Refractory Crohn Research Articles

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.

S3882 Combination Vedolizumab and Ustekinumab for Refractory Crohn’s Disease After Immune Checkpoint Inhibitors

S3882 Combination Vedolizumab and Ustekinumab for Refractory Crohn’s Disease After Immune Checkpoint Inhibitors

Real-life effectiveness of allogeneic expanded adipose-derived mesenchymal stem cell therapy for perianal fistulizing refractory Crohn's disease

BackgroundReal life data about the long-term efficacy of darvadstrocel for treating perianal fistulas in Crohn's disease (CD) remain scarce. Aim: To report the effectiveness and safety of darvadstrocel therapy to close perianal fistula in a real-life cohort of CD patients. MethodsAll patients with CD suffering complex draining perianal fistulas who consecutively underwent administration of a single local injection of darvadstrocel at two centres were followed up and evaluated. The primary endpoint was clinical remission (closure of all external openings with no discharge at pressure) at week 24. Combined remission (defined as clinically plus MRI-assessed fistula closure) were also assessed at week 24 and 52. ResultsA total of 36 CD patients (19 Male, mean age 38.5 years) were included with a median follow up of 16 months. Clinical remission was achieved in 17 out of 36 patients (47.2 %) and combined remission in 15 out of 36 patients (41.6 %) at week 24. At week 52, clinical and combined remission was achieved in 17 out of 36 patients (47.2 %) and in 15 out of 33 evaluable patients (45.4 %), respectively. ConclusionIn this real-world setting, a successful response to darvadstrocel therapy based on clinical remission was reported in around half of the patients and combined remission including radiological assessment in more than 4 out of 10 patients.

Subcutaneous infliximab in Crohn’s disease patients with previous immunogenic failure of intravenous infliximab

PurposeImmunogenicity is a major reason for secondary loss of response to infliximab (IFX). Recent work suggested potentially lower immunogenicity of subcutaneous (SC) compared to intravenous (IV) IFX. However, it is unknown whether re-exposure to IFX SC after secondary loss of response and immunogenicity to its intravenous formulation is safe and effective.MethodsIn a retrospective cohort study conducted at two medical centers, patients with clinically (Harvey-Bradshaw Index ≥ 5) and/or biochemically (fecal calprotectin > 250 µg/g) active Crohn’s disease (CD) and previous immunogenic failure of IFX IV underwent exposure to IFX SC. Harvey-Bradshaw Index, fecal calprotectin, IFX serum concentration, and anti-drug antibodies were assessed until month 12.ResultsTwenty CD patients were included. The majority of patients (90%) had previous treatment with three or more biologics. Fifteen (75%) and ten (50%) of 20 patients continued IFX SC treatment until months 6 and 12, respectively. No immediate hypersensitivity reactions were observed. Two patients discontinued IFX SC treatment because of delayed hypersensitivity at week 2 and week 4. IFX serum concentrations increased from baseline to month 12, while anti-drug antibody levels decreased. Combined clinical and biochemical remission at month 12 was observed in seven of 20 patients (35%).ConclusionSubcutaneous infliximab treatment of Crohn’s disease patients with previous immunogenic failure of intravenous infliximab was well tolerated and effective in a cohort of patients with refractory Crohn’s disease.

Effectiveness of risankizumab induction and maintenance therapy for refractory Crohn’s disease: a real-world experience from a preapproval access programme and early access to medicines scheme

ObjectiveSince approval in Crohn’s disease (CD) of risankizumab, there has been widespread use. Real-world data are, however, limited and our aim is to address that gap.Design/methodWe performed a retrospective, observational...

NLRP12 c.1382dup promotes the development of Crohn’s disease through the ERK/NLRP3/ IL-1β pathway

Whole-genome sequencing was used to identify a dominant inherited NLRP12 c.1382dup mutation in refractory familial Crohn’s disease (CD) patients. Additionally, we observed a T insertion at position 1382 in the third exon of NLRP12, leading to a frameshift mutation. Isolation of peripheral blood from mutation carriers and subsequent experiments demonstrated increased interleukin (IL)-1β in CD patients with the NLRP12 c.1382dup mutation. However, the mechanisms by which the NLRP12 c.1382dup mutation mediates IL-1β remain unclear. Our research findings reveal a close correlation between elevated p-ERK levels and increased expression of NLRP3 and IL-1β in the presence of the NLRP12 c.1382dup mutation. Further experiments demonstrate that inhibiting p-ERK with PD98059 effectively reduces the production of NLRP3 and IL-1β. This discovery provides new insights into the pathogenesis of CD, highlighting the significant role of the ERK/NLRP3/IL-1β pathway in the progression of CD. Not only does this offer novel therapeutic targets for treating CD, but it also lays the groundwork for the development of treatment strategies targeting this pathway.

Mesenchymal stem cell therapy for therapy refractory complex Crohn’s perianal fistulas: a case series

BackgroundMesenchymal stem cell treatment (MST) has emerged as a new therapeutic strategy for Crohn’s perianal fistulas. It has been demonstrated that a fibrotic tract on MRI with a MAGNIFI-CD score ≤ 6 is the best predictor for long-term clinical closure. Therefore, the aim of the current study was to analyse the effectiveness of MST for complex Crohn’s perianal fistulas based on MRI.MethodsConsecutive patients with complex Crohn’s perianal fistulas, previously failing both anti-TNF treatment and surgical closure, who had surgical closure of the internal opening with MST were included. The primary endpoint was radiological remission of the fistula(s) defined as a MAGNIFI-CD ≤ 6 on MRI, read by an experienced radiologist.ResultsBetween December 2019 and March 2023, 30 patients (15 males) with 48 fistula tracts were included with a median follow-up of 16.5 months. Radiological remission was achieved in thirteen patients (43.3%) after a median follow-up of 5.0 months (IQR 3.0–6.0). The median MAGNIFI-CD at baseline was 15.0 (IQR 7.0–20.0) which significantly decreased to 8.0 (IQR 3.0–15.0) after treatment (p = 0.001). Clinical closure was achieved in 21 patients (70.0%). Three patients (14.3%) developed a recurrence during long-term FU, all with clinically closed fistula(s), but no radiological remission. The median PDAI decreased significantly from 10.5 (IQR 7.0–14.0) to 4.0 (IQR 0.0-7.3) (p = 0.001).ConclusionMST is a promising treatment strategy for therapy refractory Crohn’s perianal fistulas, resulting in > 40% radiological remission, clinical closure in 70% and a significant improvement in quality of life. No recurrences were seen in patients with radiological remission.

The reparative immunologic consequences of stem cell transplantation as a cellular therapy for refractory Crohn's disease.

Treatment strategies for Crohn's disease (CD) suppress diverse inflammatory pathways but many patients remain refractory to treatment. Autologous hematopoietic stem cell transplantation (SCT) has emerged as a therapy for medically refractory CD. SCT was developed to rescue cancer patients from myelosuppressive chemotherapy but its use for CD and other immune diseases necessitates reimagining SCT as a cellular therapy that restores appropriately responsive immune cell populations from hematopoietic progenitors in the stem cell autograft (i.e. immune "reset"). Here we present a paradigm to understand SCT as a cellular therapy for immune diseases and reveal how SCT re-establishes cellular immunity utilizing high-dimensional cellular phenotyping and functional studies of the stem cell grafts. Immunophenotyping using CyTOF, single cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) sequencing was performed on peripheral blood and intestinal tissue samples from refractory CD patients who underwent SCT. The stem cell graft from these patients was analyzed using flow cytometry and functionally interrogated using a murine model for engraftment. Our study revealed a remodeling of intestinal macrophages capable of supporting mucosal healing that was independently validated using multimodal studies of immune reconstitution events including CyTOF and scRNA-seq. Functional interrogation of hematopoietic stem cells (HSCs) using a xenograft model demonstrated that HSCs shape the timing of immune reconstitution, the selected reconstitution of specific cell lineages and potentially the clinical efficacy of SCT. These studies indicate that SCT serves as a myeloid-directed cellular therapy re-establishing homeostatic intestinal macrophages that support intestinal healing and suggest refractory CD evolves from impairment of restorative functions in myeloid cells. Furthermore, we report heterogeneity among HSCs from CD patients which may drive SCT outcomes and suggests an unrecognized impact of CD pathophysiology on HSC in the marrow niche.

Refractory Crohn’s Disease Responsive to Dietary Therapy: A Case Report

Refractory Crohn’s Disease Responsive to Dietary Therapy: A Case Report

Cyclophosphamide-free Mobilisation Increases Safety While Preserving the Efficacy of Autologous Haematopoietic Stem Cell Transplantation in Refractory Crohn's Disease Patients.

Autologous haematopoietic stem cell transplantation [AHSCT] is a therapeutic option for refractory Crohn's disease [CD]. However, high adverse event rates related to chemotherapy toxicity and immunosuppression limit its applicability. This study aims to evaluate AHSCT's safety and efficacy using a cyclophosphamide [Cy]-free mobilisation regimen. A prospective, observational study included 14 refractory CD patients undergoing AHSCT between June 2017 and October 2022. The protocol involved outpatient mobilisation with G-CSF 12-16 μg/kg/daily for 5 days, and optional Plerixafor 240 μg/d [1-2 doses] if the CD34 + cell count target was unmet. Standard conditioning with Cy and anti-thymocyte globulin was administered. Clinical, endoscopic, and radiological assessments were conducted at baseline and during follow-up. All patients achieved successful outpatient mobilisation [seven patients needed Plerixafor] and underwent transplantation. Median follow-up was 106 weeks (interquartile range [IQR] 52-348). No mobilisation-related serious adverse events [SAEs] or CD worsening occurred. Clinical and endoscopic remission rates were 71% and 41.7% at 26 weeks, 64% and 25% at 52 weeks, and 71% and 16.7% at the last follow-up, respectively. The percentage of patients who restarted CD therapy for clinical relapse and/or endoscopic/radiological activity was 14% at 26 weeks, 57% at 52 weeks, and 86% at the last follow-up, respectively. Peripheral blood cell populations and antibody levels post-AHSCT were comparable to Cy-based mobilisation. Cy-free mobilisation is safe and feasible in refractory CD patients undergoing AHSCT. Although relapse occurs in a significant proportion of patients, clinical and endoscopic responses are achieved upon CD-specific therapy reintroduction.

Ustekinumab or vedolizumab for refractory metastatic Crohn's disease?

Metastatic Crohn's disease is a rare skin manifestation of Crohn’s disease. A variety of treatment options are available for this condition. But there is a lack of clarity regarding the treatment of resistant cases. There is ongoing debate as to which agent should be selected (vedolizumab or ustekinumab) in patients that are not responding to anti-tumor necrosis factor agents. This study identifies a unique patient who has developed a disease (metastatic Crohn's disease) under treatment with vedolizumab. Following treatment with ustekinumab, the patient regressed completely. Therefore, we recommend ustekinumab primarily in metastatic Crohn's disease.

Surgical management of complicated Crohn's disease

Surgical management of pediatric Crohn's disease is fundamentally palliative, aiming to treat the sequalae of complicated disease while preserving intestinal length. Multidisciplinary discussion of risk factors and quality of life should take place prior to operative intervention. Though the surgical management of pediatric Crohn's disease is largely based on the adult literature, there are considerations specific to the pediatric population – notably disease and treatment effects on growth and development. Intrabdominal abscess is approached with percutaneous drainage when feasible, reserving surgical intervention for the patient who is unstable or failing medical therapy. Pediatric patients with fibrostenotic disease should be considered for strictureplasty when possible, for maximum preservation of bowel length. Patients with medically refractory Crohn's proctocolitis should be treated initially with fecal diversion without proctocolectomy.

Optimal Management of Refractory Crohn's Disease: Current Landscape and Future Direction.

Refractory Crohn's disease, defined as ongoing inflammation despite the trial of multiple advanced therapies, impacts a number of individuals with Crohn's disease, and leads to significant burden in quality of life and cost. Interventions such as early implementation of advanced therapies, optimization of current therapies prior to switching to an alternative, as well as understanding the overlapping pathophysiology between immune-mediated disorders, however, can help shift the current landscape and reduce the number of patients with refractory disease. As such, in this review we summarize the key takeaways of the latest research in the management of moderate-to-severe Crohn's disease, focusing on maximization of our currently available medications, while also exploring topics such as combination advanced therapies. We also describe evidence for emerging and alternative therapeutic modalities, including fecal microbiota transplant, exclusive enteral feeding, hyperbaric oxygen, stem cell therapy, bone marrow transplant, and posaconazole, with a focus on both the potential impact and specific indications for each.

A new surgical technique: robotic intracorporeal Kono-S anastomosis in Crohn's - a safety and feasibility case series on short-term outcomes.

The Kono-S anastomosis was introduced as a possible solution to the high surgical recurrence rates in Crohn's disease. However, this technique is known to be challenging, which is why it was originally performed in an extracorporeal setting. The aim of this case series was to assess safety, in terms of intra-/postoperative complications, and feasibility, in terms of successful performance of anastomosis, of a robot-assisted intracorporeal Kono-S anastomosis. This is a prospective single-centre consecutive case series. Patients were considered eligible if they were diagnosed with refractory Crohn's disease with significant bowel stenosis of the terminal ileum. All patients underwent robot-assisted intracorporeal Kono-S anastomosis. Perioperative care was provided according to the Enhanced Recovery After Surgery® protocol. Follow-up for postoperative complications was 30 days. Twenty patients were included, of whom 11 (55%) were men. The median age was 30 years [interquartile range (IQR) 22-51 years] and the median BMI was 25 kg/m2 (IQR 19-28 kg/m2). Intracorporeal Kono-S anastomosis was successfully performed in all cases. The median operating time was 155 min (IQR 144-176 min) and the median length of stay was 3 days (IQR 1-5 days). No conversions or 30-day mortality were observed. One patient experienced anastomotic leakage, which was treated with radiologically guided drainage. A total of three patients experienced postoperative complications in the first 30 days. Performance of intracorporeal robot-assisted Kono-S anastomosis seems safe and feasible in this case series for Crohn's disease. Since this is a first case series, further research is required to confirm results in a larger population-based cohort.

Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial

A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population. This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18-60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m2 with granulocyte colony-stimulating factor (G-CSF) 5 μg/kg) and stem-cell harvest (minimum 2·0 × 106 CD34+ cells per kg), before conditioning (fludarabine 125 mg/m2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440. Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure. Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease. Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

P1086 Re-administration of infliximab in patients with extremely refractory perianal Crohn’s disease

Abstract Background This study aims to evaluate the efficacy of infliximab re-administration to a cohort of patients with extremely refractory perianal Crohn's Disease (CD). Methods Retrospective analysis of prospectively collected data in CD patients with perianal disease, who despite being treated with infliximab, had to change treatment either because of primary non-response, secondary loss of response, or due to the occurrence of an allergic reaction. They then became resistant to the other therapies tested, resulting in Infliximab being given again. We then evaluated the clinical response to fistula management (Perianal Disease Activity Index PDAI ≤ 4), as well as the occurrence of adverse reactions in these patients. Results We included 14 patients (8 women), with a mean age (SD) of 38.2 (9.5) years. According to the Montreal classification our patients had L1 (n=2), L2 (n=2) and L3 (n=10) disease. After the initial Infliximab failure (even after dose escalation), patients received vedolizumab, ustekinumab and adalimumab without response or with secondary loss of response. Therefore, it was decided to re-administer infliximab with concomitant administration of azathioprine. After 1 year of follow up clinical response (PDAI ≤ 4) was seen in 4 patients (28.5%). Re-administration of infliximab was discontinued in 2 patients due to severe allergic reaction; however, the remaining patients did not experience side effects. Conclusion Re-administration of Infliximab may be able to help a small percentage of treatment resistant patients with perianal CD.

P1049 Effectiveness and safety of subcutaneous infliximab in Crohn’s disease patients with immunogenic failure of intravenous infliximab

Abstract Background Immunogenicity is a major reason for secondary loss of response to infliximab (IFX). Recent work suggested potentially lower immunogenicity of subcutaneous compared to intravenous infliximab. However, it is unknown whether re-exposure of patients with immunogenic failure of IFX to its subcutaneous formulation is safe and effective. Here, we analysed the safety and effectiveness of subcutaneous IFX (CT-P13) in patients with Crohn’s disease (CD) and history of secondary loss of response of intravenous IFX due to anti-drug antibodies (ADA). Methods In a retrospective analysis conducted at medical centers in Germany (Dresden) and the Czech Republic (Prague), patients with clinical (Harvey-Bradshaw Index ≥ 5) and/or biochemical (faecal calprotectin >250 µg/g) active CD and previous treatment failure in the context of IFX immunogenicity underwent re-exposure to subcutaneous IFX. Treatment was initiated with either 4 subcutaneous injections 120 mg CT-P13 weekly followed by biweekly injections, or directly with 120 mg CT-P13 subcutaneous biweekly. Harvey-Bradshaw Index, faecal calprotectin, IFX serum concentration and ADA were assessed until month 12. Results Twenty CD patients were included (table 1). The majority of patients (90 %) had previous treatment with ≥ 3 biologics. 75% and 50 % of patients continued IFX treatment until month 6 and 12, respectively. No immediate hypersensitivity reactions were observed. Two patients (10%) discontinued IFX due to delayed hypersensitivity. Lack of treatment effectiveness led to infliximab withdrawal in 7 cases (35%) and one patient (5%) was lost to follow up after month 6. IFX serum concentrations increased from baseline (median 0 µl/ml ± 0 interquartile range/IQR) until month 12 (median 22.8 µl/ml, 10.0 IQR), while ADA levels decreased (50.6 AU/ml, 48.3 IQR and 0.0 AU/ml, 0 IQR at baseline and month 12, respectively). Clinical remission at month 12 was observed in 27% and biochemical remission in 38% of patients with active Crohn's disease at baseline. 67 % of patients with clinical inactive Crohn's disease at baseline remained in clinical remission until month 12. Conclusion Subcutaneous infliximab after previous failure and immunogenicity of intravenous infliximab was well tolerated and effective in a cohort of patients with refractory Crohn’s disease.

P552 Clinical factors associated with ustekinumab therapy persistence in a refractory Crohn’s disease cohort

Abstract Background Ustekinumab (UST) is a monoclonal antibody that binds to the p40 subunit shared by pro-inflammatory interleukins 12 and 23. UST has demonstrated efficacy for the induction and maintenance of remission in patients with Crohn’s disease (CD). A proportion of patients with CD do not respond to UST at the standard dose of 90 mg every 8 weeks. Methods A multi-centre retrospective study of CD patient who commenced UST therapy at two specialist tertiary referral centres between October 2012 and March 2021 was performed. Patient demographics, baseline characteristics, medication history and disease behaviour were characterised. Duration of UST therapy and UST dose escalation were documented. UST therapy persistence, was considered a proxy for treatment response, and was expressed as time to discontinuation of UST therapy. The study evaluated whether UST dose optimisation was associated with increased UST therapy persistence; and clinical factors associated with UST therapy persistence. Optimised dosing was defined as a dosing regimen of UST 90mg at less than an 8-weekly interval. Statistical analysis was performed using survival analysis and multivariate cox logistic regression with effect of covariates on outcome expressed as odds ratios (OR). Results 133 patients commenced UST during the study period (age [mean, range] 39 years, 16-79; 59% female; disease duration [mean, range] 12.4 years, 1-35). 99% of patients had failed at least 1 biologic and 72 patients (54%) required dose escalation during the study period. The mean duration of UST therapy was 74 weeks (range 2-427). 75 (56%) patients were still receiving UST at end of study period. Survival analysis demonstrated that there was no significant difference in UST persistence between patients receiving standard and optimised UST dosing regimens, p=0.58. Patients with early UST dose optimisation (within 6 months of therapy initiation) had increased UST therapy persistence, p=0.003. A multivariate regression analysis demonstrated that early UST dose optimisation (within 6 months of therapy initiation) was independently associated with a longer time to UST therapy discontinuation (OR 0.31 (95%CI 0.15-0.68), p=0.003). Neither disease duration (OR 1.11, p=0.66), male sex (OR 0.91, p=0.83), concomitant immunomodulator use (OR 1.03, p=0.95), perianal disease (OR 1.09, p=0.85), smoking status (OR 1.16, p=0.68) nor previous surgery (OR 1.47, p=0.33) were independently associated with time to UST therapy discontinuation. Conclusion UST is an effective treatment for CD patients with prior biologic therapy exposure. Optimised UST dosing regimens are frequently utilised in routine clinical practice. There appears to be an increased likelihood of treatment success with early UST dose optimisation.

P716 Efficacy and safety of upadacitinib during induction in Crohn’s disease: Real-world experience

Abstract Background Upadacitinib is a selective JAK1 inhibitor that has recently been approved for treatment of moderate-severe Crohn’s disease, with Phase III clinical trials showing positive efficacy and safety profiles. Our aim was to evaluate the real-world experience of upadacitinib in a refractory cohort of Canadian patients with Crohn’s disease. Methods This was a two-centre retrospective study looking at 12-week induction data for patients with active Crohn’s disease from McGill University Health Centre and Hamilton Health Sciences. The primary outcome was clinical remission at 12 weeks, with secondary outcomes including clinical response, biochemical remission, and biochemical response. Clinical remission was defined as a Harvey-Bradshaw index (HBI) < 5. Clinical response was defined as an HBI reduction of ≥ 3. Biochemical remission was defined as a c-reactive protein (CRP) < 5 mg/L and/or fecal calprotectin (FCP) < 250 μg/g. Biochemical response was defined as a reduction of CRP or fecal calprotectin by 50% from baseline. These parameters were all evaluated at 8 and 12 weeks. Adverse events were summarized for patients who had follow up data available and included in the efficacy analysis. Results There were 28 patients who were treated in total, all of which had multiple biologic treatment failures. Baseline median age was 37, median HBI was 9, median CRP was 9.41 mg/L, and median FCP was 580 μg/g. The median disease duration was 13.5 years. Four patients discontinued upadacitinib due to no response or side effects. For all available data including patients who discontinued upadacitinib, clinical remission was achieved at 12 weeks in eight patients (8/11, 72.7%). Clinical response was achieved in eight patients (8/11, 72.7%), biochemical remission was achieved in four patients (4/11, 36.4%), and biochemical response was achieved in six patients (6/11, 54.6%). Of those that were initially on steroids (n=5), four patients (4/5, 80.0%) were able to wean off steroids and achieved a steroid-free clinical or biochemical response at 12 weeks. Of those who had previously been on off-label tofacitinib (n=5), clinical follow-up data was available for three patients at the end of the 12-week induction period. Two patients achieved clinical remission (2/3, 66.7%) and three patients had a clinical response (3/3, 100%). Among 13 patients with follow-up data, adverse events were observed in three patients (3/13, 23.1%), with two having non-serious infections (2/13, 15.4%) and one having fevers of unknown origin (1/13, 7.69%). Conclusion This real-world multicentre Canadian induction study shows favourable efficacy and tolerability of upadacitinib in refractory active Crohn’s disease.