BACKGROUND & AIMS:Secondary loss of response to ustekinumab is observed in patients with Crohn's disease (CD). Multiple dose-intensification regimens have been proposed. We aimed to test prospectively 2 different dose-intensification regimens with ustekinumab in patients with CD experiencing secondary loss of response. METHODS:This was an investigator-initiated, multicenter, randomized, placebo-controlled trial conducted at 15 hospitals in Belgium. Eligible patients were adults with CD treated with ustekinumab on maintenance dosing of 90 mg subcutaneous every 8 weeks and experiencing a secondary loss of response (Patient-Reported Outcomes 2: abdominal pain score >1 and liquid or very soft stool frequency >3 and an objective documentation of disease). Patients were randomized 1:1 to receiving a single intravenous reinduction with ustekinumab ≈6 mg/kg followed by either subcutaneous ustekinumab 90 mg every 4 weeks or every 8 weeks until week 48. The primary endpoint was the proportion of patients with steroid-free clinical remission at week 48, defined as Patient-Reported Outcomes 2 remission: (abdominal pain ≤ 1 and stool frequency ≤3) and fecal calprotectin <250 μg/g and no steroids in the 90 days before week 48. RESULTS:Between March 2020 and October 2023, 108 patients were randomized. Steroid-free clinical remission at week 48 was reached in 15% vs 19% of patients in the every 4 weeks vs the every 8 weeks group (difference 4%; P = 0.5). Serious adverse events occurred in 17% vs 13% of patients. CONCLUSIONS:In patients with CD and secondary loss of response to ustekinumab, dose intensification with a single intravenous administration and followed by 4 weekly subcutaneous dosing of ustekinumab was not more effective than 1 intravenous administration followed by 8 weekly subcutaneous dosing of ustekinumab. (ClinicalTrials.gov, Number: NCT04245215).

BACKGROUND AND AIMS:Evidence from rheumatology supports a within-class treatment switch for JAK-inhibitors (JAKi), but data in ulcerative colitis (UC) remain limited. We aimed to assess the effectiveness and safety of initiating a second JAKi in patients with UC previously treated with another JAKi. METHODS:We conducted a multicenter retrospective study, including patients with UC starting a second JAKi after prior JAKi exposure. The primary endpoint was Week 12 steroid-free clinical remission (SFCR-rectal bleeding subscore = 0, stool frequency subscore ≤ 1, and no steroids). RESULTS:We included 243 patients (median follow-up: 38 [21-57] weeks). At Weeks 12, 26, and 52, SFCR was achieved in 116/243 (48%), 120/243 (49%), and 69/243 (28%), respectively. Secondary loss of response to the first JAKi was associated with higher SFCR at Week 12 compared to primary failure (odds ratio [OR] = 1.92, 95% confidence interval [CI] = 1.11-3.30, P = 0.02). Higher baseline disease activity (OR = 0.68, 95% CI = 0.68-0.55, P < 0.01) and steroid use (OR = 0.23, 95% CI = 0.13-0.42, P < 0.01) had lower odds of Week 12 SFCR. Endoscopic remission occurred in 22/243 (9%) (<Week 26) and 27/243 (11%) (26-78 weeks), and endoscopic improvement in 53/243 (22%) and 45/243 (19%), respectively. Sixty-seven (28%) patients discontinued the second JAKi, mostly due to primary (36/67) or secondary failure (22/67). Sixty-six adverse events (mostly acne and infections) occurred in 56 (23%) patients, without major thromboembolic or cardiovascular events. CONCLUSION:Treatment with a second JAKi is effective and safe in patients with UC already exposed to JAKi. Primary failure to a first JAKi and steroid use at initiation of the second JAKi might reduce the likelihood of success with the second JAKi.

BACKGROUND AND AIMS:Extraintestinal manifestations (EIMs) and immune-mediated inflammatory diseases (IMIDs) are common in inflammatory bowel diseases (IBD) and contribute substantially to morbidity. The aim was to evaluate the real-world effectiveness of JAK inhibitors on EIMs/IMIDs. METHODS:This multicenter retrospective study included adults with ulcerative colitis (UC) or Crohn's disease (CD) and one or more EIM/IMID initiating a JAK inhibitor (tofacitinib, upadacitinib, or filgotinib). Baseline was defined as treatment initiation; EIM/IMID and IBD activity were assessed at fixed timepoints using physician global assessment. Response rates are reported as observed, with patients discontinuing for worsening of the manifestation counted as non-responders. Logistic and Cox regression analyses identified factors associated with response and treatment discontinuation. RESULTS:A total of 246 patients were included; 67% had two or more prior advanced therapies. Peripheral spondyloarthritis (SpA) (48%) and axial SpA (43%) were the most prevalent EIMs/IMIDs. Peripheral SpA response rates were 82% post-induction and 74% at month 12; axial SpA response rates were 71% and 59%, respectively. Psoriasis response was observed in 65% post-induction and in 50% at month 12, and hidradenitis suppurativa response in 91% and 78%, respectively. Steroid-free clinical IBD remission was 58% at month 12, and was independently associated with peripheral SpA response (adjusted odds ratio [aOR] 4.2, 95% CI 1.2-14.7). Treatment was discontinued in 31%; factors associated with discontinuation were filgotinib use (adjusted hazard ratio [aHR] 3.0, 95% CI 1.4-6.2) and co-existing axial and peripheral SpA (aHR 2.8, 95% CI 1.5-5.1). CONCLUSIONS:JAK inhibitors were associated with favorable physician-assessed outcomes for EIMs/IMIDs in treatment-experienced IBD patients. Co-existing axial and peripheral SpA was associated with treatment discontinuation, suggesting a more complex phenotype.

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are often complicated by immune-related adverse events, particularly colitis. With increasing ICI use, understanding the clinical course and management of ICI-induced colitis is essential. Objectives: To characterize the clinical, endoscopic, and histological features of ICI-induced colitis and evaluate treatment outcomes, focusing on the use of corticosteroids and second-line biologicals (infliximab and vedolizumab) in a real-world setting. Methods: A retrospective cohort study was conducted at Ghent University Hospital, including 77 adult patients diagnosed with ICI-induced colitis in between 2012 and 2023. Clinical, biochemical, endoscopic, and histological data were analyzed, along with treatment response and safety outcomes. Results: Patients with ICI-induced colitis received anti-PD-1/PD-L1 (64.9%), anti-CTLA-4 (9.1%), or combination of both (26.0%). In patients with normal endoscopic findings, histological signs of colitis were observed in 88.0%. Combination ICI therapy was associated with higher Mayo scores (p = 0.029) and increased need for biologicals (p = 0.011) compared to anti-PD-1/PD-L1 monotherapy. Clinical response rates were 79.6% with corticosteroids and 100.0% with biologicals. Rechallenge with ICIs lead to a 17.4% relapse rate. No colitis-related deaths were observed. Conclusions: In this retrospective study, we demonstrate that random colon biopsies reveal microscopic ICI-induced colitis in most patients with absence of endoscopic disease. Combination ICI therapy predicts a corticosteroid-refractory course, supporting the need for early escalation to biologicals. ICI rechallenge appears feasible, as relapse rates were relatively low and colitis morbidity remained manageable. Prospective studies are needed to refine therapeutic strategies and improve patient outcomes.

Abstract Background The anti-TNF agent infliximab (IFX) CT-P13 is now available as a subcutaneous (SC) formulation. Unanswered questions persist regarding the use of SC IFX in patients previously on optimized intravenous (IV) regimens. The AMARETTO study investigates if switching to weekly SC IFX 120 mg is associated with better outcomes than bi-weekly dosing in patients with prior optimized IV therapy. Methods This multicentre, randomized, open-label superiority trial includes adult IBD patients treated with optimized IV IFX in steroid-free clinical (PRO-2) and biological remission (CRP <10 mg/L, and faecal calprotectin <250 μg/g) on optimized IV IFX (ClinicalTrials.gov ID: NCT06113913). Eligible patients may continue their IV treatment (IV comparison group) or switch to SC IFX. Those switching to SC are randomized 1:1 to open-label weekly (SC intervention) or bi-weekly 120 mg SC IFX (SC comparison). Primary endpoint is the proportion maintaining steroid-free clinical and biological remission at week 52 without treatment optimization. Here we focus on the secondary endpoints of patient expectations, experience and satisfaction using a 11-point Likert scale (0 = lowest and 10 = highest). Results From May to October 2024, 163 patients were screened, with 120 included (66 SC, 54 IV; Table 1). Among the 66 SC patients willing to switch, 57 (37 CD, 20 UC/IBDU) already had their baseline visit with first SC IFX and completed the treatment expectations questionnaire, and 29 have already been treated with SC IFX for at least 8 weeks and completed a satisfaction questionnaire (Figure 1). The pen was preferred by 42 (74%), the syringe by 4 (7%), and 11 patients (19%) had no preference. Key reasons for pen preference were needle visibility (38%) and injection control (48%). Training for SC injection was mainly provided by IBD nurses (N=45, 79%). Median (interquartile range, IQR) satisfaction with training, confidence, and ease of use were 10 (9–10), 9 (8–10), and 9 (8–10), respectively. By week 8, median (IQR) scores for confidence remained stable at 9 (9–10) and increased for ease of use 10 (8–10). Median (IQR) scores for injection pain and fear at week 8 were 2 (0–4) and 0 (0–1). Satisfaction and likelihood of recommending SC treatment were both 9 (8–10). No significant differences at week 8 were observed between both SC groups. Conclusion Preliminary data suggest a highly positive patient experience with SC IFX among those previously treated with optimized IV IFX, highlighting strong preferences for the pen and good satisfaction rates regarding training, ease of use, confidence and injection pain. The AMARETTO trial will further clarify if weekly SC dosing offers superior outcomes compared to bi-weekly SC IFX.

Abstract Background In Crohn’s disease (CD), an exposure-response relationship exists for ustekinumab, with higher serum levels associated with better outcomes. Although several retrospective and observational studies demonstrate dose-escalation of ustekinumab can be effective in case of secondary loss of response (LOR), prospective placebo-controlled data are lacking. The aim of the REScUE study (NCT04245215) was to investigate the effect of 2 different re-induction regimens with ustekinumab on clinical, endoscopic, biological and pharmacological outcomes in patients with CD. Methods This Belgian multicentre prospective double-blind randomized placebo-controlled trial included adult patients with CD treated with ustekinumab who presented with secondary LOR to ustekinumab after documented primary response. Secondary LOR was defined by PRO-2 (AP> 1 AND SF> 3) and confirmed by either an elevated biomarker (CRP >5 mg/L or faecal calprotectin >250 µg/mg) or endoscopic signs of inflammation. All patients received a single IV re-induction with ustekinumab (≈6mg/kg) and were then randomized 1:1 to blinded maintenance ustekinumab 90 mg SC Q4W (intervention) or 90 mg SC Q8W (control) for 48 weeks. Primary endpoint was proportion of patients with steroid-free clinical remission (definition in fig 1) at week 48, with missing data were handled using non-responder imputation. Results In total, 132 patients were screened, and 108 patients were included: 67% female, median [IQR] age 41 [32-54] year, median disease duration 14 [7-22] years. Prior anti-TNF exposure was reported in 92% of patients, while ustekinumab was the first-line advanced treatment in 7% of patients. The primary endpoint of steroid-free clinical remission at week 48 was achieved by 9/54 (17%) patients in the q4w regimen vs 8/54 (16%) in the q8w regimen (p=0.96) (fig 1). Endoscopic remission (SES-CD <3) was achieved in 5/54 (10%) vs 3/54 (6%) (p=0.52), endoscopic response (≥50% decrease in SES-CD from baseline) was achieved in 11/54 (22%) vs 6/54 (12%) (p=0.23) and 0.52biomarker remission was achieved in 20/54 (38%) vs 13/54 (26%) (p=0.19) in the q4w regimen vs the q8w regimen, respectively. Time to first clinical remission was similar between groups (fig 2). Association with ustekinumab serum levels will be reported. No new safety signals were observed. Conclusion In patients with CD experiencing secondary LOR to ustekinumab, dose optimization with a single IV re-induction followed by intensified maintenance dosing (90 mg SC q4W) was not superior to a single IV re-induction followed by conventional maintenance dosing (90 mg SC q8W) in achieving steroid-free clinical remission. The secondary endpoints were numerically higher but not significant in the intensified regimen.

Background/Objectives: Gastrointestinal diseases are a major cause of morbidity in common variable immunodeficiency disorder (CVID), clinically often mimicking other conditions including celiac disease and inflammatory bowel disease (IBD). Hence, diagnosis of CVID remains challenging. This study aims to raise awareness and highlight histopathological clues for CVID in intestinal biopsies, emphasizing diagnostic pitfalls for the pathologist/gastroenterologist. Methods: We reviewed 63 (18 duodenal, 23 ileal, 22 colonic) biopsies and case histories from seven CVID patients, obtained over a 31-year period, with attention to active inflammation, intraepithelial lymphocytes, plasma cells, lymphoid hyperplasia, crypt/villous architecture, subepithelial collagen, apoptosis, granulomas, and infections. Clinical information of 41 pathology requests was reviewed. Results: Gastrointestinal symptoms were variable. Histological features included IBD-like (3/7), celiac disease-like (2/7), graft-versus-host disease (GVHD)-like (2/7), lymphocytic sprue/colitis-like (3/7), collagenous colitis-like (2/7), and acute colitis-like (4/7) patterns, often overlapping (2/7) and/or changing over time (3/7). Lymphoid hyperplasia was seen in 3/7 patients; 1/7 had giardiasis; and 5/7 had few plasma cells, usually only in part of the gut (3/5). Clinical information of 12/41 (29%) pathology requests mentioned known/suspected CVID, despite being known in 33/41 (80%). Conclusions: Clinical/histological features of CVID in the gut are diverse, often mimicking IBD, microscopic colitis, celiac disease and/or GVHD, hence the importance of adequate clinical information. Some histological features are atypical of these established entities and may indicate CVID, as may overlapping/changing histological patterns and/or few plasma cells in part of the gut. Awareness of the heterogenous clinical presentation and histopathological indicators of CVID may improve diagnosis.

BACKGROUND & AIMS:Perianal fistulation is a challenging phenotype of Crohn's disease, with significant impact on quality of life. Historically, fistulae have been classified anatomically in relation to the sphincter complex, and management guidelines have been generalized, with lack of attention to the clinical heterogenicity seen. The recent 'TOpClass classification system' for perianal fistulizing Crohn's disease (PFCD) addresses this issue, and classifies patients into defined groups, which provide a focus for fistula management that aligns with disease characteristics and patient goals. In this article, we discuss the clinical applicability of the TOpClass model and provide direction on its use in clinical practice. METHODS:An international group of perianal clinicians participated in an expert consensus to define how the TOpClass system can be incorporated into real-life practice. This included gastroenterologists, inflammatory bowel disease surgeons, and radiologists specialized in PFCD. The process was informed by the multi-disciplinary team management of 8 high-volume fistula centres in North America, Europe, and Australia. RESULTS:The process produced position statements to accompany the classification system and guide PFCD management. The statements range from the management of patients with quiescent perianal disease to those with severe PFCD requiring diverting-ostomy and/or proctectomy. The optimization of medical therapies, as well as the use of surgery, in fistula closure and symptom management is explored across each classification group. CONCLUSION:This article provides an overview of the system's use in clinical practice. It aims to enable clinicians to have a pragmatic and patient goal-centered approach to medical and surgical management options for individual patients with PFCD.

EDITORIAL article Front. Med., 13 April 2023Sec. Gastroenterology Volume 10 - 2023 | https://doi.org/10.3389/fmed.2023.1195201

Abstract Background Rigorous donor preselection, strict anaerobic processing, and repeated faecal microbiota transplantation (FMT) administration did not improve outcomes for induction of clinical remission in the RESTORE-UC trial1. We studied the luminal, and mucosal microbiota composition as well as gene expression throughout the RESTORE-UC study, to further understand the results and instruct future FMT trial design. Methods The RESTORE-UC trial was a multi-centric double-blind, sham-controlled randomized trial. Patients with moderate to severe UC (total Mayo 4-10) were randomly allocated to receive 4 anaerobic-prepared allogenic or autologous donor FMT. Mucosal biopsies were collected for RNA- and 16S sequencing at week 0 and 8. Quantitative microbiota profiling was performed on donor samples, and in patients at weeks 0, 1, 2, 3, 4, 8, 12, 26, and 52 (n=756). Clinical success (steroid free clinical remission) and -response (≥3 points or ≥50% reduction in combined Mayo subscores for rectal bleeding and stool frequency) were evaluated at week 8. Metagenomic success (week 8) was defined as restoration of eubiosis (Bacteroides 2 (B2) to non-B2 enterotype) and failure was considered with subtypes being no transition, non-B2 to other non-B2 transition, lead dysbiosis (non-B2 to B2), and maintenance of dysbiosis (B2 to B2). Results Baseline beta diversity (metric for overall microbial similarity) was significantly associated with future clinical and metagenomic success (resp. p=0.035; p=0.003). Similar trends were observed at week 8 (resp. p=0.056; p=0.001). Restoration of eubiosis was characterized by a rapid increase in bacterial richness after the first FMT administration, which was maintained up to 12 months after intervention (Fig A). A greater difference (Fig B) in donor-recipient richness determined the metagenomic success (p=0.06) and clinical response (p=0.01), while this was not observed for clinical success (p=0.16). Metagenomic success was accompanied by increased engraftment after FMT (Fig C, p<0.01). Independently from clinical success, patients with dysbiotic faecal communities at baseline had distinctive mucosal communities in their intestinal biopsies (p<0.01), which were significantly changed in samples where eubiosis was restored (p=0.012), but not in those where clinical success was observed (p=0.34). However, this could be explained by the low overall response rate. No specific transcriptomic profiles in mucosal biopsies at baseline were reminiscent of metagenomic (p=0.24), nor clinical success (p=0.22). Conclusion Patient and donors should be rigorously selected in future FMT trials, and selection should be based on microbial composition and by obtaining a great difference in richness between receptor and donor. References 1 Caenepeel*, Deleu*, Vazquez* et al., 2024

BACKGROUND:Pouch disorders are common and may present with symptoms of increased stool frequency, urgency, incontinence, pelvic cramping, obstructed defecation, and perianal drainage, which can result in poor sleep, fatigue, and disability. This topical review aims to offer expert consensus practice recommendations for the diagnosis and management of the most common inflammatory, functional, structural, and neoplastic J-pouch disorders. METHODS:A multidisciplinary panel of gastroenterologists and colorectal surgeons performed a systematic review of the relevant literature on pouch disorders and developed current practice positions. RESULTS:Seventeen current practice positions were developed on the diagnosis and management of inflammatory, functional, structural, and neoplastic pouch disorders. CONCLUSIONS:A multidisciplinary approach is essential for the diagnosis and management of pouch disorders.

Abstract Background Histological remission is an aspirational therapeutic target in Ulcerative Colitis (UC) associated with lower relapse rates.1Ustekinumab (UST), a monoclonal antibody against the p40 subunit of interleukin (IL) 12 and 23 has shown in the UNIFI trials to be effective and safe in patients with moderate-to-severe UC. However, real-life data on histological remission rates are sparse. The aim of the study was to assess the real-life histological response and remission rates of UST in patients with UC across Belgian hospitals. Methods In this multicentric, retrospective observational study, patients with UC who initialised UST treatment between September 2020 and July 2023 were included. Histological remission was defined as Nancy score = 0, response as Nancy ≤ 1 and assessed at week 16 and 52 by the local pathologist. Other endpoints included steroid-free clinical remission (partial Mayo ≤ 2 with no subscore >1), endoscopic remission (endoscopic Mayo = 0), endoscopic response (Mayo score ≤ 1) and clinical response (decrease in partial Mayo score ≥ 3 points and ≥ 30% plus a decrease in rectal bleeding score ≥ 1 or an absolute rectal bleeding score ≤ 1). UST drug persistence was analyzed by Cox regression analysis, predictors of other endpoints by logistic regression. Results 120 patients with moderate to severe UC (86% patients with ≥S2 severity) were included across 16 participating centers. Median disease duration was 11 years (IQR 9) and 81 (68%) of patients had previously failed 2 or more biologicals. Histological remission was achieved in 3/37 (8%) and 5/45 (11%) at W16 and W52, while histological response was seen in 10.8% (4/37) and 26.7% (12/45) respectively. Steroid-free clinical remission rates were 41/120 (34%) and 38/85 (44%) while endoscopic remission was seen in 23/120 (19%) and 13/52 (25%) at W16 and 52 respectively. Two patients (40%) in histological remission at W52 had an endoscopic Mayo 0 score, while 3 had a Mayo 1 (60%) at the time of evaluation. Active smoking was a negative predictor for achieving steroid-free remission (OR 0.412, p=0.011). No significant predictors for histological remission or response could be identified. UST drug persistence by week 52 was 70.8%. Active smoking (OR 3.058, p=0.02), vedolizumab non-response (OR 2.592, p=0.03) and a high Nancy baseline score (OR 2.46, p=0.04)) were associated with UST failure Conclusion In this multi-centric, real-life cohort with highly refractory UC patients, UST shows acceptable clinical and endoscopic remission rates, but histological remission rates remain low after one year of treatment. References 1.Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology 2021;160:1570–1583.

Management of extraintestinal manifestations (EIMs) and concomitant immune-mediated inflammatory diseases (IMIDs) in patients with inflammatory bowel disease (IBD) represents a significant clinical challenge, often requiring the combination of advanced therapies to achieve adequate disease control. This review aims to provide a comprehensive and practical framework for the implementation of dual advanced therapy (DAT) in this complex patient population.We performed a narrative review of randomised trials, real-world cohorts and case series on combinations of biologics and small molecules in IBD with EIMs/IMIDs, appraising mechanistic complementarity, safety and economic implications.Although evidence remains limited, DAT appears appropriate for selected profiles: refractory IBD with active EIMs, concomitant IMIDs with divergent tissue responses and ‘bridge’ strategies during class switching. Combinations leveraging non-overlapping pathways (eg, anti-tumour necrosis factor with vedolizumab or ustekinumab; Janus Kinase (JAK) inhibitors with gut-selective or cytokine-targeted agents) are most promising. We outline monitoring targets by domain and a safety checklist (infections, malignancy, thromboembolism, vaccination).This review translates heterogeneous data into a pragmatic Who/What/When/Cost framework to guide DAT in IBD with EIMs/IMIDs and delineates research priorities for cross-organ outcomes and long-term safety.

BACKGROUND & AIMS: Rigorous donor preselection on microbiota level, strict anaerobic processing, and repeated fecal microbiota transplantation (FMT) administration were hypothesized to improve FMT induction of remission in ulcerative colitis (UC). METHODS: The RESTORE-UC trial was a multi-centric, double-blind, sham-controlled, randomized trial. Patients with moderate to severe UC (defined by total Mayo 4-10) were randomly allocated to receive 4 anaerobic-prepared allogenic or autologous donor FMTs. Allogenic donor material was selected after a rigorous screening based on microbial cell count, enterotype, and the abundance of specific genera. The primary endpoint was steroid-free clinical remission (total Mayo <= 2, no sub-score >1) at week 8. A pre-planned futility analysis was performed after 66% (n = 72) of intended inclusions (n = 108). Quantitative microbiome profiling (n = 44) was performed at weeks 0 and 8. RESULTS: In total, 72 patients were included, of which 66 received at least 1 FMT (allogenic FMT, n = 30 and autologous FMT, n = 36). At week 8, respectively, 3 and 5 patients reached the primary endpoint of steroid-free clinical remission (P = .72), indicating no treatment difference of at least 5% in favor of allogenic FMT. Hence, the study was stopped due to futility. Microbiome analysis showed numerically more enterotype transitions upon allogenic FMT compared with autologous FMT, and more transitions were observed when patients were treated with a different enterotype than their own at baseline (P = .01). Primary response was associated with lower total Mayo scores, lower bacterial cell counts, and higher Bacteroides 2 prevalence at baseline. CONCLUSION: The RESTORE-UC trial did not meet its primary endpoint of increased steroid-free clinical remission at week 8. Further research should additionally consider patient selection, sterilized sham-control, increased frequency, density, and viability of FMT prior to administration. ClinicalTrials.gov, Number: NCT03110289.