Ileocaecal resection versus infliximab for ileal Crohn's disease: retrospective 10-year follow-up of the LIR!C trial.

Crohn's disease (CD) in children poses a growing clinical challenge, with increasing incidence and variable response to biologic therapies such as infliximab (IFX). While gut bacterial dysbiosis has been extensively studied, the role of the gut virome in pediatric CD remains largely unexplored. This study provides the first longitudinal characterization of the fecal virome in children with CD undergoing IFX therapy. We reveal distinct viral community patterns, functional alterations, and virus-bacteria interactions in pediatric CD patients. Notably, integration of virome and bacteriome profiles enhances diagnostic accuracy, offering a promising avenue for predictive biomarker development. Furthermore, virome changes may be associated with the IFX treatment outcomes in children with CD. These findings highlight the gut virome as a critical but overlooked dimension of host-microbiome interactions in pediatric CD, with potential implications for personalized therapy and mechanistic understanding of treatment resistance.

Anti-tumor necrosis factor treatments for inflammatory bowel disease face challenges like primary nonresponse and secondary loss of response, often due to antidrug antibodies that increase drug clearance. The Fc-gamma receptors type3A (FCGR3A) (rs396991) polymorphism affects infliximab pharmacokinetics and immunogenicity. This study investigates its influence on trough levels, anti-infliximab antibody development, and clinical outcomes in Iraqi ulcerative colitis (UC) patients. This single-center study involved patients on maintenance infliximab therapy who were enrolled. Serum infliximab trough levels and anti-infliximab antibodies (antibodies to infliximab) (free and total) were measured using enzyme-linked immunosorbent assay. Genotyping of the FCGR3A rs396991 polymorphism was performed via polymerase chain reaction amplification and Sanger sequencing. The partial Mayo score assessed disease activity. The significance level of statistics was P < .05. Among 43 patients, those with the CC genotype achieved target infliximab trough levels more frequently (55.6%) than AA (21.1%) or AC (0%) genotypes (P = .005). Median infliximab levels were highest in CC carriers (3.41 µg/mL, P = .022). The AC genotype had a significantly higher prevalence of total anti-infliximab antibodies (53.3%) compared to CC (22.2%) and AA (10.5%) groups (P = .02). Logistic regression confirmed the CC genotype positive association with therapeutic drug levels and lower antibody positivity, while the AC genotype correlated with increased immunogenicity. The FCGR3A rs396991 CC genotype is significantly associated with improved infliximab pharmacokinetics and reduced immunogenicity in UC patients. These findings highlight the potential of FCGR3A genotyping to guide personalized therapeutic strategies and optimize clinical outcomes in UC.

The effectiveness of infliximab in Crohn's disease is often compromised by immunogenicity. Oral low-dose methotrexate may offer a promising strategy to optimize infliximab therapy, yet its real-world effectiveness and safety remain uncertain. This study aimed to compare the effectiveness and safety of infliximab plus oral low-dose methotrexate versus infliximab monotherapy. In this single-center retrospective cohort study, 119 patients with Crohn's disease received either infliximab monotherapy (n = 99) or combination therapy with oral low-dose methotrexate (10-15mg/week; n = 20). The primary outcome was endoscopic remission (Simple Endoscopic Score for Crohn's Disease ≤ 2) at week 26. Propensity score methods, including nearest-neighbor matching and inverse probability of treatment weighting, were used to adjust for confounding. Conditional and weighted logistic regression were used to estimate treatment effects. After propensity score adjustment, combination therapy was associated with a significantly higher rate of endoscopic remission (aOR 3.70, 95% CI 1.16-11.75; P = 0.027). No significant differences were observed in endoscopic response or clinical outcomes. In a pharmacokinetic subgroup, combination therapy resulted in numerically higher infliximab trough concentrations and no detectable anti-drug antibodies (0% vs. 16.7%). Higher trough concentrations were associated with endoscopic remission (P = 0.033). The incidence of elevated liver enzymes was higher in the combination group (20.0% vs. 4.0%), but this difference was not statistically significant after adjustment (P = 0.058). In patients with Crohn's disease, oral low-dose methotrexate combined with infliximab was associated with significantly improved endoscopic remission at week 26 compared to infliximab monotherapy, without a statistically significant increase in adverse events.

ObjectiveAcute severe lower gastrointestinal bleeding (SLGIB) is one of the life-threatening complications of Crohn’s disease (CD) whose therapy is being optimized constantly. We aim to evaluate the therapeutic efficacies and economic benefits of different treatments for acute SLGIB in CD.MethodA multicenter retrospective cohort study was conducted in Hunan Province of China on CD patients with acute SLGIB; here, we analyzed the clinical (hemostatic effects, hemoglobin improvement, rebleeding risk, anti-inflammatory influence, and complications) and economic (duration and cost of hospital stay) characteristics of infliximab, surgical, and traditional hemostatic therapies.ResultsAll three groups showed no obvious signs of bleeding in the first week. The negative conversion rates of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in the infliximab therapy group were significantly higher than those in the other two groups (adjusted-p < 0.05 for both CRP and ESR), while the increase in hemoglobin did not differ significantly among the three groups (p = 0.298). The incidence of post-treatment complications was significantly higher in the surgery (resection) group than the other two groups (adjusted-p < 0.05). Cumulative rebleeding risk was lowest in the infliximab therapy group (p = 0.001 vs. surgery and p = 0.032 vs. traditional therapy). The multivariate COX regression also revealed that surgery [hazard ratio (HR) = 7.270, 95% confidence interval (CI): (1.574, 33.592), p = 0.011] and traditional therapy [HR = 4.395, 95% CI: (1.011, 19.113), p = 0.048] were independently related to higher rebleeding risk than infliximab therapy. The duration and cost of hospital stay of the infliximab therapy group were significantly lower than those of the surgery group (adjusted-p < 0.05) and similar to those of the traditional therapy group (adjusted-p > 0.05).ConclusionCompared to surgery and traditional therapy (such as somatostatins or octreotide), infliximab therapy could control acute SLGIB in CD as well as achieve similar improvement in hemoglobin level with additional anti-inflammatory effects and lower rebleeding risk. Furthermore, infliximab therapy was found to be more economical than surgery.

Inflammatory bowel disease, encompassing ulcerative colitis (UC) and Crohn's disease, is increasing in prevalence in Western populations. Infliximab (IFX) is a standard treatment for severe UC. Evidence suggests combination therapy with IFX and azathioprine (AZA) improves clinical outcomes. However, AZA increases non-Hodgkin lymphoma (NHL) risk. We modeled the cost-effectiveness of combination therapy with IFX and AZA versus IFX monotherapy. We used a Markov model to simulate 25-year-old patients with UC over a 5-year time horizon in eight-week cycles. Patients received monotherapy, combination therapy for all 5years ("continuous combination therapy"), or combination therapy for 1year followed by monotherapy ("one-year combination therapy"). We measured quality-adjusted life years (QALYs) and costs of drug therapy, complications, and NHL. With monotherapy, patients experienced 3.263 QALYs and 6.84 flares; with 1-year combination therapy, 3.349 QALYs and 5.73 flares; and with continuous combination therapy, 3.351 QALYs and 5.67 flares. After 5years, NHL incidence was 0.188% with monotherapy; 0.207% with 1-year combination therapy; and 1.121% with continuous combination therapy. Healthcare costs were $312,500 for monotherapy, $264,700 for 1-year combination therapy, and $265,400 for continuous combination therapy. Results were robust across sensitivity analyses. Combination therapy with IFX and AZA is a cost-saving strategy for moderate-to-severe UC, providing superior outcomes and lower costs compared to IFX monotherapy. Both 1-year and continuous combination therapy achieve comparable health outcomes. Short-term combination therapy may be preferable, as it captures the benefits of improved UC management while avoiding the deleterious effects of long-term exposure to thiopurines.

We retrospectively reviewed 895 patients with Kawasaki disease treated at two Japanese pediatric centers between 2015 and 2024 to assess whether N-terminal pro-brain natriuretic peptide (NT-pro BNP) levels at diagnosis can predict the need for infliximab (IFX) therapy. Patients were divided into (1) the IFX group (n = 35), including patients who received IFX as third-line therapy due to resistance to first- and second-line treatments, including intravenous immunoglobulin, and (2) the non-IFX group (n = 860), including patients who responded to initial therapies. Clinical and laboratory variables were compared between the groups, and predictors of IFX use were analyzed using multivariate logistic regression and receiver operating characteristic (ROC) curves. Multivariate analysis comparing the IFX and non-IFX groups identified older age, lower hemoglobin levels, and higher NT-pro BNP Z-score at diagnosis as independent predictors of later IFX requirement. Additionally, the incidence of coronary arterial lesions did not differ significantly between the groups. ROC analysis demonstrated NT-pro BNP Z-score as a significant predictor (AUC 0.66, p < 0.001), with a cutoff of 2.2 yielding 71.4% sensitivity, 63.3% specificity, 7.3% positive predictive value, and 98.2% negative predictive value. Elevated serum NT-pro BNP Z-score at diagnosis was associated with later IFX use, whereas a low Z-score reliably identified patients unlikely to require IFX. Early assessment incorporating NT-pro BNP may optimize Kawasaki disease therapy and guide the appropriate timing of IFX administration.

Specific human leukocyte antigen (HLA) genotypes, particularly HLA-DQA1*05, have been proposed as predictors for infliximab (IFX) treatment response and immunogenicity in Western populations. However, the evidence regarding the effect of HLA-DQA1*05 remains limited in East Asian populations, including in Japan. Moreover, HLA-DQA1*05 frequency differs substantially from those in Western populations. Comprehensive analyses of the association between HLA alleles and IFX treatment outcomes may contribute to the identification of novel prognostic markers for IFX therapies. We retrospectively analyzed 301 biologic-naïve Japanese patients with inflammatory bowel disease (IBD). IFX persistence was assessed at both 2-digit and 4-digit HLA allele resolutions, and associations with anti-drug antibody levels at 1year after the initiation of IFX therapy were evaluated. At the 2-digit resolution analysis, HLA-DQB1*03 (hazard ratio [HR] = 2.39, p = 1.89E-06) and HLA-DQA1*05 (HR = 1.99, p = 3.91E-04) were significantly associated with early IFX discontinuation. At the 4-digit resolution analysis, HLA-DQB1*03:01 (HR = 2.03, p = 9.42E-05) and HLA-DQA1*05:05 (HR = 2.18, p = 4.42E-05) showed similar associations. All HLA-DQA1*05:05 alleles formed haplotypes with HLA-DQB1*03:01. Importantly, HLA-DQB1*03:01 was also associated with early discontinuation of IFX even when it formed haplotypes with alleles other than HLA-DQA1*05:05. Both HLA-DQB1*03:01 and HLA-DQA1*05:05 were significantly associated with elevated anti-drug antibody levels (p = 3.23E-03 and 3.54E-03, respectively). HLA-DQB1*03:01 encompasses the information of HLA-DQA1*05:05 and serves as a strong genetic predictor of IFX treatment persistence and immunogenicity in Japanese patients with IBD, offering a potential biomarker for personalized therapy.

The prevalence of inflammatory bowel diseases is increasing among the elderly. Older patients with inflammatory bowel disease represent a vulnerable population whose treatment strategies are significantly impacted by comorbidities and frailty. We present the case of a 69-year-old, Hungarian, nonsmoker female patient with a history of elderly-onset inflammatory bowel disease. The patient has longstanding type 2 diabetes (on insulin since 2011) and is being treated for hypertension and hyperlipidemia. In 2011, a diagnosis of left-sided ulcerative colitis was made, presenting with symptoms of fever and bloody diarrhea. Following the ineffectiveness of several conservative treatment modalities, the patient initially underwent adalimumab therapy, exhibiting primary nonresponse. Subsequently, the treatment was switched to vedolizumab, but she later developed secondary loss of response. She was diagnosed with end-stage renal disease and was started on hemodialysis in January 2022. In May 2023, because of severe endoscopic and symptomatic disease activity (endoscopic Mayo score 3, partial Mayo score 6, C-reactive protein 26.0mg/L, hemoglobin 111g/L, albumin 39g/L), infliximab therapy was initiated. We measured serial serum drug and anti-drug antibody concentrations to monitor the efficacy of the therapy and the effect of hemodialysis on drug concentrations. The patient responded to infliximab therapy, leading to clinical remission. Infliximab serum drug concentrations remained unaffected by hemodialysis. This case clearly illustrates the impact of comorbidities and the importance of a multidisciplinary approach in the management of elderly patients with inflammatory bowel disease. We demonstrated that infliximab therapy is effective and safe in the presence of concomitant severe inflammatory bowel disease and end-stage renal disease requiring hemodialysis.

Tonsillar tuberculosis as a manifestation of miliary tuberculosis in a patient with ulcerative colitis on infliximab therapy

Abstract Background Acquired hemophilia A (AHA) has never been reported in patients with pediatric inflammatory bowel disease (IBD). Aims We describe a case of AHA occurring in an adolescent with ulcerative colitis treated with infliximab. We hypothesize that in rare circumstances, anti-TNF therapy can trigger factor VIII inhibitor development in patients with IBD. Methods We reviewed the disease course of an adolescent with ulcerative colitis who developed AHA after 3 years of infliximab therapy. A focused literature review was performed to assess reports of inflammatory bowel disease and AHA. Results The patient presented at 14 years of age with a 3-month history of bloody diarrhea and raised serum and fecal biomarkers. His colonoscopy showed a Mayo 2 pancolitis. After a course of oral prednisone, he was commenced on infliximab monotherapy in September 2022. He achieved sustained clinical remission with normal serum and fecal biomarkers. Repeat scope in July 2024 showed endoscopic and histologic remission. Intestinal ultrasound in July 2025 showed transmural remission. In July 2025, he presented with spontaneous bruising and palpable purpura on his legs. Laboratory investigations revealed a prolonged aPTT, factor VIII activity &amp;lt;0.01 IU/mL, and a high-titer inhibitor (49 BU), consistent with AHA. Malignancy, infection, and systemic autoimmune disease were excluded. He was treated with recombinant activated factor VII, emicizumab, high dose prednisone plus rituximab. Infliximab was discontinued. Over four weeks he had no further bruising episodes, factor VIII levels improved (to 0.16 U/mL) and inhibitor titer decreased (to 1 BU). He remains on emicizumab, continues to wean prednisone, and will commence an alternate pathway advanced therapy in the next month. He remains in clinical, serum and fecal biomarker remission with transmural remission on intestinal ultrasound. A Literature review confirmed four adalimumab-associated AHA cases. Infliximab has not previously been associated with AHA. Moreover, there have been no prior pediatric IBD reports of AHA. Conclusions This case represents the first pediatric report of infliximab-associated AHA in ulcerative colitis. It expands the spectrum of paradoxical autoimmune complications of anti-TNF therapy in IBD. Gastroenterologists should suspect AHA in IBD patients presenting with unexplained bleeding and prolonged aPTT, even in the context of disease remission. Early recognition and multidisciplinary management are essential to avoid morbidity and guide safe transition to alternate pathway advanced IBD therapies. Funding Agencies None

Abstract BACKGROUND Sustaining therapeutic exposure aligned with disease control is essential for the long-term success of infliximab (IFX) in inflammatory bowel disease (IBD). The Bayesian Estimate Sustaining Trough (BEST) study evaluated the clinical utility of a precision-guided dosing (PGD) tool and pharmacokinetic (PK) metrics, specifically IFX concentration and clearance (CL), to inform individualized dosing strategies. METHODS Patients with IBD receiving maintenance IFX therapy were prospectively enrolled from November 2023 to January 2025 across three North American centers, representing two academic medical centers and one community-based gastroenterology practice. The PGD tool (PredictrPK IFX Maintenance test) measured current IFX and anti-drug antibody levels, estimated trough concentrations, calculated IFX CL (L/day), and proposed dosing regimens to achieve target exposure. Serum samples were processed by an accredited clinical pharmacokinetics laboratory (Prometheus Laboratories, San Diego, CA). Outcomes included changes in IFX dosing and PRO2-based clinical remission, assessed at each treatment cycle. Statistical analyses included Kruskal-Wallis, Fisher test, and logistic regression. RESULTS Ninety-seven patients were enrolled (Table 1), with 296 specimens analyzed (93% proactively). Most patients were in clinical remission (82%), with 90% of cycles showing trough IFX concentrations ≥10 μg/mL and a low incidence of immunization (3%). Following PGD reporting, IFX therapy was reduced (17 cycles, 82% in remission), continued (238 cycles, 84% in remission), intensified (37 cycles, 70% in remission), or discontinued (4 cycles, 25% in remission). Dose intensification was associated with significantly lower concentrations, while dose continuation and reduction correlated with lower CL (Table 2). Clinical remission was associated with lower CL (median 0.244 L/day [IQR: 0.180-0.308 L/day] vs. 0.279 [IQR: 0.231-0.327 L/day], p = 0.005), with no significant difference in trough concentrations. Patients with CL &amp;lt; 0.248 L/day were 2.7 times more likely to be in remission (95% CI: 1.4–5.2, p &amp;lt; 0.01), with a similar trend for those with concentrations &amp;gt;20 μg/mL (OR = 2.1, p = 0.08). CONCLUSION PGD demonstrated clinical utility in informing individualized IFX therapy for IBD, with dosing decisions aligned to pharmacokinetic profiles and clinical outcomes. CL was a strong predictor of clinical remission, reinforcing its role as a key parameter in therapeutic monitoring. PGD guided adjustments, whether intensification, continuation, or reduction, were associated with distinct PK patterns and remission rates, supporting its value in treatment optimization. Importantly, elevated CL identified a subgroup of patients with adequate drug exposure but suboptimal disease control, likely reflecting persistent inflammatory burden.

Background: Inflammatory activity in rheumatoid arthritis can be determined by normal blood count ratios such as Neutrophil Lymphocyte Ratio (NLR), Platelet Lymphocyte Ratio (PLR), Systemic Immune Inflammation Index (SII), and C-reactive Protein (CRP). Objective: The aim of this research is to determine how these markers change after therapy and whether their pre- and post-treatment differences follow patterns that allow for simple parametric analyses. Methods: A prospective cohort of 52 RA patients (30 females and 22 males) was examined. The patients' blood samples were tested at baseline and at the end of their 6-month Infliximab treatment. Hematologic markers such as NLR, PLR, and SII were calculated from the complete blood count (CBC), and CRP levels were measured. The statistical methods of Shapiro-Wilk (SW), Kolmogorov-Smirnov (KS), and Anderson-Darling (AD) were used, and later, paired t-tests were used to generate statistics where necessary. Results: Post-treatment measurements were consistently lower for all four biomarkers. QQ-plots and formal tests revealed that the differences between findings were essentially normal, allowing for paired t-tests. The mean decreases were as follows: NLR -1.10 (95% CI -1.48 to -0.71), PLR -43.0 (-55.4 to -30.7), SII -299 (-388 to -211), and CRP -11.36 (-13.18 to -9.54), all p < 0.001. CRP showed the greatest drop, with significant decreases in PLR and SII and a moderate decline in NLR, indicating therapy-related attenuation of systemic inflammation. Conclusions: The study shows that six months of infliximab therapy results in a consistent post-treatment decrease in all four biomarkers: NLR, PLR, SII, and CRP. Because the pre-post differences were roughly normal, CRP revealed the greatest decrease, with significant decreases in PLR and SII and a moderate decrease in NLR, consistent with systemic inflammation reduction. When combined, the CBC-derived indices track with CRP and can serve as practical, low-cost markers for monitoring therapy response in RA, despite the single-arm design.

Abstract Biomarkers that accurately predict responses to IBD therapy in individual patients would significantly optimize clinical outcomes. Biology and disease are complex systems from which actionable insights can be derived using algorithms. We hypothesized that algorithmic gene expression biomarkers, highly predictive of individual responses to TNF therapy in rheumatoid arthritis (RA), would also enable derivation of algorithmic biomarkers predictive of individual responses to TNF therapy in both ulcerative colitis (UC) and Crohn’s disease (CD). We assumed that similar molecular networks underlie the response to TNF therapy in different diseases, and these could be characterized algorithmically as predictive biomarkers. Applying quantitative AI, based on evolutionary computation to baseline peripheral blood gene expression data, we previously identified 8 variables that yielded algorithms using subsets of 4 variables that had 100% accuracy in predicting individual responses to TNF therapy in RA patients. Following discovery from a placebo-controlled clinical trial, these 8 variables were validated in 6 independent data sets and are in development as a clinical test: https://doi.org/10.12688/f1000research.164015.1. We then applied the 8 RA variables to two previously published data sets of baseline mucosal gene expression obtained prior to initiation of infliximab therapy in IBD patients. The first cohort included 46 UC patients (20 responders and 26 non-responders) and 6 polypectomy controls. The second cohort included 61 patients: 24 UC (8 responders and 16 non-responders), 19 CD colitis (12 responders and 7 non-responders), and 18 CD ileitis (8 responders and 10 non-responders), with 12 polypectomy controls: PMID: 19700435 and PMID: 19956723. A subset of 2 variables from the 8 previously identified in RA yielded predictive algorithms of TNF response in UC, CD colitis and CD ileitis. The software-derived algorithms, containing these 2 variables (C1orf105 and PTPRC) plus dose, correctly predicted responders versus non-responders for all patients in both data sets, giving 100% accuracy, sensitivity and specificity. This accuracy surpassed that reported in the original publications. We present illustrative algorithms to provide transparency and to enable independent verification. These findings suggest that the RA test in development will also have clinical utility in IBD. This approach may be useful for developing response predictors for other therapies, thereby realizing the vision of precision medicine to optimize outcomes. Algorithmic biomarkers might also be the basis for dynamic product labels accurately predicting therapeutic responses for individual patients. The two components of the algorithms, C1orf105 and PTPRC, may have important roles in pathogenesis of IBD that have not been previously apparent, including consideration as novel therapeutic targets.

Infliximab's efficacy as a second-line agent in moderate or severe ulcerative colitis after prior advanced therapy failure is unclear. Registration trials for infliximab did not assess its efficacy after exposure to other advanced therapies, a sequence in which it is increasingly used. We evaluate infliximab's second-line effectiveness, identify predictors of response, and compare outcomes to its first-line use. We conducted a retrospective cohort study of adults with ulcerative colitis treated with infliximab at a tertiary care center. Patients were categorized by line of therapy. Clinical and endoscopic outcomes at 1 year were compared between first-line and second-line users. Multivariable logistic regression was used to assess predictors of 1-year clinical remission. Among 225 included patients, 143 received infliximab first-line and 82 as second-line or subsequent therapy. Clinical response at 1 year was significantly lower in second-line users (odds ratio 0.53, 95% confidence interval: 0.28-0.99, P = 0.049) and remained significantly lower after adjustment for biosimilar and concurrent steroid use. Dose escalation was more common with second-line use (57.3% vs. 42.0%, P = 0.026). Endoscopic and histologic remission was numerically lower in second-line users (47.7% vs. 33.3% and 27.0% vs. 41.7%, respectively), though these were not statistically significant (P = 0.180 and 0.099, respectively). Infliximab remains effective as a second-line agent in ulcerative colitis, though with reduced response and higher rates of dose escalation as compared to use first-line. These findings support its continued use while highlighting the need for optimized patient selection and treatment strategies in therapy-exposed populations.

Abstract Background Crohn’s disease (CD) is chronic inflammatory disease (1). Evidence shows that patients with active CD present with reduced circulating levels of insulin-like growth factor (IGF) and platelet-derived growth factor BB (PDGF-BB) (2). This study aimed to investigate the changes of growth factors levels in patients with CD. Methods This was a prospective multi-center observational study. The study participants were categorized into three categories: patients diagnosed with CD on infliximab therapy (infliximab group), patients scheduled to commence infliximab treatment (bio-naïve group), and a cohort of healthy individuals serving as control group. The main outcome of the study was comparing the serum levels of the IGF subtypes numbered 1 to 6 and PDGF-BB in patients with CD compared to healthy controls. In bio-naïve patients, levels of growth factors were assessed before and after initiating infliximab. Results A total of 217 patients with CD were included in the study. Growth factors levels were lower in patients with CD compared to healthy controls. Specifically, IGF levels were significantly lower in patients with CD who have already received infliximab (382.91 ± 26.94) compared to the healthy control group (449.49 ± 76.84 ng/ml) p-value &amp;lt;0.001. While patients who are bio-naïve had the lowest levels of IGF (57.01 ± 8.96). Levels of other IGF subtypes and PDGF-BB showed similar patterns across the three different groups (figure 1). Conclusion In patients with CD there was a significant reduction of circulating PDGF-BB and certain subtypes of IGF levels compared to healthy controls. These growth factors may serve as novel markers for IBD.

Abstract Background The gut microbiota has been implicated in the pathogenesis of Crohn’s disease (CD), and infliximab (IFX) is commonly being utilized as a therapeutic option for pediatric CD patients. However,it remains unclearwhether the fecal virome is modified during IFX treatment. This study aims to characterize the alterations in the fecal virome among pediatric patients with CD and to evaluate how IFX therapy affects these changes. Methods Metagenomic sequencing of fecal viral-like particles was applied todetermine the compositions of virome communities in fecal samples. The composition and function of the fecal virome were compared between CD patients(n = 60) and healthy controls(n = 25). Among these patients, 53 received at least three IFX treatments,and 41 of them achieved remission (IFX-R), while 12 did not (IFX-NR). Results Compared with controls, CD subjects exhibited significantly lower viral richness (measured by the Chao1 index). Patients in the baseline CD remission group (Baseline-R) demonstrated significantly elevated linear discriminant analysis (LDA) scores for Anelloviridae compared to other subjcets. Conversely, Microviridae manifested higher LDA scores in healthy control subjects, while Caudovirales displayed elevated LDA scores at the baseline level of the non-remission group (Baseline-NR). Following treatment with IFX, the IFX-R group exhibited a more diverse composition of dominant viral taxa, indicating potential remodeling of the gut virome during remission. Additionally, CD patients exhibited differences in various viral functions in terms of Gene Ontologyfunctions compared with healthy controls. Moreover, the combined fecal virome and bacterial markers demonstrated diagnostic potential for CD, with AUC of 89.3%. Conclusion Fecal virome in pediatric CD is characterized by a significant decrease in fecal viral diversity, changes in specific virus taxa, and a loss of multiple viral functions. Certain patterns in the fecal virome and fecal microbiome may be predictive for diagnosis of pediatric CD. Conflict of interest: Ge, Ting: No conflict of interest Ruan, Yangming: No conflict of interest Ye, Lin: No conflict of interest Xiao, Fangfei: No conflict of interest Prof. Dr. Zhang, Ting: No conflict of interest

Abstract Background Intestinal drug concentrations in patients with inflammatory bowel disease (IBD0 under subcutaneous (SC) infliximab (IFX) therapy have not been investigated. Aim: We compared serum with tissue drug levels between patients with IBD treated with SC or intravenous (IV) IFX maintenance therapy. Methods Any IBD patients under stable dose SC or IV IFX maintenance therapy who underwent a colonoscopy were eligible. Clinical disease activity was defined by using clinical activity scores and biomarkers. Endoscopic disease activity was categorized as absent, or active graded as mild, moderate, or severe. Two biopsy specimens and a blood sample at the time of endoscopy were collected. Results In total 35 patients were enrolled. including 23 patients treated with SC (cohort SC) and 12 with IV IFX therapy (cohort IV) Serum and tissue drug levels were significantly higher in the SC IFX cohort compared with those in the IV cohort (22 µg/mL vs 9 µg/mL for serum; p &amp;lt; 0.001 and 25 µg/g vs 10 mg/g for tissue; p = 0.002, respectively) (Fig 1). Similar positive correlations were found between serum and tissue drug levels for both IV and SC cohorts (r = 0.42; p = 0.014 and r = 0.43; p = 0.001, respectively). Tissue drug levels increased gradually from patients with no endoscopic activity to those with mild, moderate or severe endoscopic activity in both the IV and the SC cohort (both, p &amp;lt; 0.001). A serum IFX level greater than 16.1 mg/mL was highly predictive of a tissue drug level &amp;gt; 14 mg/g tissue (Sensitivity: 94 %, Specificity: 94 %). Tissue and serum drug concentration was associated significantly with sustained clinical remission with a threshold value of 17 µg/g (p &amp;lt; 0.001) and 14.5 µg/mL(p:0.01) but should better tissue concentration could predict with more accuracy sustained clinical remission than serum drug levels (AUROC: 0.82 and 0.76 respectively) (Fig 2). Conclusion Serum and tissue drug IFX levels are positively correlated and are significantly higher in patients receiving SC compared to IV IFX. Tissue IFX concentration predicted strongly sustained clinical remission and should be interesting in clinical practice to optimize our patients. Conflict of interest: Prof. Dr. Roblin, Xavier: Abbvie, Celltrion, Amgen, Ferring, Takeda, Janssen, Biosynex, Pfizer Nancey, Stéphane: Abbvie, Janssen, Pfizer, Celltrion, Takeda, Amgen Fresenius Kabi, Sandoz, Lilly Barrau, Mathilde: Abbvie, Celltrion, Janssen Papamichail, Konstantinos: Personal Fees: Lecture fees from Physicians Education Resource LLC and Grifols scientific advisory board fees from ProciseDx Inc and Scipher Medicine Corporation. Other: Consultant for Prometheus Laboratories Inc. Cheifetz, Adam: Consulting and Scientific Advisory Board (SAB): Abbvie, Johnson and Johnson, Prometheus (SAB), Bisynex, Aegirbio (SAB), Artizan (SAB), Fzata, Celltrion, Eli Lilly, Adiso, BMS, Clario, Food is Good, Fresenius Kabi, Pfizer, Procise, Spherix, Samsung Speaking (non-branded): Abbvie, BMS, Johnson and Johnson Paul, Stephane: Biosynex, Celltrion, Pfizer, Takeda, Abbvie, Janssen

Abstract Background Biological therapies have transformed the management of inflammatory bowel disease (IBD). However, many patients experience loss of response (LOR), often due to the development of anti-drug antibodies (ADA).1 The aim of the study was to explore association between genetic variations and ADA development in patients with IBD treated with biologics. Methods Systematic review of the literature using a predefined search string. We searched Medline, Embase, and the Cochrane Library and identified 1,944 records, of which 27 studies were included in the analysis. Articles were screened, and data extracted, by two independent persons. Results HLA-DQA105 carriage was consistently associated with increased risk of ADA, lower drug levels, treatment failure, and secondary LOR in both infliximab (IFX) and adalimumab (ADL) treated IBD patients, with strongest effects observed in IFX. With the high prevalence in Western populations (≈31–46%), HLA-DQA1*05 represents a clinically relevant risk factor.2 Outcomes varied with population, study design, and statistical approach across studies, preventing a pooled result or summary interval. Across four studies focusing on IFX, all demonstrated increased ADA risk in HLA-DQA1*05 carriers (HR 1.65, adjusted HR 7.29), including higher rates of treatment intensification, drug discontinuation and LOR.3 Other HLA alleles were also associated with increased risk of ADA, while some haplotypes appeared protective. FCGR3A variants were similarly strong predictors of ADA formation during IFX therapy with highest risk in V allele carriers (HR 7.3, OR 6.08), reduced trough levels and increased need for dose escalation. Frequencies for FCGR3A variants (F 66%, V 34%) further highlights their potential clinical impact.4 Combined carriage of FCGR3A and HLA-DQA1*05 additionally increased the ADA risk by 10-fold. For ADL, FCGR3A showed a weaker but allele-dose–dependent association with ADA formation. Other genetic variants including TNF-related SNPs, IGHG1 allotypes, NUDT15, and CD96, showed limited, inconsistent or context-specific associations. ADA rates for ustekinumab and vedolizumab were low and no genetic associations were detected. Immunomodulator co-therapy, disease type or age had inconsistent or minimal effects on ADA risk. Conclusion HLA-DQA1*05 and FCGR3A are the most consistent predictors of immunogenicity and are strongly associated with ADA formation, LOR and drug level reductions – particularly in IFX-treated patients. Given relatively high prevalence of the genetic variants, evaluating these polymorphisms is clinically relevant. Routine testing may guide treatment optimization and therapy selection. As commercial assays are available, implementation is feasible.

Abstract Background There is currently a significant waiting time for patients referred to the IBD infusion unit to start new biologic therapies at St Marks Hospital, due to capacity issues. To address this challenge, this study proposes a new infusion administration regimen with shortened infusion times; patients will be administered their first infliximab dose over 2 hours, doses 2-3 will be administered over 1 hour, and any subsequent doses will be administered over 30 minutes. Methods Suitable patients were identified by the IBD pharmacy and nursing teams prior to infliximab initiation. Patients with previous exposure to infliximab and/or any history of cardiac disease or on escalated doses (10mg/kg) were excluded from this study. Safety protocols were in place in the event of any infusion-related reactions. Details were recorded of infusion times, occurrence of any infusion reactions and interventions or treatments provided. Results Data was collected for a total of 37 patients. At the time of reporting, 26 patients had at least three doses at the proposed infusion regimen and did not experience any infusion-related reactions. When compared with the licensed administration schedule (first three doses over 2 hours and subsequent doses may be given over 1 hour)1, this new regimen resulted in a total administration time saving of approximately 50 hours. In addition, four patients subsequently received a fourth dose at an infusion rate of 30 minutes with no infusion-related reactions, which resulted in an additional 2 hours of administration time saved. A further 17 patients were transitioned to subcutaneous infliximab after completing three intravenous doses. Three patients (8.1%) developed an infusion related reaction after their second dose. Two of these patients had previous exposure to infliximab which was not identified prior to initiation and should have been excluded from this study. Overall, our results show similar rates of infusion-related reactions to those reported in the literature. In phase III studies, 18% of patients experienced an infliximab-related reaction1. In another study for Crohn’s disease patients, 16.6% of patients treated with infliximab monotherapy and 5% of patients treated with infliximab and azathioprine combination therapy experienced an infusion-related reaction2. Conclusion Our results suggest that the proposed infusion regimen does not increase the risk of infliximab infusion-related reactions when compared with the standard licensed administration schedule. Adopting this regimen could significantly enhance infusion unit efficiency by reducing administration time burden, which may subsequently reduce wait times for patients requiring initiation of biologic therapy.