileal resection inflammation and collagen content. Fifty CD patients undergoing ileal resection were prospectively enrolled at 4 centers. Circulating CD64, extracellular matrix protein 1 (ECM1), GM-CSF autoantibodies (GM-CSF Ab), and fecal calprotectin were measured by ELISA. Ileal 3-dimensional magnetization transfer ratio (3D MTR), modified Look-Locker inversion recovery (MOLLI) T1 relaxation, diffusion-weighted intravoxel incoherent motion (IVIM), and the simplified magnetic resonance index of activity (sMaRIA) were measured by MRI. Ileal resection specimen acute inflammation was graded, and collagen content was measured quantitatively using second harmonic imaging microscopy. Associations between biomarkers and ileal collagen content were tested. Median (interquartile range [IQR]) age was 19.5 (16-33) years. We observed an inverse relationship between ileal acute inflammation and collagen content (r = -0.39 [95% confidence interval {CI}: -0.61, -0.10], P = .008). Most patients (33 [66%]) received biologics, with no variation in collagen content with treatment exposures. In the univariate analysis, CD64, GM-CSF Ab, fecal calprotectin, and sMaRIA were positively associated with acute inflammation and negatively associated with collagen content (P < .1). The multivariable model for ileal collagen content (R2 = 0.31 [95% CI: 0.11, 0.52]) included log CD64 (β = -.27; P = .19), log ECM1 (β = .47; P = .06), log GM-CSF Ab (β = -.15; P = .01), IVIM f (β = .29, P = .10), and IVIM D* (β = 1.69, P = .13). Clinically available and exploratory circulating and MRI biomarkers are associated with the degree of inflammation versus fibrosis in CD ileal resections. With further validation, these biomarkers may be used to guide medical and surgical decision-making for refractory CD.

P1191 Early Clinical, Biological, and Sonographic Response in Ileal Crohn’s Disease Patients Treated with Upadacitinib: A Single-Centre Real-World Experience

Abstract Background Upadacitinib (UPA), a selective JAK1 inhibitor, has shown efficacy in moderate-to-severe Crohn’s disease (CD), even in patients refractory to advanced therapies. This study aimed to evaluate the effectiveness, safety, and durability of UPA in refractory CD in real-world settings, with a focus on early objective assessment using biological markers and intestinal ultrasound (IUS). Methods A retrospective analysis was conducted on 41 CD patients (61% male, median age 40 years [SD: 33–53], mean disease duration 11 years [SD: 6–17]). Disease characteristics and prior treatments, including anti-TNF (100%), ustekinumab (70.7%), vedolizumab (19.5%), and risankizumab (9.8%), were recorded. Clinical (Harvey-Bradshaw Index [HBI]), biological (C-reactive protein [CRP], fecal calprotectin [FCP]), and IUS parameters (wall thickness, affected segment length, Limberg score) were assessed at 1, 2, 3, 6, and 12 months. Median follow-up was 8.2 months (SD: 4.8–12.3). Treatment patterns included standard induction (46.3%), extended induction (29.3%), and sustained high-dose (24.4%). Results Clinical response (≥2-point HBI reduction) was significant from week 4 and sustained throughout follow-up. Baseline CRP was 0.60 mg/dL (SD: 0.28–1.30), decreasing to 0.30 (SD: 0.05–0.80) at 1 month, 0.14 (SD: 0.04–0.64) at 3 months, and 0.10 (SD: 0.04–0.42) at 12 months, showing a non-significant downward trend. FCP dropped from 860 µg/g (SD: 270–1700) to 506 (SD: 186–2343) at 1 month, 260 (SD: 121–1200) at 3 months, and 205 (SD: 120–382) at 12 months, with a similar non-significant trend. Of 31 patients with baseline IUS, 55.6% showed radiological improvement in at least two IUS parameters at 12 months, though not statistically significant. Nine patients (22%) discontinued UPA due to adverse events (7.3%) or lack of response (17%). Non-severe adverse effects were reported in 53.7%, predominantly dermatological, without requiring dose adjustments or discontinuation. No severe infections, thromboembolic events, or cardiovascular complications were observed. Conclusion UPA demonstrated rapid, effective, and safe treatment for refractory CD in clinical practice. Trends toward early clinical, biological, and sonographic improvements were observed, highlighting its potential in real-world management of refractory CD.

P1056 Effectiveness and Safety of Upadacitinib Induction Therapy in Real-World Setting for 234 Patients with Crohn’s Disease: A GETAID Multicentre Cohort Study

Abstract Background While upadacitinib has demonstrated its efficacy as an induction treatment for Crohn’s disease (CD) in two phase 3 randomized, placebo-controlled trials1, real-world data remain limited. Methods From September 2022 to September 2024, all consecutive patients with refractory CD treated with once-daily upadacitinib 45 mg in 30 French and Belgian GETAID centres were retrospectively included. The primary endpoint was steroid-free clinical remission (SFCR) at week 12, defined as a Harvey-Bradshaw Index (HBI) score of &amp;lt; 4. Secondary endpoints included clinical response (decrease of ≥ 3 points in the HBI score and/or an HBI score &amp;lt; 4), clinical remission, biological remission (calprotectin ≤ 250 µg/g, or CRP ≤ 5 if calprotectin was unavailable), endoscopic or radiological (IUS and/or MRI) response, and adverse events (AEs). Results 234 patients were included, all of whom had been previously exposed to at least one biologic (median 4, IQR[3-4]), and 125 (53.9%) had undergone prior intestinal resection (Table 1). At week 12, SFCR was observed in 107 patients (n=107/197, 54%), clinical response in 120 (n=120/190, 63%) and clinical remission in 111 (n=111/197, 56%). Ninety-two (n=92/179, 51%) achieved biological remission and endoscopic or radiological response was observed in 19 (n=19/40, 48%) patients (Figure 1). Respectively 28 (n=28/37, 76%) and 20 (n=20/37, 54%) of patients with articular EIMs achieved clinical response and remission. For cutaneous EIM, clinical response was achieved in 10 patients (n=10/11, 91%), and clinical remission was achieved in nine patients (n=9/11, 82%). In multivariate analysis, body mass index &amp;lt; 18.5 kg/m2 (OR=0.09, 95%CI: 0.01-0.33, p=0.002) and HBI &amp;gt; 7 (OR=0.24, 95%CI: 0.12-0.47, p&amp;lt;0.0001) were associated with lower rates of SFCR at W12 while the number of prior biologics did not influence SFCR (OR = 0.72, 95% CI: 0.35-1.48; p = 0.36). At week 12, 35 (15%) patients discontinued upadacitinib (lack of effectiveness, n=31; AEs, n=2 and other, n=2). CD-related hospitalization was needed in 18 (7.7%) patients, and 4 (1.7%) underwent intestinal resection. Sixty-eight AEs occurred in 61 patients (26%), including 19 serious AEs, corresponding to 18 cases of CD exacerbation and one case of colonic EBV-associated lymphoproliferative disorder. Acne was observed in 25 (10.7%), justifying treatment discontinuation in one (0.4%). Conclusion In this real-world cohort of highly refractory CD patients, upadacitinib induction resulted in a clinical response in about two-thirds of patients and SFCR in half of patients.

DOP095 IL-23-activated cells as response biomarkers for risankizumab in Crohn’s disease patients

Abstract Background The interleukin (IL)-23 signaling is a vital pathway in Crohn’s disease (CD). IL-23 activates T-helper (Th) 17 cells, IL-17-secreting CD8 T (Tc)17 cells, γδ T cells, natural killer (NK) T cells, and group 3 innate lymphoid cells (ILC3) to secrete inflammatory cytokines including IL-17, IFN-γ, and TNF-α. Risankizumab is the first selective IL-23 antagonist approved for moderate-to-severe CD; however, no biomarker currently exists to predict response to this medication. Here, we characterized the phenotypes of IL-23-activated cells that predict response to risankizumab in CD patients. Methods Adult patients with active ileal/colonic CD were included (n = 28). Blood samples were collected before and after initiation of risankizumab. Peripheral blood mononuclear cells (PBMC) were isolated and cryopreserved for batch analysis. After stimulation with IL-23, PBMCs were stained using a pre-optimized and validated antibody panel for 37 lineage markers and cytokines for CyTOF. Cell clusters were resolved using UMAP (Figure 1), opt-SNE and FlowJo. Patients’ responses were evaluated 12-40 weeks after initiation of risankizumab based on clinical symptoms (e.g., CDAI) and endoscopic/radiographic assessment. Results Among the IL-23-activated cells, increased frequency of NKT cells was identified in the peripheral blood of non-responders before initiation of risankizumab (not shown). In pre-risankizumab PBMCs, we identified significantly elevated TNF-α in Th17 cells, Tc17 cells, NKT cells, and MAIT cells in non-responders vs. responders (Figure 2A). Similarly, in PBMCs 4 weeks after 1st risankizumab infusion, Tc17 cells, γδ T cells, NKT cells, and MAIT cells in non-responders produced significantly more TNF-α compared to those cells from responders. In addition, we observed increased IL-17A in multiple IL-23-activated cells in non-responders 4 weeks after starting risankizumab (Figure 2B). Peripheral and mucosal IL-23-activated cells from later non-responders before and 4 weeks after treatment spontaneously secreted TNF-α and IL-17A without stimulation. A similar correlation between therapeutic response and expression of TNF-α or IL-17A was not observed in ustekinumab, an anti-IL-12/IL-23 antibody (not shown). Conclusion CyTOF of patients’ PBMCs before and after starting risankizumab revealed previously unknown molecular signatures, especially augmented TNF-a production in multiple IL-23-activated cells, which predict non-response to risankizumab in CD patients. Those findings identified a novel mechanism of anti-IL-23 resistance, may help identify response biomarkers for IL-23 antagonists and provide a rationale for anti-IL-23/anti-TNF combination therapy in a subset of patients with refractory CD.

P0931 Induction treatment with upadacitinib is associated with high rate of clinical response in patients with refractory Inflammatory Bowel Disease

Abstract Background Upadacitinib is an oral selective Janus kinase-1 (JAK1) inhibitor, that has been approved for the treatment of moderate to severe Ulcerative Colitis (UC) and Crohn’s Disease (CD). The recommended induction dose is 45 mg once daily for 8 weeks for UC and 12 weeks for CD, followed, thereafter, by a maintenance dose of 15 mg or 30mg (for patients with refractory, severe or extensive disease). Our study aims to capture the experience of two tertiary centers on upadacitinib use in refractory UC and CD. Methods This is an ongoing, prospective cohort study. Demographic and disease-related data were collected at baseline. Our primary endpoint is clinical response (CR) at the end of induction, defined as &amp;gt;50% decrease in Patient Reported Outcomes (PROs) and secondary endpoints were steroid-free clinical remission (sf-CRem) and treatment persistence. SPSS23 was used for the statistical analysis. Results The baseline characteristics of our patients are presented in Table 1. At drug initiation, 35.4% were receiving concomitant corticosteroids. The induction period has been concluded by 23/26 patients with UC and 17/21 patients with CD, of whom 22 (95.7%) and 13 (76.5%) respectively commenced maintenance treatment. The primary endpoint of CR was achieved by 19 out of 20 (95%) patients with clinically active UC and 11 out of 16 (68.8%) patients with clinically active CD at baseline. Sf-CRem was achieved by 21/23 (91.3%) patients with UC and 13/17 (76.5%) with CD. The majority of patients with either UC (86.4%) or CD (84.6%) commenced maintenance therapy with a 30 mg dose. Adverse events occurred in 22.9% of patients in our cohort, with acne being the most frequently reported (12.5%). One patient (2.1%) experienced herpes simplex infection and two (4.2%) an increase in their lipid levels, requiring initiation of antihyperlipidemic therapy. No serious adverse events have been reported. Conclusion In our cohort of patients with Inflammatory Bowel Disease who were refractory to multiple advanced treatments, upadacitinib has been shown to be an effective and safe therapeutic option for induction of remission. Most patients with medically refractory IBD in our cohort have received increased maintenance Upadacitinib dosage.

DOP055 Upadacitinib for induction of remission in pediatric Crohn’s disease: An international multicenter study

Abstract Background Data on upadacitinib therapy in children with Crohn’s disease (CD) are scarce. We aimed to evaluate the effectiveness and safety of upadacitinib as an induction therapy in pediatric CD. Methods A multicenter retrospective study of children treated with upadacitinib for the induction of remission of active CD from 30 centers worldwide affiliated with the IBD Interest and Porto group of the ESPGHAN between 2022 and 2024. Demographic, clinical, laboratory, and imaging data as well as adverse events (AEs) were recorded at week 8 post induction. The analysis of the primary outcome was based upon the intention-to-treat (ITT) principle. Results One-hundred children (median age 15.8 [interquartile range 14.3–17.2] years) were included. All children were previously treated with biologic therapies and 89 with ≥2 biologics. At the end of the 8-week induction period, clinical response, clinical remission and corticosteroid- and exclusive enteral nutrition-free clinical remission (CFR) were observed in 75%, 56% and 52% of the children, respectively. Normal C-reactive protein was achieved in 68% of the children and fecal calprotectin (FC) &amp;lt;150 mcg/g in 58%. Combined CFR and FC remission was observed in 13/31 (42%) children with available data at 8 weeks [13% of the ITT population]. AEs were recorded in 24 children, the most frequent was acne (n=12). Two AEs (severe acne and hypertriglyceridemia) led to discontinuation of therapy. Conclusion Upadacitinib is an effective induction therapy for refractory pediatric CD. Efficacy should be weighed against the potential risks of AEs.

P1115 Short- and Mid-term Effectiveness and Safety of Risankizumab in Refractory Crohn’s Disease: A Retrospective Study

Abstract Background Risankizumab (RSK) is the first anti-IL-23 drug approved in 2022 for moderate-to-severe Crohn’s disease (CD). Data on its real-world effectiveness and safety remain limited. This study assesses the short- and mid-term effectiveness of RSK and its safety profile in a clinical practice setting. Methods A retrospective analysis was conducted on patients with refractory luminal CD treated with RSK at our tertiary centre between March 2022 and July 2024 who completed induction therapy. The primary endpoint was clinical remission at weeks 12 and 24, assessed via the Physician Global Assessment (PGA) based on symptoms, laboratory data and endoscopy/imaging if available. Secondary endpoints included at least clinical response, steroid-free remission and response, adverse events, and drug persistence. Results Sixty-three patients were included (65% male, median age 31 years, median disease duration 9.8 years), with 95.2% previously exposed to anti-TNF, 82.5% to ustekinumab, and 52.4% to vedolizumab; 60% had prior exposure to three biologics, 25.4% to four, and 44% had undergone intestinal resection. Induction (600 mg) was administered intravenously in 88.9% of cases. At week 12, remission and at least partial response rates were 25.4 % and 76.2%, respectively, while steroid-free remission and response rates were 22% and 65.1%. By week 24, 35 patients remained in the study, achieving remission/response rates of 25.7% and 62.8%, respectively, and steroid-free rates of 18.2% and 48.5%. No significant differences were found regarding prior ustekinumab exposure or response/remission outcomes between weeks 12 and 24. RSK persistence was 93%, with four patients discontinuing due to nonresponse. Additionally, by week 24, four patients had required reinduction with 1200 mg administered intravenously. Three adverse events (headache, insomnia, arthralgia) were mild and did not require treatment discontinuation. Conclusion Risankizumab demonstrated encouraging effectiveness in treating refractory Crohn’s disease, achieving clinical responses and steroid-free remission in the short- to mid-term. High drug persistence and a favorable safety profile highlight its potential as a valuable treatment option in real-world settings.

P0087 Calprotectin contributes to refractory Crohn’s disease fistula through dysregulation of epithelial wound healing responses

Abstract Background Refractory perianal fistula in Crohn’s disease (CD) still present an unmet clinical need with a high disease burden. Despite increasing interest, pathophysiology leading to the refractory phenotype remains unclear, with only epithelial-to-mesenchymal-transitioning (EMT) commonly mentioned as a contributing factor. Using a systematic approach comparing therapy refractory CD fistula, therapy responsive non-IBD fistula and normal rectum, we aimed to differentiate between general healing responses and dysregulation thereof in refractory CD fistula. Methods Total RNASeq (n=51), single cell RNASeq (n=31) and spatial transcriptomic (n=8) analysis were performed on the internal opening and tract of CD fistula and idiopathic fistula. Results were validated using immunohistochemistry. Functional studies were performed in human adult organoid cultures and intestinal cell lines. Results In the fistula tracts we identified development of a squamous epithelium characterized by expression of WFDC2, keratin 5 and keratin 13. Although some EMT markers were expressed in the squamous epithelium or its intermediates, no activation of a complete EMT program could be detected in any of the tissue types, regardless of the underlying diagnosis. Upstream analysis indicated TNFα, IL6 and TGFβ as inducers of WFDC2+ epithelium, and human adult colon organoids stimulated with these cytokines (but not TGFβ alone) indeed showed a transciptional profile similar to the fistula epithelium, confirming redifferentiation potential. While WFDC2+ epithelium did occur in CD fistula, abundance was strongly decreased compared to non-IBD fistula. In addition, those WFDC2+ cells present had a more pro-inflammatory profile and were morphologically disorganized. Surprisingly, pseudotime analysis indicated epithelial calprotectin (S100A8/9) as a key factor in the aberrant development of WFDC2+ tissue in CD. Normal intestinal epithelium does not express calprotectin, but a mix of cytokines present in fistula induced clear intracellular expression of S100A8/9 in both epithelial cell lines and primary colon organoids. In CD fistula, calprotectin expression was particularly intranuclear, suggesting a transcriptional role. CHIP analysis indeed showed binding of calprotectin to various inflammatory genes and knockdown of calprotectin abrogated expression of these genes supporting a crucial regulatory role. Conclusion These data identify redifferentiation of rectal mucosa to a squamous phenotype as a normal damage response during fistula formation. However, in CD patients, transcriptional effects of calprotectin derail this process, resulting in disorganized inflammatory tissue not amenable for surgical closure and contributing to refractory disease.

P0949 Long term real-world effectiveness and safety of upadacitinib in patients with moderate to severe Crohn’s disease: A Belgian multi-centric refractory cohort

Abstract Background The therapeutic options for Inflammatory Bowel Disease (IBD) have expanded with the introduction of JAK inhibitors. However, real-world data on upadacitinib (UPA) in patients with moderate to severe Crohn’s disease (CD) are scarce. Our aim was to assess the long-term effectiveness and safety of UPA in multi-refractory Belgian patients. Methods Data from all patients with active CD initiating UPA between September 2022 and January 2024 were retrospectively collected from 17 Belgian centres. Effectiveness endpoints were evaluated at week 24 and 52. Steroid-free clinical response and remission were defined using the two-component patient-reported outcome. Endoscopic response was defined as a decrease in baseline Simple Endoscopic Score (SES-CD) with ≥50%, and endoscopic remission as SES- CD ≤ 4 or absence of ulcers. Adverse events (AE), treatment discontinuation, CD-related hospitalization and surgery were assessed throughout follow-up. Non-response imputation was applied for clinical evaluation. Results A total of 140 patients were included (Table 1) with a median follow-up of 33 weeks (IQR: 3-97). The majority of patients (89%) were exposed to at least 3 biologics. At week 24, 53% and 40% of patients achieved steroid-free clinical response and remission, respectively (Figure 1). At week 52, these numbers were 37% and 29%. Endoscopic data were available in 48/140 patients at week 24, of whom 52% and 27% reached endoscopic response and remission. At week 52, these numbers were 63% and 37%. Of patients with active articular extra-intestinal manifestations at baseline 37% and 34% had a quiescent articular disease by week 24 and 52, respectively. 5 out of 9 patients with active perianal disease at baseline and on UPA by week 52, had persistent perianal active disease. Overall, 66 patients (47%) discontinued UPA during follow-up: 23 due to primary non response, 13 due to secondary loss of response, 16 due to AE, 3 due to patient’s choice and 11 due to CD-related surgery. 16 patients required CD-related hospitalization within 52 weeks. AE occurred in 60% of patients (84/140). Of these patients, 11% experienced serious AE of which 2 cardiovascular events: 1 transit ischemic attack and 1 deep venous thrombosis. The most common reported AE were herpes simplex reactivation (5/140), respiratory tract infection (7/140), cutaneous reactions (7/140) and acne (17/140). Only 3 patients had reactivation of herpes zoster infection. Conclusion In this real-world cohort of highly refractory CD patients, UPA effectively induced both steroid-free clinical remission and endoscopic remission by week 52. UPA was relatively well tolerated with respect to adverse events.

P0832 Real-world effectiveness of risankizumab in Crohn’s Disease: The UK Experience

Abstract Background Risankizumab is an IL-23 inhibitor which received approval for Crohn’s disease (CD) by the NICE committee in May 2023. Our aim was to evaluate the real-world outcomes of risankizumab in the United Kingdom (UK). Methods We conducted a retrospective, multicentre, cohort study across twenty health boards in the UK, of patients with CD treated with risankizumab between the 1st of January, 2021 and the 1st of November 2024. Our primary outcome was treatment persistence at 6 months. Our secondary endpoints were treatment persistence, steroid-free clinical remission (Harvey-Bradshaw index &amp;lt;5), biomarker remission (CRP ≤5 mg/L and FCAL &amp;lt;250 µg/g), at 3, 6 and 12 months, and if effectiveness was different between ustekinumab naive and exposed patients. Patients who discontinued therapy for any reason were considered treatment-failure for all indices after the time point they ceased therapy. We recorded adverse events, including hospitalisation, bowel resection, infection, and death. Results We identified 558 patients who commenced risankizumab, of which 526 patients had 3 month outcome data available with a median follow-up time of 28 weeks (IQR, 19-41 weeks). The median number of advanced therapy exposures were 3 (2-4), with 90% (475/526) having failed anti-TNF therapy, and 73% (382/526) having failed ustekinumab (Table 1). Treatment persistence was 97.5%, 94.8% and 89.5% at 3, 6 and 12 months (Figure 1). Unadjusted persistence rates for ustekinumab naïve vs ustekinumab exposed patients were 93.8% vs 95.3% and 93.8 % vs 89.3% at 6 and 12 months respectively (p=0.7). Rates of clinical remission were 59% (211/358), 50% (77/154), and 44% (14/32) at 3, 6 and 12 months. Rates of clinical remission for ustekinumab naive vs exposed were 67% (70/104) vs 55% (141/253) and 60% (21/35) vs 47% (56/119) at 3 and 6 months respectively. CRP remission rates were 57% (266/465), 52% (108/208), and 53% (28/53) at 3, 6 and 12 months. FCAL remission rates were 58% (140/243), 48% (55/114), and 44% (17/38) at 3, 6 and 12 months. There was a significant reduction in median HBI, CRP and FCAL during follow-up (Figure 1). We observed that 12% (62) of patients were hospitalised due to symptomatic CD (58) or an implicated adverse event (4). We observed that 3% (17/526) underwent CD related resectional surgery. Adverse events occurred in 16% (85/526) of the cohort. Serious adverse events occurred in 5% (28/526), of which 25 were hospitalisations. Conclusion Risankizumab was effective in a large, real-world, medically refractory CD cohort with excellent short-term persistence and good clinical and biochemical remission rates. Persistence rates were similar between ustekinumab naive and exposed patients, however clinical remission rates were higher in the naive group.

P0780 Impact of Hyperbaric Oxygen Therapy on Perianal Fistulas in Crohn’s Disease: Clinical Outcomes and Remission Rates

Abstract Background Crohn's disease (CD) is a chronic inflammatory bowel disorder with debilitating complications such as perianal fistulas, affecting 14-38% of patients (1). Conventional treatments often achieve limited success, necessitating adjunctive approaches (2,3). Hyperbaric Oxygen Therapy (HBOT), known for its wound-healing and anti-inflammatory properties, has emerged as a potential therapy for complex CD cases (4,5). This study evaluates the efficacy of HBOT in combination with standard treatments for reducing perianal fistula activity and achieving clinical remission in patients with CD. Methods A cohort of 11 patients with CD-associated perianal fistulas underwent surgical preparation followed by 30 sessions of HBOT (2.5 ATA, 90 minutes per session). Disease activity was assessed using the Crohn’s Disease Activity Index (CDAI), Simple Endoscopic Score for Crohn’s Disease (SES-CD), Perianal Disease Activity Index (PDAI), and laboratory markers (CRP, fecal calprotectin, hemoglobin, and serum iron). Outcomes were evaluated at baseline, post-treatment (6 weeks), and follow-up (9 months). Results Clinical Improvement: 81.8% of patients demonstrated a significant reduction in CDAI scores. Remission Rates: 54.5% achieved remission (SES-CD, PDAI). 72.8% exhibited normalized fecal calprotectin levels (≤250 µg/g). Improvements were maintained 9 months post-treatment. Minimal side effects, including transient hearing impairment and headaches, were reported. Conclusion HBOT as an adjunctive therapy significantly improves clinical outcomes in CD patients with perianal fistulas. It enhances remission rates, reduces inflammation, and sustains benefits over long-term follow-up. This study highlights the potential of HBOT as a therapeutic option for refractory CD cases. Further randomized controlled trials are warranted to validate these findings.

P0587 Effectiveness and safety of Risankizumab in Crohn’s disease patients from a large Italian cohort: preliminary results from the RESOLVE IgIBD study

Abstract Background Risankizumab has been recently approved for the treatment of moderate-to-severe Crohn's disease (CD). It is a humanized IgG1 monoclonal antibody that binds to the p19 subunit of IL-23, selectively inhibiting IL-23. Due to the limited available real-world data on its effectiveness, this study aims to assess the short-term effectiveness and safety of risankizumab induction in a large, real-life Italian cohort of CD patients. Methods From September 2023, following AIFA reimbursement, until now, all consecutive CD patients treated with risankizumab in 14 Italian centers were retrospectively enrolled. Only patients who completed the induction phase of risankizumab, with at least a 12-weeks follow-up were included in the final analysis. Clinical characteristics, disease activity scores, steroid usage, and adverse effects were collected. The primary endpoint was steroid-free clinical remission (SFCR) (Harvey Bradshaw Index [HBI] &amp;lt;5) at 12 weeks. Secondary endpoints included clinical response (≥3 point decrease in HBI and/or HBI &amp;lt;5), biochemical remission (CRP≤ 5 mg/L), remission of extra-intestinal manifestations (EIMs), occurrence of disease complications, and adverse events. Results To date, 147 patients have been enrolled, with 67 completing the 12-week follow-up. Of these, 34 (50.7%) patients had received ≥3 biologics, and 38 (56.7%) had previous intestinal resections. Fifty-four patients underwent colonoscopy within the last 6 months before starting risankizumab, exhibiting a mean SES-CD of 10.9±6.0 and a mean Rutgeerts score of 3.1±1.4. The rates of SFCR and clinical response at week 12 were 58.2% (39/67) and 76.1% (51/67) respectively, while 53.7% (22/41) and 65.9% (27/41) in ustekinumab exposed patients. Fecal calprotectin levels decreased from 963.6±1346.0 to 311.8±403.0 at week 12. Thirty-eight patients (56.7%) achieved normal CRP levels at week 12. Clinical remission of rheumatological and dermatological EIMs was observed at week 12 in 16.7% (3/18) and 75.0% (6/8) of patients, respectively. Two patients developed disease complications, including one case of worsening of the disease and one of new fistula development. This latter patient discontinued treatment before week 12. Additionally, two patients (3.0%) experienced minor adverse events after risankizumab administration. No patients underwent surgery during the 12-weeks follow-up. Conclusion In a large cohort of refractory CD patients with multiple prior drug failures, including frequent failures with ustekinumab, nearly 60% achieved SFCR following risankizumab induction. Risankizumab demonstrated good effectiveness in managing dermatological EIMs, but less effectiveness in rheumatological EIMs. The safety profile of risankizumab was consistent with existing literature.

P0621 Effectiveness and Safety of Induction Therapy with Upadacitinib for the Treatment of Perianal Crohn’s Disease : Real-World Data from a GETAID Multicentre Cohort Study

Abstract Background Upadacitinib has demonstrated efficacy as an induction treatment for Crohn’s disease (CD)1, and a post hoc analysis of phase 3 randomized, placebo-controlled trials has shown its efficacy in perianal fistulizing CD (pCD)2. However, real-world data in this setting remain limited. Methods From September 2022 to September 2024, all consecutive patients with CD treated with once-daily upadacitinib 45 mg in 32 French and Belgian GETAID centres were retrospectively included. Clinical remission (absence of draining pus including with pressure for fistulas and no anal ulcers for primary lesions, as per local physician’s judgement, with no need for new dedicated medical treatment for perianal lesions (antibiotics and/or topics), or surgical treatment) and clinical response (an improvement of at least 50% of ulcers or fistulas by physician’s assessment) were assessed at week 12. Univariate and multivariable analyses were performed to identify predictors of clinical response. Results Among the 243 patients treated, 54 (22.2%) had active perianal Crohn’s disease (pCD) at the time of induction. This group included 43 patients (81.0%) with fistulizing disease and 11 (19.0%) with isolated anal ulcers. Median age was 38 (IQR, 29.0-45.8) years, 28 (51.9%) were men, and 9 (17.0%) were active smokers. All had been previously exposed to at least one advanced therapy (median number: 4, IQR [3-5]), and 25 (47.2%) had undergone prior perianal surgery (Table 1). By week 12, clinical response was achieved in 37 patients (68.5%, n=37/54), and clinical remission in 10 patients (n=10/54, 18.5%). Among patients with fistulizing pCD, 29 patients (67.4%, n=29/43) achieved clinical response, while 6 (14.0%, n=6/43) achieved remission. Among patients with primary perianal CD, complete remission of ulcers was observed in 4 (n=4/11, 36.4%) (Figure 1). In multivariate analysis, penetrating phenotype (OR=14.8, 95%CI: 1.6-381.9, p=0.04) was associated with higher rates of clinical response at W12 while the number of prior biologics did not influence clinical response (OR = 1.63, 95% CI: 0.47-5.79; p = 0.47). Fifteen adverse events (AEs) occurred in 13 (24.1%) patients, including 5 (9.3%) serious AEs, all 5 cases corresponding to CD exacerbation. At week 12, 7 (13%) patients discontinued upadacitinib, all due to lack of efficacy. Conclusion In this real-world cohort of highly refractory CD patients, upadacitinib induction resulted in a clinical response of perianal CD in two-third of patients.

Dual Biologic Therapy Induces Remission in Refractory Crohn's Disease With Vedolizumab and Ustekinumab.

Despite advancements in the therapeutic armamentarium for Crohn's disease (CD), biologic and small molecule monotherapies are associated with sub-optimal response and remission rates. Utilizing dual biologic therapy (DBT) holds the potential to increase efficacy in the treatment of refractory or partially responsive CD. Evidence pertaining to this strategy remains limited. We retrospectively examined refractory CD patients treated with a combination of ustekinumab and vedolizumab. Outcomes to DBT at week (wk) 52 were compared to monotherapy. The primary outcome constituted corticosteroid-free remission. Secondary outcomes included adverse events, infections, hospitalizations, surgeries, treatment persistence, and disease clearance. Sixteen of 21 active refractory CD patients (76%) on DBT achieved disease remission at wk 52. Mucosal healing was observed in 38% (n = 6), biochemical remission in 25% (n = 4), and both clinical and biochemical remission in 38% (n = 6). Of these patients, 50% (n = 8) achieved corticosteroid-free remission. Three patients (37.5%) with corticosteroid-free remission achieved complete disease clearance. Paired median fecal calprotectin decreased from 508 to 118 µg/g (P < .0001). Paired C-reactive protein median decreased from 1.04 to 0.50mg/dL (P < .0001). Median Harvey Bradshaw Index score reduced from 7 to 2 (P = .003). Endoscopic healing was achieved with a paired simple endoscopic score for CD decrease from 6 to 3 (P = .013). Corticosteroid dependency reduced from 17 to 8 patients discontinuing altogether. Patients still requiring corticosteroids experienced a decrease in average daily dose from 9 to 6mg (P = .045). At wk 52, 5 patients (24%) did not meet the criteria for remission with 4 requiring CD-related surgical intervention. Mean CD-related hospitalizations reduced from 2.95 ± 2.33 to 0.52 ± 1.12 (P < .001) and surgeries from 1.76 ± 1.3 to 0.14 ± 0.4 (P < .001). Three infections with 1 requiring hospitalization and 1 report of headache were noted. Two patients discontinued DBT. Dual biologic therapy with ustekinumab and vedolizumab is a safe and effective strategy to induce disease remission in refractory CD. Large-scale studies are necessary to validate findings in a prospective setting.

Managing Crohn's Disease Postoperative Recurrence Beyond Prophylaxis: A Comprehensive Review with Meta-Analysis.

Postoperative recurrence in Crohn's disease remains a significant clinical challenge, with high recurrence rates despite advancements in medical therapy. This study aims to evaluate the efficacy of various treatments for managing postoperative recurrence following ileocolonic resection in Crohn's disease. A comprehensive search of PubMed, Cochrane, and Scopus databases was performed to identify studies reporting on the therapeutic management of postoperative recurrence in Crohn's disease. Studies encompassing patients with an endoscopic Rutgeerts score of at least I2 were included. Ustekinumab showed promise, achieving significant endoscopic and clinical success in difficult-to-treat patients. Anti-TNF agents demonstrated superior endoscopic and clinical remission rates compared to mesalamine and azathioprine. Retreatment with anti-TNF therapy remained effective even after preoperative failure. Thalidomide showed efficacy in refractory Crohn's disease, but carries significant toxicity risks, necessitating careful patient selection and monitoring. Combination therapies and non-pharmacologic strategies like enteral nutrition offer additional options, though patient compliance remains challenging. Personalized treatment plans based on individual risk factors and biomarkers are crucial. Infliximab is recommended as the first-line treatment, with ustekinumab and vedolizumab as alternatives in case of anti-TNF failure or intolerance. Early intervention, patient education, and ongoing evaluation are essential for optimizing long-term outcomes in managing postoperative recurrence in Crohn's disease.

Hematopoietic stem cell transplantation therapy for refractory' Crohn disease: A systematic review and meta-analysis.

Despite the availability of numerous treatments for Crohn disease, there are patients who do not respond to any therapy, thereby diminishing their quality of life. The aim of this review is to analyze the efficacy and safety of autologous hematopoietic stem cell transplantation therapy for refractory Crohn disease. This work is a systematic review with meta-analysis conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analyses. Electronic databases such as PubMed, Scopus, Web of Science, and ClinicalTrials were consulted. The searches were carried out in August 2024. To evaluate the efficacy of autologous hematopoietic stem cell transplantation in inducing remission, the mean and standard deviation of the Crohn's Disease Activity Index pre- and post- treatment were used, and a fixed-effects meta-analysis was conducted. Additionally, to assess the efficacy in perianal fistulas, a random-effects meta-analysis was performed, collecting data on the number of subjects with fistulas at the beginning and end of the intervention. All 95% confidence intervals were calculated, and the I2 statistic was used to assess the heterogeneity of the outcome variables. A total of 609 records were identified from databases, with 12 studies selected for inclusion in the review. Immediate intervention proved effective in inducing a decrease in the Crohn Disease Activity Index compared to late intervention with conventional therapies. Moreover, the meta-analysis demonstrated efficacy for Crohn disease and associated fistulas with a mean decrease in the CDAI of -217.53 ± 14.3. When evaluating the efficacy of the procedure in perianal fistulas, a risk ratio of 0.47 with a 95% CI of [0.26, 0.86] was obtained. However, the procedure showed adverse effects, such as infections, acute renal failure or deaths. Systemic autologous hematopoietic stem cell transplantation has shown efficacy in patients who fail to achieve remission of their Crohn disease with conventional therapies. This procedure has also demonstrated efficacy in treating perianal fistulas. However, it is essential to carefully evaluate de implementation of this procedure due to the associated risks.

Mycophenolate Mofetil Appears Effective for the Treatment of Patients With Refractory Crohn's Disease.

Medically refractory Crohn's disease (CD) is associated with a high risk of complications. Mycophenolate mofetil (MMF), a small molecule immunosuppressant, has limited data in patients with CD, and objective endoscopic response to MMF has not been reported. We evaluated the safety and clinical, endoscopic, and biochemical effectiveness of off-label MMF for refractory CD as monotherapy or in combination with a biologic in patients with CD. We retrospectively assessed adverse events (AEs), clinical response (Harvey-Bradshaw index), endoscopic response (simple endoscopic score in Crohn's disease), and physician global assessment at an academic medical center and county hospital. 60 patients received MMF as monotherapy (n = 40) or in combination with a biologic (n = 20) between 2008 and 2021 at a dose ranging from 1000 to 4000mg daily. Median age was 39 years and median disease duration was 12 years. All patients previously failed ≥ 1 advanced therapy (median = 4). The median MMF therapy duration was 27 weeks. 54% achieved clinical response and 19% achieved clinical remission after a mean of 19.5 weeks (SD 14.5). Endoscopic response occurred in 32%, endoscopic remission in 16%, and endoscopic healing in 4% after a mean of 46.6 weeks (SD 31.0). 48% of patients experienced AEs, most commonly mild infection, nausea/vomiting, and headache. One serious AE occurred, which was assessed as unrelated to MMF. MMF resulted in clinical, endoscopic, and biochemical benefits in some patients with refractory CD, and was tolerated by most patients. Further randomized controlled trials are needed to define optimal dosing and long-term efficacy and safety.

Efficacy of Methotrexate and Anti-TNF Combination Therapy in Adults with Refractory Crohn's Disease.

Biological medications have played a significant role in maintenance therapy for Crohn's disease (CD), but some cases become refractory to these agents. Methotrexate (MTX) appears to be a cost-effective and readily available drug for enhancing the effectiveness of maintenance therapy when used in combination with anti-tumor necrosis factor (anti-TNF) therapy in such cases. However, its effectiveness is still to be established. We aimed to assess the efficacy of MTX and anti-TNF combination therapy in patients with refractory CD. A retrospective cohort study was conducted on adult patients with CD who were refractory to anti-TNF therapy and were initiated on weekly intravenous MTX in addition to the anti-TNF therapy. These patients were then followed up for over a year. The primary outcome measured was the clinical response to treatment, based on the Harvey-Bradshaw Index. The secondary outcomes included assessing the adverse events and complications of MTX therapy. Of 70 patients, 44 were included in the final analysis. Among them, 30 patients (68.2%) achieved complete remission, four patients (9.1%) had a partial clinical response, and 10 patients (22.7%) required surgery. The adverse events and complications of MTX therapy were mild and infrequent (9.1%). None of the demographic or clinical factors were significantly associated with response to treatment (P>0.05). Combining MTX with anti-TNF therapy appears to be an effective and safe treatment for patients with Crohn's disease, particularly those with severe disease who are less responsive to monotherapy. However, further studies are needed to confirm these findings.