We report a rare case of cytomegalovirus (CMV) iridocyclitis and vitreoretinal lymphoma (VRL) that developed sequentially in the same eye during long-term infliximab (IFX) therapy for ulcerative colitis. This case highlights both the risk of opportunistic ocular infections and lymphoproliferative disorders coexisting in the same eye and the diagnostic challenges associated with prolonged immunosuppression. A 65-year-old man presented to the ocular inflammatory service at Nippon Medical School Tama-Nagayama Hospital with deteriorating vision in the left eye. His medical history included IFX therapy for 11 years for ulcerative colitis, a 7-year history of bilateral primary open-angle glaucoma, and recurrent iridocyclitis in the left eye. Slit-lamp examination revealed mutton-fat keratic precipitates and dense vitreous opacities. Multiplex PCR of the aqueous humor detected CMV and Epstein-Barr virus (EBV). The cytological grading of the vitreous fluid was class IIIb. Cytokine analysis revealed an interleukin (IL)-10/IL-6 ratio of > 1.0, and immunoglobulin heavy chain gene rearrangement revealed monoclonality. Based on these findings, the patient was diagnosed with concurrent CMV iridocyclitis and VRL in the same eye. EBV positivity in the aqueous humor may have been associated with VRL development under prolonged immunosuppression. Topical ganciclovir was initiated for CMV iridocyclitis. The patient underwent bilateral ocular radiotherapy (40Gy) and systemic chemotherapy with rituximab, methotrexate, procarbazine, and vincristine after IFX cessation. Although inflammatory and infiltrative lesions resolved, his final visual acuity was 20/200 due to glaucomatous visual field loss. The present case highlights both the risk of opportunistic ocular infections and lymphoproliferative disorders associated with prolonged immunosuppression and the diagnostic challenge when both conditions coexist in the same eye. Careful monitoring and close collaboration between ophthalmologists and internists are essential for the early diagnosis and appropriate management of such patients.

Objectives: To explore the relationships of interleukin-7 receptor (IL-7R) gene polymorphisms with the risk of Crohn's disease (CD), as well as the efficacy of infliximab (IFX) in patients with CD. Methods: The CD patients (CD group) and healthy controls (control group) at the Second Affiliated Hospital of Wenzhou Medical University between January 2020 and May 2025 were retrospectively collected. Genotypes of IL-7R gene at loci rs6897932, rs1494555, rs1494558 were examined in both groups. According to Montreal CD Classification, the disease locations were divided into terminal ileal-type, colonic-type, ileocolic-type and upper gastrointestinal-type. Among CD patients receiving IFX treatment, the clinical response was evaluated by Crohn's Disease Activity Index (CDAI) at week 14 of follow-up. The patients were divided into the clinical response group (a decline of CDAI≥100 points compared with week 0) and the clinical non-response group. The efficacy of endoscopy was assessed by Simplified Endoscopic Score for Crohn's Disease (SES-CD) at week 32. The patients were divided into the mucosal healing group (SES-CD≤2 points or absence of mucosal ulcerations) and the mucosal non-healing group. The distribution differences of IL-7R gene polymorphisms were compared between CD group and control group, among CD patients with different clinical phenotypes, between the clinical response group and the clinical non-response group, as well as between the mucosal healing group and the mucosal non-healing group. The genotypes or alleles with distribution differences were included into multivariate logistic regression model to investigate the relationships of IL-7R gene polymorphisms with the risk of CD, the clinical phenotypes, and the clinical efficacy of IFX in CD patients. Results: The CD group consisted of 303 participants [200 males and 103 females, aged 30 (23, 40) years]. The control group consisted of 514 participants [313 males and 201 females, aged 32 (26, 42) years]. The variant allele (T) [14.0% (85/606) vs 18.5% (190/1 028)] of locus rs6897932 were less frequent in the CD group than that in the control group, but the difference was not statistically significant after adjustment (adjusted P=0.054). The homozygous variant genotype (TT) of locus rs6897932 in the patients with terminal ileal-type and ileocolic-type CD group were less frequent than that with colonic-type CD [0.8% (2/261) vs 9.5% (4/42), adjusted P=0.009]. The homozygous variant genotype (TT) of locus rs6897932 (OR=0.06, 95%CI: 0.01-0.38) was the related factor influencing the terminal ileum involvement (the disease location is terminal ileal-type or ileocolic-type) in CD patients. A total of 112 CD patients were treated with IFX. There were 78 cases in the clinical response group and 34 cases in the clinical non-response group at week 14 of IFX treatment. The variant genotype (CT+TT) [38.5% (30/78) vs 11.8% (4/34), adjusted P=0.015] and variant allele (T) [20.5% (32/156) vs 5.9% (4/68), adjusted P=0.018] of locus rs6897932 in the clinical response group were more frequent than those in the clinical non-response group. The variant genotype (CT+TT) (OR=5.17, 95%CI: 1.54-17.36) of locus rs6897932 was the related factor influencing the clinical response at week 14. There were 43 cases in the mucosal healing group and 69 cases in the mucosal non-healing group at week 32 of IFX treatment. The variant genotype (TC+CC) [65.1% (28/43) vs 85.5% (59/69), adjusted P=0.036] of locus rs1494558 in the mucosal healing group was less frequent than that in the mucosal non-healing group. The variant genotype (TC+CC) (OR=0.24, 95%CI: 0.09-0.71) of locus rs1494558 was the related factor influencing the mucosal healing at week 32. Conclusions: The homozygous variant genotype (TT) of locus rs6897932 in IL-7R gene may be related with a lower risk of terminal ileum involvement (the disease location is terminal ileal-type or ileocolic-type). In CD patients receiving IFX treatment, the variant genotype (CT+TT) of locus rs6897932 in IL-7R gene may be related with an increased clinical response rate at week 14, while the variant genotype (TC+CC) of locus rs1494558 may be related with a reduced mucosal healing rate at week 32.

Background:Anti-tumor necrosis factor alpha (anti-TNFα) agents assume a significant role in the management of Crohn’s disease (CD). Exclusive enteral nutrition (EEN) is as effective as corticosteroids for inducing remission in children with active CD, but less effective in adults. Few studies have compared the relative effectiveness of these strategies in achieving endoscopic improvement and symptom relief.Objectives:We aimed to compare the efficacy of EEN, infliximab (IFX), and combination therapy in adult patients with CD.Design:Retrospective cohort study.Methods:Between March 2021 and June 2024, 270 adult patients with active CD were recruited and received EEN, IFX, or combination treatment for 14 weeks. Propensity-score (PS) matching was conducted to balance the baseline characteristics across the three groups. The fecal 16S rRNA sequencing and metabolomics analyses were applied to further analyze the underlying mechanism involved in combination and monotherapy.Results:Of the 270 reviewed patients, a total of 146 PS-matched adult CD patients who received EEN (n = 29), IFX (n = 56), and combination therapy (n = 61), respectively, were analyzed. The combination therapy of EEN plus IFX demonstrated greater improvement in endoscopic response at week 14 compared to both the EEN group (p = 0.021) and the IFX group (p = 0.032), but not in endoscopic remission. Combination therapy also exhibited a significantly higher clinical response rate compared with EEN (p = 0.027) and IFX (p = 0.038) monotherapy, but no significant difference in clinical remission. Furthermore, compared with IFX monotherapy, combination therapy increased the IFX trough level at week 14 (p < 0.001). Fecal 16S rRNA sequencing revealed that combination therapy successfully restored the abundance of Bacteroidetes and related genera. Targeted metabolomics further confirmed a significant increase in short-chain fatty acids (SCFA) and key metabolites (e.g., indolelactic acid) in fecal samples 14 weeks after combination therapy.Conclusion:Combination therapy is more effective than EEN or IFX monotherapy for short-term endoscopic and clinical response. Mechanistically, combination therapy reshapes the gut microbiota, restores levels of SCFAs, and increases key protective fecal metabolites, offering a promising strategy for the management of CD.

Infliximab (IFX) for inflammatory bowel disease (IBD) treatment may increase the risk of hepatitis B virus (HBV) reactivation, particularly in areas with high HBV prevalence such as China. This study aimed to evaluate HBV reactivation/infection, liver dysfunction, vaccination efficacy and strategies in IBD patients undergoing IFX therapy. This retrospective, multicenter study included 4183 IBD patients from 15 hospitals across China, who were divided into six groups according to the HBV status. Demographic features, HBV vaccination status, reactivation/infection rates, and liver dysfunction outcomes were collected, with data collection performed from 2009 to 2022. We found that HBV reactivation rate was notably higher in HBsAg positive group than other groups (P < 0.05) despite antiviral treatment. Although only 29% of patients were immunized at IFX initiation and almost no patients got vaccinated against HBV during IFX treatment, no patients experienced HBV infection in the susceptible population group. The study underscores a critical need for rigorous HBV screening before IFX initiation. Despite antiviral prophylaxis, the importance of continuous monitoring of HBV DNA is necessary for HBsAg positive patients. HBsAg negative patients, including the susceptible population, had a very low risk of new HBV infection, thus reassuring patients and physicians of the safety of IFX in this cohort.

Benefits of a proactive compared to a reactive therapeutic drug monitoring strategy when commencing infliximab (IFX) in children with Crohn's disease are unclear. We evaluated the 6- and 12-month outcomes in children commencing IFX with a week 14 level (W14) determined compared to without (NoW14). Single-centre, retrospective study of children with Crohn's disease aged 0-18 years with a primary response to IFX induction between 2018-2021. W14 group had a week 14 IFX drug level determined and NoW14 group did not. Baseline patient, medication and disease characteristics were compared across the two groups. Clinical and biochemical disease activity measures, and IFX dose, frequency and drug level were compared at week 0, 6- and 12-months post-induction. Failure was defined by biologic switch, corticosteroid use, hospitalisation or surgery. We included 83 children diagnosed at median 13 years, with a median disease duration of 5 years. The W14 group (40/83, 48.2%) had a higher C-reactive protein (CRP) than NoW14 group. At 12-months, there was no difference in failure rates (33% vs. 33%, p=0.50) or IFX persistence (98% vs. 95%, p>0.999) between the W14 and NoW14 groups, respectively. There was no difference in IFX drug level at 6- or 12-months. At 12-months, there was a greater reduction in CRP and rise in albumin in the W14 group. Knowledge of a week 14 level without strict thresholds on how and when to respond may be of minor benefit for children commencing infliximab for Crohn's disease.

Pathogenic Th17 cells orchestrate mucosal inflammation and drive secondary loss of response to infliximab in inflammatory bowel disease: clinical and mechanistic evidence.

The optimal infliximab (IFX) dosing strategy for acute severe ulcerative colitis (ASUC) remains unclear. Though intensified IFX dosing is frequently employed, evidence supporting its efficacy has been mixed and it is uncertain if intensified IFX more effectively captures remission than standard-dose IFX. We conducted an updated meta-analysis comparing standard- vs intensified-dose IFX in ASUC, incorporating PREDICT-UC trial data and applying a Bayesian framework to better integrate prior evidence and quantify uncertainty. Electronic databases were systematically searched from inception to December 2024 (PROSPERO ID: CRD42024616359). We conducted a 2-step meta-analysis. First, retrospective cohort studies were assessed with a frequentist random-effects meta-analytic approach. Second, because there is only 1 trial (PREDICT-UC) comparing intensified vs standard IFX in ASUC, we applied a Bayesian meta-analytic approach by using historical trials of standard-dose IFX in ASUC to define the prior probability distribution and then compared that to PREDICT-UC. Ten retrospective cohort studies (530 standard-dose and 406 intensified-dose patients) were included in the frequentist analysis. We applied a Bayesian binomial regression model with the historical randomized controlled trials of standard-dose IFX as the reference group. The estimated 3-month colectomy rate for standard-dose IFX was 27% (95% credible interval, 22%-33%). In the PREDICT-UC trial, observed colectomy rates were 15% in patients receiving rescue-dose IFX at 5 mg/kg and 6% in those receiving upfront intensified dosing at 10 mg/kg. Posterior estimates for both intensified dosing strategies in PREDICT-UC were credibly lower than the standard-dose IFX reference. Integrating observational and trial data via Bayesian methods suggests that intensified IFX dosing reduces early colectomy in ASUC. These findings support prospective, adequately powered trials to confirm benefit, identify subgroups most likely to respond, and refine individualized accelerated-dosing algorithms.

Background: Therapeutic drug monitoring (TDM) of anti-TNF biologics may help optimise treatment in rheumatoid arthritis (RA), but current therapeutic ranges do not always reflect clinical response in routine practice. Methods: We conducted a retrospective observational study including 224 adults with RA treated with infliximab (IFX), adalimumab (ADL), or etanercept (ETN) during the maintenance phase at Hospital Universitario Puerto Real between May 2016 and May 2023. Drug and anti-drug antibody levels were measured by sandwich ELISA and analysed against clinical response using DAS28. Demographic and clinical variables, associations between drug levels and response, the effect of antibodies, correlations between serum concentrations and DAS28, and the performance of current and proposed therapeutic ranges were evaluated. Results: The cohort was mainly female (62.1%), with a mean age of 57.7 years, BMI of 28.5 kg/m2, and mean DAS28 of 3.33. ETN was most frequently used (62.5%), followed by ADL (21.9%) and IFX (15.6%). Drug levels were significantly associated with response (p &lt; 0.001). Anti-drug antibodies were strongly linked to non-response, especially with IFX and ADL. Serum drug levels correlated inversely with disease activity for IFX and ADL, but not for ETN. Current therapeutic ranges showed low sensitivity, while lower proposed ranges improved sensitivity considerably. Conclusions: Current anti-TNF therapeutic ranges have limited ability to identify responders in real-world RA. Lowering the lower bound improves sensitivity and supports more individualised TDM, particularly for IFX and ADL, pending prospective validation.

The E3 ubiquitin ligase tripartite motif 27 (TRIM27) is a negative regulator of NF-κB activation and the innate immune response, and TRIM27 deficiency significantly impairs dextran sulfate sodium (DSS)-induced colitis. The function of TRIM27 in intestinal epithelial cells (IECs), the mechanism by which TRIM27 inhibits the NF-κB pathway and its dysregulation in ulcerative colitis (UC) remain unclear. Here, it is report that epithelial TRIM27 functions as an anti-inflammatory factor that inhibited intestinal inflammation in IECs in vitro and in epithelial Trim27 knockout mice in vivo. Mechanistically, TRIM27 destabilized IKKα and TRAF6 via polyubiquitination of IKKα at the K569 site and TRAF6 at the K489 site. In response to TNF-α, IKKβ phosphorylated TRIM27 at S173 to decrease TRIM27 expression by impairing its binding to ubiquitin-specific protease 7 (USP7) and USP7-mediated TRIM27 deubiquitination. Notably, overexpression of TRIM27 enhanced the anti-inflammatory effect of infliximab (IFX) in IECs. TRIM27 is downregulated in inflamed colons from UC patients and is associated with the therapeutic effect of IFX. Overall, this study identifies epithelial TRIM27 as a bona fide negative modulator of intestinal inflammation and USP7/TRIM27-IKK as a new double negative feedback mechanism of the NF-κB pathway, which supports the use of TRIM27 replenishment as a potential therapeutic strategy for UC.

There is limited data on advanced therapy outcomes in second-line vs. first-line advanced treatment of patients with ulcerative colitis (UC) and Crohn's disease (CD). We conducted a retrospective health claims study of patients with UC and CD in Germany. We analyzed claims data from 2014 to 2021, and compared therapy persistence and dose escalation in first- (1L) and second-line (2L) advanced therapy. Our analysis included the approved therapies adalimumab (ADA), infliximab (IFX), ustekinumab (UST) and vedolizumab (VDZ) for both UC and CD patients and golimumab (GOL) and tofacitinib (TOF) for UC patients. 2,948 patients were included in the study and initiated 1L advanced therapy. Of these, 823 patients started a 2L advanced therapy. Time on treatment was generally shorter in 2L compared to 1L: In UC patients, persistence rates at 2 years ranged from 52.5% to 71.9% for 1L, and from 40.1% to 69.1% for 2L. In CD patients, persistence rates ranged from 66.6% to 86.6% for 1L, and from 59.9% to 74.3% for 2L. We observed more frequent dose escalations in 2L than in 1L for all advanced therapies except GOL in UC patients. Our study indicates that advanced therapies have shorter persistence and require higher doses when used as 2L treatment compared to 1L treatment. Future studies on reliable response predictors in patients with UC or CD receiving advanced treatments are likely to improve the selection of more efficacious 1L therapy.

Background/Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition increasingly associated with dysregulated neuroimmune signaling and altered neurotrophic homeostasis. Tumor necrosis factor-alpha (TNF-α) has been implicated in ASD pathophysiology; however, the downstream effects of TNF-α blockade on cytokine-neurotrophin interactions during neurodevelopment remain insufficiently characterized. In this study, we evaluated the effects of infliximab (IFX), a monoclonal anti-TNF-α antibody, on behavioral performance, neuroinflammatory cytokine profiles, glial activation, and brain-derived neurotrophic factor (BDNF) signaling in a propionic acid (PPA)-induced experimental ASD rat model. Methods: Experimental ASD was induced by propionic acid administration in rats. Animals were divided into control and treatment groups. Behavioral performance was assessed using the Morris Water Maze, direct social interaction, and three-chamber sociability tests. Levels of TNF-α, interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and BDNF were measured in serum, hippocampal, and cerebellar tissues. Microglial and astrocytic activation were evaluated using CD11 and GFAP immunohistochemistry. Results: PPA administration resulted in pronounced impairments in learning, memory, and social behaviors, accompanied by elevated proinflammatory cytokine levels, increased BDNF expression, and marked glial activation in the hippocampus and cerebellum. Although IFX treatment significantly reduced TNF-α levels in central tissues, it did not improve behavioral deficits and was associated with persistently elevated IL-1β and IL-6 levels, sustained glial reactivity, and further alterations in BDNF levels. Conclusions: These findings suggest that TNF-α suppression alone does not normalize the disrupted cytokine-neurotrophin axis and may differentially modulate BDNF-related neuroplastic signaling during development. In conclusion, this study indicates that non-selective TNF-α blockade during neurodevelopment fails to confer behavioral benefit in experimental ASD and highlights the importance of considering cytokine-BDNF pathway interactions when designing immunomodulatory strategies for neurodevelopmental disorders.

Intestinal tissue levels of infliximab (IFX) in patients with inflammatory bowel disease (IBD) treated with subcutaneous (SC) therapy have not been previously assessed. To compare serum and colonic tissue IFX concentrations in IBD patients receiving SC versus intravenous (IV) IFX. This observational cross-sectional study included IBD patients on stable SC or IV IFX maintenance therapy undergoing routine follow-up colonoscopy. Clinical activity required elevated CDAI or Mayo score plus ≥1 biomarker (fecal calprotectin >250μg/g or CRP >5mg/L). Blood samples and two colonic biopsies were collected for serum and tissue IFX measurements. Thirty-five patients were included. Serum and tissue IFX concentrations were significantly higher in the SC versus IV group (22μg/mL vs. 9μg/mL, p<0.001; 25μg/g vs. 10μg/g, p=0.002). Serum and colonic tissue IFX levels were positively correlated in both cohorts (IV: r=0.42; p=0.014; SC: r=0.43; p=0.001). Colonic tissue IFX concentrations were higher in patients with mild-moderate endoscopic activity than in those without active disease (p<0.001). Serum and colonic tissue IFX levels both predicted sustained clinical remission, with optimal thresholds of 14.5μg/mL (p=0.015) and 17μg/g (p<0.005), respectively. Colonic tissue IFX showed higher predictive accuracy (AUROC 0.82, p=0.01) than serum (AUROC 0.76, p=0.045). SC IFX achieved significantly higher serum and colonic tissue concentrations than IV IFX. Colonic tissue IFX levels demonstrated superior clinical relevance and may support future tissue-based therapeutic drug monitoring strategies in IBD.

Very-early-onset inflammatory bowel disease (VEO-IBD), representing cases diagnosed before age 6years, is increasing in prevalence. Although VEO-IBD often presents as severe, treatment-resistant disease requiring biologic agents, studies showing the effectiveness of biologics, such as ustekinumab (UST) and vedolizumab (VDZ), remain limited. We retrospectively analyzed patients with VEO-IBD treated for at least a year from 13 institutions in Japan, evaluating clinical course including effectiveness of biologics, such as infliximab (IFX), adalimumab (ADL), UST, and VDZ. Patients with monogenic IBD were excluded. Steroid-free clinical remission (SFCR) and treatment persistence were assessed separately for first-line and for second-line or subsequent biologic therapies. We studied 101 VEO-IBD patients (56% male; median age, 3.6years), including 40 with Crohn's disease, 52 with ulcerative colitis, and 9 with unclassified IBD. Biologics were used in 67 patients, most commonly infliximab (IFX; n = 52), followed by UST (n = 38), adalimumab (ADL; n = 23), and VDZ (n = 21). As first-line therapy, IFX and ADL achieved 1-year SFCR rates of 19% and 46%, with persistence rates of 36% and 48%. Despite being used mainly as second-line or subsequent therapies, UST and VDZ showed 1-year SFCR rates of about 45% and 36%, and maintained persistence of 79% and 46%, respectively, with UST demonstrating higher persistence than TNF-α inhibitors (P < 0.01). No discontinuations due to infusion reactions or other adverse events occurred with UST or VDZ. UST and VDZ were effective and well tolerated even when used as second-line or subsequent therapies for VEO-IBD.

The THP-1 cell line as a model for the assessment of monoclonal antibodies aggregates' immunological effects.

Aminoglycoside antibiotics remain crucial for the treatment of severe infections caused by multidrug-resistant bacteria; however, their clinical use is limited by the risk of irreversible hearing loss. Previous studies have primarily attributed aminoglycoside-induced hearing loss to cochlear hair cell loss and subsequent spiral ganglion degeneration, while the contribution of the stria vascularis remains unclear. In the present study, we demonstrate that gentamicin administration induces apoptosis of stria vascularis pericytes, leading to stria vascularis dysfunction and consequent hearing loss in mice. Mechanistically, gentamicin exposure activated macrophages within the stria vascularis and significantly increased local expression of tumor necrosis factor-α (TNF-α). In vitro, we found that TNF-α triggered stria vascularis pericyte apoptosis via activation of the NF-κB signaling pathway. Importantly, in vivo pharmacological blockade of TNF-α with infliximab (IFX) or inhibition of NF-κB signaling with JSH-23 effectively preserved pericyte survival, attenuated stria vascularis damage, and mitigated gentamicin-induced hearing loss in mice. Collectively, these findings uncover TNF-α/NF-κB-dependent vascular-inflammatory mechanism underlying gentamicin ototoxicity and identify stria vascularis pericytes as a novel and druggable therapeutic target for the prevention of gentamicin-induced hearing loss.

Background and Aims The efficacy and safety of switching from intravenous (IV) to subcutaneous (SC) infliximab (IFX) have been demonstrated across multiple studies, but data on patients treated with high IV doses remain limited. This study aimed to confirm the safety of switching regardless of IV dosing regimen and examine serum drug concentrations during follow-up. Methods This prospective single-centre study included adult patients with inflammatory bowel disease in remission on maintenance IV IFX. Patients receiving IV IFX <1.5 mg/kg/week were assigned to 120 mg every 14 days, while those on ≥1.5 mg/kg/week received 240 mg. The target SC IFX serum range was 15–30 mg/L, with doses adjusted accordingly during follow-up. Results Among 267 patients, 93% were switched to standard SC dose and 7% to high dose. Remission rates remained stable over 6 months in both groups. Mean serum levels increased from 9.4 mg/L (IV) to 21.1 mg/L (SC) in the standard-dose group, and from 12.3 mg/L to 24.3 mg/L in the high-dose group. Serum IFX levels did not differ significantly by biochemical remission status. In multivariable linear regression, higher body mass index and previous intra-abdominal surgery were associated with lower serum IFX concentrations. Conclusion Patients on IV IFX can be safely switched to SC treatment when initial dosing is guided by the prior IV regimen and subsequently individualized based on serum drug concentrations. Fixed SC dosing based solely on previous IV dosing may be appropriate for patients on standard IV doses but less reliable in those treated with higher doses.

The increasing incidence of inflammatory bowel disease (IBD) in paediatric populations underscores the importance of effective management strategies. Anti-tumor necrosis factor (anti-TNF) agents, such as infliximab (IFX) and adalimumab (ADL), are key treatments for inducing and maintaining remission in IBD, but many patients experience a loss of response over time. Different strategies of therapeutic drug monitoring (TDM) are applied to optimise anti-TNF therapy. In this study, we investigated the effect of proactive and reactive TDM on clinical outcomes and pharmacokinetic parameters in paediatric IBD patients. We conducted a retrospective multicentre study involving 391 children with IBD from the CEDATA-GPGE registry. Patients were categorised into proactive (n = 285) and reactive (n = 106) TDM groups. Clinical outcomes, laboratory results, and pharmacokinetic parameters of IFX and ADL were compared between the groups. Proactive TDM was associated with higher clinical remission rates (50% vs. 24%, p < 0.0001) and reduced hospitalisation rates (17% vs. 39%, p < 0.0001) compared to reactive TDM. In Crohn's disease patients, proactive TDM was linked to lower disease activity and improved levels of C-reactive protein and erythrocyte sedimentation rate. Proactive TDM was also associated with higher IFX drug levels, lower anti-drug antibody concentrations and less frequent switches of the biological therapy. Differences in pharmacokinetic parameters during ADL-treatment were less pronounced and no significant benefit of proactive TDM was observed. Our data suggest that proactive TDM may offer clinical and pharmacokinetic benefits, particularly for paediatric IBD patients treated with IFX, while results for other outcomes and for ADL were less clear. Prospective studies are needed to confirm these findings and to further clarify the role of proactive TDM in this population.

To investigate the risk factors for Clostridioides difficile infection (CDI) in patients with ulcerative colitis (UC) during biologic therapy. Patients diagnosed with UC who received Infliximab (IFX) or Vedolizumab (VDZ) were enrolled. Their clinical characteristics and risk factors for CDI were analyzed. A total of 110 UC patients treated with IFX (61 cases) or VDZ (49 cases) were included. The overall positive rate of Clostridioides difficile (C. difficile) was 28.2%. Positive Epstein-Barr virus (EBV)-DNA, a modified Mayo score ≥11 points, and a history of glucocorticoids use within 2 months before admission were independent risk factors for CDI in UC patients receiving IFX/VDZ therapy. The incidence of CDI was the highest within 0-3 months after IFX/VDZ treatment. Positive EBV-DNA, a modified Mayo score ≥11 points, and a history of glucocorticoids use within 2 months before admission were independent risk factors for CDI in UC patients during IFX/VDZ therapy.

Vedolizumab has become the preferred first-line advanced therapy in ulcerative colitis (UC). However, the optimal second-line treatment following vedolizumab failure remains unclear. We aimed to evaluate the effectiveness and safety of second-line therapies after first-line vedolizumab. We conducted a multicenter retrospective study including UC patients from 31 centers who received infliximab (IFX), subcutaneous (SC) anti-TNFs, or ustekinumab after vedolizumab failure. The primary endpoint was steroid-free clinical remission (SFCR) at week 14. Predictors of remission were identified using multivariate logistic regression. Among 196 patients, 99 received IFX, 27 anti-TNF SC, and 70 ustekinumab. At week 14, SFCR was achieved in 78 patients (39.8%): 38 (38.4%) with IFX, 8 (29.6%) with anti-TNF SC, and 32 (45.7%) with ustekinumab, with no significant difference between groups (p=0.32). Median treatment persistence ranged from 8 to 9.2months. Baseline corticosteroid use was associated with lower odds of SFCR (OR=0.37, 95% CI [0.18-0.73]). Adverse events occurred in 15.8% of patients, including 12.2% serious events. Overall adverse events were less frequent with ustekinumab than with IFX (10.0% vs. 24.2%, p=0.02), while serious events were comparable (5.7% vs. 16.1%, p=0.08). Discontinuation due to adverse events was more frequent with IFX (12.1%) and anti-TNF SC (14.8%) than with ustekinumab (2.9%, p=0.045 and 0.049). In UC patients failing vedolizumab, second-line IFX, anti-TNF SC, and ustekinumab showed similar effectiveness and persistence. Infliximab remains a robust option for rapid control in high inflammatory burden, whereas ustekinumab may be preferred for its superior safety profile in high-risk patients.

This study provides mechanistic and clinical insights into the therapeutic effects of fecal microbiota transplantation (FMT) in inflammatory bowel disease (IBD), particularly when combined with the anti-tumor necrosis factor (anti-TNF) biologic infliximab (IFX). While both FMT and IFX achieve response in approximately 60% of IBD patients, their combined influence on the gut microbial and metabolic landscape in refractory disease has been poorly understood. Here, we demonstrate that FMT monotherapy restores gut microbial diversity and reconfigures host-microbiota-metabolite networks, correlating with clinical and endoscopic remission in patients refractory to conventional treatments. Furthermore, in Crohn's disease patients unresponsive to either therapy alone, combined IFX-FMT induced more complete microbial and metabolic normalization and achieved remission where monotherapy had failed. These findings reveal ecosystem-level network rewiring as a central mechanism of FMT efficacy and establish the additive potential of combining microbiome-targeted and immunomodulatory therapies. This work supports the development of microbiome-informed adjunctive strategies for severe or refractory IBD, highlighting an actionable path toward personalized, mechanism-based treatment regimens. This study is registered with ClinicalTrials.gov as NCT07149441.