英夫利西单抗治疗中重度儿童溃疡性结肠炎的安全性及有效性

Even with increasing numbers of biologic agents available for management of ulcerative colitis (UC), infliximab (IFX) retains an important place in treatment of pediatric patients with this disease. As few reports have addressed outcomes in pediatric UC patients who had to discontinue IFX, we examined clinical course and prognosis after IFX failure in pediatric UC.

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Purpose The long-term efficacy and safety of infliximab (IFX) in children with ulcerative colitis (UC) have not been well-evaluated. Here, we reviewed the long-term durability and safety of IFX in our single center pediatric cohort with UC. Methods This retrospective study included 20 children with UC who were administered IFX. Results For induction, 5 mg/kg IFX was administered at weeks 0, 2, and 6, followed by every 8 weeks for maintenance. The dose and interval of IFX were adjusted depending on clinical decisions. Corticosteroid (CS)-free remission without dose escalation (DE) occurred in 30% and 25% of patients at weeks 30 and 54, respectively. Patients who achieved CS-free remission without DE at week 30 sustained long-term IFX treatment without colectomy. However, one-third of the patients discontinued IFX treatment because of a primary nonresponse, and one-third experienced secondary loss of response (sLOR). IFX durability was higher in patients administered IFX plus azathioprine for >6 months. Four of five patients with very early onset UC had a primary nonresponse. Infusion reactions (IRs) occurred in 10 patients, resulting in discontinuation of IFX in four of these patients. No severe opportunistic infections occurred, except in one patient who developed acute focal bacterial nephritis. Three patients developed psoriasis-like lesions. Conclusion IFX is relatively safe and effective for children with UC. Clinical remission at week 30 was associated with long-term durability of colectomy-free IFX treatment. However, approximately two-thirds of the patients were unable to continue IFX therapy because of primary nonresponse, sLOR, IRs, and other side effects.

BACKGROUND AND AIMS We aimed to model infliximab (IFX) pharmacokinetics (PK) in pediatric acute severe ulcerative colitis (ASUC) and assess the association between PK parameters, including drug exposure, and clinical response. METHODS We studied a multicenter prospective cohort of hospitalized children initiating IFX for ASUC or IBD-unclassified. Serial IFX serum concentrations over 26 weeks were used to develop a PK model. We tested the association of PK parameter estimates with day 7 clinical response, week 8 clinical remission, week 26 corticosteroid-free clinical remission (CSF-CR) (using the Pediatric Ulcerative Colitis Activity Index) and colectomy-free survival. RESULTS 38 participants received IFX (median initial dose 9.9 mg/kg). Day 7 clinical response, week 8 clinical remission, and week 26 CSF-CR occurred in 71%, 55%, and 43%, respectively. Albumin, C-reactive protein, white blood cell count, platelets, weight, and antibodies to IFX were significant covariates incorporated into a PK model. Week 26 non-remitters exhibited faster IFX clearance than remitters (P=.013). However, cumulative IFX exposure did not differ between clinical response groups. One (2.7%) and four (10.8%) participants underwent colectomy by week 26 and two years, respectively. Day 3 IFX clearance > .02 L/h was associated with colectomy (HR 58.2, 95% CI: 6.0-568.6, P < .001). CONCLUSIONS At median higher-than-label IFX dosing for pediatric ASUC, baseline faster IFX CL was associated with colectomy and, at week 26, with lack of CSF-CR. IFX exposure was not predictive of clinical outcomes. Higher IFX dosing may sufficiently optimize early outcomes in pediatric ASUC. Larger studies are warranted to determine if sustained intensification can overcome rapid clearance and improve later outcomes.

BACKGROUND/PURPOSE Clinical outcomes in pediatric ulcerative colitis (UC) in the era of biologic agents are poorly defined. We aimed to describe risk factors for colectomy in pediatric UC in the era of infliximab therapy. METHODS We reviewed 217 pediatric patients at Texas Children's Hospital with newly diagnosed UC between 2003 and 2015; 117 had a minimum of 5 years of follow-up. Extent of disease at diagnosis, medication exposure, the presence of extraintestinal manifestations (EIMs), and need for surgery were noted. RESULTS Average length of follow up was 5.02 ± 2.27 years. Forty-two percent presented with pancolitis. Infliximab was used in 39%, immunomodulators in 65%, and steroids in 89% of patients. EIMs occurred in 24.9% of patients. The cumulative rate of colectomy was 12.9% at 5 years. Children presenting as E2 (Paris Classification) and children prescribed oral steroid monotherapy at diagnosis progressed to surgery faster than any other group. Of the children who received infliximab, females and children less than 5 years old were less likely to respond to therapy. CONCLUSIONS The natural course of pediatric UC remains aggressive despite the addition of infliximab to the standard of care and suggests a need for early aggressive clinical intervention. LEVEL-OF-EVIDENCE RATING Level IV.

AIM To assess attitudes and trends regarding the use of high-dose infliximab among pediatric gastroenterologists for treatment of pediatric ulcerative colitis (UC). METHODS A 19-item survey was distributed to subscribers of the pediatric gastroenterology (PEDSGI) listserv. Responses were submitted anonymously and results compiled in a secure website. RESULTS A total of 113 subscribers (88% based in the United States) responded (101 pediatric gastroenterology attendings and 12 pediatric gastroenterology fellows). There were 46% in academic medical institutions and 39% in hospital-based practices. The majority (91%) were treating >10 patients with UC; 13% were treating >100 patients with UC; 91% had prescribed infliximab (IFX) 5 mg/kg for UC; 72% had prescribed IFX 10 mg/kg for UC. Using a 5-point Likert scale, factors that influenced the decision not to increase IFX dosing in patients with UC included: "improvement on initial dose of IFX" (mean: 3.88) and "decision to move to colectomy" (3.69). Lowest mean Likert scores were: "lack of guidelines or literature regarding increased IFX dosing" (1.96) and "insurance authorization or other insurance issues" (2.34). "Insurance authorization or other insurance issues" was identified by 39% as at least somewhat of a factor (Likert score ≥ 3) in their decision not to increase the IFX dose. IFX 10 mg/kg was more commonly used for the treatment of pediatric UC among responders based in the United States (75/100) compared to non-United States responders (6/13, P = 0.047). Induction of remission was reported by 78% of all responders and 81% reported maintenance of remission with IFX 10 mg/kg. One responder reported one death with IFX 10 mg/kg. CONCLUSION IFX 10 mg/kg is more commonly used in the United States to treat pediatric UC. Efficacy and safety data are required to avoid insurance barriers for its use.

Objectives The role of infliximab (anti–tumor necrosis factor &agr; antibody) therapy in ulcerative colitis (UC) is not well defined. There are only two reports published describing its use in UC. The authors describe their experience with open-label use of infliximab in children with moderate to severe UC. Methods The authors collected data on all consecutive pediatric patients with UC who received infliximab at The Children's Hospital of Philadelphia until July 2001. The primary measured outcome was clinical response at 2 days and 2 weeks after infliximab infusion, as measured by the Lichtiger colitis activity index (LCAI) score and the Physician Global Assessment (PGA). Tolerance of the infusions and adverse events were recorded. Results Nine patients qualified for clinical response analysis. The median Lichtiger colitis activity index score decreased from 11 before the infusion to 1 at 2 days and 2 weeks after the infusion, respectively (P = 0.01 for 2 days and 2 weeks). Seven of nine (77%) patients had decreased activity of their disease measured by the Physician Global Assessment. Corticosteroid therapy was discontinued in six (66%) patients. An infusion reaction developed (generalized pruritus and facial flushing) in two patients and an elevated anti-nuclear antibody (ANA) titer of 1:1280 developed in one patient. Conclusion Infliximab is associated with short-term clinical improvement in children and adolescents with moderate to severe UC.

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INTRODUCTION Clinical remission has been achieved with infliximab in patients with refractory ulcerative colitis (UC). However, there is conflicting data regarding its effectiveness as rescue therapy in adult acute severe colitis. Furthermore, pediatric inflammatory bowel disease (IBD) is associated with more severe disease that may be less amenable to attempted rescue. We reviewed our experience and outcomes with pediatric severe colitis after attempted inpatient rescue with infliximab. METHODS A single-institution, retrospective review was conducted of pediatric patients with UC or indeterminate colitis who received inpatient rescue infliximab therapy from 1/2000 to 1/2019. Rescue infliximab therapy was considered if a child failed non-biologic therapy or progressed to fulminant or toxic colitis. Primary outcome was failed therapy resulting in colectomy. A p-value of <0.05 determined significance. RESULTS Thirty patients met inclusion criteria. The median age at administration of rescue infliximab treatment was 14 years [IQR 13,17]. Rescue therapy with infliximab was successful in 33% (n = 10), while 67% (n = 20) underwent colectomy. Children on maintenance steroids were less likely to be successfully rescued with infliximab and require colectomy (p = 0.03). Children requiring colectomy had a longer hospital stay (p = 0.03), more abdominal radiographs (p = 0.01), and were on a longer duration of antibiotics (p = <0.01) compared to children who were successfully rescued with infliximab. There was no difference in baseline vital signs or laboratory abnormalities between the two groups. CONCLUSION In severe acute ulcerative or indeterminate colitis cases where infliximab has not been previously used, rescue infliximab can be used to avoid colectomy but has a high failure rate. LEVEL OF EVIDENCE IV. TYPE OF STUDY Retrospective study.

BackgroundPediatric ulcerative colitis (UC) is typically more extensive and has a more active disease course than adult UC, and requires early treatment augmentation to achieve and maintain disease remission. The present study aimed to investigate the efficacy, safety, and pharmacokinetic profile of infliximab (IFX) in pediatric patients with moderate-to-severe UC and inadequate response to existing treatment.MethodsThis open-label, uncontrolled, multicenter, Phase 3 trial was conducted at 17 centers in Japan between April 2012 and September 2014. Pediatric patients (aged 6–17 years) diagnosed with moderate-to-severe UC received a treatment protocol comprising 5 mg/kg IFX at Weeks 0, 2, and 6, and Clinical Activity Index (CAI)-based responders at Week 8 also received treatment at 8-week intervals at Weeks 14 and 22, with a final evaluation at Week 30.ResultsA total of 21 patients were treated in this study. IFX therapy rapidly improved clinical symptoms, and this effect was maintained for up to 30 weeks. Overall CAI-based remission rate was 42.9% and overall Pediatric Ulcerative Colitis Activity Index (PUCAI)-based remission rate was 19.0%. Median partial Mayo score was 6.0 at baseline and 4.0 at Week 30 (overall). Among the eight patients who underwent sigmoidoscopy, Mayo response was achieved at Week 30 (overall) in three patients (37.5%). Trough serum IFX concentrations in Week 8 CAI-based responders were maintained throughout the study period. Adverse events and serious adverse events were observed in 95.2 and 14.3% of patients, respectively.ConclusionsThese results support the use of IFX in the treatment of pediatric patients with UC with inadequate response to existing treatment.Trial registrationClinicalTrials.gov, registration number: NCT01585155.

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OBJECTIVE Infliximab is approved for pediatric Crohn's disease (CD) and ulcerative colitis (UC), but is limited in children by its intravenous administration. We evaluated the effectiveness and safety of switching from intravenous to subcutaneous infliximab in pediatric patients with CD/UC. METHODS Multicenter retrospective cohort study, from January to December 2022 in two pediatric centers, that included CD/UC patients in clinical remission and weighing ≥50kg, treated with maintenance dose IV IFX. PRIMARY ENDPOINT maintenance of clinical remission at six-months post-switch; PCDAI<10 for CD, PUCAI<10 for UC. Secondary endpoints included: IFX trough levels, anti-infliximab antibodies (AIAs), adverse events, and treatment persistence. RESULTS Twenty-one patients were included: 11 (52.3%) female, median 17 years of age (range: 13-18 years), 18 (85.7%) CD and 3 (14.3%) UC. The median (range) age at diagnosis was 12 (5-15) years; at inclusion (M0; switch) it was 16 (10-18) years. All received optimized IFX regimens (10mg/kg every 8 or 4 weeks). All were in clinical remission at M0 and maintained remission throughout the 6-month follow-up. None discontinued treatment. Median (range) serum IFX trough levels was 11.3μg/mL (4.7-39μg/mL; n=13) at M0, 17.8μg/mL (8.5-20μg/mL; n=10) at M3, and 20μg/mL (17.1-20μg/mL; n=6) at M6. No patient developed AIAs. There was no serious adverse event; one patient (4.7%) experienced a mild injection site reaction. CONCLUSION Switching from IV to SC IFX appears effective and safe in pediatric IBD patients. Pharmacokinetic studies are required for children <50kg in order to determine the dosage of SC IFX that allows therapeutic trough values to be achieved.

Objectives: Inflammatory Bowel Disease (IBD), comprising Crohn’s disease and ulcerative colitis, presents a significant challenge in pediatric populations. The advent of biologics, notably infliximab, has revolutionized treatment by targeting tumor necrosis factor alpha (TNF-alpha) and reducing reliance on corticosteroids. Despite its efficacy, concerns have arisen regarding potential excessive weight gain among pediatric patients receiving infliximab. Methods: We conducted a retrospective cohort study at our institution in Doha, Qatar, spanning 2015-2022, involving 60 IBD patients (<18 years). We assessed BMI z-score changes at 3, 6, 12, and 24-months post-infliximab initiation, and correlated clinical markers with patient demographics. Statistical analyses included t-test and repeated measures analysis of variance. Results: Over a 24-month period, a significant increase in BMI z-score was observed across all age groups (p< 0.001), with peak gains noted at 6 months. Excessive weight gain was noted among all IBD types and subtypes of Crohn’s (p < 0.001); however, no difference was noted between UC and Crohn’s disease patients (p = 0.135). Conclusion: Our findings show that children with IBD can gain excessive weight following infliximab therapy in pediatric IBD patients. It suggests a metabolic effect beyond mere nutritional improvement. As a result, further research is needed to elucidate underlying mechanisms and optimize clinical management strategies.

Purpose The long-term efficacy and safety of infliximab (IFX) in Japanese children with inflammatory bowel disease (IBD) remain unclear. This study aimed to examine the long-term outcomes of IFX treatment in Japanese children with IBD. Methods We retrospectively recruited patients aged <16 years who were diagnosed with ulcerative colitis (UC) or Crohn’s disease (CD) at Kurume University Hospital in Japan between 2011 and 2022 and examined the effectiveness and safety of IFX. We characterized the responses to IFX as primary response, primary nonresponse (PNR), secondary loss of response (sLOR), or still receiving IFX. Results Among the 77 enrolled patients with UC (median age, 10 years) and 48 with CD (median age, 12 years), 55 (27 with UC and 28 with CD) received IFX treatment. IFX treatment was significantly more common in patients with CD (58.3%) than in those with UC (35.1%; p=0.016). The PNR was significantly greater in patients with UC (18.5%) than in those with CD (0.0%; p=0.023), as was the sLOR (UC, 51.9%; CD, 21.4%; p=0.026). The likelihood of continuing IFX treatment during follow-up (median, 38 months) was significantly higher in patients with CD (71.4%) than in those with UC (29.6%; p=0.003). Adverse events resulting in the discontinuation of IFX occurred in 3.6% of the patients; one patient with CD developed leukemia, and the other had a serious infusion reaction. Conclusion The long-term durability of IFX in Japanese pediatric patients with IBD was inadequate in UC compared with CD. Serious adverse events in 3.6% of patients required discontinuation.

Supplemental Digital Content is Available in the Text. Inflammatory bowel diseases, including Crohn disease and ulcerative colitis, are most often diagnosed during adolescence and young adulthood, with a rising incidence in pediatric populations. Infliximab is an effective treatment option for Crohn disease and ulcerative colitis. The most common adverse event with infliximab is an infusion reaction. Patients are often treated prophylactically with combinations of acetaminophen, intravenous steroid, and an antihistamine to prevent an infusion reaction. There is a high degree of practice variation regarding pretreatment for infliximab infusions, the efficacy of pretreatment with an antihistamine is unproven in preventing infusion-related reactions, and there is no national clinical standard. Unnecessary pretreatment in adolescence and young adulthood may be harmful, as this is a time to focus on developing self-care management skills. Antihistamine side effects including somnolence and dizziness may adversely affect adolescents and/or young adults' ability to complete schoolwork, drive, and transition toward autonomous management of their chronic illness. This report presents the findings of an evidence-based practice project reviewing the efficacy of pretreatment with an antihistamine in patients with Crohn disease and ulcerative colitis receiving infliximab. Practice implications are discussed.

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BACKGROUND Pediatric ulcerative colitis (UC) is a severe disease characterised by the presence of extensive inflammatory lesions in the colon. The administration of intravenous corticosteroids is recommended in patients with acute relapse of the disease, whereas early treatment with cyclosporine, tacrolimus or infliximab is recommended if there is no improvement. OBJECTIVES The aim of this study was to retrospectively evaluate the efficacy and safety of infliximab therapy in the treatment of moderate-to-severe and severe relapse of pediatric UC. MATERIAL AND METHODS The analysis included 42 children aged 4-18 years (23 girls, 19 boys) treated in 7 pediatric gastroenterology departments in Poland during the past 4 years. The disease duration ranged from 2 to 100 months. The clinical activity of UC ranged from 35 to 85 points according to the PUCAI scale. Twenty-one children were diagnosed with pancolitis, 10 children with extensive UC, and the remaining with the left-sided UC. In the induction therapy infliximab was administered at doses of 5 mg/kg in the 0.2 and 6 weeks, and after the clinical response every 8 weeks to 12 months. Treatment results were assessed in 10 and 54 weeks. RESULTS After the induction therapy the clinical response was achieved in 14 children (33.33%) and clinical remission in 11 children (26.19%). Two children required surgical treatment, and the remaining 2 suffered from anaphylactic shock. After the maintenance therapy clinical remission was maintained in 12 children (57.14%), whereas 3 children required surgery (colectomy). CONCLUSIONS Infliximab therapy in children with moderate-to-severe UC induces remission and, in some children, proves to be effective in preventing early colectomy.

Background and aims Favourable clinical data were published on the efficacy of CT-P13, the first biosimilar of infliximab (IFX), in pediatric inflammatory bowel disease (IBD); however, few studies have compared the effect on endoscopic healing (EH) and drug retention rate between the IFX originator and CT-P13. Therefore, we aimed to compare EH and the drug retention rate between the IFX originator and CT-P13. Methods Children with Crohn’s disease (CD) and ulcerative colitis (UC)/IBD-unclassified (IBD-U) at 22 medical centers were enrolled, with a retrospective review conducted at 1-year and last follow-up. Clinical remission, EH and drug retention rate were evaluated. Results We studied 416 pediatric patients with IBD: 77.4% had CD and 22.6% had UC/IBD-U. Among them, 255 (61.3%) received the IFX originator and 161 (38.7%) received CT-P13. No statistically significant differences were found between the IFX originator and CT-P13 in terms of corticosteroid-free remission and adverse events. At 1-year follow-up, EH rates were comparable between them (CD: P=0.902, UC: P=0.860). The estimated cumulative cessation rates were not significantly different between the two groups. In patients with CD, the drug retention rates were 66.1% in the IFX originator and 71.6% in the CT-P13 group at the maximum follow-up period (P >0.05). In patients with UC, the drug retention rates were 49.8% in the IFX originator and 56.3% in the CT-P13 group at the maximum follow-up period (P >0.05). Conclusions The IFX originator and CT-P13 demonstrated comparable therapeutic response including EH, clinical remission, drug retention rate and safety in pediatric IBD.

Background: Despite many investigations on possible associations between various biomarkers and ulcerative colitis (UC) disease activity, available serum biomarkers still have lower sensitivity and speci fi city to predict disease severity than fecal markers. In recent years, the C-reactive protein/ albumin ratio (CAR), an in fl ammatory marker that has been shown to be related to disease activity, its progression, endoscopic fi ndings

Background: Despite many investigations on possible associations between various biomarkers and ulcerative colitis (UC) disease activity, available serum biomarkers still have lower sensitivity and speci fi city to predict disease severity than fecal markers. In recent years, the C-reactive protein/ albumin ratio (CAR), an in fl ammatory marker that has been shown to be related to disease activity, its progression, endoscopic fi ndings

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Objectives: Infliximab (IFX) is commonly used to treat children with inflammatory bowel disease (IBD). We previously reported that patients with extensive disease started on IFX at a dose of 10 mg/kg had greater treatment durability at year one. The aim of this follow-up study is to assess the long-term safety and durability of this dosing strategy in pediatric IBD. Methods: We performed a retrospective single-center study of pediatric IBD patients started on IFX over a 10-year period. Results: Two hundred ninety-one patients were included (mean age = 12.61, 38% female) with a follow-up range of 0.1–9.7 years from IFX induction. One hundred fifty-five (53%) were started at a dose of 10 mg/kg. Only 35 patients (12%) discontinued IFX. The median duration of treatment was 2.9 years. Patients with ulcerative colitis (P ≤ 0.01) and patients with extensive disease (P = 0.01) had lower durability, despite a higher starting dose of IFX (P = 0.03). Adverse events (AEs) were observed to occur at a rate of 234 per 1000 patient-years. Patients with a higher serum IFX trough level (≥20 µg/mL) had a higher rate of AEs (P = 0.01). Use of combination therapy had no impact on risk of AEs (P = 0.78). Conclusions: We observed an excellent IFX treatment durability, with only 12% of patients discontinuing therapy over the observed timeframe. The overall rate of AEs was low, the majority being infusion reactions and dermatologic conditions. Higher IFX dose and serum trough level> 20 µg/mL were associated with higher risk of AEs, the majority being mild and not resulting in cessation of therapy.

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Genetically engineered biological preparations (GEBP) are successfully used in various immunosuppressive diseases. Despite the effectiveness of GEBP, some patients experience primary non-response, as well as loss of effect from therapy. There is a need to objectively assess the effect of the therapy for its timely correction. The aim of the work was to determine the survival rate of GIBP depending on the form of pathology, drug, age, and immune indices in children with Crohn’s disease (CD), ulcerative colitis (UC), psoriasis (PS), multiple sclerosis (MS). Materials and methods. Three hundred eighty three children (1394 observations) were examined in dynamics: 117 children with BC (treated by infliximab (IFX)/adalimumab (ADA), 83 children with UC (IFX/ADA), 87 children with PS (ADA), 96 children with PC (IFNβ1α) during the maintenance course therapy. Lymphocytes were immunophenotyped by flow cytometry with the determination of Treg (CD4+CD25highCD127low), Th17 lymphocytes (CD4+CD161+CD3+), succinate dehydrogenase (SDH) activity in Treg. Data processing was carried out using Statistica 16.0 application. Kaplan–Mayer survival curves are constructed. The significance of the differences between the groups was assessed using the Gehan–Wilcoxon criterion (p < 0.05). Results. The survival rate of biological therapy in CD patients on IFX therapy is significantly higher than in children with UC — 161 weeks versus 135 weeks. There was no difference in CBT on ADA therapy between patients with CD and UC. The IBT index depends on the age of the patients: on IFX therapy (159 weeks) the best indices were in CD patients over 12 years. Combination therapy improves the survival of TNF blockers in patients with IBD (azathioprine) and PS (methotrexate). The survival of GIBP is influenced by the ratio of effector and regulatory cells (Th17|Treg) and the functional activity of Treg (SDH activity). A decrease in IBD was revealed in patients with IBD, PS, and MS with an increase in the Th17/Treg index above the age norm and a decrease in the activity of SDH in Treg below the norm. Conclusion. The survival rate of biological therapy for immunosuppressive diseases in children depends on the form of pathology, the drug, the age of patients, previous therapy, combination therapy, as well as immune indices during the maintenance course. Monitoring of Th17/Treg and SDH activity in Treg may be an important laboratory criterion for the effectiveness of GIBP.

BACKGROUND The role of B cells in inflammatory bowel disease (IBD) is ambiguous, as B cells may have both pathogenic and protective functions in IBD. We studied B cell subsets before and after initiation of an anti-tumor necrosis factor alpha (anti-TNFα) therapy in pediatric IBD. The aim of the study was to examine the behavior of B cells in pediatric IBD patients undergoing an anti-TNFα therapy and, more specifically, to clarify their association with a successful or an unsuccessful infliximab (IFX) treatment. METHODS A total of N = 42 pediatric IBD patients (Crohn disease, n = 30; ulcerative colitis, n = 12) for whom an anti-TNFα therapy with and without a concomitant azathioprine (AZA) medication was administered were recruited. Fourteen healthy age-matched children served as control patients. Blood samples were collected before initiation of the anti-TNFα therapy, before the fourth infusion at the end of the induction phase, and after 6 and 12 months under therapy maintenance. Flow cytometry (CD20, CD27, CD38, CD138) and intracellular staining (interleukin 10 [IL10], TNFα, granzyme B) were performed. Responders to successful IFX therapy were classified exhibiting a fecal calprotectin level of below 100 µg/g or achieving levels of <10% of the baseline value at initiation than at the end of the 12-month follow-up period. RESULTS Before initiation of anti-TNFα therapy, flow cytometry revealed increased percentages of naïve B cells whereas transitional B cells were reduced compared with those in the healthy control patients. The IL10-producing B cells of both ulcerative colitis and Crohn disease patients were reduced at the initiation of IFX therapy, whereas TNFα-producing transitional CD24hiCD38hi B cells in ulcerative colitis patients were increased compared with those in healthy control patients. After 12 months of therapy, we detected a significant increase of IL10-producing transitional B cells in responding patients.The IFX trough levels in the responding patients showed a significant increase until 6 months after IFX initiation, attaining mean values of 9.9 µg/mL, whereas the IFX dosage was significantly lower than that in the nonresponding patients. The IFX trough levels in AZA-treated patients reached earlier therapeutic levels than in patients without AZA comedication, whereas during the course of the IFX therapy, comedication with AZA had no significant effect on the outcome. CONCLUSIONS Attaining a normalization of IL10 production among CD24hiCD38hi B cells after 12 months of therapy may represent additional information about the reconstitution of a patient's immune system in responding patients. The achievement of an IFX trough level of ~10 µg/mL at 6 months of treatment is associated with a successful anti-TNFα therapy. In addition, AZA comedication supports an earlier achievement of therapeutic IFX trough levels.

ABSTRACT Objectives: Retrospective, observational, single-center, cohort study investigating the safety profile of biological therapy in children with inflammatory bowel disease (IBD). Methods: Retrospective, observational, cohort study of pediatric patients with IBD, receiving infliximab, adalimumab, vedolizumab, or ustekinumab for at least 2 months. Data related to the immediate and delayed adverse events (AEs) were collected, focusing on the reaction type and severity, the time of onset, the outcome and the temporary or definitive therapy discontinuation secondary to the AE. Number of suspected and confirmed coronavirus disease-209 (COVID-19) cases and their outcomes, as well as flu vaccination coverage were collected. Results: One hundred eighty-five children were included (101 [55%] CD, 82 [44%] UC, and 2 [1%] IBDU): 149 received infliximab (IFX) (81%), 88 (48%) adalimumab (ADA), 18 (21%) vedolizumab, and 4 (2%) ustekinumab. The overall AE rates were 49%, 67% of whom likely medication-related. Eleven (6%) patients experienced more than 1 AE, 18 patients (10%) presented an immediate reaction, and 82 (45%) a delayed AE. Among the 90 patients experiencing at least 1 AE, 97% had mild-to-moderate AEs. Only 4 SAEs were reported (4%). Treatment discontinuation because of AE occurred in 25 patients (14%). Four COVID-19 cases were reported, all with a mild course. Conclusions: Our findings confirm a good safety profile of biologics. Infusion reactions to IFX administration remain one of the main issues, significantly linked to its immunogenicity and consequently with an impact on its efficacy and durability.

Background and Aims Children with very early onset inflammatory bowel disease (VEO-IBD) are uniquely at risk of inadequate infliximab (IFX) exposure. We studied the association between standard body weight (BW)-based and body surface area (BSA)-based dosing strategies and outcomes. Methods We identified VEO-IBD patients treated with IFX before 9 years at a single center. Patients were separated into those that received a BSA-based dose (200 mg/m2) and standard BW dosing (5 mg/kg). IFX drug levels, dose intensification, time on steroids, and long-term outcomes were compared. Receiver operator characteristic curves determined the optimal BW- and BSA-based dose to achieve a trough ≥10 μg/ml at dose 4 (IFX#4). Results Forty-three children with VEO-IBD were identified. Receiver operator characteristic curves demonstrated optimal BW- and BSA-based doses to achieve IFX trough ≥10 μg/ml at IFX#4 were 7.5 mg/kg and 180mg/m2. Children were classified to standard BW dosing (22/43) and BSA dosing (10/43). IFX#4 trough was significantly higher in those who received BSA dosing (BSA 18.6 μg/ml [interquartile range 10.8–28.1] vs BW 5.1 μg/ml [interquartile range 2.6–10.7], P = .04). BSA dosing was more likely to achieve a target drug level >10 μg/ml at IFX#4 (BSA 70% vs BW 18%, P = .02). BW dosing was associated with a greater likelihood of dose escalation (BW 82% vs BSA 30%, P < .01) and a shorter time to first escalation. BSA dosing was associated with shorter time spent on steroids (P = .02). Conclusion Young children require higher IFX dosing to achieve adequate drug exposure. Our data support the use of a BSA-based dose of 200 mg/m2 or, if a BW-based approach is used, 7.5 mg/kg. BSA dosing allows the use of a consistent dose over the age and weight spectrum.

Purpose We aimed to investigate clinical outcomes between top-down (TD) and conventional step-up (SU) therapies in pediatric patients with moderate to severe ulcerative colitis (UC). Materials and Methods All patients underwent clinical and endoscopic evaluation at diagnosis and 4 months and 1 year after treatment. Patients who started treatment with corticosteroid were grouped in the SU group, while those that initiated early infliximab (IFX) were grouped in the TD group. Among the SU group, patients who eventually changed to IFX treatment due to steroid resistance or dependency were included in the SU(R) group. Results In total, 44 children with moderate to severe UC were included for analysis. Twenty-one patients were included in the SU group, 23 were included in the TD group, and 10 were enrolled in the SU(R) group. Relapse rates were 47.6% (10/21) in the SU group and 17.4% (4/23) in the TD group (p=0.033). Among relapsed patients, the durations from remission to relapse were 17.3 months (0.9–46.9) in the SU group and 24.3 months (1.8–44.9) in the TD group. There was no statistically significant difference in the sustained durations of remission after IFX administration between the SU(R) and TD groups [3.9 (1.4–6.3) and 2.3 (0.3–5.2) years, respectively (p>0.05)]. Conclusion According to our study, early use of IFX without corticosteroid treatment for children with moderate to severe UC helps to lower relapse rates. We also found that IFX was a very effective treatment for pediatric UC, with a sustained duration of remission similar between TD and SU(R) groups.

Objectives: Anti-tumor necrosis factor antibodies have led to a revolution in the treatment of inflammatory bowel diseases (IBD); however, a sizable proportion of patients does not respond to therapy. There is increasing evidence suggesting that treatment failure may be classified as mechanistic (pharmacodynamic), pharmacokinetic, or immune-mediated. Data regarding the contribution of these factors in children with IBD treated with infliximab (IFX) are still incomplete. The aim was to assess the causes of treatment failure in a prospective cohort of pediatric patients treated with IFX. Methods: This observational study considered 49 pediatric (median age 14.4) IBD patients (34 Crohn disease, 15 ulcerative colitis) treated with IFX. Serum samples were collected at 6, 14, 22 and 54 weeks, before IFX infusions. IFX and anti-infliximab antibodies (AIA) were measured using enzyme linked immunosorbent assays. Disease activity was determined by Pediatric Crohn's Disease Activity Index or Pediatric Ulcerative Colitis Activity Index. Results: Clinical remission, defined as a clinical score <10, was obtained by 76.3% of patients at week 14 and by 73.9% at week 54. Median trough IFX concentration was higher at all time points in patients achieving sustained clinical remission. IFX levels during maintenance correlated also with C-reactive protein, albumin, and fecal calprotectin. After multivariate analysis, IFX concentration at week 14 >3.11 &mgr;g/mL emerged as the strongest predictor of sustained clinical remission. AIA concentrations were correlated inversely with IFX concentrations and directly with adverse reactions. Conclusions: Most cases of therapeutic failure were associated with low serum drug levels. IFX trough levels at the end of induction are associated with sustained long-term response.

OBJECTIVES Therapeutic drug monitoring is becoming increasingly important in clinical decision making in children with inflammatory bowel disease (IBD). However, ELISA assays do not allow results to be provided in real-time. We sought to compare two point-of-care (POC) devices for quantification of serum infliximab concentration with two validated ELISA assays in children with IBD. METHODS We studied 32 serum samples from 19 children with IBD treated with infliximab. Serum samples were collected immediately before drug infusion (trough level). Infliximab was measured using two POC infliximab assays, Quantum Blue (POC IFX/QB) and Rida Quick (POC IFX/RQ), and two ELISA assays: Lisa-Tracker (used as primary reference), and Promonitor (used as second control). Intraclass correlation coefficient (ICC) was assessed for quantitative comparison. Qualitative analysis was also performed to evaluate whether POC assays would correctly classify infliximab serum according to a target window (between 3 μg/ml and 7 μg/ml). RESULTS ICC was 0.82 and 0.87 for POC IFX/QB and POC IFX/RQ with the primary reference ELISA assay, respectively; ICC between the two ELISA assays was 0.87. Classification of results according to therapeutic intervals showed good agreement between pairs of assays, with kappa of 0.67 and 0.80 for POC IFX/QB and POC IFX/RQ, respectively, with reference ELISA, and 0.81 between the two ELISAs. Accuracy of POC assays was better for drug levels <3 μg/ml. CONCLUSIONS POC infliximab assays showed good agreement with traditional ELISA assays. POC devices may represent a viable option for real-time therapeutic drug monitoring in children treated with infliximab.

OBJECTIVES In adult inflammatory bowel disease (IBD) treated by anti-TNF antibodies, paradoxical psoriasis has an estimated prevalence of 1.6 to 22%, especially in infliximab (IFX)-treated patients. Little is known in the pediatric IBD (PIBD) populations. METHODS All patients aged from 2 to 18 years with Crohn's disease (CD) or Ulcerative colitis (UC) and treated for the first time by IFX between January 2002 and March 2014, were considered for inclusion in this retrospective study performed in a tertiary PIBD centre. Paradoxical psoriasis events together with clinical and biological data were collected in all patients. Comparisons between psoriasis and control groups were performed using univariate statistical analyses. RESULTS 123 CD patients and 24 UC patients were treated with IFX. 20 patients (13.6%) experienced a paradoxical psoriasis. All of them were affected by CD. Perianal CD was more frequent in the psoriasis group (p = 0.033). 14 patients (70%) were in remission when skin lesions occurred. Paradoxical psoriasis was diagnosed 355 days (median, IQR: 239; 532) after the initiation of IFX corresponding to the 8th injection (median, IQR: 6; 15). Psoriasis lesions were controlled by local steroids in all cases and no patients discontinued IFX therapy. CONCLUSION 13.6% of our IBD patients treated with IFX developed psoriasis during a median follow-up of 23.9 months (IQR: 11.6; 36.5). CD patients with perianal disease were at a higher risk to develop this common side effect.

Abstract Introduction: Toxic megacolon is a serious complication of ulcerative colitis (UC), characterized by marked colonic dilatation, abnormal bowel function, and systemic toxicity. Although toxic megacolon is rare in children and adolescents, it should remain in the differential diagnosis for acute severe UC in this group because delayed diagnosis and treatment can be fatal. The treatment for UC complicated by toxic megacolon is either immediate emergency surgery or short-term intensive drug therapy. If the latter does not result in significant improvement, emergency surgical intervention is necessary. Current treatment guidelines do not establish a standard medical approach for this condition. Case Presentation: In this report, we describe an adolescent case of UC complicated by toxic megacolon. In this patient, the condition was initially controlled with steroid pulse therapy followed by oral tacrolimus. However, due to an inadequate response, treatment was escalated to infliximab (IFX), leading to remission and successful avoidance of surgical intervention. Conclusion: When opting for conservative treatment of UC complicated by toxic megacolon, intensive steroid pulse, tacrolimus, and IFX therapy should be considered as a potentially effective treatment option.

Inflammatory bowel disease (IBD) in children, including Crohn’s disease (CD), ulcerative colitis (UC), and IBD-unclassified (IBD-U), requires early and effective intervention to achieve remission and prevent complications. Infliximab (IFX), an anti-TNF agent, is a mainstay of therapy, and proactive therapeutic drug monitoring (TDM) during induction may optimize outcomes, though limited pediatric data are available. A retrospective cohort study was conducted at Sidra Medicine, including pediatric IBD patients treated with IFX from 2015 to 2024. Proactive TDM involved scheduled drug level assessments before doses 2, 3, and the first maintenance dose and infliximab dose escalation were done when levels were low from target during induction. Disease activity was assessed using the Pediatric Crohn’s Disease Activity Index (PCDAI), Pediatric Ulcerative Colitis Activity Index (PUCAI), and fecal calprotectin at baseline and 12 weeks. Patients were stratified by TDM approach, and statistical analyses were performed using R software and Jamovi software. Of 148 patients included, 82.4% underwent proactive monitoring. By week 12, PCDAI and PUCAI scores significantly decreased (mean PCDAI: 42.3 to 5.93, p < 0.0001 and mean PUCAI: 42.6 to 7.19, p = 0.0044). Fecal calprotectin mean levels declined from 1544 µg/g to 425.7 µg/g (p < 0.0001). Patients with proactive monitoring demonstrated superior remission rates and lower disease activity scores. Proactive therapeutic drug monitoring during infliximab induction is associated with improved early clinical remission and biochemical response in pediatric Inflammatory bowel disease. This approach might result in early sustained remission that might modify the course of the disease. Conflict of interest: Dr. Abbas, Rasha: No conflict of interest Haidar, Omer: No conflict of interest Al Neirab, Abdallah: No conflict of interest Ibrahim, Nazira: No conflict of interest Abdelrahman, Hatim: No conflict of interest Al-Mudahka, Fatma: No conflict of interest Akobeng, Anthony k: No conflict of interest Elawad, Mamoun Abdelrahman: No conflict of interest

Although biologics are widely used in pediatric inflammatory bowel disease (IBD), the long-term durability of the biologics in children remains incompletely understood. Using the Korean Health Insurance Review and Assessment Service database (2007-2023), we identified patients aged 6-17 years with Crohn’s disease (CD) or ulcerative colitis (UC) who initiated infliximab (IFX) or adalimumab (ADA) as first biologic therapy. Persistence was evaluated using Kaplan-Meier analysis at 6 months, 1 year, and 5 years. Subgroup analyses assessed concomitant immunomodulator (IM) use and duration. Among 2542 CD patients, 1895 initiated IFX and 647 ADA; 581 UC started IFX. Among CD, IFX persistence was 97.47%. 88.0%, and 78.64%, while ADA showed 95.58%, 87.17%, and 72.79%. In UC, IFX persistence was 76.21%, 40.35% and 24.66%. In CD, IFX with IM improved durability compared with monotherapy (HR 0.67, 95% CI 0.52-0.85, p = 0.0003 at 1 year; HR 0.77, 95% CI 0.63-0.95, p = 0.0078 at 5 years), mainly when IM was continued ≥6 months, while ADA showed no clear durability benefit from the combination therapy. In UC, IFX durability improved with IM ≥ 6months at 1 year (HR 0.65, 95% CI 0.44-0.96, p = 0.023), while the effect was attenuated over time. In this nationwide, real-world study, IFX and ADA demonstrated comparable persistence in CD, while IFX durability in UC declined substantially. Sustained IM use for ≥6 months enhanced IFX durability, whereas short-term use offered limited benefit. These findings underscore the importance of IM duration in optimizing anti-TNF therapy in pediatric IBD and provide robust evidence from a nationwide population-based cohort.

AIM To verify the impact of induction therapy with infliximab (IFX) on mucosal healing in children with ulcerative colitis (UC). METHODS The study included all UC pediatric patients treated with IFX at our center over the last 10 years. The data were collected from patients' medical charts and analyzed retrospectively. A total of 16 patients with UC underwent colonoscopy with sample collection before and after three IFX injections. Pediatric Ulcerative Colitis Activity Index (PUCAI) was used to assess the clinical condition; endoscopic features were classified according to the Baron scale; and histological changes were evaluated according to the protocol of The British Society of Gastroenterology and Geboes Index. Clinical response was defined as a ≥ 20-point reduction in PUCAI index, and clinical remission as PUCAI index < 10 points. Endoscopic mucosal remission was defined as completely normal (score 0) on the Baron scale. Histological remission was defined as grade 0 in the Geboes Index. To assess correlation between variables, Spearman's rank correlation coefficient was used. RESULTS Clinical remission (PUCAI < 10) at week 8 was achieved in 68.75% of investigated subjects. Endoscopic mucosal remission at week 8 (Baron 0) was observed in 12.5% of patients. Histological remission (Geboes 0) after induction therapy with IFX was noticed in 18.75% cases. A general histological improvement, expressed by normal surface and crypt architecture, number of crypts, and lamina propria cellularity, was observed in six (37.5%) patients; there was no improvement in nine (56.25%) individuals, and worsening was observed in one (3.75%) case. Changes were not related to UC location. A reduction of inflammatory process was observed in 10 (62.5%) patients; there were no changes in four (25%) individuals, and the inflammation became more severe in two (12.5 %) cases. Simultaneous clinical, endoscopic and histological improvement of parameters assessing disease activity at week 8 was noticed in six (37.5%) patients. 55.5% of investigated patients with normal mucosa seen on endoscopy showed no inflammation on histology. A Baron score of 2 and 3 showed a good correlation with histology results (78.2% of patients with a Geboes Index ≥ 3). CONCLUSION IFX has a positive histological effect in more than one-third of UC patients. IFX reduces intestinal inflammation and improves clinical condition.

OBJECTIVES The severe course of inflammatory bowel diseases (IBDs) refractory to advanced therapies in children results in the search for new therapeutic methods. The aim of this study was to evaluate the efficacy and safety of dual therapy with biologics in a cohort of children with IBD. METHODS Retrospective analysis of data from 29 children with a diagnosis of IBD, 19 with ulcerative colitis (66%), 10 with Crohn's disease (CD) (34%) qualified for dual biological therapy (DBT). The median age of patients was five (interquartile range [IQR], 1-15) years at diagnosis of IBD and 14 (IQR, 3-17) years at eligibility for dual therapy. Thirteen (45%) patients were treated with vedolizumab/adalimumab (VDZ + ADA), 13 (45%) with ustekinumab/adalimumab (UST + ADA), three (10%) with infliximab/vedolizumab (IFX + VDZ). RESULTS Clinical remission was achieved in 13 (45%; seven UC and six CD) and 12 (41%; seven UC and five CD) Pediatric Weighted Crohn's Disease Activity Index (wPCDAI)/Pediatric Ulcerative Colitis Activity Index (PUCAI) patients after 4 and 12 months at the initiation of dual therapy. Clinical response based on wPCDAI/PUCAI was reported in 16 (55%; nine UC and seven CD) and 12 (41% seven UC and five CD) children after 4 and 12 months of follow-up, respectively. The median fecal calprotectin decreased significantly from 1240 µg/g (53-10,100) to 160 µg/g (5-2500; p = 0.004) between baseline and Month 4 and from 749 at baseline (57-10,100) to 17 (5-3110; p = 0.12) over 12 months. Moreover, 34% (six UC and four CD) of patients achieved endoscopic remission. CONCLUSIONS DBT seems to be an effective alternative therapeutic option for patients with moderate and severe IBD.

The pharmacokinetics and pharmacodynamics of biosimilar infliximab (IFX-BioS) in pediatric inflammatory bowel disease (IBD) are poorly understood. We examined some factors predicting IFX-BioS trough levels (TLs) in children. Children with Crohn's disease (CD) and ulcerative colitis (UC) with an indication to start IFX-BioS in our center were prospectively included (January 2021-June 2022). TLs were measured with an in vitro lateral flow immunoassay (therapeutic range:3-7 microg/mL) at the 4th and 6th infusions and correlated with several covariates. A total of 110 TLs in 55 children (34 UC and 21 CD) were included. The mean TLs were 8.8±7.6 microg/mL and 9.8±6.7 microg/mL at the 4th and 6th infusions, respectively. The multivariate linear regression model at the 4th infusion found a positive correlation between TLs and age at diagnosis (B: 1.950, 95% CI: [0.019, 3.882], p=0.048) and IFX-BioS dose/kg (B: 1.962, 95% CI: [0.238, 3.687], p=0.029), and a negative correlation with clinical scores (B: -0.401, 95% CI: [-0.738, -0.064], p=0.023). At the 6th infusion, female gender (B: 6.887, 95 CI: [0.861, 12.913], p=0.029), hemoglobin (B: 1.853, 95% CI: [0.501, 3.204], p=0.011), and IFX-BioS dose/kg (B: 1.792, 95% CI: [0.979, 2.605], p<0.001) were found to be positively correlated to TLs. Clinical remission was achieved in 71% (4th infusion) and 67.2% (6th infusion) of patients. Logistic regression analysis revealed no significant association between combined clinical and biochemical remission and TLs at the 4th (OR: 0.010, 95% CI: [0.928; 11.099], p=0.819) or 6th (OR: 0.017, 95% CI: [0.924; 1.119], p=0.732) infusion, corrected for IFX-BioS dose/kg and interval between infusions. We discovered some predictors IFX-BioS TLs in IBD children. Understanding the IFX-BioS pharmacokinetics and pharmacodynamics could allow physicians to identify which patients are at higher risk of poor outcomes and adjust treatment accordingly.

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OBJECTIVES While higher infliximab (IFX) trough concentrations (TCs) are associated with better outcomes in patients with inflammatory bowel disease (IBD), they could pose a risk for adverse events (AEs), including IFX-induced skin lesions. Therefore, we studied correlations between IFX TCs and occurrence of AEs in paediatric IBD patients. METHODS In this single-centre study, all children with Crohn's disease (CD) and ulcerative colitis (UC) receiving IFX maintenance therapy who underwent proactive drug monitoring between March 2015 and August 2022 were included. IFX doses/intervals/TCs and patient characteristics were systematically registered, as well as AEs and skin lesions appearance. RESULTS A total of 109 patients (72 CD and 37 UC) contributed 2913 IFX TCs. During a median follow-up of 3.0 [1.5-4.5] years, we observed 684 AEs in 101 patients and 49 skin lesions in 35 patients. There was no significant difference (p = .467) in median TCs between patients with and without skin lesions. However, higher median IFX doses were associated with an increased hazard rate of skin lesions [HR 1.084 (1.024-1.148), p = .005], in addition to female sex [2.210 (1.187-5.310), p = .016] and diagnosis of CD [1.695 (1.241-1.877), p = .011]. Considering IFX therapeutic TC cut-offs of 5.0 and 9.0 µg/mL, there was no significant difference in AE rate (p = .749 and p = .833, respectively). Also, no significant association between IFX doses and AE rate (p = .159). CONCLUSIONS Increasing the IFX dose to achieve therapeutic TCs may not increase the overall risk of AEs in paediatric IBD patients. However, concerns arise regarding the risk of skin lesions, especially in female CD patients.

Background The role of therapeutic drug monitoring for infliximab [IFX] therapy in children with inflammatory bowel disease [IBD] is poorly investigated. We determined if IFX exposure correlates with long-term remission in children. Methods In this retrospective study, all children with Crohn's disease [CD] and ulcerative colitis [UC], receiving maintenance IFX at our centre, were included. Serum trough levels and cumulative drug exposure were correlated with clinical, biological, and endoscopic remission. All children received proactive drug monitoring and dose adaptation aiming to target a therapeutic window of 3-7 µg/mL. All data are presented as median [interquartile range]. Results A total of 686 serum levels during IFX maintenance in 52 paediatric patients [33 CD and 19 UC] were included (median 9 [4-18] per patient). With a median of 17 [8-36] months under IFX therapy, 39/52 [75%] patients were in clinical remission and 29/40 [73%] patients were in endoscopic remission. Median IFX trough levels were significantly higher when children achieved clinical remission (5.4 [3.8-8.0] µg/mL versus 4.2 [2.6-6.7] µg/mL), biological remission (5.2 [3.7-7.7] µg/mL versus 4.2 [2.6-6.5] µg/mL), combined clinical and biological remission (5.7 [4.0-8.2] µg/mL versus 4.4 [2.7-6.8] µg/mL) and endoscopic remission (6.5 [4.2-9.5] µg/mL versus 3.2 [2.3-5.6] µg/mL) compared with not meeting these criteria [all p ≤ 0.001]. Conclusions In this large paediatric cohort, children with clinical and/or endoscopic remission had significantly higher IFX exposure during maintenance therapy. We showed excellent outcome data using serial and systematic measurements of drug levels. This could provide a rationale for the use of proactive drug monitoring in children in order to improve long-term outcomes.

Background: Inflammatory bowel diseases in children are characterized by a wide variety of symptoms and often a severe clinical course. In the treatment, we aimed to induce and maintain remission. We focused on assessing the efficacy and safety of the concomitant use of two biologic therapies including: anti-TNF (infliximab, adalimumab) vedolizumab and ustekinumab in a refractory pediatric IBD cohort. Methods: Fourteen children (nine ulcerative colitis, one ulcerative colitis/IBD-unspecified, four Crohn’s disease) with a disease duration of 5.2 (8 months–14 years) years, initiated dual therapy at an age of 11.7 (3–17) years after failure of monotherapy with a biological drug. Five patients (36%) were treated with vedolizumab/adalimumab (VDZ + ADA), five (36%) with ustekinumab/adalimumab (UST + ADA), and three (21%) with infliximab/vedolizumab (IFX + VDZ). One patient (7%) was switched from a combination of vedolizumab and adalimumab to ustekinumab and adalimumab during follow-up. Results: A clinical improvement was obtained in ten children (73%; 5 UC, 1 UC/IBD-unspecified, 4 CD) on the PCDAI/PUCAI scale after 4 months of a second biological drug being added. The median fecal calprotectin decreased from 1610 µg/g (140–10,100) to 586 µg/g (5–3410; p = 0.028) between baseline and 4 months. Conclusions: Our clinical experience suggests that dual therapy may be an option for pediatric patients with moderate and severe courses of IBD with limited therapeutic options

children(72%; 11 UC; 7 CD) in PCDAI/PUCAIscale after 4 months of dose a second biological drug. The median PCDAIdecreased from 52,5 points (35 – 65) to12,5 points (0 – 30) in seven patients with Crohn ’ s disease and PUCAI reduced from 45 points (0 – 85) to 15 points (0-65) between baseline and 4 months in fi fteen patients diagnosed with ulcerative colitis, who were treated for a minimum of 4 months. The median fecal calprotectin decreased from 1300 ug/g (53-10100) to 383 ug/g (5-3410; P 5 0,03) at the same time. Three patients (12%; 3UC) did not complete 4 months induction phase. One patient despite clinical improvement, dual biological therapy was discontinued because of anal abscess. (UC, VDZ 1 ADA). Another required a colectomy two months after starting therapy (UC, VDZ 1 IFX). Third patient had cardiac complications after su ff ering from Covid infection (UC, IFX 1 VDZ). Conclusion: Our clinical experience suggests that dual therapy may be an option for paediatric patients with moderate and severe courses of IBD with limited therapeutic options.

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BACKGROUND Biological therapies have modified the disease course of pediatric inflammatory bowel disease (IBD) and are routinely used in clinical practice. Our observational study aims to evaluate effectiveness and safety of biologics in IBD. METHOD Clinical benefit and safety data of 93 children with IBD, receiving biologics (Infliximab - IFX, Adalimumab - ADA, Golimumab - GOL) from January 2013 to December 2017, were extracted from the cohort of the Sicilian Network of IBD. RESULTS Among 87 children aged 7-17 years (63 Crohn's disease [CD], 24 Ulcerative colitis [UC]), 101 out of 108 biologic treatments were considered. Evaluation of 74 biologic treatments in CD patients at 26, 52, 104 weeks showed clinical benefit rates of 84.2%, 93.3%, 66.7% with IFX (n= 38) and 88.9%, 84.4%, 65.2% with ADA (n= 36). Biologic treatments (n=27) evaluated in the UC group at 26, 52, 104 weeks, led to clinical benefit rates of 85.7%, 83.3%, 50% in IFX subgroup (n=21) and 40%, 50%, 33% in the ADA subgroup (n=5), respectively. One patient treated with GOL showed 100% clinical benefit at 26 and 52 weeks. Overall adverse events (AEs) rate was 9.25%. Six younger children, <6 years, receiving 8 treatments (4 ADA, 4 IFX) presented a clinical remission rate of 75% at 12 weeks and 25% at 52 weeks. AEs rate was 25% in this group. CONCLUSION Our data show that biologic therapy in children, even at a younger age, is effective in allowing long-term remission with a good safety profile.

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Background and aims Recent adult evidence suggests that infliximab (IFX) trough levels (TL) in patients with severe ulcerative colitis (UC) may be decreased. The aims of our study were to compare post-induction IFX TL of children with severe versus moderate UC and to evaluate short- and long-term outcomes. Methods In this single-center retrospective study, children with a diagnosis of UC starting IFX with a Pediatric Ulcerative Colitis Activity Index (PUCAI) ≥35 and with available post-induction TL were recruited. UC characteristics, IFX dosage and interval, primary non-response, IFX failure, and surgery after 24 months were collected. Post induction TL, anti-IFX antibodies, and laboratory evaluations at the time of starting IFX were also acquired. Results A total of 90 children were enrolled, of whom 39 (43.3%) were classified as severe UC and 51 (56.6%) as moderate UC. Median post-induction IFX TL were lower in severe UC versus moderate group (5.5 vs 10.3; p = 0.03), despite a more frequently intensified IFX regimen. Children in the higher TL quartiles showed increased rates of clinical, biological, and combined remission (p = 0.04, p < 0.001, and p = 0.01, respectively). In a multivariate analysis, a PUCAI ≥65 and time interval from last IFX infusion were the only predictors associated with IFX TL. At 24 months, children in the higher TL quartiles had a decreased risk of IFX failure (p = 0.002). The severe UC group showed a higher risk of IFX failure at 24 months (16/23 (41%) vs. 11/40 (21.6%); p = 0.05). Kaplan–Meier methods demonstrated a trend toward statistical significance, with a two-year cumulative colectomy rate of 15.38% (95% confidence interval (CI) 8.1–15.6%) in children with severe UC and 3.92% (95% CI 2.9–10.8%) in patients with moderate UC (logrank test p = 0.06). Conclusions Children starting IFX with severe UC showed lower post-induction TL and poor disease outcomes. Achieving adequate TL was associated with better efficacy outcomes.

Aim: This multicenter study is the first one on Iranian children with very early onset ulcerative colitis (UC) and one of the few studies about the effect of biological therapy in children with UC under 7 years of age. Background: Children with very early onset inflammatory bowel disease (IBD) are diagnosed before 6 years of age Methods: The current study was performed on 14 children under 7 years of age with severe UC. Children with severe UC whose therapy with corticosteroid and azathioprine as conventional treatment had failed were treated with infliximab (IFX) and later with adalimumab (ADA). Results: Among the total 14 participants, 6 (43%) patients were female. Mean patient age was 4.9 years (range = 3–7 years), mean age at diagnosis was 3.4 years (range = 1.5–6 years), and mean duration of illness was 1.5 years. At the end of 54 weeks of therapy with IFX, 2 (14%) patients were in remission, 2 (14%) patients were mild, and 4 (29%) patients were moderate, with no secondary treatment failure (during the maintenance phase). A total of 6 (43%) patients had primary treatment failure (no response after 14 weeks of therapy). These patients were treated with ADA. At the end of 52 weeks of therapy, 3 (50%) of those 6 (100%) patients were referred for colectomy, 1 (17%) was in remission, and 2 (33%) patients had mild severity. Conclusion: The current study has shown that IFX is a safe and effective therapy for children with very early onset UC. ADA may be effective in the treatment of children with UC who are refractory to IFX.

Objectives: Despite existence of international guidelines for diagnosis and management of inflammatory bowel diseases (IBD) in children, there might be differences in the clinical approach. Methods: A survey on clinical practice in paediatric IBD was performed among members of the ESPGHAN Porto IBD working group and interest group, PIBD-NET, and IBD networks in Canada and German-speaking countries (CIDsCANN, GPGE), using a web-based questionnaire. Responses to 63 questions from 106 paediatric IBD centres were collected. Results: Eighty-four percentage of centres reported to fulfil the revised Porto criteria in the majority of patients. In luminal Crohn disease (CD), exclusive enteral nutrition is used as a first-line induction therapy and immunomodulators (IMM) are used since diagnosis in the majority of patients. Infliximab (IFX) is mostly considered as first-line biological. Sixty percentage of centres have experience with vedolizumab and/or ustekinumab and 40% use biosimilars. In the majority of ulcerative colitis (UC) patients 5-aminosalicylates are continued as concomitant therapy to IMM (usually azathioprine [AZA]/6-MP). After ileocaecal resection (ICR) in CD patients without postoperative residual disease, AZA monotherapy is the preferred treatment. Conclusions: A majority of centres follows both the Porto diagnostic criteria as well as paediatric (ESPGHAN/ECCO) guidelines on medical and surgical IBD management. This reflects the value of international societal guidelines. However, potentially desirable answers might have been given instead of what is true daily practice, and the most highly motivated people might have answered, leading to some bias.

children(72%; 11 UC; 7 CD) in PCDAI/PUCAIscale after 4 months of dose a second biological drug. The median PCDAIdecreased from 52,5 points (35 – 65) to12,5 points (0 – 30) in seven patients with Crohn ’ s disease and PUCAI reduced from 45 points (0 – 85) to 15 points (0-65) between baseline and 4 months in fi fteen patients diagnosed with ulcerative colitis, who were treated for a minimum of 4 months. The median fecal calprotectin decreased from 1300 ug/g (53-10100) to 383 ug/g (5-3410; P 5 0,03) at the same time. Three patients (12%; 3UC) did not complete 4 months induction phase. One patient despite clinical improvement, dual biological therapy was discontinued because of anal abscess. (UC, VDZ 1 ADA). Another required a colectomy two months after starting therapy (UC, VDZ 1 IFX). Third patient had cardiac complications after su ff ering from Covid infection (UC, IFX 1 VDZ). Conclusion: Our clinical experience suggests that dual therapy may be an option for paediatric patients with moderate and severe courses of IBD with limited therapeutic options.

We present the case of a 15-year-old female with ulcerative colitis who developed an asymptomatic rise in creatine kinase and transaminases while on infliximab therapy. Additional rheumatologic workup revealed high-titer anti-nuclear antibody and positive anti-histone antibody, with the absence of myositis-specific autoantibodies. A drug-induced autoimmune phenomenon was suspected, with the patient lacking any muscle weakness or lupus features. The patient was subsequently switched to ustekinumab, which resulted in complete normalization of her labs while maintaining remission of her ulcerative colitis.

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 <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

A 17-year-old female was diagnosed with inflammatory bowel disease and started on infliximab. A few weeks after starting infliximab, she developed a recurrence of daily fevers associated with an intermittent dry cough, which worsened over the course of a month. A chest radiograph, abdominal ultrasound, and computed tomography scan of the chest and abdomen revealed a heterogeneous spleen with multiple hyperechoic areas, tiny splenic micronodules, and diffuse micronodularity throughout the lungs. She was transferred to a tertiary care hospital because of hypotension, new oxygen requirements, and ongoing fever. Her bloodwork on presentation to tertiary care revealed pancytopenia and elevated inflammatory markers; she had splenomegaly on MRI. As her clinical picture evolved, she continued to have persistent fevers and anorexia despite ongoing management. Infectious diseases, rheumatology, and gastroenterology were consulted to guide the evaluation and management of this patient's complex clinical course.

Background. Genetically engineered biological therapy has revolutionized the treatment of many chronic inflammatory diseases. It often allows to achieve significant clinical effect and improve the patient's quality of life. However, sometimes it leads to adverse events, and physicians encounter them more often. One of such side effects is paradoxical psoriasis (PP) that can be revealed during the therapy with tumor necrosis factor alpha (TNF-α) inhibitors. PP is the debut or exacerbation of pre-existing psoriasis.Clinical case description. Patient A., 17 years old, has suffered from ulcerative colitis since 2020; biological therapy with infliximab has been initiated in March 2022. Numerous rashes were revealed, as well as development of confluent alopecia foci on the background of scalp psoriatic damage, during the next hospitalization in December 2022. The patient was examined by dermatologist; diagnosis of PP was established according to the clinical picture and medical history. Skin rashes progressed and ulcerative colitis worsened (diarrheal syndrome, fecal calprotectin levels increased up to 526 μg/g) after cessation of infliximab therapy. Biological therapy with the inhibitor IL-12/23 (ustekinumab) was initiated due to the aggressive cutaneous pathological process and the aggravation of inflammatory bowel disease (IBD) symptoms. The gradual regression of rashes with the restoration of scalp hair growth and ulcerative colitis clinical and laboratory remission were noted during the treatment.Conclusion. PP is a rare complication that develops during therapy with TNF-α inhibitors, and it is most often observed in patients with IBD. In our case there was aggressive course of psoriasis with severe scalp lesion and hair loss (it is specific type of lesion in such patients). The ustekinumab, inhibitor IL-12/23, treatment efficacy correlates with the literature data on this drug successful use in both nosologies. Ustekinumab can be a first-line therapy in such pediatric patients. This clinical case is the first case in the Russian literature on effective management of PP and ulcerative colitis with ustekinumab in children.

We report the first described case of pulmonary tularaemia in the pediatric patient receiving infliximab for ulcerative colitis. We highlight the importance of considering Francisella tularensis in diagnostically challenging cases of persistent respiratory symptoms to facilitate early diagnosis and adequate therapy. The TCR‐γδ + DN T cells are gaining important role in clinical practice. Polymerase chain reaction assays and serology guarantee early recognition.

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The optimal regimen of infliximab salvage in acute severe ulcerative colitis (ASUC) patients remains controversial. This retrospective multicenter study aimed to compare accelerated and standard infliximab induction in a Chinese cohort of ASUC patients, and to explore risk factors associated with poor prognosis. Data were collected retrospectively from steroid-refractory ASUC patients who received infliximab induction as rescue therapy at seven tertiary centers across China. Accelerated infliximab induction was defined as receiving two doses of infliximab on or before day 13 and/or receiving intensified doses of ≥ 7.5 mg/kg. Outcomes including colectomy and clinical remission (Mayo score ≤ 2 and every subscore ≤ 1 at day 14) rates were compared using propensity score adjustment for potential confounders. The variables in propensity score model was determined by logistic regression analysis for accelerated induction. A total of 76 patients were included: 29 received standard induction and 47 received accelerated induction. The overall disease severity was significantly higher in patients of accelerated group (Table). The 30-day colectomy rates did not differ between two groups (4.3% vs. 0%, P=0.522). However, the accelerated group had a higher 90-day colectomy rate (17.8% vs. 0%, P=0.019) and lower clinical remission rate (27.7% vs. 65.5%, P=0.001). (Figure. A) After adjusting with propensity score and institution, there was no significant difference in colectomy (P=0.20) or no clinical remission (P=0.48) hazards. Dose-effect curves plotted by restricted cubic splines (adjusted for propensity score and institution) showed decreased colectomy hazard with higher cumulative infliximab dosage within 5 days, while no improvement was observed for increasing cumulative infliximab dosage within 28 days. (Figure. B) Multivariate logistic regression analyses revealed female gender (OR=7.69, 95%CI: 1.96-33.33) and C-reactive protein (CRP) >10 mg/L at infliximab initiation (OR=5.00, 95%CI: 1.27-24.34) as independent risk factors for no clinical remission. (Figure. C) After adjusting for confounders, there were no significant differences in colectomy or clinical remission rates between accelerated and standard infliximab induction among steroid-refractory ASUC patients. Elevated CRP at infliximab initiation indicated more intensive treatment or earlier surgery to be considered. And it would be better to give early intensified dosage within 5 days if needed.

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Failure of anti-TNF therapy is a real concern in children with inflammatory bowel disease (IBD) owing to the limited therapeutic arsenal. Anti-TNF drugs modulate the immune response, a key driver of chronic inflammation in IBD. Accordingly, we analyzed changes in the frequency of T-lymphocyte and cytokine levels after 6 weeks of treatment to identify potential biomarkers of response to anti-TNF drugs. We recruited 77 patients under 18 years of age diagnosed with IBD and treated with an anti-TNF drug. Using flow cytometry and multiplex ELISA, we analyzed 31 T-lymphocyte populations and four cytokines. We identified changes in 10 populations of T lymphocytes after 6 weeks of treatment. Naïve Tregs were associated with a primary response to anti-TNF drugs, while activated Tregs were associated with long-term response. Serum INF-γ levels were decreased after anti-TNF treatment in children with Crohn’s disease (CD), but not in those with ulcerative colitis (UC). The memory CD8+ Type 2 Cytotoxic T (Tc2) subset increased in non-responders with CD and the CD4+ memory Th17 cells increased in non-responders with UC. These findings could help us to understand the cellular regulation of anti-TNF therapy, to identify children at a higher risk of treatment failure, and, potentially, to develop more personalized therapeutic strategies.

INTRODUCTION: We evaluated the impact of immunosuppressants (IS) and antitumor necrosis factor (TNF) introduction on long-term outcomes of ulcerative colitis (UC) in a large population-based pediatric-onset cohort. METHODS: All patients included in the EPIMAD registry with a diagnosis of UC made before the age of 17 years between 1988 and 2011 were followed up retrospectively until 2013. Medication exposure and disease outcomes were compared between 3 diagnostic periods: 1988 to 1993 (period [P] 1; pre-IS era), 1994 to 2000 (P2; pre-anti-TNF era), and 2001 to 2011 (P3; anti-TNF era). RESULTS: A total of 337 patients (female, 57%) diagnosed with UC were followed up during a median duration of 7.2 years (interquartile range 3.8–13.0). The IS and anti-TNF exposure rates at 5 years increased over time from 7.8% (P1) to 63.8% (P3) and from 0% (P1) to 37.2% (P3), respectively. In parallel, the risk of colectomy at 5 years decreased significantly over time (P1, 17%; P2, 19%; and P3, 9%; P = 0.045, P-trend = 0.027) and between the pre-anti-TNF era (P1 + P2, 18%) and the anti-TNF era (P3, 9%) (P = 0.013). The risk of disease extension at 5 years remained stable over time (P1, 36%, P2, 32%, and P3, 34%; P = 0.31, P-trend = 0.52) and between the pre-anti-TNF era (P1 + P2, 34%) and the anti-TNF era (P3, 34%) (P = 0.92). The risk of flare-related hospitalization at 5 years significantly increased over time (P1, 16%; P2, 27%; P3, 42%; P = 0.0012, P-trend = 0.0006) and between the pre-anti-TNF era (P1 + P2, 23%) and the anti-TNF era (P3, 42%) (P = 0.0004). DISCUSSION: In parallel with the increased use of IS and anti-TNF, an important decline in the risk of colectomy in pediatric-onset UC was observed at the population level.

Pediatric Inflammatory Bowel Disease (IBD) remains challenging to treat and difficult to prognosticate. Although multiple immune cell types coordinate pathology in both Crohns disease (CD) and ulcerative colitis (UC), specifying which cell types and cell states portend better or worse response to major IBD treatment strategies, including anti-TNF therapies (the only FDA-approved therapy for pediatric IBD), remains challenging. Here, we present the results of the PREDICT study, which enrolled 79 treatment-naive pediatric patients at the time of diagnostic endoscopy, enabling a comprehensive transcriptomic, histologic, and serologic analysis of 40 CD patients and 16 UC patients, as well as 23 patients with functional gastrointestinal disorders (FGID) who served as pediatric non-inflamed controls. Leveraging these data, we performed a comprehensive analysis of colonic immunology in each of these clinical conditions. Our results indicate that, within the complex landscape of immune pathology in pediatric CD and UC, there is a coordinated shift across the TH1-to-TH17 immune activation continuum among T cells that is pertinent to anti-TNF response. For CD, this shift defines partial response to anti-TNF treatment. For UC, the landscape is more complex, with both TH17 and TFH biology defining disease, and pre-treatment TH17 biology contributing to anti-TNF treatment resistance. Related to this, polyreactive TCR phenotypes within UC TFH cells are correlated with both germinal center activity and the frequency of IgG1 plasma cells, yet opposed to the TH17 signatures associated with anti-TNF nonresponse. The elucidation of these distinct mechanisms of T cell-dependent disease pathology, treatment response, and TCR polyreactivity suggests a model in which sustained TH17 signaling in CD and baseline TH17 signaling in UC are associated with disease pathogenesis, forming a basis for a generalized understanding of IBD pathogenesis and underscoring the need for endotype-specific approaches to IBD therapy.

BACKGROUND Anti-TNF agents are the first biologic treatment option in inflammatory bowel disease (IBD). The long-term effectiveness of this strategy at the population level is poorly known, particularly in pediatric-onset IBD. METHODS All patients diagnosed with Crohn's disease (CD) or ulcerative colitis (UC) before the age of 17 between 1988 and 2011 in the EPIMAD population-based registry were followed retrospectively until 2013. Among patients treated with anti-TNF, the cumulative probabilities of anti-TNF failure defined by primary failure, loss of response (LOR) or intolerance were evaluated. Factors associated with anti-TNF failure were investigated by a Cox model. RESULTS Among a total of 1,007 patients with CD and 337 patients with UC, respectively 481 (48%) and 81 (24%) were treated with anti-TNF. Median age at anti-TNF initiation was 17.4 years (IQR, 15.1-20.9). Median duration of anti-TNF therapy was 20.4 months (IQR, 6.0-59.9). In CD, the probability of failure of 1st line anti-TNF at 1, 3 and 5 years was respectively 30.7%, 51.3% and 61.9% for infliximab and 25.9%, 49.3% and 57.7% for adalimumab (p = 0.740). In UC, the probability of failure of 1st line anti-TNF therapy was respectively 38.4%, 52.3% and 72.7% for infliximab and 12.5% for these 3 timepoints for adalimumab (p = 0.091). The risk of failure was maximal in the first year of treatment and LOR was the main reason for discontinuation. Female gender was associated with LOR (HR, 1.48; 95%CI 1.02-2.14) and with anti-TNF withdrawal for intolerance in CD (HR, 2.31; 95%CI 1.30-4.11) and disease duration (≥ 2 y vs. < 2 y) was associated with LOR in UC (HR, 0.37; 95%CI 0.15-0.94) in multivariate analysis. Sixty-three (13.5%) patients observed adverse events leading to termination of treatment (p = 0.57). No death, cancer or tuberculosis was observed while the patients were under anti-TNF treatment. CONCLUSION In a population-based study of pediatric-onset IBD, about 60% in CD and 70% in UC experienced anti-TNF failure within 5 years. Loss of response account for around two-thirds of failure, both for CD and UC.

Background Poor outcome of inflammatory bowel disease (IBD) is associated with malnutrition. Our aim was to compare body composition (BC) and physical activity (PA) between patients with IBD and healthy controls, and to assess the changes in BC, PA and health related quality of life (HRQoL) in children with IBD during anti-TNF therapy. Methods 32 children with IBD (21 with Crohn’s disease (CD), (age: 15.2 ± 2.6 years, 9 male) and 11 with ulcerative colitis (UC), (age: 16.4 ± 2.2 years, 5 male) participated in this prospective, observational follow up study conducted at Semmelweis University, Hungary. As control population, 307 children (age: 14.3 ± 2.1) (mean ± SD) were included. We assessed BC via bioelectric impedance, PA and HRQoL by questionnaires at initiation of anti-TNF therapy, and at two and six months later. The general linear model and Friedman test were applied to track changes in each variable. Results During follow-up, the fat-free mass Z score of children with CD increased significantly (-0.3 vs 0.1, p  = 0.04), while the BC of patients with UC did not change. PA of CD patients was lower at baseline compared to healthy controls (1.1 vs. 2.4), but by the end of the follow up the difference disappeared. Conclusions The fat-free mass as well as PA of CD patients increased during the first six months of anti-TNF treatment. As malnutrition and inactivity affects children with IBD during an important physical and mental developmental period, encouraging them to engage in more physical activity, and monitoring nutritional status should be an important goal in patient care.

Abstract Objectives The aim of the study is to evaluate the efficacy of anti‐tumor necrosis factor (TNF)‐α monotherapy versus combination anti‐TNF‐α and immunosuppressive therapy. Methods A single‐center, retrospective, observational study was conducted on inflammatory bowel disease (IBD) children. Patients with at least 6 months of follow‐up were enrolled and divided into two groups based on therapy. Combo group included children on combination anti‐TNF‐α and immunosuppressant therapy; children undergoing anti‐TNF‐α monotherapy were assigned to Mono group. Results One hundred and seventeen children were enrolled, of whom 74 (63.2%) were affected by Crohn's disease (CD) and 43 (36.8%) by ulcerative Colitis (UC) (median age at diagnosis: 11.6 years; range 2.1–16.9; M/F: 56/61). Eighty patients (68.4%) were included in combo group and 37 (31.6%) in mono group. The median follow‐up was 2.6 years (0.5–11.3). Twenty‐three patients out of 80 (28.7%) in Group 1 showed therapy failure compared with 21/37 (56.8%) children in Mono group (p = 0.04). CD patients in monotherapy showed a significantly increased risk of therapy failure than those treated with combination therapy (p < 0.001). Conversely, no difference was found in UC children (p = 0.7). Children undergoing a reactive approach showed more frequent therapy failure compared to proactive in both groups (combo group: 41.7% vs. 4.3%; p = 0.01; mono group: 87.5% vs. 20%; p = 0.01). In a multivariate regression model, the use of a proactive approach and combination therapy was independently associated with anti‐TNF‐α durability (odds ratio [OR] = 22.1, OR = 12.9). Conclusion Combination therapy reduced overall anti‐TNF‐α failure in CD children, but not in UC patients. Additionally, a proactive approach was associated with increased anti‐TNF‐α durability.

Anti-integrin αvβ6 antibody (V6Ab) has emerged as a promising diagnostic marker for differentiating ulcerative colitis (UC) from Crohn’s disease (CD) in adult. However, approximately 30% of pediatric-onset CD cases reportedly exhibited V6Ab positivity. The impact of V6Ab on the clinical characteristics and treatment response of pediatric inflammatory bowel disease (IBD) remains unknown. This retrospective single-center study aimed to investigate the clinical characteristics and relevance of V6Ab in pediatric IBD as a pilot study. We retrospectively reviewed the records of 60 children with IBD whose V6Ab status was measured (V6Ab+CD: 22 cases, V6Ab-CD: 17 cases, V6Ab+UC: 18 cases, V6Ab-UC: 3 cases). Associations between V6Ab and reclassification of diagnosis, perianal lesions, endoscopic and clinical activity scores, and anti-TNF failure were analyzed. V6Ab positivity was defined as an optical density (O.D.) >0.2525 at 450 nm. Clinical remission was determined by a weighted Pediatric Crohn’s Disease Activity Index (wPCDAI) ≤2, while endoscopic remission was based on a Simple Endoscopic Score for Crohn’s Disease (SES-CD) ≤2. Anti-TNF failure referred to discontinuation due to insufficient efficacy, excluding cases related to side effects. 13 V6Ab+CD cases were initially diagnosed as UC and later reclassified to CD based on the revised-Porto criteria. The prevalence of perianal lesions was significantly lower in V6Ab+CD compared to V6Ab-CD (3/22 vs 11/18, respectively, p<0.05). Furthermore, UC-like colonic findings, such as granular mucosa and loss of vascular pattern, were significantly more common in V6Ab+CD than in V6Ab-CD (22/22 vs 3/18, respectively, p<0.05). Anti-TNF failure occurred in 10/17 V6Ab+CD cases was significantly higher than that in UC (1/9, p<0.05) but comparable to V6Ab-CD (8/13, p>0.99). Among CD cases treated with ustekinumab (UST) following anti-TNF failure, V6Ab+CD demonstrated a significantly higher endoscopic remission rate (5/7) compared to V6Ab-CD (0/6, p<0.05), even though clinical remission rates did not differ significantly between the groups. (7/7 vs 5/6, respectively, p<0.05) V6Ab+CD cases may have a higher risk of anti-TNF failure compared to V6Ab+UC. Additionally, ustekinumab (UST) appears to be effective for V6Ab+CD patients who experience TNF failure. These findings suggest the potential of V6Ab as a valuable biomarker for precision medicine. Further analyses from ongoing multi-center prospective studies in Japan are eagerly awaited.

Abstract Objectives To assess treatment patterns and initial and maintenance dosing of biologics over 3 years in pediatric patients with ulcerative colitis (UC) or Crohn’s disease (CD), utilizing data from the ImproveCareNow registry. Methods Pediatric patients diagnosed with UC or CD and aged 2–17 years were included in the study. Descriptive statistics were employed to summarize baseline demographics. The proportion of patients on medication for UC or CD were analyzed at the baseline visit, 1-year, and 3-year time points (Cohort 1). Biologic maintenance dosage was calculated only for patients who had data for dose and weight at all-time points (Cohort 2). Results In Cohort 1 (UC = 1784; CD = 4720), baseline treatment in UC included corticosteroid, 5-ASA, and 6-MP/AZA; at 1-year and 3-year time points, treatment with 5-ASA and corticosteroid decreased, whereas 6-MP/AZA and anti-TNFs increased. In CD, baseline treatment included corticosteroid, anti-TNF, 6-MP/AZA, and methotrexate; use of corticosteroids decreased, whereas the use of methotrexate and anti-TNFs increased over 3 years. In Cohort 2 (UC = 350; CD = 1537), at first maintenance dose, UC patients on infliximab received a mean dose of 10.5 mg/kg/8 wk, adalimumab (weight < 40 kg and ≥40 kg) 1.3 mg/kg/2 wk and 0.8 mg/kg/2 wk, and vedolizumab 6.9 mg/kg/8 wks. At the first maintenance dose, CD patients on infliximab received a mean dose of 8.1 mg/kg/8 wk, adalimumab (weight < 40 kg) 1.1 mg/kg/2 wk, adalimumab (weight ≥ 40 kg) 0.8 mg/kg/2 wk, and vedolizumab 10.5 mg/kg/8 wks. Conclusion The use of corticosteroids was common at the initial visit in patients. Anti-TNFs remain the most used class of biologics, however, reported doses in our study were substantially higher than the standard dosing guidelines.

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Pediatric-onset inflammatory bowel diseases (IBD) are associated with an elevated risk of venous thromboembolism (VTE). However, data on the VTE risk in these patients treated with novel biologics, particularly vedolizumab, remain limited. To evaluate the association between vedolizumab and the risk of VTE compared with other biologics in patients with pediatric-onset Crohn’s disease (CD) or ulcerative colitis (UC). We emulated a target trial using electronic health records from the TriNetX research network. The study included patients with CD or UC diagnosed before the age of 18 years who were treated with vedolizumab, ustekinumab, or anti-tumor necrosis factor (TNF) agents. Comparative groups were generated using 1:1 propensity-score matching based on relevant confounders. The primary outcome was the occurrence of any VTE within 12 months of follow-up. Cox proportional hazards models were used to compare the risk of VTE between vedolizumab-treated patients and those treated with anti-TNF agents and ustekinumab. A total of 1806 matched patient pairs were analyzed across four comparisons: patients treated with vedolizumab versus anti-TNF agents (CD = 407 pairs; UC = 443 pairs), and vedolizumab versus ustekinumab (CD = 563 pairs; UC = 393 pairs), respectively. Patients with CD receiving vedolizumab had a significantly higher risk of VTE compared with those receiving anti-TNF therapy (hazard ratio [HR] 8.63; 95% confidence interval [CI] 1.08–69.10; p = 0.014). A higher VTE risk was also observed in vedolizumab-treated patients with CD compared with those treated with ustekinumab (HR 4.64; 95% CI 1.35–15.97; p = 0.007). In contrast, no significant difference in VTE risk was found between vedolizumab and either comparator group in patients with UC. Treatment with vedolizumab was associated with a higher incidence of VTE than anti-TNF agents or ustekinumab among individuals with CD. Prospective cohort studies are warranted to validate the safety of biologic therapy for pediatric patients with CD.

Background/Aims Anti-drug antibodies (ADAs) can develop during treatment with anti-tumor necrosis factor (TNF) agents. We aimed to investigate the factors associated with immunogenicity of anti-TNF agents in pediatric patients with inflammatory bowel disease (IBD) and observe the clinical course of ADA-positive patients. Methods Pediatric IBD patients receiving maintenance treatment with anti-TNF agents who had been tested for ADAs against infliximab (IFX) or adalimumab (ADL) were included in this cross-sectional study. Factors associated with ADA positivity were investigated by analyzing clinicodemographic, laboratory, and treatment-related factors. Results A total of 76 patients (Crohn’s disease, 65; ulcerative colitis, 11) were included. Among these, 59 and 17 patients were receiving IFX and ADL, respectively. ADAs were found in 10 patients (13.2%), all of whom were receiving IFX. According to multivariable logistic regression analysis, the IFX trough level (TL) was associated with ADA positivity (odds ratio, 0.25; 95% confidence interval [CI], 0.08 to 0.51; p=0.002). According to the receiver operating characteristic analysis, the optimal cutoff of the IFX TLs for stratifying patients based on the presence of ADAs against IFX was 1.88 μg/mL (area under curve, 0.941; 95% CI, 0.873 to 1.000; sensitivity, 80.0%; specificity, 95.9%; p<0.001). Among the 10 patients with ADAs against IFX, five patients (50%) switched to ADL within 1 year, while five patients (50%) kept receiving IFX. Transient ADAs were observed in three patients (30%). Conclusions IFX TL was the only factor associated with ADA formation in pediatric IBD patients receiving IFX. Future studies based on serial and proactive therapeutic drug monitoring are required in the future.

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OBJECTIVES Antitumor necrosis factor (anti-TNF) therapies are first-line therapies for children with inflammatory bowel disease (IBD) (Crohn's disease [CD], ulcerative colitis [UC] and IBD-unclassified [IBD-U]). Limited studies describing anti-TNFs durability and loss of response in children. This study evaluates predictors of primary Nonresponse and 3-year drug durability in children with IBD. METHODS This was a single-center retrospective review of patients with IBD less than 18 years old who initiated anti-TNF (infliximab or adalimumab) from January 1, 2014, to December 31, 2019. Clinical and laboratory data were recorded at the time of anti-TNF initiation, 14 weeks, 12 months, and 3 years. Predictors of primary nonresponse (discontinuation within 14 weeks) and durability were assessed. RESULTS A total of 456 patients initiated anti-TNF therapy (183 adalimumab and 273 infliximab). Thirty-seven (8%) patients were primary nonresponders. The 3-year drug durability for both therapies was >70%. Among patients with CD, the 3-year durability was >75% for both therapies. The 3-year durability with UC/IBD-U was 37% for adalimumab and 56% for infliximab. Predictors of primary nonresponse were an erythrocyte sedimentation rate > 55 mm/h in CD on infliximab, and baseline albumin <4 g/dL and <15.6 years at diagnosis in UC/IBD-U. CONCLUSIONS Anti-TNF therapies had a 3-year durability of >75% in patients with CD, while the durability was lower (37%-56%) for patients with UC/IBD-U. Less than 10% of patients were considered primary nonresponders, which lends support to the long-term durability of anti-TNF therapies for pediatric IBD while keeping in mind predictive factors of Nonresponse.

OBJECTIVES Deficiency of serum 25-hydroxyvitamin D [25(OH)D] was associated with decreased short-term response to anti-tumor necrosis factor-alpha (TNF-α) agents in adults with inflammatory bowel disease (IBD). The aim of this study was to evaluate the association between serum 25(OH)D levels and the outcome of children with IBD undergoing anti-TNF-α therapy. METHODS Children with IBD who were treated with anti-TNF-α agents and whose 25(OH)D levels had been measured at the initiation of therapy were included. Demographic, clinical, and laboratory data were collected retrospectively between 1/2012 and 1/2022. 25(OH)D levels above 30 ng/mL were considered sufficient. RESULTS A total of 150 children with IBD were treated with anti-TNF-α agents, and 84 of them (58 Crohn's disease, 26 ulcerative colitis, median [interquartile range] age 15.2 [12.8-16.5] years) met the inclusion criteria. Sixty-five (77%) patients were 25(OH)D-deficient. Adequate 25(OH)D levels were associated with clinical response (hazard ratio [HR] = 4, 95% confidence interval [CI] 1.43-11.11, p = 0.008), and clinical remission (HR = 4.62, 95% CI 2.56-8.33, p < 0.001). While anti-TNF-α trough levels were comparable between 25(OH)d-deficient and non-deficient children, intensification of anti-TNF-α therapy was more prevalent among children with 25(OH)D deficiency (65% vs. 21%, p < 0.001). CONCLUSIONS Adequate serum 25(OH)D is an independent predictor of a favorable outcome of pediatric IBD under anti-TNF-α therapy.

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Long-term data on the efficacy and safety of biologics in pediatric inflammatory bowel disease (IBD) are crucial for guiding clinicians in optimizing their use. This study aims to evaluate real-life durability, usage patterns, and factors influencing treatment discontinuation in pediatric IBD. This registry-based study analyzed data of patients from the IBD registry of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) who started biologic therapy between 2009 and 2022, with a minimum 1-year follow-up. 1184 patients (749 Crohn’s Disease [CD], 437 Ulcerative Colitis or IBD-undetermined [UC/IBD-U]) were retrieved. The median follow-up was 43 months (IQR 28-64). Infliximab was the first biologic in 807 patients (68%) followed by adalimumab in 378 patients (31%). 393 patients (33%) received a second-line biologic, 107 (9%) a third-line and 24 (2%) a fourth-line. At last follow-up, 544 patients (47%) had discontinued the first biologic, with a median time to discontinuation of 14 months (IQR 5-27). Main reasons were loss of response (36%) followed by primary non-response (33%) and infusion reactions (13%). For first-line biologics, treatment durability was superior in patients who received adalimumab compared to infliximab (Figure 1a) and in patients managed with TDM (Figure 2b). In the multivariate analysis risk factors for first biologic discontinuation were age < 6 years (HR 1.8, 95%CI 1.3-2.4), UC/IBD-U (HR 1.4, 95%CI 1.1-1.8), moderate/severe disease activity (HR 1.3, 95%CI 1.1-1.6) and Infliximab vs adalimumab (HR 2.1; 95% CI 1.6-2.7) while the use of TDM emerged as protective, significantly lowering the risk (HR 0.50; 95% CI 0.40-0.63). Combination therapy did not influence biologic durability (HR 0.95; 95% CI 0.77-1.18). strategies for optimizing treatment efficacy of biologics in pediatric IBD should be tailored considering patients age, IBD type and severity and integrating TDM in patients’ management. The contribution of concomitant immunomodulation in the pediatric setting might be negligible.

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Background: Infliximab (IFX) and calcineurin inhibitors (cyclosporine [CYS] and tacrolimus [TAC]) were considered as rescue therapy in steroid-refractory ulcerative colitis (UC). The objective of our study was to perform a meta-analysis evaluating the short-term and long-term efficacy and safety of IFX and calcineurin inhibitors in steroid-refractory UC. Methods: We systematically searched the databases from inception to September 2020 that evaluated IFX, CYS, and TAC in steroid-refractory UC. The primary outcome was the response rates, remission rates, mucosal healing rates, and colectomy rates after therapy initiation. The secondary outcomes were the rates of adverse events (AE), serious adverse events (SAE), and mortality. Odds ratios (OR) with 95% confidence intervals (CIs) were calculated. Results: Nineteen studies comprising 1323 Acute severe ulcerative colitis (ASUC) patients were included in the meta-analysis. Among the non-randomized studies, a significantly higher therapeutic response rate was seen with IFX treatment, with a pooled OR of 3.15 (95% CI 2.26–4.40). Among non-randomized studies, IFX was associated with a significantly lower first-year OR (0.46 [95% CI 0.27–0.79]), second-year (OR 0.53 [95% CI 0.28–0.97]), third-year (OR 0.43 [95% CI 0.24–0.75]) colectomy rate. But the randomized controlled trials (RCTs) did not suggest any difference between IFX and CYS as rescue therapies for steroid-refractory UC. There were no significant differences among IFX, CYS, and TAC in the rates of AE, SAE, or mortality. Conclusion: Our meta-analysis suggested a better treatment response rate and lower risk of colectomy in the first, second and third year, with IFX, compared with CYS in steroid-refractory UC patients. There was no significant difference among IFX and calcineurin inhibitors in AE, SAE, and mortality.

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Biological therapies have revolutionized the treatment of inflammatory bowel diseases enabling mucosal healing and sustained remission. However, their long-term effectiveness is substantially limited by immunogenicity, namely the development of anti-drug antibodies, which may lead to secondary loss of response. The aim of our study was to evaluate real-world immunogenicity data in Hungary among patients treated with tumor necrosis factor inhibitors infliximab (IFX) and adalimumab (ADA), as well as second-line biological agents vedolizumab (VDZ) and ustekinumab (UST). We performed a cross-sectional analysis of 153 inflammatory bowel disease patients receiving IFX or ADA and 183 patients treated with UST or VDZ, followed at Semmelweis University between 2020 and 2025. Both pediatric and adult patients were included. Immunogenicity data were assessed using modern immunoassay techniques, and results were analyzed according to treatment groups, disease characteristics, age, and sex. The overall prevalence of anti-drug antibodies was comparable between treatment groups (IFX/ADA: 21%, 32/153; UST/VDZ: 20%, 37/181; p = 0.98). In molecule-specific analyses, IFX was associated with significantly higher immunogenicity (33.0%) compared with ADA (12.0%; p = 0.001). Antibody positivity was low in patients treated with UST (15.0%), while a non-significantly higher rate was observed with VDZ (28.0%; p = 0.105). No significant differences in immunogenicity were detected according to inflammatory bowel diseases subtype, age, or sex. Although the overall immunogenicity of biological therapies may appear similar, substantial differences exist between individual agents. The higher immunogenicity of IFX compared with ADA supports the need for proactive therapeutic drug monitoring and, where appropriate, combination therapy. In the case of VDZ and UST, a more nuanced interpretation is required, considering the potential presence of transient antibodies. Our findings further emphasize the pivotal role of therapeutic drug monitoring in optimizing biological treatment strategies in inflammatory bowel diseases. Orv Hetil. 2026; 167(8): 291-299.

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BACKGROUND Vedolizumab (VDZ) is effective for treating both adult and pediatric onset IBD. Clinical outcomes, however, have been reported to be superior in patients naïve to anti-TNF. With the growing interest in endoscopic endpoints, we aimed to describe rates of mucosal healing in pediatric patients being treated with VDZ and examine the influence of anti-TNF on outcomes. METHODS We conducted a retrospective review of all IBD patients ≤21 years of age who initiated VDZ and underwent endoscopy. Primary outcome was mucosal healing (composite of endoscopic (SES-CD and Mayo score UC) and histological remission (Nancy index-UC and CD histologic activity). Descriptive statistics summarized the data. Comparisons were made for endpoints based on anti-TNF exposure using univariate testing. RESULTS Sixty-eight patients were included in the final analysis; 35 with UC and 33 with CD. Thirty-two patients (22 UC and 10 CD) were anti-TNF naïve and 36 patients (13 UC and 23 CD) were anti-TNF exposed. The median duration on VDZ prior to endoscopic assessment was 49 (IQR 32-73) weeks. A total of 38% (25/66) of patients met the primary outcome of mucosal healing and did not differ between anti-TNF naïve or exposed. Endoscopic remission was achieved by 51% with significantly more anti-TNF naïve patients reaching this endpoint (66% v. 40%, p = 0.03). Histologic remission was achieved by 42% of patients with a non-significant trend towards improved histologic remission rates in anti-TNF naïve patients (52% v. 33%, p = 0.13). CONCLUSION VDZ is associated with mucosal healing in pediatric IBD. Anti-TNF exposure significantly impacted endoscopic remission, but not histologic remission in children on VDZ.

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In patients with inflammatory bowel disease (IBD) on biologic therapy, once remission has been achieved, withdrawal is a frequent issue in clinical practice that generates uncertainty in aspects such as the reduction of adverse effects and costs, but also the risk of recurrence of activity and the need to restart treatment. The aim of this study was to determine the rate of long-term reintroduction of biologics after withdrawal due to mucosal healing (MH) in IBD, the response to reintroduction and the associated factors. Observational, descriptive, single-centre, retrospective, descriptive study of 178 cases in 164 patients diagnosed with ulcerative colitis (UC) or Crohn's disease (CD) who were withdrawn from anti-tumor necrosis factor (anti- TNF) therapy once MH had been demonstrated, between July 2009 and February 2022. Demographic and phenotypic characteristics of IBD, characteristics of biologic and immunosuppressive therapy, analytical and endoscopic/histological variables at the time of withdrawal were collected. We analysed the risk of restarting biologics due to clinical relapse and response to reintroduction of treatment. We evaluated possible factors related to the risk of restarting treatment and response to treatment. We included 178 cases. 123 CD and 55 UC. Most had received infliximab (62.9%) and the main indication was corticodependence (68%). Median follow-up was 78 months (IQR 59-95). Clinical relapse occurred in 69% of cases and 61.2% required reintroduction of biologics, with the probability of retreatment at 1, 3, 5 and 7 years being 19.4%, 50%, 60% and 63.4%, respectively (Figure 1). The response to reintroduction was 86.2%. Only 1.68% required surgery during follow-up. Univariate analysis showed higher risk of re-introduction at younger age at diagnosis (23 vs 30 vs 30, p 0.022) and at withdrawal (32 vs 40, p 0.019) and longer follow-up time after withdrawal (82 vs 71, p 0.026). Multivariate analysis also identified the indication for corticodependence (p 0.046). The risk of relapse and re-starting treatment is high in the long term after withdrawal of biologic therapy for MH in IBD. Younger age at diagnosis and withdrawal, indication for corticodependence and long-term follow-up are risk factors for poor outcome. Reintroduction of treatment is very effective with low complication rates.

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BACKGROUND Mucosal healing improves clinical outcomes in patients with inflammatory bowel disease (IBD) and is associated with higher infliximab trough levels (ITLs). Transmural healing, assessed by intestinal ultrasound (IUS), is emerging as an objective target in Crohn's disease (CD) and ulcerative colitis (UC). This study explores the correlation between maintenance ITLs and sonographic transmural healing. METHODS Patients on maintenance infliximab therapy were prospectively enrolled to undergo paired IUS examination and serum ITL. Infliximab trough levels were compared between patients with and without sonographic markers of inflammation using the Mann-Whitney U test. RESULTS A prospective cohort of 103 patients (51% male; 79 CD; 24 UC; median duration of disease 8 years) underwent IUS and serum ITL testing. Forty-one percent of CD and 66% of UC patients demonstrated sonographic healing (bowel wall thickening ≤3 mm with no increase in color Doppler signal). Crohn's disease patients with sonographic healing had higher median ITL compared with those with sonographic inflammation (4.8 μg/mL vs 3.1 μg/mL; P = .049). Additionally, the presence of hyperemia on Doppler was independently associated with lower ITL compared with those without hyperemia (2.1 μg/mL vs 4.2 μg/mL, respectively; P = .003). There was no significant association between ITL and other sonographic markers of inflammation. In UC, lower ITL was associated with hyperemia on Doppler imaging (P = .04). There was no association between ITL and sonographic healing or any other individual sonographic parameter of inflammation. CONCLUSIONS Lower maintenance infliximab levels are associated with sonographic parameters of inflammation in UC and CD. Further studies are needed to determine whether targeting higher infliximab levels can increase sonographic healing.

Infliximab is a first line therapy for severe pediatric IBD, but only 50% of patients achieve and maintain clinical remission by 1 year. We investigated the gut microbiome in pediatric IBD patients to determine its impact on Infliximab response. 100 pediatric IBD patients on maintenance Infliximab therapy were enrolled and prospectively followed over a two-year period at a tertiary children’s hospital from 2021-2024. Disease activity was evaluated using the Harvey-Bradshaw Index (HBI) in CD patients or the Pediatric Ulcerative Colitis Activity Index (PUCAI) in UC patients and stool samples were collected every 1-2 months as patients presented to the infusion clinic. The difference in beta-diversity and abundance of individual taxa of the gut microbiome were evaluated in 40 patients (29 with CD 11 with UC) 1 year post Infliximab and 36 patients (29 CD, 7 UC) 3-5 years post Infliximab using 16s rRNA sequencing. Patients were classified into biochemical remission or persistent inflammation by clinical activity index score (Remission: HBI < 5, PUCAI < 10) and fecal calprotectin level (Remission: < 250 υg/g in CD, < 150 υg/g in UC). At one year post Infliximab, there were 25 patients in remission (22 CD, 3 UC) with mean calprotectin 28.6 υg/g (95% CI 9.9, 47.4) and 15 patients with persistent inflammation (7 CD, 8 UC) with mean calprotectin 486.3 υg/g (95% CI 355.6, 616.9). At 3-5 years post Infliximab, there were 26 patients in remission (23 CD, 3 UC) with mean calprotectin 34.4 υg/g (95% CI 12.6, 56.2) and 10 patients with persistent inflammation (6 CD, 4 UC) with mean calprotectin 985.1 υg/g (95% CI 304.7, 1665.5). There were no differences in beta diversity identified by non-metric multidimensional scaling at either 1-year or 3-5 years post Infliximab between patients in remission vs those with persistent inflammation. Significant differences in the abundance in the taxa Faecalitalea and Faecalibacterium were found at 1 year post Infliximab (Figure 1) and in the taxa Hungatella, Parabacteroides, and Eisenbergiella at 3-5 years post Infliximab (Figure 2). The overall composition of gut microbiota in pediatric IBD patients on maintenance Infliximab therapy was similar between patients achieving remission and those with persistent inflammation; however, in patients with persistent inflammation there were decreased Short Chain Fatty Acid (SCFA) producing taxa (Faecalitalea, Parabacteroides) and increased mucous degrading taxa (Hungatella) which have been implicated in the pathogenesis of IBD. Further evaluation with metagenomic and metabolomic approaches may uncover the functional mechanisms through which these taxonomic differences determine the response to Infliximab in pediatric IBD. Figure 1. Taxonomic abundance 1 year post Infliximab. Figure 2. Taxonomic abundance 3-5 years post Infliximab.

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The Phase 3 LIBERTY-UC study (NCT04205643) demonstrated that subcutaneous (SC) CT-P13 had superior efficacy to placebo as maintenance therapy and was well tolerated in patients with moderately-to-severely active ulcerative colitis (UC) who responded to intravenous CT-P13 induction. This post hoc analysis investigated whether the presence of anti-drug antibodies (ADAs) impacted efficacy and/or drug levels in patients treated with CT-P13 SC during LIBERTY-UC. This post hoc analysis evaluated the impact of ADAs on clinical outcomes in patients with UC who received CT-P13 SC maintenance treatment. Presence and titer of ADA were measured using a new generation, highly sensitive, drug-tolerant assay. The following clinical outcomes were evaluated at Week (W) 54 according to ADA occurrence: clinical remission, clinical response, endoscopic-histologic mucosal improvement, and corticosteroid-free remission. Persistence up to W54, as well as safety and serum infliximab concentrations were assessed according to ADA occurrence. The ADA-positive population was further divided according to relative titers of ADA at W54 and analyzed for the clinical outcomes. The analysis included 294 patients with UC (ADA-positive, n=187; ADA-negative, n=107) who were randomized to CT-P13 SC maintenance at W10. Baseline characteristics were comparable between ADA-positive and ADA-negative groups (Table). There were no statistically significant differences in efficacy outcomes at W54 between the ADA-positive and ADA-negative patients across imputation methods. Based on observed data at W54 in the ADA-negative vs. ADA-positive groups, 45.8% vs 41.7% achieved clinical remission (p=0.5413); 50.5% vs. 55.6% achieved clinical response (p=0.3982); 37.4% vs. 34.8% achieved endoscopic-histologic mucosal improvement (p=0.7047); and 40.7% vs 33.3% achieved corticosteroid-free remission (p=0.4493). In a survival analysis, 1-year persistence was comparable between the ADA-positive and ADA-negative groups (log-rank p= 0.12; Figure). Safety data were also generally comparable between the two groups. From W6 to W54, mean serum infliximab concentrations ranged from 11.8 to 13.9 µg/mL in ADA-positive patients, and from 15.2 to 21.3 µg/mL in ADA-negative patients, respectively. In the subgroup analysis by ADA titer at W54, patients with ADA titers ≥ 1,000 achieved efficacy outcomes at lower rates compared to those with lower ADA titers. While results by ADA occurrence did not indicate significant difference in efficacy and persistence, the subgroup analysis by titer revealed that patients with higher ADA titers showed a diminished clinical response. Further studies are warranted focusing on longer-term effects of immunogenicity using data from the extension study of LIBERTY-UC and titer thresholds that can affect clinical outcomes and drug pharmacokinetics. Table. Baseline patient demographic characteristics by ADA occurrence in the LIBERTY-UC study. Figure. Survival analysis for persistence in ADA-positive and ADA-negative individuals.

An elective switching to the subcutaneous (SC) formulation of infliximab (IFX) has shown effectiveness and safety in patients with inflammatory bowel disease (IBD) on intravenous (IV) IFX maintenance therapy. However, data on long-term outcomes in patients not in clinical remission during maintenance therapy is limited. This study aims to evaluate the long-term outcomes of SC switching in patients who were in clinical remission and not in remission during IV IFX maintenance therapy. This retrospective multicentre study was conducted from January 2021 to October 2023. Clinical remission was defined as Crohn’s Disease Activity Index (CDAI) <150 for Crohn’s disease (CD) and partial Mayo score <2 for ulcerative colitis. Biological remission was defined as faecal calprotectin (FC) <250 µg/g and C-reactive protein (CRP) <0.5 mg/dL. The primary outcome measure was 1-year treatment persistence of SC IFX. Among 127 patients included in the study, 80 (62.9%) had CD, and 47 (37.1%) had UC. At the time of switching, 90 patients (70.9 %) were in clinical remission; whereas, 37 (29.1 %) were in a non-remission state. The treatment persistence rate at 1 year was high at 92.9%. Treatment persistence rates between the clinical remission and non-remission groups did not differ significantly (94.4% vs. 89.2%, p=0.287). In both groups, IFX pharmacokinetics and biomarkers between baseline and 12 months (p<0.01) significantly improved. The median infliximab levels increased from a baseline of 3.3 µg/mL (interquartile range [IQR] 1.3–5.1) to 14.4 µg/mL (IQR 9.4–23.0, p<0.001) at 12 months. Disease activity index was stable in the remission group, and decreased in the non-remission group (partial Mayo score, p<0.001; CDAI, p=0.063). At the one-year follow-up, clinical remission and biological remission were achieved in 86.6% and 60.6%, respectively, an increase from baseline (70.9% and 48.0%, respectively). Biologics exposure before IFX was the only significant variable associated with treatment persistence (odds ratio 5.138, 95% confidence interval 1.150–22.951, p=0.032). The concomitant use of immunomodulators was not associated. The incidence of IFX-related adverse events was 14.2%, with only three patients discontinuing treatment. Switching to SC IFX from IV IFX maintenance therapy demonstrated high treatment persistence and favourable safety profiles, irrespective of remission status at the time of switching. Patients in both remission or non-remission states showed significant improvement in pharmacokinetics and biomarkers, and/or stable disease activity indices.

The optimal maintenance regimen after rescue therapy for Acute Severe Ulcerative Colitis (ASUC) is unknown. We aimed to evaluate prospectively the impact of different maintenance regimens after successful infliximab (IFX) rescue, along with factors associated with Month 12 remission. Clinical responders at 3 months from PREDICT UC, a randomised trial (NCT02770040) comparing standard and intensified IFX rescue strategies, were evaluated in this prospective cohort study up to Month 12. Maintenance therapies were as follows: (1) Thiopurine monotherapy (azathioprine or mercaptopurine) for thiopurine naïve patients or prior suboptimal thiopurine therapy (TP); (2) Combination thiopurine and IFX therapy 5mg/kg 8-weekly for thiopurine-experienced patients (IFX+TP combo); (3) IFX monotherapy 5mg/kg 8-weekly for thiopurine-intolerant patients (IFX mono). All patients received oral 5-aminosalicylates. Clinical and endoscopic assessments were performed at baseline (Month 3) and Month 12. Clinical remission was defined as a partial Mayo score of 0-1 and endoscopic remission as Mayo Endoscopic Score (MES) of 0-1. Of 138 patients randomised, 79 entered the maintenance phase. Of these, 56 (71%) received TP, 16 (20%) received IFX+TP combo and 7 (9%) received IFX mono. Baseline characteristics were similar across the 3 maintenance groups. At 12 months, 42 patients (53%) were in clinical remission, 44 patients (56%) were in endoscopic remission, and one patient underwent colectomy. The 3 maintenance groups had similar rates of clinical remission (TP 55%, IFX+TP combo 56%, IFX mono 29%; P=0.39) and endoscopic remission (TP 55%, IFX+TP combo 56%, IFX mono 57%; P=0.99) at 12 months. On univariable and multivariable analysis, no factors were associated with clinical remission at 12 months, including baseline CRP, albumin, partial Mayo score, MES, UCEIS or maintenance strategy. Factors associated with endoscopic remission at 12 months included baseline partial Mayo score of 0 (OR 3.36, 95% CI 1.24-9.10, P=0.017), MES of 0-1 (OR 3.48, 95% CI 1.08-11.27, P=0.037) and UCEIS of 0-1 (OR 3.30, 95% CI 1.24-8.76, P=0.016). However, a partial Mayo score cut-off of 0-1 did not reach significance (OR 3.46, P=0.09). No factors associated with endoscopic remission were identified on multivariable analysis. In steroid-refractory ASUC patients who received IFX rescue, clinical and endoscopic remission at Month 3 were associated with endoscopic remission at Month 12, particularly among patients with greater depth of remission. Month 3 assessment helps identify patients at higher risk of disease progression for whom more intensive treatment may be required.

Infliximab (IFX) was the first TNF alpha inhibitor approved for treatment of inflammatory bowel disease (IBD). Since 2013 biosimilars of IFX and since 2023 sc formulation of IFX have been available. Remswitch study laid down the ground rules and additional studies provided data for designing algorithm for switching from iv to sc IFX. Start of sc IFX would best be foreseen earlier than 8 weeks after the last iv dose, but exact timeline is not fixed. We performed a prospective, observational, single center, cohort study in IBD patients treated with maintenance IFX (mIFX). Objective was to switch patients from mIFX iv to sc at fixed time interval of 4 weeks between last iv and first sc injection independent of IFX type (originator or biosimilar) and of iv dosing regime (switch to 120 mg or 240 mg sc). Interim analysis was done at week 24. Maintenance of clinical remission at week 24 (partial Mayo score <2 in UC and Harvey Bradshaw Index <5 in CD) was observed primary outcome, achiving target serum IFX trough levels (TL) (≥7 mg/L in perianal CD and ≥5 mg/L in non-perianal CD and UC) before switching to sc formulation and patients’ satisfaction (TSQM-9 questionnaire) and quality of life (QoL) using short IBDQ were secondary outcomes. Serum IFX TL were measured with fluorescence immunoassay; ez-Trecker, Theradiag, France. Descriptive statistics was used to interpret results. Altogether 40 IBD patients treated with mIFX were included, 28 patients with CD and 12 patients with UC. Demographic data, disease characteristics and prior treatment data are presented in table 1. Primary outcome results: At week 24 92.6% of CD patients maintaned clinical remission and 7.4% had mild disease clinical activity (HBI 5-7 points), 100% of UC patients were in clinical remission according to pMayo score (<2 points). Secondary outcomes: At baseline 35.7% of perianal CD patients and 71.4% non-perianal CD and UC patients were at target IFX TL on iv mIFX therapy. At week 4, before switching to sc formulation, significantly (p < 0.001) higher percentage of patients reached target IFX TL, 92.9% of perianal CD patients and 96.4% of non-perianal and UC patients (graph 1). QoL and patients’ satisfaction on sc was comparable to iv administration during observed period until week 24. The 4-week interval between last iv and first sc administration proved to be appropriate, as the vast majority of patients achieved target serum IFX TL before switching to sc. In both CD and UC patients treatment persistence after switch to sc IFX remained high at week 24 which in our opinion was a result of reaching target IFX TL at week 4. QoL and patients’ satisfaction on sc was not inferior to iv administration at week 24. References: 1. Buisson A, Nachury M, Reymond M, Yzet C, Wils P, Payen L, et al. Effectiveness of Switching From Intravenous to Subcutaneous Infliximab in Patients With Inflammatory Bowel Diseases: the REMSWITCH Study. Clin Gastroenterol Hepatol. 2023 Aug;21(9):2338-46.e3. 2. Fierens L, Liefferinckx C, Hoefkens E, Lobatòn T, Dreesen E, Sabino J, Ferrante M; IBD Research and Development (BIRD) group. Introduction of Subcutaneous Infliximab CT-P13 and Vedolizumab in Clinical Practice: A Multi-Stakeholder Position Statement Highlighting the Need for Post-Marketing Studies. J Crohns Colitis. 2022 Aug 4;16(7):1059-69. 3. Smith PJ, Critchley L, Storey D, Gregg B, Stenson J, Kneebone A, et al. Efficacy and Safety of Elective Switching from Intravenous to Subcutaneous Infliximab [CT-P13]: A Multicentre Cohort Study. J Crohns Colitis. 2022 Sep 8;16(9):1436-46. Conflict of interest: Dr. Ocepek, Andreja: No conflict of interest Bukovnik, Nejc: No conflict of interest Pernek, Robert: No conflict of interest Velkovski, Cvetanka: No conflict of interest Homšak, Evgenija: No conflict of interest Putniković, Dunja: No conflict of interest Nikolic, Sara: No conflict of interest

No real-world data are available on subcutaneous infliximab (SC-IFX) in pediatric inflammatory bowel disease (PIBD). We report a single-center cohort experience of an elective switching program from biosimilar intravenous infliximab to SC-IFX, 120 mg fortnightly, as maintenance. Clinical and laboratory data were collected for 7 patients with infliximab trough levels collected prior and at 6 and 40 weeks after the switch. High treatment persistence was registered with a single patient discontinuing the treatment due to high IFX antibodies, already present before switching. All patients remained in clinical remission with no significant changes in laboratory markers and median infliximab trough levels (12.3 µg/mL at baseline; 13.9 and 14.0 µg/mL at 6 and 40 weeks respectively). No newly-developed IFX antibodies were detected and no adverse reactions or rescue therapies were recorded. Our real-world data support the feasibility of an elective switch to SC-IFX in PIBD as maintenance with potential advantages concerning medical resources and patient satisfaction.

BACKGROUND Despite long-term use of infliximab (IFX) in IBD treatment, its optimized use is unclear due to its complicated pharmacokinetics/dynamics. Hence, the predictive value of IFX trough levels (TL) is important in treatment management. METHODS We performed a prospective, cross-sectional, observational study with 74 IBD patients treated with IFX (mean 9.1 years, SD ± 3). TL was measured during maintenance therapy, in which maintenance of remission was followed for 5 years. RESULTS  TL > 3 µg/ml during maintenance therapy was a significant predictor of clinical remission in 5 years in UC patients (82 % vs 62 %, p 3 µg/ml during maintenance therapy in a cohort of IBD patients (p = 0.05). Deviations in percentage of remission and fraction of relapses in TL categories were insignificant in a cohort of CD patients (85 % vs 74 %, p > 0.05). CONCLUSIONS  TL > 3 µg/ml during maintenance therapy is a strong predictor of sustained clinical remission for 5 years in UC patients. The use of combination therapy with AZA, due to its significant association with high TL, may have a practical benefit in achieving better clinical outcomes in UC patients (Tab. 2, Fig. 10, Ref. 20).

Aim To report on the efficacy and safety of elective switching from intravenously (IV) to subcutaneously (SC) administered Infliximab (IFX) in patients with immune mediated diseases. Methods Retrospective analysis of patients with Crohn’s disease (CD), Ulcerative Colitis (UC), Spondyloarthritis (SpA), Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA) and chronic plaque Psoriasis (PsO) who were receiving IFX-IV for maintenance of remission in tertiary referral centers and were switched to IFX-SC based on their physician’s choice. All patients with gastrointestinal and skin diseases were in clinical remission, while those with musculoskeletal disease had inactive disease or low disease activity. The primary endpoint was disease deterioration during a follow up period, of at least 6 months, according to disease specific composite measures. Results Between April 2023 and April 2024, a total of 344 patients (CD = 136, UC = 62, SpA = 52, PsA = 38, RA = 7, PsO = 44, co-existence of more than one disease = 5) were switched from IFX-IV to IFX-SC. After a mean±SD follow up period of 8 ± 4 months, 12 patients (3.5%) discontinued treatment with IFX-SC. Five of them (1.5%) because of disease worsening and the remaining 7 (2.0%) because of the occurrence of side effects. All 332 other patients (96.5%) showed favorable response, none of them requested an unscheduled visit, or developed an adverse event (clinical or laboratory) or needed escalation of treatment. Conclusion Elective switching from IFX-IV to IFX-SC seems to be an effective and safe approach in real-world every day clinical practice to maintain long-term clinical remission, inactive disease or low disease activity in patients with immune-mediated diseases.

We aimed to report on the efficacy and safety of elective switching from intravenously (IV) to subcutaneously (SC) administered Infliximab (IFX) in patients with immune mediated diseases. This was a multicenter retrospective study in which we analyzed data collected from consecutive patients with immune mediated diseases treated in a hospital setting. Each hospital department was considered a study center and overall, 8 gastroenterology departments, 6 rheumatology departments and 1 dermatology department from 13 Greek hospitals, that are all referral centers, recruited patients for the study. Patients with Crohn’s disease (CD), Ulcerative Colitis (UC), Spondyloarthritis (SpA), Rheumatoid Arthritis (RA), Psoriatic Arthritis (PsA) and chronic plaque Psoriasis (PsO) who were receiving IFX-IV for maintenance of remission and were switched to IFX-SC based on their physician’s choice were included. All patients with gastrointestinal and skin diseases were in clinical remission, while those with musculoskeletal disease had inactive disease or low disease activity. The primary endpoint was disease deterioration during the follow up period, according to disease specific composite measures. Between April 2023 and April 2024, a total of 344 patients (CD=136, UC=62, SpA=52, PsA=38, RA=7, PsO=44, co-existence of more than one disease=5) were switched from IFX-IV to IFX-SC. The mean duration of treatment with IFX before switching was a mean (SD) 53.7 (36.2) months. Eleven patients (3.2%) were receiving combination treatment with an immunomodulator and 2 patients (0.6%) were using oral or iv steroids at the time of switch. After a mean (SD) follow up period of 8 (4) months, 12 patients (3.5%) discontinued treatment with IFX-SC. Five of them (1.5%) because of disease worsening and the remaining 7 (2.0%) because of the occurrence of side effects. All other 332 patients (96.5%) showed favorable response, none of them requested an unscheduled visit, or developed an adverse event (clinical or laboratory) or needed escalation of treatment. Elective switching from IFX-IV to IFX-SC seems to be an effective and safe approach in real-world every day clinical practice to maintain long-term clinical remission, inactive disease or low disease activity in patients with immune-mediated diseases.

BACKGROUND AND AIMS CT-P13 subcutaneous (SC), an SC formulation of the intravenous (IV) infliximab biosimilar CT-P13 IV, creates a unique exposure profile. We aimed to demonstrate superiority of CT-P13 SC versus placebo as maintenance therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS Two randomized, placebo-controlled, double-blind studies were conducted in patients with moderately-to-severely active CD or UC and inadequate response/intolerance to corticosteroids and immunomodulators. All patients received open-label CT-P13 IV 5 mg/kg at weeks (W) 0, 2, and 6. At W10, clinical responders were randomized (2:1) to CT-P13 SC 120 mg or placebo every 2 weeks until W54 (maintenance phase) using pre-filled syringes. (Co-)primary endpoints were clinical remission and endoscopic response (CD) and clinical remission (UC) at W54 (all-randomized population). RESULTS Overall, 396 patients with CD and 548 patients with UC received induction treatment. At W54 in the CD study, statistically significant higher proportions of CT-P13 SC- versus placebo-treated patients achieved clinical remission (62.3% versus 32.1%; P < 0.0001) and endoscopic response (51.1% versus 17.9%; P < 0.0001). In the UC study, clinical remission rates at W54 were statistically significantly higher with CT-P13 SC versus placebo (43.2% versus 20.8%; P < 0.0001). Achievement of key secondary endpoints was significantly higher with CT-P13 SC versus placebo across both studies. CT-P13 SC was well tolerated, with no new safety signals identified. CONCLUSION CT-P13 SC was more effective than placebo as maintenance therapy and well tolerated in patients with moderately-to-severely active CD or UC who responded to CT-P13 IV induction. CLINICALTRIALS gov, NCT03945019 (CD) and NCT04205643 (UC).

Ulcerative colitis (UC) is a chronic inflammatory condition requiring lifelong management, with anti‐tumor necrosis factor α (anti‐TNF‐α) agents often used for refractory cases. However, secondary loss of response (LOR) to these agents, due to anti‐drug antibodies, poses a significant therapeutic challenge. This report describes a case where granulocyte and monocyte adsorptive apheresis (GMA) maintenance therapy successfully restored the efficacy of an anti‐TNF‐α agent in a 26‐year‐old male with active UC experiencing LOR to infliximab. Following GMA induction therapy and continued infliximab administration, clinical symptoms improved, fecal calprotectin levels decreased, and clinical remission was achieved. Long‐term maintenance with GMA enabled sustained clinical remission, with mucosal healing observed one year post‐therapy. This case suggests that GMA maintenance therapy may serve as a novel therapeutic approach for patients with active UC experiencing LOR to anti‐TNF‐α agents. However, further studies are warranted to elucidate the underlying mechanisms and validate its efficacy.

Objective To provide data on the use of infliximab biosimilars (IFX-BioS) in children with inflammatory bowel disease (IBD). Methods A multicenter, observational, retrospective study was performed among the cohort of the Sicilian Network for IBD. All consecutive IBD children who had at least completed the induction with IFX-BioS from its introduction in Sicily to January 2021 were enrolled. Clinical remission at weeks 14 and 52, treatment persistence, and adverse events were the study outcomes. Results Eighty-seven patients [Crohn’s disease (CD): 57.5% and ulcerative colitis (UC): 42.5%] were included: 75 (86.2%) were antitumor necrosis factor-α (anti-TNF-α) agent naïve, while three (3.45%) were switched from the originator to IFX-BioS. Twenty (23%) patients were multiply switched from the biosimilar CT-P13 to SB2 or GP1111 or vice versa. The median follow-up time was 15 months. Clinical remission was achieved by 55.2 and 65.5% of patients at weeks 14 and 52, respectively, with no differences between CD and UC. Dose escalation was needed in 8.0 and 35.7% of patients during induction and maintenance, respectively. Nine adverse events occurred (incidence rate: 6.13/100 person-year). Treatment persistence was 90.8% at 1 year and 75.7% at 2 years (patients on IFX-BioS at 2 years, n = 28). The risk of treatment discontinuation was higher in patients with extraintestinal manifestations (P = 0.018) and in those who were nonnaïve to anti-TNF-α (P = 0.027). Conclusion This is the largest cohort of pediatric IBD patients treated with IFX-BioS. Real-life data show that IFX-BioS is efficacious in IBD children, with high percentages of treatment persistence and a low incidence of nonserious adverse events.

Background/Objectives: The introduction of anti-tumor necrosis factor-α (anti-TNF-α) agents, particularly infliximab (IFX) and adalimumab (ADA), has significantly expanded the therapeutic arsenal for inflammatory bowel disease (IBD). While these biologics have demonstrated substantial efficacy, they are associated with a spectrum of potential adverse events (AEs). This study aims to evaluate and document these AEs to facilitate optimal patient selection and monitoring strategies of patients undergoing these therapies. Methods: This retrospective, single-center study examined pediatric IBD patients receiving anti-TNF-α therapy at the “Grigore Alexandrescu” Emergency Hospital for Children in Bucharest, Romania, from January 2015 to October 2024. AEs were categorized into non-infectious complications (acute infusion reactions, anti-drug antibody formation), dermatological effects (erythema nodosum, vasculitis), neurological effects (Guillain–Barré syndrome), and infections. AEs were analyzed in relation to the specific anti-TNF-α agent administered and comprehensively characterized. Results: Of 40 patients enrolled, 22 (55%) had Crohn’s disease (CD). The median (IQR) age at diagnosis was 14.8 years [10.8–15.9]. IFX was used in 34 (85%) patients while 6 (15%) patients received either ADA or IFX/ADA sequential therapy. Twenty-seven AEs were documented in 19 (47.5%) patients, the most prevalent being antidrug antibody formation (44.4%), infections (22.2%), and acute infusion reactions (22.2%). All ADA-exposed patients experienced at least one AE, compared to 41.2% (n = 14) patients treated with IFX, p = 0.01. Conclusions: AEs were observed in approximately half of the study cohort, with anti-drug antibody formation emerging as the most frequent complication. ADA therapy was associated with a significantly higher rate of AEs compared to IFX. These findings underscore the critical importance of vigilant monitoring for patients undergoing anti-TNF-α therapy in pediatric IBD management.

Purpose Infliximab (IFX) is considered safe and effective for the treatment of ulcerative colitis (UC) in both adults and children. The aim of this study was to evaluate the short- and long-term clinical course of IFX in Korean children with UC. Methods Pediatric patients with UC who had received IFX infusions between November 2007 and May 2013 at Samsung Medical Center were retrospectively investigated. The clinical efficacy of IFX treatment was evaluated at 8 weeks (short term) and 54 weeks (long term) after the initiation of IFX treatment using the Pediatric Ulcerative Colitis Activity Index (PUCAI). The degree of response to IFX treatment was defined as complete response (PUCAI score=0), partial response (decrement of PUCAI score≥20 points), and non-response (decrement of PUCAI score <20 points). Adverse events associated with IFX treatment were also investigated. Results Eleven pediatric patients with moderate to severe UC had received IFX. The remission rate after IFX treatment was 46% (5/11) and 82% (9/11) at 8 weeks and 54 weeks after IFX treatment, respectively. All patients who were steroid-dependent before treatment with IFX achieved remission at 54 weeks and were able to stop treatment with corticosteroids, while all steroid-refractory patients failed to achieve remission at 54 weeks after treatment with IFX. Conclusion Response to IFX treatment after 8 weeks may predict a favorable long-term response to IFX treatment in Korean pediatric UC patients.

Objectives The role of infliximab in treating pediatric ulcerative colitis (UC) is not defined. The authors previously have described their experience with the open label use of infliximab in nine children with moderate to severe UC. The aim of this study was to describe the outcome of these patients after a minimum 2-year follow-up and to describe the responses of eight additional patients to this medication. Methods The authors reviewed all pediatric patients with UC who received infliximab at The Children's Hospital of Philadelphia from its first use until February 2003. Tolerance of the infusions and adverse events were recorded. Results Follow-up information for a minimum of 2 years was reviewed for the nine initial patients. A total of 73 infliximab infusions were administered to these patients. Seven of nine (78%) patients were considered to be responders to the initial dose of infliximab. Two of these patients became nonresponders within 9 months of the first dose of infliximab and underwent colectomy. Of the remaining five (56%) patients with sustained response, two continue to receive infliximab infusions and three are doing well without infliximab. One patient experienced an infusion reaction, and one experienced herpes zoster infection. We have treated eight additional UC patients with infliximab. Seven (88%) patients were considered responders. One responder experienced relapse within 2 months. Overall, a short-term improvement was seen in 14 of 17 (82%) patients, and sustained improvement in 10 of 16 (63%) patients followed up for more than 9 months. All five patients with severe or fulminant UC, unresponsive to 2 weeks of intravenous corticosteroid therapy, experienced improvement with infliximab. Infliximab was well tolerated. Conclusion Infliximab is associated with short- and long-term clinical improvement in children and adolescents with moderate to severe UC.

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The incidence of pediatric inflammatory bowel disease (IBD) significantly increased recently. Infliximab (IFX) and adalimumab (ADA), both TNF-α inhibitors, are the only FDA-approved treatments for pediatric IBD. Due to the unique physiological and developmental characteristics of children, postmarketing pharmacovigilance requires ongoing attention. We aimed to evaluate the safety of IFX and ADA in pediatric IBD using FAERS database data from Q1 2004 to Q1 2024. Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) algorithms were used to identify drug-related adverse events (AEs). In total, we retrieved 10,905 IFX-related reports and 5,446 ADA-related reports in pediatric IBD. Common AEs associated with IFX were infusion reactions; for ADA, they were injection site reactions. While most AEs align with approved labeling, continued vigilant monitoring appears important for specific postmarketing AEs observed with IFX, including suicide attempts, weight increased, and psoriasis. The median onset (TTO) for IFX-related AEs was 579 days (interquartile range [IQR]: 159.25–1357 days), occurring mostly after 360 days. For ADA, TTO was 79 days (IQR: 21.75–295 days), with most within 90 days of treatment initiation. Our study revealed that although most AEs matched labeled information, rigorous post-marketing monitoring of severe AEs remains important for IFX and ADA in pediatric IBD, with additional confirmatory research warranted.

Objectives: Inflammatory bowel disease (IBD) requires long-term drug therapy in most patients, posing a risk for adverse drug events with the need for discontinuation. In this study, we investigated adverse events (AE) necessitating drug discontinuation in pediatric and adolescent IBD patients. Methods: We used data prospectively collected from IBD patients below the age of 18 enrolled in the Swiss Inflammatory Bowel Disease Cohort Study (SIBDCS), namely demographic variables, medical characteristics, drug treatments, and related AE. We analyzed the frequency, type, and risk factors for AE necessitating drug discontinuation. Results: A total of 509 pediatric IBD patients fulfilled the inclusion criteria of which 262 (51.5%) were diagnosed with Crohn disease (CD), 206 (40.5%) with ulcerative colitis (UC), and 41 (8%) with IBD-unclassified (IBD-U). In total, 132 (25.9%) presented with at least 1 drug-related AE that required drug cessation. Immunomodulators [methotrexate 29/120 (24.2%), azathioprine 57/372 (15.3%)] followed by tumor necrosis factor (TNF)-alpha antagonists [adalimumab 8/72 (11.1%), infliximab 22/227 (9.7%)] accounted for the highest proportions of AE necessitating treatment discontinuation. Treatment schemes with at least 3 concomitant drugs significantly amplified the risk for development of drug-related AE [odds ratio = 2.50, 95% confidence interval (1.50–4.17)] in all pediatric IBD patients. Conclusions: Drug-related AE necessitating discontinuation are common in pediatric and adolescent IBD patients. Caution needs to be taken in the case of concomitant drug use.

ABSTRACT Anti-tumor necrosis factor alpha (anti-TNFα) therapy is commonly used to treat refractory pediatric inflammatory bowel disease (IBD) and carry risks for adverse events. We aimed to assess the relationship between anti-TNFα trough concentrations and adverse events rate among pediatric patients with IBD. The medical records of pediatric patients with IBD who were treated with anti-TNFα agents from 2015 to 2020 and had sequential monitoring of trough concentration (TC) were reviewed retrospectively for the presence of adverse events. The study cohort included 135 eligible patients (59 [43.7%] girls, mean age at diagnosis 12.9 [±3] years, 111 [82.2%] Crohn disease) who had 1589 measurements of TCs (1037 [63%] infliximab). During a median follow-up period of 1.7 years (IQR 1.1–2.7), we recorded 156 adverse events in 50 patients (37%). Higher TCs were not associated with higher rate of anti-TNFα-related adverse events whereas these events (excluding increase in liver transaminases) were associated with younger age.

Subcutaneous infliximab (IFX-SC) provides logistical advantages and more stable pharmacokinetics than intravenous infliximab (IFX-IV). Real-world evidence in pediatric inflammatory bowel disease (PIBD) remains limited. We assessed clinical effectiveness, pharmacokinetics, and safety after switching from IFX-IV to IFX-SC across three pediatric IBD units in the Canary Islands, Spain. Retrospective multicenter study including patients <18 years who underwent elective switch from IFX-IV to IFX-SC between 2023–2025. Clinical indices (PCDAI/PUCAI), fecal calprotectin (FC), C-reactive protein (CRP) and trough infliximab levels (TDM) were collected at baseline (last IFX-IV), 3, 6 and 12 months. Paired changes were evaluated using Wilcoxon tests. Primary endpoint: clinical remission at 6 months. Secondary endpoints: biomarker evolution, TDM stability, adverse events, hospitalizations and treatment persistence. Eleven patients were included (73% Crohn’s disease; 18% ulcerative colitis; 9% unclassified; mean age 15.4 years; 82% male). Six (54.5%) switched from optimized IFX-IV and five (45.5%) initiated IFX-SC for convenience or logistical reasons. 9/11 have completed 12 month of follow up. All were in clinical remission at baseline, which was maintained in 100% at the end of the follow up 6 or 12 months . PCDAI improved from baseline to 3 months (median 9 → 3; p = 0.042) and remained stable thereafter; PUCAI was 0 at all timepoints. CRP remained low without significant changes. FC decreased from 444 µg/g at baseline to 191 µg/g at 3 months and 180 µg/g at 6 months, although not statistically significant. TDM values were high and stable (baseline 15.5 µg/mL; 3 months 18.8 µg/mL; 6 months 18.7 µg/mL; all p > 0.2). No adverse events, hospitalizations, steroid use or discontinuations were recorded. Treatment persistence was 100% at the end of the follow up (9/11 12 month). Switching from IFX-IV to IFX-SC in this multicenter pediatric cohort was highly effective and safe, with stable therapeutic exposure and full maintenance of clinical remission. IFX-SC appears to be a practical and well-tolerated alternative to intravenous therapy in PIBD, particularly in settings where logistical burden and treatment autonomy are relevant. Larger cohorts with longer follow-up are needed Conflict of interest: Alberto, José Ramón: No conflict of interest De La Barreda Heusser, Laura: No conflict of interest Marquez Rodriguez, Juan Alberto: I have provided scientific advice/participated in medical meetings for Kern and Takeda. I am receiving a gratification for this presentation. Rodríguez Díaz, Ana Eva: No conflict of interest Carrillo Palau, Marta: No conflict of interest Fuentes Ferrer, Manuel Enrique: No conflict of interest Dr. Hernandez Camba, Alejandro: I have served as a speaker or has received research or education funding or advisory fees from Lilly, Takeda, J and J, FAES Pharma, Falk, Abbvie, Adacyte Therapeutics, Tyllots, Ferring, Kern Pharma, Alfasigma and Chiesi.

Introduction Inflammatory bowel disease (IBD) consisting of Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory conditions affecting the gastrointestinal tract. Infliximab (IFX) is a chimeric anti‐tumor necrosis factor antibody used to treat moderate to severe IBD. Eosinophils are commonly found in chronically inflamed tissues in IBD. Peripheral eosinophilia (PE) was previously implicated as a marker of disease severity at diagnosis. The main aim of this study was to investigate whether in IBD patients on IFX, development of PE is associated with adverse outcomes and poor IFX efficacy. Methods A comprehensive retrospective chart review of IBD patients on IFX (January 2006 to July 2015) treated at a tertiary pediatric IBD center was performed. Data was collected at time specified points over a 24 month period and included demographics, atopy, disease severity, development of PE, human antichimeric antibodies (HACA), infusion reactions, cancer, psoriasis, and loss of clinical response. Results One hundred twenty‐one IBD patients starting IFX (67 male), mean age of 12.4 years (range 4–22 years old), met inclusion criteria. Of them, 36.3% had ≥1 PE episode (CD: 25 male, 11 female; UC: 6 male, 2 female). Mean absolute eosinophil count (AEC) did not change over time. PE was associated with clinically active disease. Among patients who developed PE, adverse outcomes were not significantly different versus those who did not have PE. Conclusions In a cohort of primarily pediatric IBD patients on IFX, PE was associated with clinically active disease; however, PE was not related to increased incidence of adverse outcomes or loss of drug efficacy.

Real - life data on the effectiveness and safety of biosimilar and biologic drugs licensed for treatment of inflammatory bowel diseases (IBD) is lacking. AIM To investigate efficacy of original Infliximab (IFX) and its biosimilar in treating patients with ulcerative colitis (UC) and determine the frequency of adverse events during 1 year follow - up period. MATERIALS AND METHODS Our cohort consisted of 98 ulcerative colitis patients, treated with original IFX and its biosimilar since December 2017 till December 2018 years. Original Infliximab was prescribed in 56 UC patients (57.1%) during 5 years and longer; 16 patients (16.3%) were switched to IFX biosimilar; 13 UC bio - naïve patients (13.3%) received original IFX, 29 (29.6%) patients - biosimilar IFX. In 14 patients (14.3%) original infliximab was rotated with biosimilar. We picked out 42 patients to assess efficacy of original IFX and biosimilar. RESULTS AND DISCUSSION Twelve patients, received original IFX and 28 patients, treated with its biosimilar, showed significant clinical improvement by decreasing Mayo index from 9.7±0.4 and 10.2±0.2 points to 1.9±0.09 and 2.1±0.1 points, accordingly. Also we noticed positive change in laboratory markers - CRP decrease from 89.6±8.7 mg/l and 77.5±8.0 mg/l to 6.5±0.8 mg/l and 6.9±0.8 mg/l (p>0.05), albumin increase from 30.1±4.7 g/l and 29.6±3.6 g/l to 34.1±6.3 g/l and 32.8±5.9 g/l (p>0.05), increase of serum iron levels from 6.4±0.5 mcg/l and 7.1±0.65 mcg/l to 14.6±4.4 mcg/l and 15.9±5.1 mcg/l (p>0.05), hemoglobin increase from 104.7±9.8 g/l and 102.2±8.8 g/l till 124±11.3 g/l and 121±10.9 g/l (p>0.05), and fecal calprotectin decrease from 1680±134 mcg/g and 1720±126 mcg/g till 245.5±33.4 mcg/g and 230.5±29.8 mcg/g (p>0.05). During 1 year follow - up 12 UC patients, treated with original IFX and its biosimilar, developed adverse events. The majority of adverse events (n=8) were registered in patients, rotating administration of original IFX and its biosimilar. CONCLUSION IFX biosimilar is effective as well as original IFX. Frequency of adverse events, occurred in patients, treated with original IFX, was comparable with adverse events frequency in patients, received biosimilar IFX. Frequency of adverse events was significantly higher in UC patients, rotating original IFX and its biosimilar.

Since the 90’s, biologics, as a novel class of drugs, have revolutionized the therapeutic field of autoimmune and inflammatory diseases in children by providing effective treatment options. Biologics aim to modify targeted pathways to interfere with the immunologic aberration creating the clinical disease, However, alteration of the pathways increase the risk of infection. We report a series of severe infectious adverse events (SIAE) in children treated with biologics. This is a retrospective study over a period of 10 years (January 2012-October 2022) conducted in the Department of Pediatric Rheumatology and internal Medicine, A. Harouchi Mother and Child Hospital CHU Ibn Rochd, Casablanca, Morocco. The aim of our study is to assess SIAE in children treated with The study included 76 patients on biologics with different diseases dominated by systemic juvenile idiopathic arthritis. Six patients developed SIAE, sex-ratio was 1, four patients received TNF-alpha inhibitors (Infliximab, Adalimumab, Etanercept), 1 on Tocilizumab and 1 on Rituximab. Our 6 patients were on other immunosuppressive agents simultaneously (Corticosteroids, MMF, Azathioprine, Methotrexate). The delay of occurrence of SIAE after the initiation of biologics ranged from 10 days to 7 years. We report 3 cases of Tuberculosis, 2 of which were treated with anti-TNF agents, 1 case of CMV hepatitis, 1 case of Herpes zoster and 1 case of orbital cellulites. Treatment consisted of temporary discontinuation of biologic with specific management of the SIAE by an appropriate anti-infectious agent. The evolution was favorable except one case of death. Biologics have become an important component of effective management of patients with autoimmune and inflammatory diseases. However, there is an increased risk of SIAE for those patients, especially the risks of Tuberculosis and viral infections, even though systematic screening is performed prior to the start of biotherapy, requiring physician vigilance.

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Ulcerative colitis (UC) is a chronic inflammatory bowel disease that has significant morbidities in the pediatric population. Goals of medical therapy include induction and maintenance of remission while preserving the colon and it's function, while minimizing the risk of treatment related morbidities. For those children who do not respond to initial therapies and progress to develop moderately-to-severely active UC, there has been a dearth of available treatments to help induce remission, necessitating long-term corticosteroid usage, with associated comorbidities of chronic steroid treatment. Significant advances have been made in medical management, including the use of biologic therapies, specifically anti-tumor necrosis factor-α monoclonal antibodies. With the Food and Drug Administration's recent approval of the use of infliximab, a chimeric anti-tumor necrosis factor-α antibody, for children ≥6 years of age with moderately-to-severely active UC, care providers now have a new treatment regimen to offer this pediatric population.

The FDA approved adalimumab, an anti-tumor necrosis factor alpha agent, for the treatment of moderate to severe pediatric ulcerative colitis (UC) in February 2021. There are no real-world publications, however, on adalimumab as the first-line biologic in pediatric UC, a form of chronic inflammatory bowel disease (IBD). A retrospective review was conducted to characterize the clinical courses of nine patients with moderate to severe pediatric UC who received adalimumab as their first biologic and had documented drug monitoring trough levels. Seven of the nine patients, or 78%, were switched from adalimumab to another therapy due to continued symptoms or steroid-dependence at an average of 5 months from initiation. Six of these seven patients, or 86%, had adalimumab drug trough levels in the consensus therapeutic range. Three patients were successfully switched to infliximab. Both the Crohn's disease-based dosing and the new FDA-approved pediatric UC dosing of adalimumab were ineffective in inducing remission in the majority of patients in our case series. This study indicates that further real-world observations are needed to optimize and position adalimumab in the treatment paradigm of moderate to severe pediatric UC.

Total proctocolectomy with ileal pouch anal anastomosis (IPAA) is a common surgical approach to chronic ulcerative colitis (CUC). Preoperative use of Infliximab (IFX) has raised concern of increased postoperative complications. We sought to compare outcomes of pediatric patients (≤ 18 years) who were treated with IFX before IPAA to those who did not. Patients (≤ 18 years of age) who underwent IPAA from 2003 to 2008 for CUC were included, and their records were retrospectively reviewed for preoperative medications, operative technique, and 1-year postoperative complications (leak, wound infection, small bowel obstruction, pouchitis). Subjects were divided into 2 groups--those who received IFX preoperatively and those who did not. Eleven patients received IFX preoperatively, and 27 children did not. All complications following IPAA were more frequent in the IFX group compared to controls (55% vs 26%). Small bowel obstruction was significantly higher in the IFX group (55% vs 7%). Long-term complications occurred in 64% of the IFX group and 61% of the controls. Children that were treated with IFX prior to IPAA suffered twice as many postoperative complications. Long-term outcomes are similar. Currently, we recommend colectomy with end ileostomy for patients that receive IFX within 8 weeks of colectomy for CUC.

In Korea, infliximab was approved for use in children with ulcerative colitis (UC) in October 2012. To compare the clinical course of UC before and after the introduction of biological agents, and to compare with the IBSEN study. Patients under 18 years of age, who were diagnosed with UC and followed from January 2003 to October 2020, were included in the study. Group A ( After 2 years of treatment, colonoscopy evaluation revealed different outcomes in the two treatment groups. Remission was confirmed in 14 patients (29.2%) of Group A, and in 31 patients (50.0%) of Group B ( The incidence of relapse has decreased and the steroid-free period has increased after the introduction of the biological agent. The clinical course also showed a different pattern from that of IBSEN study. The active use of biological agents may change the long-term disease course in moderate to severe pediatric UC.

Many features of pediatric ulcerative colitis (UC) are similar to adult-onset disease, but the rate of extensive disease is doubled in children. It is, therefore, not surprising that the admission rate for severe UC is higher in childhood-onset UC, reaching 28% by the age of 16 years. Approximately 30-40% of children will fail corticosteroids and require second-line medical therapy or colectomy. A pediatric UC activity index (PUCAI) score of >65 indicates severe disease and the index can assist in determining the need and timing of second-line medical therapy or colectomy early during the admission. A PUCAI score of >45 points on day 3 identify patients likely to fail corticosteroids (negative predictive value 90-95%), and a score >70 points on day 5 identify patients who will require short-term treatment escalation (positive predicting value 95-100%). Data in children are limited, but it seems that cyclosporine, tacrolimus and infliximab achieve a similar short-term response rate, in the range of 60-80%. Infliximab has the advantage that it may be given for a prolonged period of time while calcineurin inhibitors should not be used for more than 3-4 months, bridging to a thiopurine regimen. Colectomy is indicated in toxic megacolon or in cases refractory to one salvage therapy. The choice of colectomy in other cases should carefully consider its effect on the patient's quality of life, its impact on the physical and emotional development at a critical age of personality development, and its association with a high infertility rate in females undergoing pouch procedure before childbearing age.

Infliximab (IFX) is an established treatment modality for moderate to severe pediatric ulcerative colitis (UC). The purpose of this study was to identify clinical and laboratory parameters, which predict response to IFX in pediatric UC defined by colectomy as the primary outcome measure. Postsurgical complications were examined as well. A retrospective chart review was performed on children younger than 19 years who received IFX therapy at Texas Children's Hospital, Houston, Texas for the treatment of UC from January 2005 to April 2012. Demographics, laboratory data, clinical subtype, duration of disease, transfusion requirement, number of IFX infusions, concurrent medications, and postoperative complication with regard to IFX exposure were examined. Forty-seven patients (22 male and 25 female; average age at diagnosis: 11.4 y) received IFX. Twenty-six (55.3%) required colectomy, 20 (42.6%) of which occurred within a year of therapy initiation. Disease duration <20 months before IFX initiation, increased the likelihood of a colectomy within a year [OR: 3.8 (95% CI, 1.6-13.3), P=0.044]. Blood transfusion requirement before IFX was associated with higher rates of colectomy within a year [OR: 9.78 (95% CI, 2.2-43.3), P=0.0028]. Preoperative exposure to IFX within 8 weeks did not significantly increase postoperative complications (P=0.26). Serum albumin levels at diagnosis did not predict colectomy. Shorter disease duration and need for blood transfusion may be useful indicators of limited response to IFX in pediatric UC.

Ulcerative colitis (UC) is a chronic inflammatory condition. Previous reports suggested that UC may have a worse prognosis when associated with auto-immune diseases. We compared characteristics at diagnosis and natural history of the disease between classical ulcerative colitis (CUC) and UC associated with auto-immune diseases (CAI) in children. In this study, 67 children followed for UC at Nancy University Hospital between 1993 and 2012 were included: 45 patients in the CUC group and 22 in the CAI group. Median follow-up was 4.8 years. Median age at diagnosis was 11.6 years in the CAI group and 9.8 years in the CUC group. Time between symptoms onset and diagnosis was broadly similar in the two groups (<3 months) and there were no significant differences regarding biological and histological findings. At 5 years, the need for corticosteroids and azathioprine did not differ between the CAI and the CUC groups. There was also no significant difference between the two groups regarding infliximab use at 1 and 5 years. In this pediatric study, CAI had similar characteristics at baseline as CUC. The course of CAI does not seem to be influenced by the presence of concomitant auto-immune diseases.

Infliximab is a widely used drug for treating inflammatory bowel disease (IBD). This drug is known to rarely cause pericarditis in adult populations. This report details the case of a 14-year-old boy with ulcerative colitis who developed pericarditis after a second infliximab infusion. After discontinuation of therapy, the patient's symptoms were resolved. To our knowledge, this is the first reported paediatric case of pericarditis as a possible complication of infliximab therapy in IBD. Among infliximab-related delayed adverse reactions, cardiac complications should be monitored in the paediatric population.

This study evaluated the long-term effectiveness and safety of a multidisciplinary early proactive therapeutic drug monitoring (TDM) program combined with Bayesian forecasting for infliximab (IFX) dose adjustment in a real-world dataset of paediatric patients with inflammatory bowel disease (IBD). A descriptive, ambispective, single-centre study of paediatric patients with IBD who underwent IFX serum concentration measurements between September 2015 and September 2023. The patients received reactive TDM before September 2019 (n = 17) and proactive TDM thereafter (n = 21). We analysed for clinical, biological, and endoscopic remission; treatment failure; hospitalisations; emergency visits; and adverse drug reactions. The IFX doses were adjusted to maintain trough concentrations ≥ 5 µg/mL, with specific targets for proactive TDM. Of the 38 patients, 21 had Crohn's disease (CD), 16 ulcerative colitis (UC), and 1 undetermined IBD. The mean (standard deviation) IFX trough concentrations were 6.83 (5.66) µg/mL (reactive) and 12.38 (9.24) µg/mL (proactive) ( Proactive TDM showed no significant differences in treatment outcomes compared to reactive TDM. However, the results in both the reactive and proactive TDM groups were not worse than those reported in other studies. Further studies with larger samples are needed to optimize the treatment strategies for pediatric IBD patients.

Currently, there is no clinical data reported on the therapy of dual biological agents in pediatric-onset inflammatory bowel disease (PIBD) patients in China. The purpose of this study was to evaluate the efficacy and safety of dual biologic therapy or biologics combined with small molecule drugs in refractory PIBD patients in China. Clinical, laboratory, endoscopic, and ultrasound data of PIBD patients from the Department of Gastroenterology of Beijing Children's Hospital between January 2021 and October 2024 were retrospectively analyzed. PIBD patients who received dual biologic treatment or a combination of biologic and small molecule therapy were included in this study. Steroid-free clinical remission and adverse events were recorded. In this retrospective study, out of 520 children with IBD, twelve children (2.3%) were diagnosed with refractory PIBD and met the criteria for dual biotherapy, including four with UC (33%) and eight with CD (67%). The median age of patients was 13.64 (range, 1.2-17.1) years at eligibility for dual biologic therapy. There are eight (67%) patients treated with infliximab/ustekinumab (IFX + UST), three (25%) patients with upadacitinib/ustekinumab (UPA + UST), one (8%) patient with infliximab/vedolizumab (IFX + VDZ). At 3, 6, and 12 months of dual biological treatment, 91.2% (11/12), 100% (12/12), and 100% (12/12) patients showed steroid-free clinical remission, respectively. The median fecal calprotectin decreased significantly from 1852.5 µg/g (IQR, 762.5-1988.25) at baseline to 359.0 (IQR, 217.5-730.25) μg/g at 3 months, 113 (IQR, 73.7-256) μg/g at 6 months, and 82.5 (IQR, 40.25-122.25) μg/g at 12 months. Only one CD patient with IFX + UST reported mild elevation of aminotransferase, who recovered after symptomatic treatment. Dual biologic or small molecule therapy may be effective and safe for children with refractory PIBD in China.

PERFUSE is a non-interventional study of 1233 patients [inflammatory rheumatic disease, n = 496; inflammatory bowel disease (IBD), n = 737] receiving infliximab (IFX) biosimilar SB2 therapy. This analysis describes response to treatment and persistence on SB2 for up to 12 months in pediatric IBD patients (n = 126). Pediatric IBD patients with Crohn disease (CD) or ulcerative colitis (UC), either naïve or switched from originator IFX, who started SB2 in routine practice after September 2017 were eligible. Data were captured for 12 months following SB2 initiation. Disease activity was measured using C-reactive protein (CRP) levels and the Harvey-Bradshaw Index or Pediatric Ulcerative Colitis Activity Index for CD and UC patients, respectively. Body mass index and height z scores were used to assess patient growth between initiation (M0) and month 12 (M12). One hundred twenty-six pediatric IBD patients were included (102 CD patients, 51 naïve and 51 switched; 24 UC patients, 9 naïve and 15 switched). Naive patients' disease scores decreased between M0 and M12. CRP measurements also decreased in naïve CD patients. Switched patients' disease scores and CRP levels remained stable between M0 and M12. Height z scores improved significantly over the course of the treatment for all groups except for naïve UC patients. SB2 provides effective disease control for naïve and switched pediatric patients. Clinical remission rates improved in naïve patients and no loss of control was observed in switched patients after 1 year. Growth failure is not observed in IBD patients under SB2 treatment.

We report the rare entity of ulcerative colitis-related severe enteritis (UCRSE) following colectomy in a child. This entity has been described primarily in adults and is characterised by diffuse enteritis with histology identical to ulcerative colitis (UC). The mainstay treatment is steroids and in recent years anti-tumour necrosis factor agents.A boy in early adolescence required urgent colectomy for medically refractory severe acute colitis. Colectomy specimen histology confirmed UC. Postoperatively, he developed fevers, severe abdominal pain and excessive stoma output (5 L/day). Endoscopy revealed severe extensive enteritis, histologically resembling UC. Infliximab (IFX) was commenced with significant improvement. He remains asymptomatic 28 months post-colectomy on maintenance IFX monotherapy. To our knowledge, this is the youngest patient with this complication.This case illustrates the need to consider UCRSE in a child with otherwise unexplained fever, severe abdominal pain and high stoma output post colectomy. IFX monotherapy is a successful treatment option.

The efficacy of infliximab in ulcerative colitis (UC) and indeterminate colitis has been poorly assessed and preliminary results are conflicting. The records of 30 patients treated with infliximab for ulcerative colitis (n=19) or indeterminate colitis (n=11) were reviewed. Infliximab was given because of steroid resistance (n=18), dependence (n=5) or intolerance (n=7); five patients had failed on cyclosporin; 19 patients had a severe flare-up. Median duration of follow-up was 10 months. In 28 patients with active disease, the response rate was 75% at day 7, with 43% having a complete remission, and 50% at month 1, with 32% having a complete remission. Among the 22 responders, the probability of relapse was 73% at month 6. The probability of complete remission without steroids, taking into account the re-treatment for relapse (n=11), was 57% (95% confidence interval (CI): 45% to 69%) at month 6. The probability of colectomy was 33% (95% CI: 23% to 43%) at month 12. In indeterminate colitis, response rate was only 50% at day 7 and 30% at month 1. Concomitant use of antimetabolite agents was associated with better results. Infliximab was able to induce a rapid response in some patients with UC or indeterminate colitis refractory to conventional treatment. Long-term results were less favourable, with frequent relapses, and about one-third of the patients required a colectomy.

In acute steroid-refractory ulcerative colitis, rescue therapy with infliximab has become a therapeutic option in patients facing colectomy. Data on efficacy and safety in this setting are sparse. Patients with ulcerative colitis and acute and severe steroid-refractory disease, who were given infliximab as rescue therapy, were identified by a review of patients' records and databases of infliximab-treated patients. Data on patient background, concomitant medication, endoscopic and laboratory results, clinical activity and adverse events were collected. Fifty-six patients, all admitted because of high disease activity of short duration, and failing high-dose glucocorticoid treatment, received infliximab treatment and were followed up for a median of 538 days (range 2-1769). Colectomy was avoided in 61% of cases. No fatalities were observed. Concomitant medication at the end of follow-up indicated a low number of relapses in patients without colectomies. Our results show a lasting benefit of infliximab rescue therapy in 61% of patients with acute, steroid-refractory ulcerative colitis, a low incidence of late colectomies, and low frequency of steroid use in patients who avoided colectomy. High levels of C-reactive protein on admittance and at the first infliximab infusion were associated with colectomy. Our study adds to the growing experience of infliximab treatment of patients with acute, steroid-refractory ulcerative colitis.

The role of infliximab in the treatment of acute severe ulcerative colitis is established. However, all the data available in the literature are from western countries. This is the first report on the use of infliximab in patients with severe steroid-refractory ulcerative colitis from India. Retrospective analysis of 28 patients who had received infliximab therapy for induction of remission, with three doses of 5 mg/kg at 0, 2, and 6 weeks, was performed. Twenty-four (85.6 %) patients had shown a clinical response by week 8 and, hence, avoided urgent colectomy. In 2 years of follow up, 9/16 (56 %) patients had not required colectomy. Infliximab averted colectomy in a proportion of patients with severe steroid-refractory ulcerative colitis.

To suggest infliximab (IFX) is effective for acute severe ulcerative colitis, from real-life clinical practice. All patients receiving IFX for the treatment of acute severe ulcerative colitis in a single centre were included. Data were extracted from clinical records in order to assess response to IFX therapy. The primary endpoint was colectomy-free survival, and secondary outcomes included glucocorticosteroid-free remission and safety, which was evaluated by recording deaths and adverse events. Demographic and clinical characteristics of those who underwent colectomy and those who were colectomy-free, both at discharge from their index admission, and during follow-up after an initial response to IFX were compared. Forty-four patients (16 females, mean age 36 years) received IFX between May 2006 and January 2012 for acute severe ulcerative colitis. The median duration of follow-up post-first infusion was 396 d (interquartile range = 173-828 d). There were 21 (47.7%) patients with < 1 year of follow-up, 10 (22.7%) with 1 years to 2 years of follow-up, and 13 (29.5%) with > 2 years of follow-up post-first infusion of IFX. Overall, 35 (79.5%) responded to IFX, avoiding colectomy during their index admission, 29 (65.9%) were colectomy-free at last point of follow-up (median follow-up 396 d), and 25 (56.8%) were in glucocorticosteroid-free remission at end of follow-up. There was one death from post-operative sepsis, 20 d after a single IFX infusion. Colectomy rates were generally lower among those "bridging" to thiopurine. Of 18 patients "bridged" to thiopurine therapy, 17 (94.4%) were colectomy-free, and 15 (83.3%) were in glucocorticosteroid-free remission at study end. No predictors of response were identified. IFX is effective for acute severe ulcerative colitis in real-life clinical practice. Two-thirds of patients avoided colectomy, and more than 50% were in glucocorticosteroid-free remission.

To evaluate the efficacy of infliximab treatment in children and adolescents with ulcerative colitis (UC) defined as short and long-term clinical response and surgical avoidance. Infliximab has been found to be effective at improving clinical symptoms, sparing steroid use, and inducing remission in children with medically refractory Crohn's disease. Several retrospective studies in children have shown clinical improvement with colectomy avoidance, but the numbers have been small. Medical records of all patients with steroid-resistant or dependent UC who received infliximab 5 to 10 mg/kg in a 36-month period at Children's Hospital and Regional Medical Center, Seattle, Washington were reviewed. Response to the medication was defined by posttreatment recategorization into Trulove and Witts "mild" category or better. The duration of response was defined as time between infusion and clinical relapse or colectomy. Forty children and adolescents aged 2 to 20 years, received infliximab during the study period. Duration of follow-up ranged from 1 to 36 months with a median of 19 months. Four patients were lost to follow-up. Seventy percent of subjects responded to infliximab. Infliximab responders proceeded to surgery less frequently than nonresponders (P<0.001). No laboratory variables correlated with response. Infliximab was well tolerated. Most children and adolescents with steroid-resistant or dependent UC respond to infliximab with clinical improvement. Response to infliximab also delays and may prevent need for surgery. Laboratory and clinical indicators do not predict response. Infliximab has a role in clinical improvement and surgery avoidance in pediatric patients with UC.

The authors report their experience with infliximab in pediatric patients with ulcerative colitis (UC). Fourteen patients were reviewed. Group 1 included five patients with newly diagnosed, fulminant colitis refractory to 7 to 10 days of intravenous steroids. Group 2 included four patients with ulcerative colitis in remission off steroid therapy who experienced relapse and were hospitalized with fulminant colitis refractory to intravenous steroids for 7 to 10 days. Group 3 included five patients chronically dependent on steroids with colitis refractory to medical management. All patients were treated on an open-label basis with infliximab infusions of 5 mg/kg/dose at 0, 2, and 6 weeks and every 6 to 8 weeks thereafter. Follow-up was maintained for at least 6 weeks. Clinical status was scored with the Lichtiger Colitis Activity Index (LCAI) at each visit. LCAI >or=10 was considered treatment failure. We defined success as LCAI <or=2, a score consistent with UC remission. Response was categorized for each group. All patients began the study with LCAI >or=11 before infliximab treatment. All group 1 patients experienced response to infliximab. All but one (75%) patient in group 2 had a response. Only one (20%) group 3 patient had a response to infliximab. Infliximab was an effective agent in the treatment of acute UC in our patients. Long-term steroid use and emergency colectomy were avoided. Infliximab was less effective in patients who were dependent on steroids.

The management of pediatric inflammatory bowel disease (PIBD) has drastically changed in the last decade. The limited availability of new biologics or small molecule therapies, and concerns about durability in children has necessitated the development of other advances in management to optimize care. This review covers guidance for management targets and advances in optimizing biologic therapies, new medical therapies, adjuvant therapies, precision medicine and mental health concerns in PIBD. This review focused on recent advances and was not intended as a complete overview of the investigations and management of pediatric IBD. Advancements include standardization of treatment goals via a treat-to-target strategy, optimizing anti-TNF biologics through combination therapy or proactive drug monitoring, earlier initiation of treatment for Crohn's disease, the emergence of new biologic/advanced therapies and a growing focus on adjuvant therapies targeting the microbiome. Future progress relies on the inclusion of children/adolescents in clinical trials to facilitate faster regulatory approval for pediatric therapies and the integration of precision medicine and mental health screening to improve patient care and outcomes.

Loss of response in pediatric inflammatory bowel disease patients treated with biologic medications can be due to development of anti-drug antibodies. Natural history of anti-drug antibodies development has not been well described in pediatric inflammatory bowel disease. The primary aim of this study was to describe a single-center experience for the temporal onset of anti-drug antibodies detection. We performed a retrospective, single-center chart review of pediatric inflammatory bowel disease patients at the Division of Pediatric Gastroenterology, Hepatology, and Nutrition at Rainbow Babies and Children's Hospital from 2010 to 2015. Patients were treated with infliximab or adalimumab and had at least two evaluations for anti-drug antibodies with the homogenous mobility shift assay. Demographics, laboratory and medication data, and clinical disease activity were collected. A total of 75 subjects are included in the analysis. Eighty-one percent of subjects were treated with infliximab. Eleven subjects developed anti-drug antibodies; average time to anti-drug antibodies detection was 13.2 ± 7.3 months. Longer duration of inflammatory bowel disease, L1 location in Crohn's disease, and not having immunomodulatory therapy before biologic was associated with higher risk of antibody detection. Antibody detection occurred more frequently with infliximab vs. adalimumab. Time-to-antibody detection for infliximab and adalimumab was 14.83 and 23.48 months, respectively. Chances of anti-drug antibodies detection in the infliximab group were higher than the adalimumab group. Time-to-antibody detection was 8.65 months longer in patients who received adalimumab when compared to infliximab. These results may have implications for long-term therapy and help guide use of concomitant immunomodulators.

No abstract

Fecal calprotectin (F-CPT) represents one of the most widely used biomarkers for intestinal inflammation. However, the levels may be false negative or false positive in some situations. To evaluate the usefulness of immunohistochemical (IHC) detection of tissue calprotectin (T-CPT) in bowel mucosa in children with ulcerative colitis (UC). We focused at correlation of T-CPT with levels of F-CPT and endoscopic and microscopic disease activity at the time of diagnosis and tested whether T-CPT could serve as predictor of complicated course of the disease. Forty-nine children with newly diagnosed UC between 6/2010-1/2018 entered the study. Endoscopic activity was objectified using the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), clinical activity by Pediatric Ulcerative Colitis Activity Index (PUCAI) and microscopic activity by Geboes and Nancy score. The IHC staining for CPT antigen was performed on bioptic samples from 6 bowel segments and the number of CPT + cells were counted per 1HPF. During the minimal follow-up of 12 months we searched for presence of complications. As outcome for Cox regression model we used composite endpoints: A) Acute Severe Colitis, colectomy, anti-TNF treatment; B) systemic corticotherapy; C) systemic 5-aminosalicylic acid therapy. Neither levels of T-CPT nor values of UCEIS, Geboes or Nancy score predicted the given complications. We found F-CPT levels (HR 2.42 and 2.52) and PUCAI > 40 points (HR 2.98) as predictors of time to endpoints B and C. Good correlation was found between T-CPT levels and Geboes score (k = 0.65) and Nancy score (k = 0.62) and modest with F-CPT (k = 0.44), UCEIS (k = 0.38) and PUCAI (k = 0.42). T-CPT correlated well with microscopic scores. F-CPT and PUCAI appear to be better predictors of unfavorable outcome in patients with UC.

Population-based studies examining the prevalence of anti-tumor necrosis factor (anti-TNF) antagonist utilization in children and young adults with inflammatory bowel disease (IBD) are lacking. We aimed to describe the trend of anti-TNF utilization in pediatric IBD over time. Survival analyses were performed for all patients diagnosed with IBD before age 18 years in the province of Manitoba to determine the time from diagnosis to first anti-TNF prescription in different time eras (2005-2008, 2008-2012, 2012-2016). There were 291 persons diagnosed with IBD (157 with Crohn's disease [CD] and 134 with ulcerative colitis [UC]) over the study period. The likelihood of being initiated on an anti-TNF by 1, 2, and 5 years postdiagnosis was 18.4%, 30.5%, and 42.6%, respectively. The proportion of persons aged <18 years utilizing anti-TNFs rose over time; in 2010, 13.0% of CD and 4.9% of UC; by 2016, 60.0% of CD and 25.5% of UC. For those diagnosed after 2012, 42.5% of CD and 28.4% of UC patients had been prescribed an anti-TNF antagonist within 12 months of IBD diagnosis. Initiating an anti-TNF without prior exposure to an immunosuppressive agent increased over time (before 2008: 0%; 2008-2012: 18.2%; 2012-2016: 42.8%; P < 0.001). There was a significant reduction in median cumulative dose of corticosteroids (CS) in the year before anti-TNF initiation (2005-2008: 4360 mg; 2008-2012: 2010 mg; 2012-2016: 1395 mg prednisone equivalents; P < 0.001). Over a period of 11 years, anti-TNFs are being used earlier in the course of pediatric IBD, with a parallel reduction in the cumulative CS dose.

Children with active inflammatory bowel disease (IBD) are frequently underweight. Anti-tumor necrosis factor (anti-TNF) agents may induce remission and restore growth. However, its use in other autoimmune diseases has been associated with excess weight gain. Our aim was to examine whether children with IBD could experience excess weight gain. A centralized diagnostic index identified pediatric IBD patients evaluated at our institution who received anti-TNF therapy for at least 1 year between August 1998 and December 2013. Anthropometric data were collected at time of anti-TNF initiation and annually. Excess weight gain was defined as ΔBMI SDS (standard deviation score) where patients were (1) reclassified from "normal" to "overweight/obese," (2) "overweight" to "obese," or (2) a final BMI SDS >0 and ΔSDS >0.5. During the study period, 268 children received anti-TNF therapy. Of these, 69 had sufficient follow-up for a median of 29.3 months. Median age at first anti-TNF dose was 12.8 years. At baseline, mean weight SDS was -0.7 (SD 1.4), while mean BMI SDS was -0.6 (1.3). Using baseline BMI SDS, 11.6% were overweight/obese. At last follow-up (LFU), however, the mean ΔBMI SDS was 0.50 (p < 0.0001). However, 10 (17%) patients had excess weight gain at LFU; 3 patients were reclassified from "normal" to "obese," and 7 had a final BMI SDS >0 and ΔSDS >0.5. Pediatric patients with IBD may experience excess weight gain when treated with anti-TNF agents. Monitoring for this side effect is warranted.

Inflammatory bowel disease (IBD) is considered to result from interplay between host and intestinal microbiota. While IBD in adults has shown to be associated with marked changes in the intestinal microbiota, there are only a few studies in children, and particularly studies focusing on therapeutic responses are lacking. Hence, this prospective study addressed the intestinal microbiota in pediatric IBD especially related to the level of inflammation. In total, 68 pediatric patients with IBD and 26 controls provided stool and blood samples in a tertiary care hospital and 32 received anti-tumor necrosis factor-α (anti-TNF-α). Blood inflammatory markers and fecal calprotectin levels were determined. The intestinal microbiota was characterized by phylogenetic microarray and qPCR analysis. The microbiota varied along a gradient of increasing intestinal inflammation (indicated by calprotectin levels), which was associated with reduced microbial richness, abundance of butyrate producers, and relative abundance of Gram-positive bacteria (especially Clostridium clusters IV and XIVa). A significant association between microbiota composition and inflammation was indicated by a set of bacterial groups predicting the calprotectin levels (area under curve (AUC) of 0.85). During the induction of anti-TNF-α, the microbial diversity and similarity to the microbiota of controls increased in the responder group by week 6, but not in the non-responders (P<0.01; response related to calprotectin levels). The abundance of six groups of bacteria including those related to Eubacterium rectale and Bifidobacterium spp. predicted the response to anti-TNF-α medication. Intestinal microbiota represents a potential biomarker for correlating the level of inflammation and therapeutic responses to be further validated.

Very early onset inflammatory bowel disease (VEOIBD) is defined as disease onset in patients younger than 6 years. Challenges in treatment of VEOIBD include lack of approved therapies and increased incidence of monogenic immunodeficiencies. We report on patterns of anti-TNF use, efficacy, and safety in a large cohort of patients with VEOIBD. Very early onset inflammatory bowel disease patients receiving care at a single center were prospectively enrolled in a data registry and biorepository starting in 2012. Whole exome sequencing was available to all patients. Clinical data including IBD medication use and response were extracted from the medical record. We examined antitumor necrosis factor (anti-TNF) cumulative exposure and time to failure and evaluated the effect of covariates on anti-TNF failure using Cox proportional hazard regression. In this cohort of 216 VEOIBD patients with median 5.8-year follow-up, 116 (53.7%) were TNF-exposed. Sixty-two TNF-exposed patients (53.4%) received their first dose at younger than 6 years. Cumulative exposure to anti-TNF was 23.6% at 1 year, 38.4% at 3 years, and 43.4% at 5 years after diagnosis. Cumulative exposure was greater in patients with Crohn's disease (P = .0004) and in those diagnosed in 2012 or later (P < .0001). Tumor necrosis factor failure occurred in 50.9% of those exposed. Features predictive of anti-TNF failure included ulcerative colitis/IBD-unclassified (hazard ratio, 1.94; P = .03), stricturing (hazard ratio, 2.20; P = .04), and younger age at diagnosis (hazard ratio, 1.25; P = .01). Adverse events occurred in 22.6% of infliximab-exposed and 14.3% of adalimumab-exposed. Efficacy and safety of anti-TNFs in VEOIBD is comparable to what has previously been reported in older patients. Half of VEOIBD patients followed for a median 5.8 years used anti-TNF. Anti-TNF failure occurred in half of those exposed. Stricturing, UC/IBD-U, and younger age at diagnosis were predictors of failure. Adverse events were similar to those reported in older patients.

Infliximab appears to be efficacious in the treatment of pediatric Crohn disease (CD). There are few large-scale pediatric studies on the complications of infliximab therapy. A retrospective review of all infliximab infusions administered to IBD patients at a tertiary children's hospital was undertaken. Data was obtained from an infliximab infusion database maintained in the section of Pediatric Gastroenterology, pharmacy records and patient charts. 594 infusions were administered to 111 IBD patients (88 CD and 23 UC; 55 male and 56 female; ages 4 to 20 years; mean age, 13.4 years). The number of infusions ranged from 1 to 24 with a mean of 5.4/patient. Infusion reactions occurred in 8.1% of patients (seven early and two delayed) and in 1.5% of all infusions. Reactions occurred more frequently in female patients (14% versus 2%; P = 0.03). All reactions were mild and responded rapidly to treatment. Four patients had infections deemed unusual, including three cutaneous tinea infections and one case of shingles. Infliximab is safe in pediatric IBD patients with a low incidence of generally mild reactions that respond rapidly to intervention. Infusion reactions are more common in female patients. Our patients had no serious infectious complications, although cutaneous tinea infection may represent a newly reported associated complication.

Treatment with biological agents such as anti-tumor necrosis factors (TNFs) has become standard of care in moderate to severe pediatric inflammatory bowel disease (IBD). However, a significant proportion of patients experience loss of response to anti-TNFs, need treatment escalation, or develop side effects. There is no data in the literature regarding combination of biological agents in pediatric IBD. At our hospital, which is a tertiary referral center, we have combined the anti-TNF infliximab with either vedolizumab or ustekinumab in patients with severe pediatric IBD. The indications for dual biological therapy were insufficient efficacy of infliximab or vedolizumab monotherapy, or side effects such as psoriasis due to anti-TNFs. Eight patients (four boys) aged 14-17.5 years received a combination of infliximab and vedolizumab due to only a partial response to infliximab, four with Crohn's disease (CD) and four with ulcerative colitis (UC). Clinical remission was achieved in four patients (3 UC) and four had a colectomy (3 CD, 1 UC). Five CD patients (3 girls) aged 11-17 years, on maintenance therapy with infliximab, developed psoriasis resistant to topical treatment. A combination of infliximab and ustekinumab resulted in clinical remission of CD without skin symptoms. No serious adverse events occurred in any of the patients on combination therapy. Thirteen publications report on combining biologicals, all in adult IBD. In pediatric IBD, combining biological agents seems to be safe and beneficial in selected patients. The safety should be addressed in long-term follow-up studies.

To study the response to infliximab in pediatric inflammatory bowel disease (IBD), as reflected in fecal calprotectin levels. Thirty-six pediatric patients with IBD [23 Crohn's disease (CD), 13 ulcerative colitis (UC); median age 14 years] were treated with infliximab. Fecal calprotectin was measured at baseline, and 2 and 6 wk after therapy, and compared to blood inflammatory markers. Maintenance medication was unaltered until the third infusion but glucocorticoids were tapered off if the patient was doing well. At introduction of infliximab, median fecal calprotectin level was 1150 μg/g (range 54-6032 μg/g). By week 2, the fecal calprotectin level had declined to a median 261 μg/g (P < 0.001). In 37% of the patients, fecal calprotectin was normal (< 100 μg/g) at 2 wk. By week 6, there was no additional improvement in the fecal calprotectin level (median 345 μg/g). In 22% of the patients, fecal calprotectin levels increased by week 6 to pretreatment levels or above, suggesting no response (or a loss of early response). Thus, in CD, the proportion of non-responsive patients by week 6 seemed lower, because only 9% showed no improvement in their fecal calprotectin level when compared to the respective figure of 46% of the UC patients (P < 0.05). When treated with infliximab, fecal calprotectin levels reflecting intestinal inflammation normalized rapidly in one third of pediatric patients suggesting complete mucosal healing.

To assess infliximab pharmacokinetics in pediatric ulcerative colitis (UC). This phase 3, randomized, open-label multicenter study enrolled 60 children (6-17 yr) with moderate-to-severely active UC (Mayo score, 6-12; endoscopic subscore, ≥2), despite conventional therapy. Patients received infliximab 5-mg/kg induction infusions at weeks 0, 2, and 6. Week 8 clinical responders (n = 45) were randomized to infliximab 5 mg/kg given every 8 weeks (q8w) through week 46 or every 12 weeks (q12w) through week 42. Patients losing response during maintenance infliximab were eligible to increase the dose (5→10 mg/kg) and/or shorten the dosing interval (q12w→q8w). Blood samples were collected for infliximab concentration and pharmacokinetic determinations. Infliximab pharmacokinetics were not influenced by age (6-11 yr versus 12-17 yr), baseline immunomodulator use, or the extent of UC. At week 8, higher serum infliximab concentrations (≥41.1 μg/mL) were associated with greater proportions of patients achieving efficacy endpoints (clinical response, 92.9%; mucosal healing, 92.9%; and clinical remission, 64.3%) versus those with lower serum concentrations (<18.1 μg/mL; 53.9%, 53.9%, and 30.8%, respectively). At week 30, higher median trough serum infliximab concentrations were observed with infliximab 5 mg/kg q8w (1.9 μg/mL) versus q12w (0.8 μg/mL) and with infliximab 10 mg/kg (2.9 μg/mL) versus 5 mg/kg (1.1 μg/mL) among patients who are regimen adjusted. Infliximab pharmacokinetics/exposure-response relationship in patients with UC aged 6 to 17 years were generally comparable with those observed in reference adult UC populations, supporting using infliximab 5 mg/kg at weeks 0, 2, and 6 followed by maintenance dosing with 5 mg/kg q8w in these patients. A positive relationship was noted between serum infliximab level and clinical effect following induction therapy similar to adults.

Parents and pediatric patients with ulcerative colitis (UC) who progressed to systemic immunotherapy are concerned about lifelong risks from such treatments. There is limited knowledge about withdrawal of such agents and step-down (SD) to enteral 5-aminosalicylic acid (mesalamine) before transitioning to adult care. We studied nine pediatric cases with moderate to severe UC who after a median of 2.18 years of clinical remission on systemic immunotherapy stepped down to oral mesalamine treatment. Average follow-up time from SD was 3.49 years. Five patients (55.5%) had sustained remission (without any flare noted) after SD during follow-up. Sustained clinical remission was 88.9% (8/9) at 1 year, 87.5% (7/8) at 2 years, and 66.7% (4/6) at 3 years after SD. Out of those tested (one patient was not tested), 62.5% (5/8) had fecal calprotectin <50 μg/g. Four out of six patients examined (66.6%) had mucosal healing on post-SD colonoscopy. We propose that SD to mesalamine can be a reasonable therapeutic consideration for pediatric patients with UC before transitioning to adult gastroenterology care. Shared decision-making is important before such treatment changes.

Presently, there is no consensus on endpoint measures to assess clinical outcomes for pediatric ulcerative colitis (UC). This study reviewed the endpoints used in the registration trials of approved drugs for pediatric UC. The primary efficacy endpoints of all registration trials completed from 1950 to 2008 that led to Food and Drug Administration approval for indications in pediatric and adult UC were reviewed. Colazal and Remicade have been approved for pediatric UC indication, and clinical response was used as a primary endpoint in these registration trials. The clinical response in the adult Colazal trials was defined as a reduction of rectal bleeding and improvement in at least one of the other assessed symptoms (stool frequency, patient functional assessment, abdominal pain, sigmoidoscopic grade, and physician's global assessment) assessed by the Sutherland UC Activity Index. The pediatric Colazal trial defined clinical response using the Modified Sutherland UC Activity Index, which excluded abdominal pain and functional assessment. Both adult and pediatric Remicade trials used clinical response defined by the Mayo score as the primary endpoint. The Pediatric Ulcerative Colitis Activity Index was used to measure various secondary endpoints in the pediatric Remicade trial. Pediatric-specific endpoints were used, but outcome measures and definition of clinical response were not consistent in pediatric UC trials. Consensus on the definition of successful treatment outcome (clinical response and/or remission) and collaboration in the development of well-defined and reliable measures of signs and symptoms for use in conjunction with endoscopic parameters of mucosal healing will facilitate pediatric drug development.

Infliximab pharmacokinetics in steroid-refractory [SR] ulcerative colitis [UC] suggest a need for higher dosing, but data concerning efficacy of intensification in this setting are lacking in children and inconsistent overall. Paediatric patients [N = 125] treated with infliximab for SR or steroid-dependent UC were retrospectively reviewed. Outcomes [clinical response and remission, colectomy, mucosal healing, safety] with standard vs intensified induction [mean induction dose ≥7 mg/kg or interval ≤5 weeks between doses 1 and 3] were compared. Among 125 patients [median age 14 years, median UC duration 0.7 years, 74 SR], 73 [58%] received standard induction and 52 [42%] received intensified induction. Overall, 73 [58%] achieved remission (judged by physician global assessment [PGA] and paediatric UC activity index [PUCAI]≤10]. Among patients in remission, 7 [10%] experienced secondary loss of response by a median of 0.7 [IQR 0.4-1.0] years. Of the 74 SR patients, 17 [23%] underwent colectomy, and of the 51 steroid-dependent patients, 12 [24%] underwent colectomy. Intensified induction in SR patients was associated with a higher chance of remission (hazard ratio [HR] 3.2, p = 0.02) and a lower chance of colectomy [HR 0.4, p = 0.05], but did not improve outcomes in steroid-dependent patients. During follow-up, 46/73 [63%] patients in remission had regimen individualization, with similar rates of return to standard dosing after 1 year between those with initial intensified or standard induction. Follow-up endoscopy, performed in 35/73 patients in remission, demonstrated mucosal healing for 66%. Adverse events were rare, despite use of intensified regimens. These data suggest a benefit from intensified infliximab induction specifically among children with steroid-refractory UC. Prospective studies comparing dosing regimens and incorporating therapeutic drug monitoring should be undertaken.

Epidemiological data on pediatric inflammatory bowel disease (PIBD) have been reported in Asian countries. However, short-term follow-up data, especially in Southeast Asian countries, are limited. Analyze and compare the baseline and 1-year follow-up (1FU) data for PIBD in Asian children. The multinational network included patients with PIBD (aged <19 years) in 5 Asian countries (Malaysia, Philippines, Singapore, Sri Lanka, and Thailand). The diagnosis of PIBD requires gastrointestinal endoscopy. The patients' demographics, clinical information, disease- related outcomes, and treatment data at 1FU were collected. In 1995-2021, 368 patients were enrolled (Crohn disease [CD], 56.8%; ulcerative colitis [UC], 38%; and inflammatory bowel disease [IBD]-unclassified, 5.2%). At 1FU, symptoms including diarrhea, bloody stools, and nausea/vomiting subsided in <3%, while abdominal pain persisted in 10.5% of patients with CD and 7.1% of patients with UC. Assessment endoscopy was performed at 1FU in 38% of CD and 31% of UC cases, of which 21% and 23% showed mucosal healing, respectively. Oral prednisolone was administered to 55.3% of patients at diagnosis and 26.8% at 1FU, while infliximab was administered to 2.5% and 7.2% of patients at diagnosis and 1FU, respectively. Independent factors of 1-year clinical remission for CD were oral prednisolone (odds ratio [OR], 0.20; 95% confidence interval [CI], 0.06-0.68), antibiotic use (OR, 0.09; 95% CI, 0.01-0.54), and immunomodulator use (OR, 5.26; 95% CI, 1.52-18.22). A history of weight loss at diagnosis was the only independent risk factor of an IBD flare by 1FU (OR, 2.01; 95% CI, 1.12-3.63). The proportion of children with PIBD and abdominal pain at 1FU remained high. The rates of repeat endoscopy and infliximab use were suboptimal with high rates of systemic corticosteroid use. Quality improvement based on the aforementioned predictors may enhance PIBD care in this geographic region or similar settings.

To assess current practices around the use of combination immunosuppression in paediatric inflammatory bowel disease (PIBD) with a focus on the subsequent withdrawal process. A web-based, 43-question survey. Surveys were completed by 70 paediatric gastroenterologists (PGs) from 27 nations across Europe, North America, Oceania and Asia from 62 centres covering approximately 15,000 PIBD patients (median of 200 patients [interquartile range (IQR) 130-300] per centre). Routine use of co-immunosuppression was significantly higher with infliximab (IFX) versus adalimumab (ADL) ([61/70, 87.1%] compared with [23/70, 32.9%]; P < 0.01). Thiopurines (azathioprine [AZA] or 6-mercaptopurine) were the preferred option overall for co-immunosuppression. They were favoured with either IFX or ADL (76% and 77%, respectively) and in both ulcerative colitis (UC) and Crohn disease (CD) (84% and 69%) compared with methotrexate (MTX).Immunomodulators were the preferred choice as the initial drug to be withdrawn from the combination therapy rather than anti-tumour necrosis factor-alpha (anti-TNFα) therapy (59/67, 88% [P < 0.01]). The most common withdrawal time was after 6-12 months, with this decision usually based on clinical assessment rather than a scheduled withdrawal time (51/67, 76% vs 16/67, 24%). Indicators of mucosal healing and therapeutic drug monitoring results tended to be the most important "clinical factors" in the withdrawal decision (P = 0.05). Most PG's favour initial withdrawal of immunomodulator (usually thiopurines) rather than biologic therapy in the step-down process, usually after 6-12 months based on sustained clinical remission. This survey precedes an in-depth, multicentre study of clinical outcomes of withdrawal of co-immunosuppression in PIBD.

To assess contemporary outcomes in children with acute severe ulcerative colitis [ASUC] at initial presentation. Between April 2014 and January 2019, children aged <17 years, with new onset ASUC (Paediatric Ulcerative Colitis Activity Index [PUCAI ≥65) were prospectively followed in a Canadian inception cohort study. 16S rRNA amplicon sequencing captured microbial composition of baseline faecal samples. Primary endpoint was corticosteroid-free clinical remission with intact colon at 1 year [PUCAI <10, no steroids ≥4 weeks]. Of 379 children with new onset UC/IBD-unclassified, 105 [28%] presented with ASUC (42% male; median [interquartile range; [IQR]) age 14 [11-16] years; extensive colitis in all). Compared with mild UC, gut microbiome of ASUC patients had lower α-diversity, decreased beneficial anaerobes, and increased aerobes; 54 [51%] children were steroid-refractory and given infliximab [87% intensified regimen]. Corticosteroid-free remission at 1 year was achieved by 62 [61%] ASUC cohort (by 34 [63%] steroid-refractory patients, all on biologics; by 28 [55%] steroid responders,13 [25%] on 5- aminosalicylic acid [5-ASA], 5 [10%] on thiopurines, 10 [20%] on biologics). By 1 year, 78 [74%] escalated to infliximab including 24 [47%] steroid-responders failed by 5-ASA and/or thiopurines. In multivariable analysis, clinical predictors for commencing infliximab included hypoalbuminaemia, greater PUCAI, higher age, and male sex. Over 18 months, repeat corticosteroid course[s] and repeat hospitalisation were less likely among steroid-refractory versus -responsive but -dependent patients (adjusted odds ratio [aOR] 0.71 [95% CI 0.57-0.89] and 0.54 [95% CI 0.45-0.66], respectively). The majority of children presenting with ASUC escalate therapy to biologics. Predictors of need for advanced therapy may guide selection of optimal maintenance therapy.

The growing incidence of inflammatory bowel disease (IBD) in children necessitates the use of biological treatments. Recently, an infliximab biosimilar was authorized in the European Union, which may result in switching patients. We present our preliminary experiences with such switches. The prospective study included 32 paediatric patients diagnosed with Crohn's disease (CD) and 7 children with ulcerative colitis (UC) at 3 academic hospitals, who were switched from infliximab originator to its biosimilar (Remsima). Patient characteristics, disease severity, laboratory parameters and adverse events were recorded. Means, medians and ranges were calculated. Mean age at diagnosis of CD and UC was 11.1 (2.7-15.3) and 12.3 years (8.5-14.8), respectively. Mean number of infliximab originator infusions before switching to the biosimilar was 9.9 (median 8, range 4-29) and 5.1 (5, 1-12) for the CD and UC group, respectively. Evaluation efficacy of last biosimilar doses of all patients revealed rates of clinical remission of 88 and 57% for CD and UC patients, respectively. Last follow-up assessment of patients who continued with biosimilar therapy showed that 16/20 (80%) CD patients and all 4 UC individuals were in remission. One infusion reaction to infliximab biosimilar was observed in a CD patient, which led to treatment discontinuation. The incidence of sporadic mild adverse events prior to and after switching did not differ significantly and was consistent with the safety profile of the infliximab molecule. Switching from infliximab originator to its biosimilar seems to be a safe option in children with CD. After the switch the biosimilar was just as effective as the originator.

ABSTRACT Introduction In children, ulcerative colitis (UC) is often more severe and extensive than in adults and hospitalization for acute exacerbations occurs in around a quarter of subjects. There is a need for effective drugs, which could avoid or reduce the use of corticosteroids which, especially in children, are burdened by a number of severe side effects. The introduction in therapy of monoclonal antibodies has completely changed the therapeutic scenario and the prognosis of the disease. Areas covered In this review, the use of the monoclonal antibodies directed against tumor necrosis factor (TNF)α or other inflammatory targets for the treatment of pediatric UC will be discussed. A search of the literature was done using the keywords ‘pediatric,’ ‘ulcerative colitis,’ ‘inflammatory bowel disease,’ ‘monoclonal antibodies;’ ‘infliximab,’ ‘adalimumab,’ ‘golimumab,’ vedolizumab,” ‘ustekinumab’ and ‘risankizumab.’ Expert opinion The use of monoclonal antibodies has greatly increased in recent years in pediatric UC, both in patients who did not respond to conventional therapies, and, more often, as initial therapy. Thanks to therapeutic drug monitoring and to the availability of biologics with different targets, therapy has become more targeted and personalized, with a significant improvement in response, in quality of life, and with a good safety profile.

Pediatric ulcerative colitis is likely to be more severe than adult ulcerative colitis. Failure to thrive should be considered during therapy. A 10-year-old boy was diagnosed with ulcerative colitis based on his clinical presentation and colonoscopy and biopsy results. The administration of 5-aminosalicylic acid and prednisolone resulted in remission ; however, the symptoms reappeared after the discontinuation of prednisolone. Then, infliximab was administered ; however, the patient was resistant to it and appeared to be dependent on prednisolone. Vedolizumab, a monoclonal antibody against ?4?7 integrin, was administered, which resulted in rapid remission. A steady decrease in prednisolone followed, and remission was maintained even after prednisolone discontinuation. Vedolizumab may be effective in pediatric patients with moderate-to-severe refractory ulcerative colitis. Vedolizumab prevents lymphocytes from binding to MAdCAM-1, which is selectively expressed in the gastrointestinal submucosa, leading to the mitigation of the systemic side effects of immunosuppression, such as infections. In Japan, vedolizumab use is not yet approved for use in children, but its effectiveness and safety in children is expected to be investigated in the future. J. Med. Invest. 70 : 294-297, February, 2023.

ABSTRACT Introduction: More extensive disease, high rates of corticosteroid refractory and dependent disease, and the potential impact of disease on growth and development differentiate inflammatory bowel disease in children from adults. This is particularly evident in ulcerative colitis where pancolitis predominates, success of mesalamine alone in achieving remission is less than 50%, and there is a high need for immunomodulator or biologic therapies. Areas Covered: This review describes the use of infliximab, adalimumab, golimumab, and vedolizumab in the treatment of children with ulcerative colitis but is limited in scope due to the paucity of controlled clinical trials. A search of existing literature with keywords of these specific biological therapies as well as ‘pediatric’, ‘ulcerative colitis,’ and ‘inflammatory bowel disease’ was used to complete this review. Expert Opinion: Therapeutic drug monitoring has become standard of care when assessing dosing and changes in therapy and will play a role in future treatment planning.

Ulcerative colitis is a chronic inflammatory bowel disease that can lead to derangements in the growth, nutritional status, and psychosocial development of affected children. There are several medical options for the induction and maintenance of disease remission, but the benefits of these medications need to be carefully weighed against the risks, especially in the pediatric population. As the etiology of the disease has become increasingly understood, newer therapeutic alternatives have arisen in the form of biologic therapies, which are monoclonal antibodies targeted to a specific protein or receptor. This review will discuss the classical treatments for children with ulcerative colitis, including 5-aminosalicylates, corticosteroids, thiopurine immunomodulators, and calcineurin inhibitors, with a particular focus on the newer class of anti-tumor necrosis factor-α agents.

Purpose Golimumab (GLM) is an anti-tumor necrosis factor (TNF)-α antibody preparation known to be less immunogenic than infliximab (IFX) or adalimumab. Few reports on GLM in pediatric patients with ulcerative colitis (UC) are available. This study aimed to review the long-term durability and safety of GLM in a pediatric center. Methods The medical records of 17 pediatric patients (eight boys and nine girls) who received GLM at the National Center for Child Health and Development were retrospectively reviewed. Results The median age at GLM initiation was 13.9 (interquartile range 12.0–16.3) years. Fourteen patients had pancolitis, and 11 had severe disease (pediatric ulcerative colitis activity index ≥65). Ten patients were biologic-naïve, and 50% achieved corticosteroid-free remission at week 54. Two patients discontinued prior anti-TNF-α agents because of adverse events during remission. Both showed responses to GLM without unfavorable events through week 54. However, the efficacy of GLM in patients who showed primary nonresponse or loss of response to IFX was limited. Four of the five patients showed non-response at week 54. Patients with severe disease had significantly lower corticosteroid-free remission rate at week 54 than those without severe disease. No severe adverse events were observed during the study period. Conclusion GLM appears to be safe and useful for pediatric patients with UC. Patients with mild to moderate disease who responded to but had some adverse events with prior biologics may be good candidates for GLM. Its safety and low immunogenicity profile serve as favorable options for selected children with UC.

Abstract Background Inflammatory Bowel Disease (IBD) refractory to first-line agents is challenging in pediatrics due to limited therapeutic options, especially in Acute Severe Colitis (ASC). Upadacitinib (UPA) is a selective Janus-Kinase (JAK) inhibitor approved for use in adults. Its use in pediatrics for refractory moderate to severe colitis is off label, but its oral route of administration and quick onset of action make it a promising therapy. Intestinal Ultrasound (IUS) in this context may be a useful tool for monitoring treatment response. Aims To describe the efficacy of UPA as a second-line agent for pediatric ASC and report IUS findings to demonstrate its use in monitoring IBD. Methods Single-center chart and literature review of pediatric patients with IBD on UPA. Results Case 1: A 12-year-old female with pancolonic Ulcerative Colitis (UC) since age 9 maintained on Infliximab (IFX). Despite adequate IFX levels, re-induction and steroids, she had a Pediatric Ulcerative Colitis Activity Index (PUCAI) of 50, elevated C-Reactive Protein (CRP) and fecal calprotectin (FC) leading to repeat admissions. Intravenous (IV) steroids, followed by UPA 45mg for 8 weeks, led to rapid clinical response by Day 4. At discharge, PUCAI was 5 and CRP <5. On Day 20 of UPA, IUS showed normal bowel wall thickness (BWT) and Modified Limberg (ML) score of 0. At 6 months, she remains in steroid-free remission with a normal FC. Case 2: A 16-year-old female presented with a Pediatric Crohn’s Disease Activity Index (PCDAI) of 45 and was diagnosed with Crohn’s colitis with perianal fistula. Due to inadequate response to 6 days of IV steroids, she received IFX. Despite robust IFX levels, IUS showed pancolonic inflammation with increased BWT of 4.6 mm and ML score of 1-2. [1] She was readmitted with severe anemia and elevated CRP. Concurrent C. jejuni infection was treated without symptom resolution. Given severe colitis despite IFX and steroids, UPA 45mg for 12 weeks was started with clinical response and discharge by Day 4; PCDAI of 20. At 1 month, she remains asymptomatic on a steroid taper with a normal hemoglobin. Repeat IUS and FC is pending. Case 3: A 15-year-old male with IBD favouring UC since age 14, who initially did well on steroids and IFX was re-admitted with a PUCAI of 65 and elevated FC while weaning steroids. Repeat endoscopy showed Mayo 2 colitis to hepatic flexure correlating to increased BWT of 3.5 mm and ML score of 2 on IUS. Despite appropriate IFX levels, due to steroid dependence at discharge (PUCAI 25), UPA 45mg for 8 weeks was started as an outpatient. By Day 21 his PUCAI was 0, with normal FC. At 2 months, IUS showed normal BWT and ML Score 0 with steroid-free remission. Conclusions These cases demonstrate the efficacy of UPA in refractory pediatric ASC with rapid clinical response, normalization of biochemical tests and IUS findings. Funding Agencies None

Abstract Objectives Upadacitinib (UPA), a selective Janus kinase‐1 inhibitor, has demonstrated efficacy in inducing and maintaining remission in moderate to severe ulcerative colitis (UC) in adults. Current standard management for acute severe ulcerative colitis (ASUC) involves intravenous corticosteroids (IVCS) followed by infliximab (IFX) salvage therapy. Limited data exist on the utility of UPA in ASUC, particularly in adolescents. This case series reports the use of UPA as salvage therapy in hospitalized adolescents experiencing ASUC refractory to IFX. Methods We performed a retrospective chart review of hospitalized patients with ASUC who received UPA as salvage therapy after initiation of IVCS and failure of IFX. Results Three adolescents were hospitalized with ASUC for which IFX infusion treatments were unsuccessful. Initiation of UPA enabled patients to improve their Pediatric Ulcerative Colitis Activity Index scores to ≤35 and be discharged home. Hospitalization course, complications, and follow‐up information are provided. Conclusion UPA is a promising short‐term salvage therapy in adolescent ASUC cases resistant to conventional treatments. Prospective studies are warranted to elucidate its long‐term efficacy and safety in this specific population. These findings provide a novel therapeutic avenue for managing ASUC in adolescents, offering hope for those encountering treatment challenges.

No abstract available

Background: Ustekinumabis ahumanizedmonoclonalantibody(mAb)thattargetsthep40subunit shared by interleukins 12 and 23, and is FDA-approved for the treatment of Crohn ’ s disease and ulcerative colitis. Hypersensitivity reactions to intravenous ustekinumab are reported to occur in 0.9-4.5% of cases. The cause of these reactions is uncertain, as type I IgE-mediated hypersensitivity reactions are unexpected without prior exposure to a given drug. One possible explanation involves IgE to galactose-a -1,3-galactose ( a -gal), a glycan implicated in mammalian meat allergy and fi rst-dose anaphylactic reactions to the monoclonal antibody cetuximab. Given that both cetuximab and ustekinumab are produced in the murine Sp2/0 cell line, we hypothesized that pre-existing IgE to a -gal could explain some fi rst-dose infusion reactions to ustekinumab. Methods: Patients with Crohn ’ s disease who experienced fi rst-dose infusion reactions to usteki-numab and were found to have detectable alpha-gal speci fi c IgE in their serum were described from the practice of 2 academic providers ’ clinics. An ImmunoCA P-basedassay wasused to test whether a separate cohort of patients with mammalian meat allergy had IgE that could bind to ustekinumab. We also tested serum reactivity of these patients against vedolizumab,a mAb generated in CHO cells that is not thought to express alpha-gal. Results: We identi fi ed 6 patients who hadacute infusion reactionsto theintravenous formulation of ustekinumab and had IgE speci fi c for a -gal in their serum. All patients developed urticaria as part of the reaction and all went on to tolerate subcutaneous administration of ustekinumab at future visits. Serum-based ImmunoCAP testing in patients with mammalian meat allergy, but not controls, revealed high levels of IgE binding to cetuximab, moderate binding to ustekinumab, and no significant binding to vedolizumab. CONCLUSION: In this study, patients with the alpha-gal mammalian meat allergy exhibited IgE binding to ustekinumab, but not to a representative mAb generated in CHO cells. The level of IgE binding to ustekinumab was lower than that for cetuximab, but still detectable in the assay. The di ff erence may be due to the established presence of a -gal on the Fab portion of cetuximab, whereas for ustekinumab it is reportedly limited to the Fc domain. When administered subcutaneously, ustekinumab was successfully tolerated by all of the patients who had reacted to the initial intravenous infusion. Additional studies evaluating the degree of IgE binding and basophil activation with exposure to various mAb concentrations would help determine if a dose-response relationship exists and could aid clinicians in optimizing the safe use of these monoclonal antibodies for patients with a -gal syndrome. For patients with mild to moderate hypersensitivity reactions to intravenous ustekinumab, switching to subcutaneous ustekinumab and considering referral to an allergist for monitored administration is advisable. In our experience, pre-medication before subcutaneous injections is reasonable but not required

BACKGROUND Tofacitinib has emerged as a new potential treatment for acute severe ulcerative colitis (ASUC). We conducted a systematic review to assess efficacy, safety, and integration in ASUC algorithms. METHODS Systematic search in MEDLINE, EMBASE, Cochrane Library, and Clinicaltrials.gov until August 17, 2022, including all studies reporting original observations on tofacitinib for ASUC, preferably defined according to Truelove and Witts criteria. Primary outcome was colectomy-free survival. RESULTS Of 1,072 publications identified, 21 studies were included of which three were ongoing clinical trials. The remaining comprised a pooled cohort originating from 15 case publications (n=42), a GETAID cohort study (n=55), a case-control study (n=40 cases), and a pediatric cohort (n=11). Of these 148 reported cases, tofacitinib was used as second line treatment after steroid failure in previous infliximab failures or third line after sequential steroid and infliximab or cyclosporine failure, 69 (47%) were female, age median ranged 17-34 years, disease duration 0.7-10 years. Overall, 30-day colectomy-free survival was 85% (n=123 of 145; n=3 without colectomy had follow-up <30 days), 90-day 86% (n=113 of 132; n=16 follow-up <90 days), and 180-day 69% (n=77 of 112; n=36 follow-up <180 days). Tofacitinib persistence at follow-up was 68-91%, clinical remission 35-69%, and endoscopic remission 55% reported. Adverse events occurred in 22 patients, predominantly being infectious complications other than herpes zoster (n=13), and resulted in tofacitinib discontinuation in seven patients. CONCLUSION Tofacitinib appears promising for treatment of ASUC with high short-term colectomy-free survival among refractory patients otherwise deemed for colectomy. However, large high-quality studies are needed.

No abstract available

Background and Aims: Thiopurines are an established treatment for pediatric ulcerative colitis (UC). However, data regarding safety and efficacy are lacking. We aimed to determine short and long-term outcome following thiopurines use in children with UC. Methods: We conducted a retrospective review of children (2–18 years) with UC treated with thiopurines between January 2008 and January 2019 at 7 medical centers in Israel. The primary outcome was corticosteroid (CS)-free clinical remission at week 52 following thiopurines initiation without the need for rescue therapy (infliximab, calcineurin inhibitors, or colectomy). Results: A total of 133 children were included [median age at diagnosis of 12.4 (interquartile range 11.0–15.8) years, 30 (23%) left-sided colitis, 113 (85%) with moderate or severe disease at diagnosis]. At diagnosis 58 patients (44%) were treated with 5-aminosalicylates and 72 (54%) with CS. Sixty patients (45%) received thiopurines as 1st line maintenance therapy. Seventy-four patients (56%) had CS-free clinical remission at week 52 without rescue therapy. Predictors of clinical remission were not identified. In a sub-analysis among patients with steroid-responsive moderate to severe UC, 59 (55%) patients achieved this outcome. The likelihood of remaining free of rescue therapy among thiopurines-treated patients was 83%, 62%, 45%, and 37% at 1, 2, 3, and 4 years, respectively. Conclusion: More than half of children with UC starting thiopurines without previous or concomitant biologic therapy have CS-free clinical remission at 52 weeks later without the need for rescue therapy. Thiopurines are effective in pediatric UC and could be considered prior to biologics.

Introduction: Inflammatory bowel disease (IBD) is associated with Takayasu arteritis (TAK). Chronic recurrent multifocal osteomyelitis (CRMO) is a non-bacterial osteomyelitis that occurs at multiple sites, some of which are associated with IBD. We herein report a pediatric patient diagnosed with CRMO and TAK 13 years after the onset of very-early-onset ulcerative colitis (VEO-UC). Concurrent presentations of UC, TAK, and CRMO are extremely rare. Case presentation: A 15-year-old female diagnosed with very early-onset UC at 22 months developed CRMO and TAK 13 years later despite maintained remission on infliximab. The patient was presented with knee pain and fever. 18- fluorodeoxyglucose positron emission tomography revealed not only multiple bone uptake but also arterial wall thickening. Contrast-enhanced magnetic resonance imaging showed circumferential wall thickening from distal aortic arch to descending aorta. Bone biopsy confirmed chronic osteomyelitis without infection. TAK (type IIb) and CRMO were diagnosed. Methylprednisolone pulse therapy was administered for induction. Treatment was switched to adalimumab (ADA), which has reported efficacies for all three conditions. However, only TAK did not achieve remission. ADA was switched to tocilizumab (TCZ) without changing other medications to treat TAK, successfully achieving remission of all three diseases and allowing steroid reduction. Conclusion: Clinicians should consider concurrent vasculitis and CRMO when inflammatory bowel disease patients present with unexplained inflammatory responses. TCZ may effectively treat TAK developing in anti-tumor necrosis factor-treated UC patients.

Objectives: Infliximab is considered superior to adalimumab in patients with ulcerative colitis, especially in severe cases. Whether this is true for Crohn disease (CD) patients with colonic involvement is unclear. Our aim was to compare the clinical effectiveness of infliximab versus adalimumab in pediatric ileocolonic (L3) CD. Methods: This retrospective study included patients <18 years with ileocolonic CD treated with infliximab or adalimumab between 2014 and 2021. Primary outcome was steroid-free clinical remission by week 52. Secondary outcomes were treatment modifications, drug discontinuation, inflammatory bowel disease (IBD)-associated hospitalizations, and surgery during the first year of treatment. Results: We identified 74 patients treated with adalimumab and 41 with infliximab, with comparable demographic features. Concomitant immunomodulator therapy at biologic initiation was significantly lower in the adalimumab group (28% vs 85%, P < 0.001). Rates of drug intensification were higher in the infliximab group at end of induction (EOI) and at 52 weeks (55% vs 32% and 88% vs 46%, P < 0.001). Given significant differences between initial median Pediatric Crohn Disease Activity Index scores (20.0 [interquartile range, IQR 15.0–27.5] vs 11.0 [IQR 7.5–20.0] for infliximab and adalimumab groups, respectively, P < 0.001), propensity score matching was performed. Following matching, the rate of patients in steroid-free clinical remission by EOI was significantly higher in the adalimumab group (93.8% vs 46.9%, P < 0.001), but comparable by 1 year. Moreover, inflammatory markers and fecal calprotectin values were also similar at these time points. Rates of drug discontinuation, IBD-associated admissions, and surgery were similar between groups. Conclusions: In a retrospective study of patients with ileocolonic CD, adalimumab and infliximab had comparable outcomes by 52 weeks.

Objectives: We aimed to identify early noninvasive predictors of clinical and endoscopic remission in children with Crohn disease (CD) under infliximab (IFX). Methods: Prospective observational study conducted in children with moderate-to-severe CD starting IFX. All patients underwent weighted pediatric CD activity index (wPCDAI) assessment, C-reactive protein and fecal calprotectin (FC) at week 0, 14, and 48. Endoscopy was performed at 0 and 48 weeks. The primary outcome was to determine the ability of 14-week wPCDAI, C-reactive protein, and FC to predict 1-year steroid-free clinical remission and mucosal healing. As a secondary outcome we evaluated their concordance with Simple Endoscopic Score for CD (SES-CD) at week 48. Results: Forty-one children were enrolled. At 1 year, 21 (51%) and 16 (39%) were in clinical and endoscopic remission. Only combined postinduction FC and wPCDAI were able to predict 1-year clinical and endoscopic remission (hazard ratio 4.81 [95% confidence interval 1.76–20.45], P = 0.05 and hazard ratio 5.51 [95% confidence interval 1.83–26.9], P = 0.03). One-year SES-CD moderately correlated with FC (r = 0.52; P = 0.001). The FC cut-off value for mucosal healing was 120.5 &mgr;g/g (area under the curve 0.863, 83% sensitivity, 75.5% specificity; P = 0.005). The concordance between wPCDAI and SES-CD was excellent and good for severe disease and remission (k 0.87 and 0.76). Conclusions: Post induction FC combined with wPCDAI can predict 1-year clinical and endoscopic response to IFX in pediatric CD. FC shows a moderate correlation with SES-CD, whereas wPCDAI has a good concordance with endoscopic remission or severe disease, but not with mild and moderate disease.

No abstract available

Little is known about morbidity of Covid-19 infection in pediatric patients with inflammatory bowel diseases (IBD) treated with biologic medications. The aim of this study was to evaluate the frequency of SARS-CoV-2 infection in children with IBD who received biologic therapies. A prospective, observational cohort study to evaluate coronavirus disease 2019 (COVID-19) vaccination state, and its effect on the disease course among pediatric patients with IBD. The questionnaire included information concerning numbers of vaccine doses, patients’ medication and disease activity. Disease flare was defined by worsening IBD symptoms and change in IBD medications. Outcomes were stratified by vaccine type and IBD medication classes. A total of 320 children with IBD, 169 with Crohn’s disease (CD)-52,8%, 150 with ulcerative colitis (UC) - 46,9%, 1 unclassified -0,3%, responded to the questionnaire concerning COVI-19 vaccination. In our cohort 141 (49,7%) patients received biologic therapy: 13 patients (9,2%) adalimumab (ADA), 54 (38,3%) infliximab (IFX), 27 (19,1%) vedolizumasb (vedo), 29 (20,6%) ustekinumab (ust), 6 - vedo + ADA (4,3%), 1 - IFX + vedo (0,7%), 11 - ust + ADA (7,8%). 32 (22,7%) patients had COVID-19 infection during biological therapy (ust 6- 4,3%, vedo 7- 5,0%, ada 2-1,4%, ifx 12- 8,5%, ust + ada 2- 1,4%, vedo + ada 3- 2,1%). Among the patients on biologic treatment suffering from COVID-19, 25 (78,1%) children had mild course of the infection, 4 moderate (12,5%), 2 severe (6,3%), and 1 unknown (3,1%). A total of 127 (39,7%) patients received at least 1 COVID-19 vaccine, and among them 8 (6,3%) patients who received 1 dose of COVID-19 vaccine got the infection during biologic therapy. In our group, 193 (60,3%) patients have not been vaccinated against COVI-19, and 24 (12,4%) suffered from the disease during biologic therapy. Based on the outcomes from our questionnaire concerning COVID-19 vaccination state on the large cohort of pediatric patients with IBD, we conclude that unvaccinated patients get sick more often than vaccinated ones, and that the use of biological treatment has no impact the frequency of covid infections or their course.

No abstract available

No abstract available

Objectives: The aim of this study was to evaluate the effectiveness and safety of adalimumab (ADA) in children with ulcerative colitis (UC) previously treated with infliximab (IFX). Methods: Retrospective study including children with UC from a national registry who received ADA therapy. The primary endpoint was the rate of corticosteroid-free remission at week 52. Secondary outcomes were the rate of sustained clinical remission, primary nonresponse, and loss of response at weeks 12, 30, and 52 and rate of mucosal healing and side effects at week 52. Results: Thirty-two children received ADA (median age 10 ± 4 years). Median disease duration before ADA therapy was 27 months. All patients received previous IFX (43% intolerant, 50% nonresponders [37.5% primary, 42.5% secondary nonresponders], 6.7% positive anti-IFX antibodies). Fifty-two weeks after ADA initiation, 13 patients (41%) were in corticosteroid-free remission. Mucosal healing occurred in 9 patients (28%) at 52 weeks. The cumulative probability of a clinical relapse-free course was 69%, 59%, and 53% at 12, 30, and 52 weeks, respectively. Ten patients (31%) had a primary failure and 5 (15%) a loss of response to ADA. No significant differences in efficacy were reported between not-responders and intolerant to IFX (P = 1.0). Overall, 19 patient (59%) maintained ADA during 52-week follow-up. Seven patients (22%) experienced an adverse event, no serious side effects were observed and none resulted in ADA discontinuation. Conclusions: Based on our data, ADA seems to be effective in children with UC, allowing to recover a significant percentage of patients intolerant or not-responding to IFX. The safety profile was good.

OBJECTIVE Infliximab (IFX) is a frequent therapeutic option for Crohn disease (CD) patients. Early detection of responders to IFX is critical for the management of CD in order to avoid long-term exposure to the drug without benefit. This retrospective study aimed at analysing which early parameters recorded during the induction period are able to predict response to IFX during the maintenance period in pediatric CD. PATIENTS AND METHODS Medical records of all CD patients ages from 2 to 18 years who received IFX at a tertiary IBD center were retrospectively analyzed. Children were classified in 3 groups according to their response at week 14 (W14) (1) remission, (2) clinical response or (3), no response. The factors recorded at W0, W2, and W6, which were associated with remission at W14 were analyzed using a logistic regression. RESULTS Among the 111 patients included, 74.8% patients were responders to IFX at W14, including 38.7% in clinical remission and 36% with partial clinical response. Clinical remission at W14 was associated with normal growth (P < 0.01), and normal albuminemia (P = 0.01) at baseline, It was also associated with trough levels to IFX >8.3 μg/ml at week 6 (P < 0.01). CONCLUSION Trough levels to IFX >8.3 μg/ml at week 6 are predictive of remission at W14 for luminal disease.

CASE Tofacitinib is an anti-JAK/STAT small molecule approved for treatment of adults (but not children and adolescents) with moderate to severe ulcerative colitis. Data is limited in children and teens although two major centers have shown efficacy as both mono- and dual - combination therapy using tofacitinib in pediatric patients refractory to anti-TNF agents. We present a 16-year-old female diagnosed with inflammatory ileocolonic Crohn's disease without upper gastrointestinal involvement after presenting with several months of abdominal pain, diarrhea, and unintentional weight loss. Laboratory evaluation was notable for normal inflammatory markers, albumin and complete blood count and an elevated stool lactoferrin. Initial endoscopic evaluation revealed moderate to severe pancolitis and patchy ileitis; biopsies noted mild chronic active ileitis and moderate to severe chronic active pancolitis without dysplastic or atypical changes. She was started on infliximab for induction and maintenance therapy and dosage was increased due to suboptimal levels and marginal symptomatic improvement. However, despite increased dosing plus a course of budesonide (Uceris), she had minimal improvement in her symptoms and ongoing elevation of her lactoferrin. Given an equivocal result on a Clostridium difficile testing (GDH antigen positive only), she was started on oral vancomycin which resulted in mild improvement, but not resolution, of diarrhea and abdominal pain. This was continued after completion of a 14-day course (and subsequent negative testing) due to increased stool frequency with discontinuation of the medication and improvement with reinitiating it. She had severe pancolitis (Mayo 2 - 3) but normal TI on repeat colonoscopy 5 months after diagnosis. Biopsies (reviewed by a panel of adult GI pathologists) were notable for reactive atypia with features concerning for early dysplasia in the ascending and descending colon. Due to disease severity and rapid progression plus histologic changes concerning for possible dysplasia despite optimized therapy with infliximab and repeat negative C. difficile testing, she was started on tofacitinib 10 mg twice daily along with oral vancomycin. She had complete resolution of diarrhea, abdominal pain, and early satiety within a week; repeat fecal lactoferrin was negative (<30). She underwent repeat colonoscopy with chromoendoscopy 5 months after initiation of tofacitinib which revealed mild acute ileitis but no active colonic inflammation, atypia or dysplasia. This is the first report to our knowledge that an adolescent patient with colonic predominant Crohn's disease has complete resolution of atypia and possible early dysplasia with tofacitinib therapy.

No abstract available

Up to 40% of patients with acute severe ulcerative colitis (ASUC) do not respond to infliximab (IFX)(1). Insufficient drug exposure with low IFX serum concentrations is associated with non-response (1, 2). We investigated whether personalised TDM-driven induction dosing of IFX was superior to standard dosing. In this prospective open-label, multi-centre randomised controlled trial (Netherlands, Norway and Ireland), hospitalised adult IFX-naïve and steroid-refractory ASUC patients were randomised 1:1 to standard (SD) or personalised dosing of IFX (PD). After an initial 5 mg/kg IFX infusion, SD consisted of 5 mg/kg IFX at week 2 and 6. In the PD group, additional 5 mg/kg IFX infusions were administered guided by a Bayesian pharmacokinetic algorithm (iDose) aiming at IFX serum concentrations >28 ug/mL from day 0-28 and >15 ug/mL from day 29-42 (measured with Quantum Blue IFX rapid test). After day 42, all patients received 5 mg/kg IFX maintenance every 8 weeks until day 182, with escalation at physician’s discretion. The primary composite endpoint was clinical and endoscopic response at day 42 (Lichtiger score <10 and ≥3 points decrease from baseline and UCEIS ≥2 points decrease with double central endoscopy read and adjudication). Key secondary endpoints included day 42 clinical response, day 42 endoscopic response, day 182 clinical remission (Lichtiger score ≤3), day 182 endoscopic remission (UCEIS ≤1 on all components), and safety (SAEs). Endoscopies were performed at baseline, day 42 and 182. 48 patients were included and received study treatment (23 PD/25 SD), 31 of whom completed treatment through week 26 (19 PD/12 SD). Median cumulative IFX dose until day 42 was 18.41 mg/kg [14.77, 20.27] for PD vs 13.79 mg/kg [10.38, 14.82] for SD (Table 1). The primary composite endpoint of clinical and endoscopic response at day 42 was not met (13/23 (56.5%) in PD vs 11/25 (44.0%) in SD; p=0.564) (Figure 1). PD showed a higher day 42 clinical response vs SD (21/23 (91.3%) vs 16/25 (64.0%); p=0.039), Day 42 endoscopic response was observed in 13/23 (56.5%) in PD and 11/25 (44.0%) in SD (p=0.564). Numerically more patients on PD had day 182 clinical remission (14/23 (60.9%) vs 9/25 (36.0%); p=0.148) and endoscopic remission (15/23 (65.2%) vs 9/25 (36.0%); p=0.082) compared to SD. SAEs occurred in 3/23 (13.0%) of patients on PD vs 5/25 (20.0%) of patients on SD (p=0.703) and included infection (2/23 (8.7%) vs 1/25 (4.0%)), thromboembolic event (0 vs 1/25 (4.0%)), colectomy (1/23 (4.4%) vs 2/25 (8.0%)), and death (0 vs 1/25 (4.0%)). Following an interim analysis, the trial was discontinued based on futility. Personalised dosing of infliximab was not superior to standard dosing in acute severe ulcerative colitis. 1.Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2010;59(1):49-54. 2.Papamichael K, Van Stappen T, Vande Casteele N, Gils A, Billiet T, Tops S, et al. Infliximab Concentration Thresholds During Induction Therapy Are Associated With Short-term Mucosal Healing in Patients With Ulcerative Colitis. Clin Gastroenterol Hepatol. 2016;14(4):543-9.

BACKGROUND The optimal dosing strategy for infliximab in steroid-refractory acute severe ulcerative colitis (ASUC) is unknown. We compared intensified and standard dose infliximab rescue strategies and explored maintenance therapies following infliximab induction in ASUC. METHODS In this open-label, multicentre, randomised controlled trial, patients aged 18 years or older from 13 Australian tertiary hospitals with intravenous steroid-refractory ASUC were randomly assigned (1:2) to receive a first dose of 10 mg/kg infliximab or 5 mg/kg infliximab (randomisation 1). Block randomisation was used and stratified by history of thiopurine exposure and study site, with allocation concealment maintained via computer-generated randomisation. Patients in the 10 mg/kg group (intensified induction strategy [IIS]) received a second dose at day 7 or earlier at the time of non-response; all patients in the 5 mg/kg group were re-randomised between day 3 and day 7 (1:1; randomisation 2) to a standard induction strategy (SIS) or accelerated induction strategy (AIS), resulting in three induction groups. Patients in the SIS group received 5 mg/kg infliximab at weeks 0, 2, and 6, with an extra 5 mg/kg dose between day 3 and day 7 if no response. Patients in the AIS group received 5 mg/kg infliximab at weeks 0, 1, and 3, with the week 1 dose increased to 10 mg/kg and given between day 3 and day 7 if no response. The primary outcome was clinical response by day 7 (reduction in Lichtiger score to <10 with a decrease of ≥3 points from baseline, improvement in rectal bleeding, and decreased stool frequency to ≤4 per day). Secondary endpoints assessed outcomes to day 7 and exploratory outcomes compared induction regimens until month 3. From month 3, maintenance therapy was selected based on treatment experience, with use of thiopurine monotherapy, combination infliximab and thiopurine, or infliximab monotherapy, with follow-up as a cohort study up to month 12. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02770040, and is completed. FINDINGS Between July 20, 2016, and Sept 24, 2021, 138 patients were randomly assigned (63 [46%] female and 75 [54%] male); 46 received a first dose of 10 mg/kg infliximab and 92 received 5 mg/kg infliximab. After randomisation 1, we observed no significant difference in the proportion of patients who had a clinical response by day 7 between the 10 mg/kg and 5 mg/kg groups (30 [65%] of 46 vs 56 [61%] of 92, p=0·62; risk ratio adjusted for thiopurine treatment history, 1·06 [95% CI 0·94-1·20], p=0·32). We found no significant differences in secondary endpoints including time to clinical response or change in Lichtiger score from baseline to day 7. Two patients who received 10 mg/kg infliximab underwent colectomy in the first 7 days compared with no patients in the 5 mg/kg group (p=0·21). Three serious adverse events occurred in three patients in both the 10 mg/kg group and 5 mg/kg group. After randomisation 2, the proportions of patients with clinical response at day 14 (34 [74%] of 46 in the IIS group, 35 [73%] of 48 in the AIS group, and 30 [68%] of 44 in the SIS group, p=0·81), clinical remission at month 3 (23 [50%], 25 [52%], 21 [48%], p=0·92), steroid-free remission at month 3 (19 [41%], 20 [42%], 18 [41%], p=1·0), endoscopic remission at month 3 (21 [46%], 22 [46%], 21 [48%], p=0·98), and colectomy at month 3 (three [7%] of 45, nine [19%] of 47, five [12%] of 43, p=0·20) were not significantly different between groups. Between day 8 and month 3, the proportion of patients with at least one infectious adverse event possibly related to infliximab was two (4%) of 46 in the IIS group, eight (17%) of 48 in the AIS group, and eight (18%) of 44 in the SIS group (p=0·082). No deaths occurred in the study. INTERPRETATION Infliximab is a safe and effective rescue therapy in ASUC. In steroid-refractory ASUC, a first dose of 10 mg/kg infliximab was not superior to 5 mg/kg infliximab in achieving clinical response by day 7. Intensified, accelerated, and standard induction regimens did not result in a significant difference in clinical response by day 14 or in remission or colectomy rates by month 3. FUNDING Australian National Health and Medical Research Council, Gastroenterology Society of Australia, Gandel Philanthropy, Australian Postgraduate Award, Janssen-Cilag.

No clinical trial has previously assessed the best therapeutic strategy between switching to another anti-TNF or swapping to another class of biologic class after the failure of a first anti-TNF in ulcerative colitis (UC). The aim of the EFFICACI trial was to compare the efficacy of vedolizumab with infliximab in patients who had failed a first sub-cutaneous anti-TNF (golimumab and/or adalimumab). EFFICACI was a French double-blind multicenter randomized controlled trial (1:1) comparing intravenous vedolizumab 300 mg at weeks 0-2-6 to intravenous infliximab 5 mg/kg at weeks 0-2-6. Eligible patients had moderate-to-severe UC, defined by a total Mayo score ≥ 6, despite at least 12 weeks (W) of treatment with adalimumab or golimumab as first line of advanced therapy. The primary endpoint was steroid free clinical remission at W14. The number of patients (N=150) was estimated for a 20% difference in favor of vedolizumab with a type 1 risk of 5% and a power of 80%. Patients were subsequently followed in an open-label fashion until week 54. The analysis was performed on an intention-to-treat basis. Only results at W14 will be presented. (CPP: 2018-002673-21; ClinicalTrial: 35RC17_8841_EFFICACI) From January 2018 to December 2023, 151 patients were randomized among 19 centers: 78 in the vedolizumab arm and 73 in the infliximab arm. Characteristics and demographics at inclusion were similar between groups, with 102/151 (67.5%) patients failing adalimumab and 49/151 (32.5%) failing golimumab. Concomitant immunosuppressive treatment with thiopurine or methotrexate was associated with infliximab and vedolizumab for 37/72 (51.4%) patients and 43/78 (55.1%) patients, respectively. At W14, proportions of patients in clinical remission (primary endpoint) were 34.6% (27/78) with vedolizumab and 19.2% (14/73) with infliximab (p=0.033). The clinical response rates were 46/78 (59.0%) with vedolizumab and 36/72 (50.0%) with infliximab (p=0.27). Proportions of patients in clinical response at W2, W6 and W14 are shown in Figure 1. At W14, endoscopic improvement (Mayo endoscopic subscore 0 or 1) was observed in 36/77 (46.8%) patients in the vedolizumab arm and 21/72 (29.2%) in the infliximab arm (p=0.027). No factor at inclusion was predictive of remission at week 14, including pharmacokinetic data for the first-line anti-TNF. Adverse event rates were similar in both groups - 46 (63.9%) infliximab arm, 55/78 (70.51%) vedolizumab arm. Eight patients were hospitalized for a severe flare (5 in the infliximab arm and 3 in the vedolizumab arm). After failure of a first subcutaneous anti-TNF, induction therapy with vedolizumab was superior to infliximab in achieving steroid free clinical remission at week 14 in patients with UC.

The utility of infliximab (IFX) therapeutic drug monitoring (TDM) in acute severe ulcerative colitis (ASUC) is unclear. We aimed to assess whether IFX levels are associated with outcomes in ASUC. PREDICT-UC (NCT02770040) was a randomised controlled trial that compared dosing strategies in 138 steroid-refractory ASUC patients.1 Serum and faecal IFX levels were quantified by ELISA (MabTrack level infliximab, Essange Reagents, Netherlands) after conclusion of the trial and correlated with outcomes: IFX response by day 7 (Lichtiger score [LS]<10, with ≥3-point reduction and decrease in rectal bleeding and stool frequency ≤4/day); eventual response by day 14 (LS<10); and colectomy by month 3. Individual IFX clearance was estimated using a two-compartment pharmacokinetic model with fixed V1, V2 and Q. 681 serum IFX levels were available across 135 patients; 91 received an initial 5mg/kg and 44 an initial 10mg/kg IFX dose. 85 responded by day 7 and 17 required colectomy by month 3. Post-IFX serum levels were higher on days 1 and 3 (median ug/mL, IQR) in the 10mg/kg group (175.4, 137.2-202.7 and 116.3, 83.4-132.9) compared to the 5mg/kg group (91.8, 77.2-109.4 and 56.0, 46.0-67.0; each P<0.001). Day 1 and day 3 serum IFX levels were not significantly different in responders and non-responders. A higher day 3:day 1 serum IFX ratio predicted response (63.1%, IQR 56.0-72.1 vs 58.1%, IQR 51.6-62.8, P=0.006; AUC 0.67). A lower day 3 serum IFX level predicted colectomy (51.0, IQR 39.2-57.4 vs 69.0, IQR 51.1-101.7, P=0.003; AUC 0.23). IFX clearance using serum levels between days 1-7 was higher in non-responders compared to responders (0.72L/day, IQR 0.55-0.89 vs 0.56L/day, IQR 0.39-0.72, P<0.001) and in patients who had colectomy (P=0.011). Patients with high clearance (≥0.62L/day) were more likely to respond to an initial 10mg/kg vs 5mg/kg IFX dose (RR 1.50, 95%CI 1.01-2.23, P=0.046), and more likely to require colectomy if they received an initial 5mg/kg vs 10mg/kg dose (HR 4.81, 95%CI 1.09-21.37, P=0.039). In patients with high clearance who did not respond initially, response by day 14 was higher in those receiving a second 10mg/kg dose compared to 5mg/kg (10/26 [38%] vs 1/9 [11%]; RR 3.43, 95%CI 1.05-11.19, P=0.041). Day 1 and 3 faecal IFX correlated with IFX clearance (both rho=0.36, both P<0.001), CRP and the UCEIS (including bleeding and erosion/ulcer sub-scores). Elevated day 3:day 1 serum IFX ratio was associated with IFX response by day 7. Early IFX clearance predicted IFX response and month 3 colectomy. High IFX clearance may be overcome by higher IFX dosing, resulting in improved response and reduced colectomy rates. Early IFX level quantification can help predict outcomes in ASUC. 1.Choy MC, Li Wai Suen CFD, Con D, et al. Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol 2024; 9(11): 981-96.

Acute severe ulcerative colitis (ASUC) represents a medical emergency necessitating admission and prompt commencement of intravenous steroids. Up to 40% of patients may require rescue therapy with infliximab, traditionally administered on day 3 of admission based on the Modified Oxford Criteria. This study aimed to evaluate the impact of early (≤ 72 hours) versus standard (> 72 hours) infliximab administration on clinical outcomes. A single centre retrospective cohort study was conducted for patients admitted with ASUC as defined by the Truelove and Witt’s criteria who received infliximab therapy between January 2016 and October 2024. Patients were divided into 2 groups: early infliximab therapy (≤ 72 hours of admission) and standard infliximab therapy (>72hrs of admission). Patient demographics and disease characteristics were accessed from the electronic medical records (EMR). Outcomes assessed included length of stay, 12-month readmission and colectomy rates. 84 patients (53% male, 37% female) were included in this study. Of these 31/84, (37%) received early infliximab therapy (median 52 [IQR 45-56] hours) and 53/84 (63%) had standard (median 105 [IQR 94-149] hours) infliximab therapy. Disease characteristics are shown in table 1. Mean albumin on admission was higher in the early infliximab group (36g/L vs 32.5g/L, p= 0.01). No other significant differences were noted. The median length of stay was shorter in patients who received early vs standard infliximab therapy at 6 vs 7 days (p= 0.048). No significant difference was seen in requirement for colectomy between the early and standard groups at index admission (3.2% vs 3.8%, (p = 1.0) or at 12-months follow up (6.6% vs 6.9%, (p = 1.0). Similarly, there was no significant difference in readmission rates at 6-months (33.3% vs 26%, p= 0.67) and at 12-months (40% vs 28.8% p= 0.63) for both ulcerative colitis-related and non-ulcerative colitis causes across the two groups. There was no difference in rate of infective complications in the first 30 days (6.4% vs 7.5%, p = 0.85). A propensity matched cohort of 30 patients (matched 1:1 for age, HR, albumin on admission, Hb on admission, and dose of first infliximab dose) further confirmed shorter length of stay in the early vs standard group at a median of 6 vs 7 days (p= 0.039). In patients admitted with ASUC, early infliximab therapy as defined by administration ≤ 72 hours from presentation was associated with shorter hospitalisation, with no difference in rates of colectomy, re-admission or infective complications. An early treatment strategy may reduce the burden of this condition upon health care utilisation.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with remissions and flares. Approximately 20% of UC Patients develop acute severe ulcerative colitis (ASUC), a serious condition that is refractory to standard therapies and leads to morbidity and mortality. Rescue therapy (salvage therapy) with steroids, cyclosporine, and/or infliximab is recommended by guidelines.1 The colectomy rate in ASUC remains at around 36% even in the biological millennium.2 Upadacitinib (UPA) is a JAK1 selective inhibitor used effectively to treat UC. The role of UPA as a rescue therapy in ASUC is not clear. This study aims to evaluate the outcomes of UPA as a rescue therapy in ASUC patients. A total of 31 steroid- and infliximab-refractory ASUC patients from 10 IBD centers from all over Türkiye were included between April 2023 and October 2024 in our study. Demographics of the patients and disease characteristics were recorded. Stool frequency (per day), rectal bleeding scores, and C reactive protein (CRP) were assessed from the electronic database at baseline (week 0), week 1, 4, 8, and 16 retrospectively. Complete clinical response was defined as stool frequency ≤3 per day and rectal bleeding score 0-1. Mean age was 36±13years; 16(51.6%) were female, mean disease duration was 6.9±5.4 years, 30(96.8%) had immunomodulator experience (Table1). A total of 10 patients had ≥ 3 biologics failures. Complete clinical response at weeks, 4, 8, and 16 were in 13 (42%), 16 (64%), 12 (67%), and 10 (77%) patients respectively. Rescue therapy responses were not statistically significant between ≥3 and <3 biologics failure groups (p=0.580) at week1. CRP normalization (<3 mg/L) at week 4 was found in 9(36%) patients. By the end of the week, 6 (33%) patients had undergone colectomy. Clinical responses and surgery rates of UPA at week1,4,8, and 16 were detailed in Figure 1. UPA provided a complete clinical response as a rescue therapy within the first week in 42% of cases in anti-TNF and steroid non-responders even with multiple biologics experience. Over half of the patients showed clinical remission by weeks 4 and 8. 1.Raine T, Bonovas S, Burisch J, et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. J Crohns Colitis. 2022;16(1):2-17. doi:10.1093/ecco-jcc/jjab1782. 2.Moore AC, Bressler B. Acute Severe Ulcerative Colitis: The Oxford Criteria No Longer Predict In-Hospital Colectomy Rates. Dig Dis Sci. Feb 2020;65(2):576-80.

Acute severe ulcerative colitis (ASUC) is a medical emergency with a potential need for emergency colectomy. Infliximab (IFX) is a safe and effective rescue therapy for patients with steroid-refractory ASUC. Despite being increasingly practiced, there is no evidence that intensified/accelerated IFX regimens are superior to standard induction dosing [1]. However, insight into the IFX pharmacokinetics (PK) and personalized dosing in ASUC are lacking. We performed a multicenter, retrospective population PK (popPK) and exposure–response modeling study using pooled individual data from ASUC patients diagnosed via Truelove and Witts score. Data on IFX dosing, exposure, patient demographics, and treatment outcomes were collected. A popPK model was developed to predict the relationship between IFX dosing and exposure. Parametric time-to-event analysis was used to predict colectomy within 3 months, considering patient characteristics and PK projections. An algorithm for personalized, risk-stratified IFX rescue dosing was developed. Modeling and simulation tasks were performed in NONMEM. Eight medical centers contributed data from 74 patients with ASUC (18 female; median [interquartile range] age 33 [22–47] years; body weight 63 [56–75] kg), including 157 IFX concentrations (Table 1). Baseline C-reactive protein (CRP) and serum albumin were 30 [7–87] mg/L and 31 [27–38] g/L, respectively. Eleven patients (15%) underwent colectomy within 90 days after start of IFX therapy. The one-compartmental popPK model with typical IFX clearance (CL) 0.48 L/day (14% relative standard error) and volume of distribution (V) 12.9 L (21%) described the IFX concentration–time data well. IFX CL and V increased with higher body weight. CL increased with higher CRP. The ratio of the Bayesian forecasted (hence simulated) area under the IFX concentration–time curve between weeks 2 and 4 (AUCw2–w4) over the estimated CL (AUCw2–w4/CL), was the best predictor of colectomy (area under the receiver operating characteristic curve, 0.80 [95%CI 0.54–1.00]). The higher the Ln(AUCw2–w4/CL), which we defined as the colectomy index (C-index), the lower the hazard risk for colectomy. A C-index of 5.84 discriminated best between patients with and without colectomy (sensitivity 83%, specificity 84%) (Figure 1). The classification accuracy was 82% [95%CI 71%–91%]. We performed the first model-based dose–exposure–response analysis of IFX in patients with ASUC. We developed the C-index as a predictor for colectomy, which combines AUCw2–w4 (modifiable risk factor) and IFX CL (unmodifiable risk factor). Personalized dosing for IFX rescue therapy using individuals’ AUCw2–w4 target is feasible using an early TDM sample and a precision dosing software tool. [1] Choy et al. Lancet Gastroenterol Hepatol. 2024;9(11):981–996

Abstract Background and Aims In the LIBERTY phase 3 studies in Crohn’s disease (CD) or ulcerative colitis (UC), maintenance CT-P13 subcutaneous (SC) 120 mg was more effective than placebo after 1 year. Here we report 2-year data from the LIBERTY open-label extensions. Methods Two randomized, placebo-controlled, double-blind studies evaluated the efficacy and safety of CT-P13 SC maintenance in moderate-to-severe CD or UC. Responders to CT-P13 intravenous induction were randomized at week (W) 10 to CT-P13 SC 120 mg or placebo biweekly, until W54. From W22, dose adjustment to CT-P13 SC 240 mg was permitted for loss of response. At W56, patients could enter an open-label extension, receiving CT-P13 SC 120 mg (or 240 mg if dose-adjusted), biweekly, until W102. Results The extension comprised 278/343 (81.0%) and 348/438 (79.5%) patients in the CD and UC studies, respectively. In those continuing on-study, efficacy (non-responder imputation) was well maintained in the CT-P13 SC group at W102: 63.5% (as-observed: 70.5%) and 49.0% (as-observed: 58.8%) of CD patients (N = 192) achieved clinical remission and endoscopic response, respectively; 45.1% (as-observed: 60.1%) and 41.4% (as-observed: 52.4%) of UC patients (N = 237) achieved clinical remission and endoscopic-histologic mucosal improvement, respectively. No new safety signals were identified from longer-term CT-P13 SC treatment or starting CT-P13 SC 120 mg after placebo, with similar adverse event rates for patients undergoing dose adjustment to CT-P13 SC 240 mg from CT-P13 SC 120 mg or placebo. Conclusion CT-P13 SC is an effective and well-tolerated long-term maintenance treatment in moderate-to-severe CD and UC. ClinicalTrials.gov identifiers NCT03945019 (CD) and NCT04205643 (UC).

Acute severe ulcerative colitis (ASUC) often requires rescue therapy with infliximab, typically administered at an initial dose of 5mg/kg or 10mg/kg. There is some uncertainty regarding the optimal dose of infliximab for rescue therapy and current guidance leaves this to the discretion of the treating clinician. A previous multicentre randomised controlled trial (PREDICT-UC) did not find a significant difference in clinical response or colectomy rates between 5mg/kg and 10mg/kg of infliximab in steroid-refractory ASUC 1. This study aimed to compare the clinical outcomes of patients receiving either 5mg/kg or 10mg/kg infliximab in the management of ASUC. This retrospective cohort study examined patients with ASUC who were treated with rescue infliximab between 2019 and 2022. Patients were categorised into two groups based on the dose received; 5mg/kg and 10mg/kg. Demographic and clinical variables, including age, sex, disease extent (Montreal classification), and prior treatments (no prior treatment, 5-ASA, biologics), were recorded. The outcomes measured included remission (defined as sustained remission at 1 year), the need for surgery, the requirement for additional doses of infliximab, or change in biological agent. Outcomes at 1 month, 6 months, and 1 year were also recorded. Chi-square tests were used to analyse differences between the two treatment groups. Of the 50 UC patients, 60% received 5 mg/kg, and 40% received 10 mg/kg. No significant differences were found between the 5 mg/kg and 10 mg/kg infliximab treatment groups for outcomes including surgery (p = 1.00), remission (p = 0.22), and biologic switch (p = 0.22). Additionally, no significant differences were observed when categorising patients by pre-existing treatment (p = 0.06) or disease severity subgroups (E1, E2, E3). When assessing the effect of severe disease markers on treatment outcomes, no significant difference in colectomy rates was found between the two groups for CRP > 50 mg/L (p = 0.34) and albumin < 25 g/L (p = 0.13). This study showed no significant difference in the clinical outcomes between patients receiving 5mg/kg and 10mg/kg infliximab for the management of ASUC. These findings suggest that escalating the dose to 10mg/kg does not provide a clear clinical advantage in reducing the need for surgery or achieving sustained remission. Larger, multicentre studies with more diverse patient populations are needed to further investigate the potential benefits of higher infliximab dosing in this clinical context. 1.Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial. Choy, Matthew C et al. The Lancet Gastroenterology & Hepatology, Volume 9, Issue 11, 981 - 996

The combined achievement of endoscopic and histologic remission is an emerging therapeutic target in ulcerative colitis (UC) and is associated with lower clinical relapse rates and reduced corticosteroid use.1,2 Here, we present endoscopic and histologic outcomes following maintenance treatment with subcutaneous (SC) infliximab (IFX) using data from the LIBERTY-UC study.3 In the LIBERTY-UC study,3 patients (pts) received induction doses of IFX 5 mg/kg via intravenous infusion at Weeks (W) 0, 2 and 6. Clinical responders at W10 were randomised 2:1 to receive either IFX SC every other week or a placebo (PBO) during maintenance therapy. All pts randomised at W10 were included in this post hoc analysis. Endoscopic and histologic assessments were performed at screening, W8, W22 and W54 (centrally evaluated). Endoscopic improvement (Mayo endoscopic subscore [MES] ≤1), endoscopic normalisation (MES=0), histologic remission (Robarts Histopathology Index [RHI] <3 without neutrophils in the epithelium or lamina propria) and the combination of histologic remission and endoscopic normalisation were assessed. Non-responder imputation was used for pts who underwent dose adjustment or had missing data. Data were analysed descriptively with nominal p-values. Baseline characteristics were similar between IFX SC and PBO groups, with 48.6% and 53.5% of pts having severe disease (MES=3); and mean histologic activity (RHI) of 17.0 and 18.0, respectively (Table). At W8, half of the pts achieved endoscopic improvement in both groups (IFX SC: 53.1%; PBO: 50.0%). From W22 onwards, the difference in rates of endoscopic improvement between the two groups was statistically significant (50.7% vs 34.0%; p=0.0011) up to W54 (43.9% vs 22.2%; p<0.0001). Similar findings were observed for histologic remission. Endoscopic normalisation rate in the IFX SC group increased with continued treatment (23.8% at W8, 26.9% at W22 and 32.7% at W54), while it declined in the PBO group (21.5% at W8, 18.8% at W22 and 11.1% at W54). Furthermore, a greater proportion of pts in the IFX SC group achieved combined histologic remission and endoscopic normalisation compared to the PBO group from W22 up to W54 (22.1% vs 16.7% at W22; p=0.2072; 27.9% vs 11.1% at W54; p<0.0001) (Figure). Maintenance treatment with IFX SC resulted in significantly greater improvements in endoscopic and histologic outcomes at W54 compared to PBO. Endoscopic improvements were observed as early as W8, along with enhancements in stringent endpoints such as endoscopic normalisation and the combined endpoint of histologic remission and endoscopic normalisation over time, supporting the sustained benefit of a maintenance therapy with IFX SC. 1. Yoon H, et al. Gastroenterology. 2020;159(4):1262-1257.e7. 2. Bryant RV, et al. Gut. 2016;65(3):408-414. 3. Hanauer SB, et al. Gastroenterology. 2024;167(5):919-933.

Infliximab (IFX) is the first anti-TNF biologic drug approved for treating moderate to severe ulcerative colitis (UC). While IFX is effective in inducing mucosal healing and enhancing quality of life, concerns persist about the long-term safety and cost-effectiveness of extended immunosuppression. Current guidelines lack clarity on when to discontinue treatment after achieving stable deep remission. Moreover, existing literature is limited to studies characterised by small sample sizes and heterogenous criteria for defining remission. We aimed to evaluate the outcomes in UC patients who discontinued IFX after achieving stable deep remission, to identify predictors of relapse post-discontinuation, and to examine the clinical course in those who experienced a relapse. In this single-center, retrospective, observational study, we analyzed UC patients at our tertiary IBD Referral Center who discontinued IFX due to sustained deep remission, defined as the combination of partial Mayo subscore ≤ 1 and endoscopic Mayo score = 0, and who had at least 1 year of follow-up post treatment withdrawal. We assessed the relapse rates at intervals of 6 months, 1 year, 2 years, and beyond 2 years post-IFX discontinuation. For patients who relapsed, we recorded the therapeutic strategy and its effectiveness, including the necessity for colectomy. We performed univariate and multivariate analyses to identify relapse predictors post-treatment suspension. From 2006 to 2022, 790 UC patients received IFX treatment at our center; 113 patients suspended IFX due to stable deep remission with at least 1 year of follow-up and were included in this study. Of these, 41.6% maintained remission over a median of 5.17 years. Flare rates were 14.2%, 23.9%, and 35.5% within 6, 12, and 24 months, respectively, with 58.4% experiencing a flare overall. Multivariate analysis showed that longer treatment duration reduced relapse risk (p=0.001), while steroid use during IFX treatment and early IFX initiation post-diagnosis increased relapse risk (p=0.004 and p=0.043, respectively). Most patients who relapsed were successfully managed medically either with a course of steroids, restarting IFX, or initiating a different type of biologic/small molecule, whereas the rate of colectomy was 7.1%. This study is one of the largest to date with the longest follow-up that evaluates outcomes post-IFX discontinuation in UC patients in deep remission. Our findings suggest that withdrawal of IFX treatment can be considered in carefully selected cases. In patients who relapse after IFX suspension, medical treatment is often effective, and the rate of colectomy is low. Further studies are warranted to better identify ideal candidates for treatment withdrawal.

Acute severe ulcerative colitis (ASUC) occurs in 25% of patients with ulcerative colitis (UC) resulting in hospital admission and treatment with corticosteroids followed by rescue therapy with infliximab, if needed. High baseline infliximab clearance at admission has been associated with risk of colectomy supporting an intensified infliximab regimen in case of insufficient effect.1 However, a recent randomized controlled trial did not find superior outcomes of different intensified infliximab regimens.2 We investigated if admitted patients with severe UC have increased clearance of infliximab. Infliximab concentrations from 154 UC patients were retrieved from our biobank resulting in 248 (81%) induction phase and 58 (19%) maintenance phase samples. These data were used to build a non-linear mixed effect model describing infliximab pharmacokinetics (PK) in UC. Variables tested for potentially influencing clearance comprised clinical disease activity (Mayo/SCCAI, 86% of assessments; physician’s global assessment, 14%), endoscopic activity (Mayo) (56%), CRP, albumin, patient demographics, and whether patients were treated as outpatients or hospitalised, including formal fulfilment of Truelove Witt’s criteria. A 2-compartment model with a linear clearance described infliximab PK, in line with previous reports.3 Hence, central and peripheral volumes of distribution were 6.52 L and 2.56 L, respectively, clearance 0.339 L/day and intercompartmental clearance 0.146 L/day. Hospitalisation status was the most impactful variable significantly influencing infliximab clearance in the model. Hence, hospitalised patients with severe UC (32% of study population) had a 35% [90%CI 14-56%] increased infliximab clearance compared to outpatients (median clearance of 0.463 L/day vs. 0.339 L/day, p<0.0001). This resulted in a substantial decreased IFX exposure from week 2 onwards. Thus, 74% of hospitalised patients had sub-therapeutic infliximab concentration at week 2 (<20 ug/mL4), 69% at week 6 (<15 ug/mL4), and 56% at week 14 (<7 ug/mL4). Formal fulfilment of Truelove Witt’s criteria did not result in additional increase in infliximab clearance among hospitalized patients (ASUC median clearance 0.442 L/day vs non-ASUC 0.516 L/day, p=0.08). Addition of albumin did not significantly improve the model. Infliximab clearance is substantially increased among hospitalised patients with severe UC, resulting in underexposure in the majority of patients treated with a standard dosing regimen. An intensified regimen should be considered preferably supported by therapeutic drug monitoring and PK modelling. 1. Battat R et al. Clin Gastroenterol Hepatol. 2020; 19:511-518. 2. Choy MC et al. Lancet Gastroenterol Hepatol. 2024;9: 981-996. 3. Démaris A al. Pharmaceutics. 2022;14: 2095. 4. Cheifetz AS al. Am J Gastroenterol. 2021;116:2014-2025.

Vedolizumab (VDZ) and infliximab (IFX) are both recognized as first-line treatment options for moderate to severe ulcerative colitis (UC). However, there is a paucity of comparative studies examining their real-world efficacy. Patients with moderate to severe UC were consecutively enrolled from 11 centers. Efficacy were evaluated after 14 and 52 weeks. Logistic regression was conducted to identify independent risk factors for clinical remission. A total of 235 patients were enrolled, of which 154 received VDZ treatment and 81 received IFX treatment. 154 (65.5%) were male, with a median age of 40 (32, 49) years, a median disease duration of 7.0 (2.8, 11.9) years. The median baseline Mayo score was 9 (7, 11), and the median baseline partial Mayo score was 6 (4, 8). 16 patients (6.8%) had perianal lesions, and 41 patients (17.4%) had extraintestinal manifestations. At week 14, patients treated with IFX had higher clinical response rate (84.6% vs 66.2%, p = 0.003) but lower endoscopic remission rate (14.5% vs 34.3%, p = 0.003) compared to those treated with VDZ. There were no statistical difference in clinical remission rate between the two groups (39.7% vs 44.8%, p = 0.462). At week 52, there were no statistically difference in the modified Mayo score, partial Mayo score, clinical response rate, clinical remission rate, and endoscopic remission rate between IFX treatment group and VDZ treatment group (p>0.05). Multivariate regression analysis demonstrated that baseline disease extent was a predictor of clinical remission at week 14 of VDZ treatment (OR = 3.55, 95% CI 1.39–9.06, p = 0.008). IFX group received higher clinical response rate but not endoscopic remission rate at week 14. The efficacy of IFX was comparable to VDZ at week 52. Disease extent was a predictor of clinical remission at 14 weeks with VDZ.

The role of intensified (>5mg/kg), accelerated (>1 dose within first 14 days) infliximab (IFX) as rescue therapy in patients with acute severe ulcerative colitis (ASUC) remains controversial. This project evaluated the association between evolving strategies with length of stay, 12-month cumulative steroid burden, colectomy and readmission rates. Patients admitted with ASUC between January 2016 and October 2024 to a single tertiary IBD centre were identified and reviewed. IFX rescue therapy was defined as standard dose if up to 5mg/kg or intensified/accelerated if ≥10mg/kg (further categorised as 10mg/kg or ≥20mg/kg) was administered within 14 days of admission. Outcomes assessed included length of stay, 12-month cumulative steroid exposure (in prednisolone mg equivalent), 12-month readmission and colectomy rates. 147 patients (61 [41.5%] female, median age 33 [range 16-87] years) met Truelove and Witts criteria for ASUC. 83 (56.5%) patients required IFX therapy, of whom 29 (34.9%) patients received 5mg/kg IFX dose, 35 (30.1%) patients received 10mg/kg and 19 (22.9%) patients ≥20mg/kg. Disease severity as defined by CRP:albumin ratio was similar between patients receiving 5mg/kg vs 10mg/kg (p=0.880), but higher in those receiving 20mg/kg vs 5mg/kg (p=0.012); vs 10mg/kg (p=0.008). There was an increasing trend in the proportion of patients receiving intensified/accelerated IFX (≥10mg/kg) from 2016-2019 (26.3%) to 2020-2024 (76.5%) (p<0.001). Length of stay was less in patients who received 5mg/kg and 10mg/kg compared to ≥20mg/kg (median 6 vs 6 vs 11 days p=0.001). 12-month cumulative steroid usage was similar in 5mg/kg (median 1850 mg), 10mg/kg (1642.5 [1297.5-1935]mg) and ≥20mg/kg (1600 [1452.5-1715]mg), p=0.135. Readmission (19.2% (5mg/kg), 28.6% (10 mg/kg) and 11.1% (≥20mg/kg), p=0.527) and colectomy (8.7% (5mg/kg), 10.5% (10 mg/kg), 12.5% ≥20mg/kg, p = 0.958) rates were similar across IFX groups. Median length of stay was similar (p=0.193) between 2016-2019 (6 days) and 2020-2024 (6 days). 12-month cumulative steroid exposure (median 1705mg vs 1617.5mg, p=0.282) and readmission rates (15.8% vs 21.2%, p=0.488) remained stable when comparing 2016-2019 and 2020-2024. 12-month colectomy rates[MG1] declined across all ASUC patients (15.8% in 2016-2019 to 1.5% in 2020-2024, p = 0.004), and ASUC patients receiving IFX (21.1% 2016-2019 to 2.8% in 2020-2024, p = 0.025). Despite higher disease severity, intensified and accelerated dosing for IFX at ≥20mg/kg resulted in similar length of hospital stay, 12-month steroid exposure, readmission and colectomy rates to lower doses. Intensified and accelerated IFX dosing has increased over time, associated with reduction in colectomy rate.

Biological therapy has revolutionized the treatment of Ulcerative Colitis (UC), but biomarkers that predict response are still lacking. MicroRNAs (miRNAs) are small non-coding RNA molecules that participate in cellular processes such as proliferation, differentiation, migration, maturation and apoptosis, and therefore are related to immune regulation in physiological and pathological conditions such as Inflammatory Bowel Diseases. Therefore, the objective of the study is to investigate the expression profile of miRNAs in responding and non-responding patients treated with Infliximab and to identify a profile of miRNAs that predict therapeutic response. Twelve miRNAs: miR-21-5p, miR-31-5p, miR-192-3p, miR-192-5p, miR-215-5p, miR-326, miR-378-3p, miR-378-5p, miR-422a, miR-429, miR-551a and miR-1258-3p were evaluated in naïve patients with UC before and after treatment with Infliximab (week 54). MiRNA was extracted from formalin-fixed, paraffin-embedded (FFPE) colon tissue and qRT-PCR was performed from 12 patients, of which: 5 responding and 7 non-responding, both groups evaluated pre and post treatment (n=24 samples). Decreased expression was found for miR-31-5p (p=0.03) when comparing responding patients pre and post treatment, meanwhile miR-192-5p (p > 0.99) and miR-378-3p (p > 0.99) were suggestive but not statistically different. The other miRNAs had not had expressive results. Infliximab-responding patients with UC presented decreased expression of miR-31-5p. MiR-31-5p regulates IL-25 and activates Th1/Th17 mediated inflammation in UC. Therefore, our results reinforce the importance of miR-31-5p expression in UC and indicate a relationship between this miRNA and the effectiveness of the treatment.

The ability to predict failure of infliximab (IFX) in acute severe ulcerative colitis (ASUC) is crucial to identify patients who may benefit from dose-escalation, sequential rescue or early colectomy. PREDICT-UC (NCT02770040) was a randomised controlled trial that compared IFX dosing strategies in ASUC.1 Clinical factors and biomarkers were collected daily between day 0 to 3 post-IFX and assessed on their ability to predict IFX failure (Lichtiger score ≥10 on day 14) and 3-month colectomy. Stepwise logistic regression was used to develop a Risk of IFX Failure (RIF) index, which was calibrated against the observed risk of IFX failure. The RIF index represents the predicted probability of IFX failure and takes on values between 0 and 1. Internal validation was performed using bootstrap validation. Of 138 patients, 46 received a first IFX dose of 10mg/kg and 92 received 5mg/kg; 39 (28%) experienced IFX failure and 17 (12%) required colectomy by 3 months. There was no difference in lymphocyte count (LC, ×109/L) on day 0 (prior to IFX) in patients who failed or responded to IFX (median [IQR] 1.1 [0.9–1.6] vs 1.3 [0.9–1.8], P=0.47). LC rose by day 3 in both groups, though to a lesser degree in patients who failed IFX (median [IQR] 1.9 [1.4–2.8]) compared to responders (3.3 [2.1–4.9]; P=0.004), and lower in patients requiring colectomy (median [IQR] 1.4 [1.1–1.9] vs 3.0 [2.0–4.8]; P<0.001). A lower day 3 LC was predictive of IFX failure (AUC 0.71, 95% CI 0.60–0.81) and colectomy (AUC 0.83, 95% CI 0.74–0.92). A higher CRP was predictive of both IFX failure and colectomy at all time-points from days 0 to 3 (day 3 CRP AUC 0.68, P=0.003 and 0.70, P=0.019 respectively). A lower day 3 albumin predicted IFX failure (AUC 0.63, P=0.039) while a lower day 2 albumin predicted colectomy (AUC 0.66, P=0.042). The final RIF index comprised day 3 stool frequency, rectal bleeding score, CRP and LC. The RIF index had a naïve AUC of 0.80 and an optimism-adjusted AUC of 0.73 (95% CI 0.65–0.80) for predicting IFX failure, and a naïve AUC of 0.90 and an optimism-adjusted AUC of 0.88 (95% CI 0.81–0.94) for predicting colectomy. A RIF index threshold of ≥0.15 had an 85% sensitivity and 90% negative predictive value (NPV) for IFX failure and a 94% sensitivity and 98% NPV for colectomy, while a threshold of ≥0.50 had a 92% specificity and 69% positive predictive value (PPV) for IFX failure, and an 88% specificity and 42% PPV for colectomy. Lymphocytosis by day 3 is a novel predictor of response to IFX rescue in ASUC. The RIF index is a simple on-treatment risk index that predicts IFX failure and colectomy, and may be used to inform IFX dose-optimisation or switch to alternate therapies. 1Choy MC, Li Wai Suen CFD, Con D, et al. Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol 2024; 9(11): 981-96.

Anti-TNF treatment with infliximab (IFX) and adalimumab (ADA) are established first-line biological therapies in patients with ulcerative colitis (UC). No head-to-head studies between the two drugs exist but meta-analysis of RCTs indicate that IFX might be more effective than ADA for the induction of clinical remission1,2. However, observational studies conclude that ADA seems to have similar effect as IFX 3,4. Our aim was to evaluate any difference in effect between IFX and ADA in bio-naive patients with UC in the short and long term in a real world setting during the modern era of therapeutic drug monitoring and dose optimization. We performed a retrospective multicentre observational cohort study. Bio-naive patients with active UC, initiating treatment with IFX or ADA at four major out-patient IBD-units 2018-2022, were included. Data was received by a structured review of medical records. 271 patients were included, 105 in the IFX group and 166 in the ADA group. The primary endpoint steroid-free clinical remission (SFCR) at 12 months was reached in 43% (n=37) of patients with IFX and 35% (n=55) with ADA (aOR: 1.41 (0.81-2.45), p=ns). Regarding secondary endpoints, clinical remission at 3 months was more common with IFX than ADA (68% vs 57%, aOR 1.83 (1.07-3.14), p<0.05) but no difference was observed regarding clinical response at 3 months (74% vs 67%, p=ns), clinical remission at 12 months (49% vs 47%, p=ns) and biochemical remission at 3 months (51% vs 45%, p=ns) and at 12 months (36% vs 40%, p=ns)(Table 1). In the subpopulations with moderate and mild disease activity, IFX and ADA were equally effective regarding clinical remission at 3 months and SFCR at 12 months. In patients with severe disease activity, IFX had higher remission rates than ADA at 3 months; 70% (n=32) vs 46% (n=26) (p<0.05) and numerically at 12 months; 41% (n=14) vs 25% (n=14) (p=0.11)(Figure 1). Dose escalation was more frequent with IFX than ADA (44% vs 31%, p<0.05) but did not differ between patients failing to achieve SFCR at 12 months (44% vs 37%, p=ns). Use of thiopurines during the study period was more common with IFX than ADA (76% vs 50%, p<0,05) and was associated with higher rates of SFCR at 12 months in the ADA group 44% (n=32) vs 27% (n=23) (p<0.05), but not in the IFX group; 44% (n=27) vs 40% (n=10) (p=ns). Adalimumab seem to have similar effect as infliximab in achieving steroid-free clinical remission after one year in bio-naive patients with ulcerative colitis. However, infliximab was associated with higher remission rate after induction therapy and subgroup analysis indicate that infliximab is superior to adalimumab in patients with severe disease. Differences in dose escalation did not seem to affect the outcomes. 1.Bonovas S, Lytras T, Nikolopoulos G, Peyrin-Biroulet L, Danese S. Systematic review with network meta-analysis: comparative assessment of tofacitinib and biological therapies for moderate-to-severe ulcerative colitis. Aliment Pharmacol Ther. 2018 Feb;47(4):454-465. 2.Singh S, Murad MH, Fumery M, Dulai PS, Sandborn WJ. First- and second-line pharmacotherapies for patients with moderate to severely active ulcerative colitis: an updated network meta-analysis. Clin Gastroenterol Hepatol. 2020 Sep;18(10):2179-2191. 3.Sandborn WJ, Sakuraba A, Wang A et al. Comparison of real-world outcomes of adalimumab and infliximab for patients with ulcerative colitis in the United States. Curr Med Res Opin. 2016 Jul;32(7):1233-41. 4.Pouillon L, Baumann C, Rousseau H et al. Treatment Persistence of Infliximab Versus Adalimumab in Ulcerative Colitis: A 16-Year Single-Center Experience. Inflamm Bowel Dis. 2019 Apr 11;25(5):945-954.

The optimal dosing strategy of infliximab (IFX) in Acute Severe Ulcerative Colitis (ASUC) is unknown. We compared intensified and standard dose IFX strategies in ASUC. In this open-label randomised trial (NCT02770040), patients from 13 Australian centres with intravenous steroid-refractory ASUC were randomised to receive a first dose of 10mg/kg or 5mg/kg IFX in a 1:2 ratio. Patients in the 10mg/kg group (intensified induction [II]) received a second dose at day 7 or earlier at time of non-response; all 5mg/kg patients were re-randomised 1:1 to standard (SI) or accelerated induction (AI), which produced three induction groups: II, SI and AI. SI patients received 5mg/kg at week 0, 2 and 6, with an extra 5mg/kg dose before day 7 if non-response. AI patients received 5mg/kg at week 0, 1 and 3, with the week 1 dose increased to 10mg/kg and given earlier if non-response. Primary outcome: clinical response by day 7 (reduction in Lichtiger score to <10, with decrease of ≥3 points and improvement in rectal bleeding and stool frequency to ≤4/day). Secondary outcomes compared induction regimens until month 3. Analysis was by intention to treat. Between July 2016 & September 2021, 138 patients were randomised; 46 received a first IFX dose of 10mg/kg and 92 received 5mg/kg. Primary outcome: day 7 clinical response was observed in 65% (30/46) of 10mg/kg vs 61% (56/92) of 5mg/kg patients (P=0.76). In the 5mg/kg group, the rate of day 7 response was numerically lower in those with albumin <25g/L vs ≥25g/L [47% (15/32) vs 68% (41/60), P=0.07]. No difference in clinical response was observed in the 10mg/kg group when stratified by albumin [64% (9/14) vs 66% (21/32) P>0.99]. There was no difference in time to clinical response, change in Lichtiger score or CRP from baseline to day 7. Two patients who received 10mg/kg IFX underwent colectomy in the first 7 days vs 0 in the 5mg/kg group (P=0.21). Comparison of induction regimens (II, SI & AI): no difference in clinical remission rates between weeks 2 and 6 were observed. AI and II groups had higher rates of combined clinical and biochemical remission compared to SI between weeks 2 and 6 (P=0.042). At 3 months, there was no difference in rates of endoscopic and steroid-free remission, as well as rates of colectomy (II 7%; SI 12%; AI 19%, P=0.20). In steroid-refractory ASUC, a first dose of 10mg/kg or 5mg/kg IFX achieved similar clinical response rates by day 7. Patients receiving intensified or accelerated induction achieved clinical and biochemical remission earlier compared to standard induction; however, outcomes at three months were similar. Patients with a lower albumin may benefit from proactive intensified dosing strategies.

In patients admitted for acute severe ulcerative colitis (ASUC) responding to intravenous (IV) steroids, the most effective treatment is unknown. In thiopurine-naive patients, thiopurines are appropriate to maintain remission according to current guidelines while the benefit of early infliximab (IFX) therapy remains to be established. In this multicentre, parallel group, open-label randomised controlled trial, thiopurine and biologics-naïve adults admitted for ASUC defined by a Lichtiger score >10 were included between 2016 and 2021 if they responded to IV steroids. They were randomly assigned to receive either combination therapy with IFX and azathioprine (AZA) with a quick steroid discontinuation (IFX+AZA arm), or AZA and standardized steroid tapering regimen (AZA arm). The primary endpoint was treatment failure at W52, defined as absence of steroid-free clinical remission (MCS≤2 with no individual subscore >1), absence of endoscopic response (Endoscopic subscore ≤1), use of a prohibited treatment, adverse event leading to interruption of allocated treatment, colectomy or death. A sample size of 73 patients per group was initially calculated. Due to challenges in recruiting patient, the steering committee decided to prematurely terminate the study blindly of any study results, after including 64 patients. 64 were randomised (32 males, age of 34.5 [26.3-50.3] years, Lichtiger score of 13.0 [12-14], CRP of 29.0 [12.8-96.8] mg/L and serum albumin of 31.2 [27.7-35.6] g/L at baseline): 32 were assigned to IFX+AZA arm and 32 to AZA arm. In ITT population, treatment failure at w52 was observed in 81.5% in the AZA arm versus 53.3% in the IFX+AZA arm (OR 3.85 [1.15-12.88], p=0.03). Components of the composite primary endpoint are given in table 1. In PP population, treatment failure at week 52 was observed in 81.5% (22/27) in the AZA arm versus 50.0% (13/26) in the IFX+AZA arm (OR 4.40 [1.28-15.18], p=0.02). In total 121 adverse events (AE) were reported in 40 patients including 23 serious AE in 18 patients (11 in the IFX + AZA arm and 7 in the AZA arm, p=0.24) and 8 leading to treatment interruption (5 in the IFX+AZA arm and 3 in the AZA arm, p=0.39). Serious AE included infectious AE in 6 cases (1 in the AZA arm and 5 in the IFX+AZA arm, p=0.20) and UC relapse in 9 (4 in the AZA arm and 5 in the IFX+AZA arm, p=0.60). No death was reported. At w52, combination therapy with IFX + AZA and quick steroids discontinuation was more effective than AZA with standard steroids tapering regimen to prevent treatment failure in patients with ASUC responding to IV steroids. Combination therapy with IFX and AZA should be encouraged in ASUC patients responding to IV steroids (EudraCT 2014-005212-42; study funded by Pfizer).

Superiority of CT-P13 subcutaneous (SC) infliximab formulation over placebo in maintenance therapy was demonstrated in both ulcerative colitis1 and Crohn’s disease2. LIBERTY-UC study was continued up to Week 102 as an extension phase treatment. We now present the efficacy and safety results up to Week 102 of CT-P13 SC 120 mg group in the LIBERTY-UC study (NCT04205643). Patients who completed the maintenance phase up to Week 54 and, in the opinion of the investigator, would benefit from continued treatment continued the open-label extension phase from Week 56 to Week 102. During extension phase, all patients received CT-P13 SC regardless of previous treatment group randomised at the start of maintenance phase. The patients who had received the adjusted dose of CT-P13 SC 240 mg during the maintenance phase continued receiving CT-P13 240 mg in the extension phase. Patients with dose adjustment to CT-P13 SC 240 mg prior to Week 54 were considered as not to achieve each endpoint. At Week 54 and 102, clinical remission, clinical response, endoscopic-histologic mucosal improvement and corticosteroid-free remission were assessed by among patients who entered and treated in extension phase (Figure 1A), and who entered and treated in extension phase and had valid efficacy results at the visit of interest (Figure 1B). Safety was evaluated throughout the extension phase. A total of 237 patients in CT-P13 SC 120 mg group entered into extension phase. Among them, 208 (87%) patients completed extension phase. Proportion of patients who achieved clinical remission, clinical response, endoscopic-histologic mucosal improvement and corticosteroid-free remission at Week 54 and Week 102 among patients who entered and treated in extension phase (i.e., patients who had missing or invalid data were considered as not to achieve each endpoint) are presented in Figure 1A. Among patients who entered and treated in extension phase based on the no imputation for missing or invalid data, each endpoints are generally well maintained or slightly higher in Week 102 compared to Week 54 (Figure 1B). During extension phase, no new safety signals were observed compared to maintenance phase1 (table 1). The efficacy of CT-P13 SC 120 mg in UC patients was generally sustained through extension phase. No new safety concerns were found during the extension phase as well. These results indicate that long term use of CT-P13 SC can maintain clinical benefit as well as safety with the convenience of SC administration for patient with moderately to severely active UC. [1] Sands et al., Journal of Crohn's and Colitis, 2023.17(Supplement_1), i623-i624. [2] Colombel et al., Journal of Crohn's and Colitis, 2023.17.Supplement_1: i161-i162

Acute severe ulcerative colitis (ASUC) affects approximately 20% of patients with ulcerative colitis (UC). Patients failing initial corticosteroid therapy receive salvage therapy with either infliximab (IFX) or calcineurin inhibitors, cyclosporine (CYS) or tacrolimus (TAC). We aimed to compare the effectiveness and safety of IFX and the oral calcineurin inhibitor, TAC, in this setting. This retrospective cohort study included consecutive patients with ASUC, based on the Truelove and Witts criteria, admitted to Tel Aviv Medical Center between 2017 and 2022 and treated with salvage therapy. Demographic, clinical, and laboratory data were retrieved. The primary endpoint was successful salvage therapy defined as clinical response resulting in discharge without colectomy. Secondary endpoints included the colectomy rates at 90 days and the safety profile of the treatments. During the study period 96 patients with ASUC were admitted to our center. Of these, 40 patients received salvage therapy – 21 patients received IFX and 16 received TAC and were included in the analysis; 3 patients received CYS and were excluded from the study. Demographic data are detailed in Table 1. Disease duration was significantly longer in patients receiving TAC (mean (±SD) 9.7 years (±7.1) vs 4.5 (±5.9), p=0.04). In addition, patients receiving TAC had significantly greater prior exposure to advanced therapies (14 (87.5%) vs 6 (28.6%), p<0.001) and 12 (75%) patients had previous exposure to IFX. Baseline markers of disease severity including disease extent, hemoglobin, C-reactive protein (CRP), albumin and body mass index (BMI) were similar between the treatment groups (Table 1). Therapeutic success was similar between treatment groups (IFX: 18 (86%) vs TAC: 15 (94%), p=0.62). The 90-day colectomy rate (IFX: 4 (19%) vs TAC: 2 (12.5%), p=0.68), CRP upon discharge (median (IQR) IFX: 15 mg/L (3.3-27) vs TAC: 11 mg/L (5.4-25, p=0.64) and length of hospitalization (mean (±SD) IFX: 23.5 days (±19.46) vs TAC: 17.56 days (±5), p=0.19) were similar between the groups. Safety profiles were similar between the treatment groups with mild electrolyte disturbances treated conservatively in both groups and no observed infections, deaths or other adverse events. This real world, retrospective study shows that IFX and TAC have similar effectiveness and safety in the setting of ASUC. In this study, patients receiving TAC had significantly longer disease duration and advanced therapy exposure than those receiving IFX and still maintained excellent effectiveness highlighting TAC’s value in this setting.

In the last 25 years, the introduction of biological therapies has been a significant milestone in the management of inflammatory bowel diseases. Despite the recent emergence of new biological therapies and small molecules, Anti-TNF agents still play a crucial role in treatment. In a number of countries, anti-TNF agents are still reimbursed as a first line treatment following either a failure or intolerance to conventional therapies such as thiopurines and aminosalycilates. Many studies have been conducted previously to compare the efficacy of these drugs, but a clear conclusion could not be reached. In this study, we aimed to compare the persistence of infliximab (IFX) to adalimumab (ADA) in the treatment of ulcerative colitis at a tertiary IBD center in Turkey. This was a retrospective cohort analysis of patients with ulcerative colitis either received adalimumab or infliximab as a first line biologic treatment. A total of 234 patients were included to this analysis. Demographic information such as gender, age, montreal classification, smoking and prior medications were noted from patients electronic medical records. Weighted Kaplan-Meier and Cox models were used to assess the outcomes. Out of the 234 patients included in the study, 116 had used infliximab, and 118 had used adalimumab as a first-line treatment. Age and gender of the patients in both groups did not differ from each other statistically. 88% of the patients treated with adalimumab and 84% of the patients treated with infliximab were thiopurine experienced. Montreal classification did not differ between two groups (in IFX group, 73% of the patients had Montreal E3 involvement where as in ADA group, 66% of the patients had Montreal E3 involvement, p>0.05). Primary non-response rates were not different between IFX and ADA group, 13.6% vs 13.4% respectively. In addition, clinical response rates after first year were 60% and 53% respectively. Drug persistency rates of adalimumab and infliximab in moderate to severe ulcerative colitis patients were not statistically different from each other (Figure 1). Neither clinical efficacy rates nor drug persistency rates of adalimumab and infliximab in ulcerative colitis treatment were not different from each other. Factors such as age, gender, location of involvement, concomitant therapies, and smoking did not alter the outcome.

Vedolizumab (VDZ) and infliximab (IFX), are considered first-line agents in the treatment of moderate to severe Ulcerative Colitis (UC). However, there are no head-to-head studies comparing the relative effectiveness of the two agents, and Real-world data on the effectiveness and safety of VDZ and IFX in UC are lacking in the Brazilian population. We aimed to compare effectiveness and safety of VDZ to IFX in Biologic-naïve UC patients. We conducted a multicenter retrospective cohort study, including patients with moderate to severe UC (Total Mayo score 6-12, with an endoscopic subscore of 2 or 3) who treated with VDZ or IFX. The primary endpoints were: clinical remission, defined as a partial Mayo score (PMS) ≤2, endoscopic remission (endoscopic Mayo subscore of 1 or 0) and steroid-free clinical remission at week 52. Secondary endpoints included; clinical response at weeks 12 and 26, need for drug optimization, adverse events (AEs), need for hospitalization and colectomy, loss of response and biochemical remission (C-reactive protein [CRP] ≤ 0.5 mg/dl and/or fecal calprotectin [FC] ≤ 150 mcg/g) at week 52. A total of 174 UC (79 VDZ and 95 IFX) patients were included. Clinical remission and endoscopic remission at week 52 were achieved by 56 (70.8% vs 68.4%, p= 0.44) and 46 (58.2% vs 55.7%, p=0.18) of VDZ and IFX patients, respectively. Steroid-free clinical remission at week 52 was 84.2% and 54.1% in the VDZ and IFX group, respectively (p = 0.03). Clinical response at weeks 12 and 26 was reached in 80.0% vs 76.2%, p = 0.74 and in 71.4% vs 77.3%, p = 0.71 in the VDZ and IFX group, respectively. The need for drug optimization was higher for IFX than for VDZ (36.8% vs. 21.5%, p = 0.03). The incidence of AEs (26.3% vs 12.6%, p=0.03) and need for hospitalization (26.3% vs 11.4%, p=0.02) were higher for IFX than to VDZ patients. Secondary loss of response was similar in the two groups (16.4 % for VDZ and 16.8% for IFX, p = 1.00). Biochemical remission at week 52 was 75.0% for VDZ, and 63.9% for IFX, respectively (p=0,42). In this real-world study VDZ and IFX had similar efficacy in inducing clinical remission, endoscopic remission, clinical response and biochemical remission at week 52. Compared to IFX, VDZ was superior in inducing steroid-free remission, in addition to having a better safety profile and less need for dose escalation. Both VDZ and IFX were effective treatment options in bio-naïve UC patients.

Despite the increasing armamentarium of advanced therapies for the treatment of ulcerative colitis (UC), data comparing the effectiveness of biologics in early disease are scarce. We aimed to categorize selection of patients and assess the effectiveness, therapeutic persistence and safety of biologics used to treat early UC in a bio-naïve patient cohort. This single-center, retrospective study included all bio-naïve UC patients who commenced advanced therapy within two years of diagnosis between 2012-2023. We collected demographic, clinical, and laboratory data. Clinical disease activity was assessed using the Simple Clinical Colitis Activity Index; clinical response was defined as a decrease of ≥ 3 points from baseline and clinical remission defined as an SCCAI of ≤2 Out of the 1117 patients with UC who were treated at our center during the study period, 46 bio-naïve patients (mean age 36.7 years (±17)) were treated with either infliximab (IFX) or vedolizumab (VDZ), within 2 years from diagnosis. IFX was the first biologic in 19 (41%) patients and VDZ in 27 (58%) patients. At therapy initiation, 38 (82%) patients were receiving corticosteroids and 7 (15%) concomitant immunomodulators (Table 1). Patients treated with IFX had significantly lower hemoglobin (10.4 (IQR 8.5-11.3) vs 12.1 (IQR 10.8-13.9) g/dL, p=0.007) and albumin (3 (IQR 2.8-3.8) vs. 3.8 (IQR 3.4-4.2) g/dL, p=0.01) and significantly higher C-reactive protein (CRP) (48.5 (IQR 9-119) vs. 2.5 (IQR 2-3) mg/L, p<0.001) compared with patients starting VDZ. Following induction (week 14) clinical response and remission rates were similar in both treatment groups (IFX: 73% and 63%; VDZ: 74% and 67%, respectively; p=0.75). At week 52, clinical response and remission rates were similar in both treatment groups (IFX: 50% for both; VDZ: 50% for both, p=n/s). Corticosteroid (CS)-free remission rates amongst patients receiving CS at baseline (17 patients IFX and 21 patient VDZ) at week 52 were similar in both groups (IFX: 58% vs VDZ 57%, p=n/s). Treatment persistence over 2 years of follow-up was similar between IFX and VDZ (Figure 1). Safety profiles were similar in both treatment groups with no new signals noted. In these real-world data in patients with early and bio-naïve UC, first line IFX was used in more severe baseline disease as highlighted by lower albumin and hemoglobin levels and higher CRP at baseline. Despite this, IFX showed equal effectiveness in induction and long-term maintenance and showed similar treatment persistence compared with VDZ.

Studies on elective switching to the subcutaneous (SC) formulation of infliximab revealed comparable efficacy and safety and higher infliximab level than those exhibited by intravenous (IV) infliximab. However, no studies have reported on the effectiveness of SC switching in ulcerative colitis (UC) patients who experienced IV infliximab failure during maintenance treatment. This retrospective study included UC patients who had been switched to SC infliximab because of IV infliximab failure, between January 2021 and January 2023. Group A was defined as having clinically and biochemically active UC (secondary loss of response), and group B consisted of patients with stable symptoms but biochemically active UC. Twenty-three patients met the inclusion criteria: 15 in group A and 8 in group B. The serum infliximab levels significantly increased after SC switching in both groups. Electively switched group also exhibited increased infliximab levels after SC switching. Group A showed improved partial Mayo score with a significant decrease in faecal calprotectin (FC) and C-reactive protein after switching. In group B, the FC level significantly decreased without clinical relapse after switching. A high proportion of patients (≥ 80%) in both groups achieved clinical and/or biochemical response at last follow-up. During the follow-up period, only two patients in group A discontinued SC infliximab, and only one complained of severe injection site reaction. In UC patients who experience IV infliximab failure during maintenance treatment, switching to SC infliximab may be a promising option because of its efficacy and safety.

Hepatitis B virus (HBV) infection has been associated with chronic hepatitis and cirrhosis. Patients with inflammatory bowel disease (IBD) maybe at higher risk of HBV infection, especially those on biologic therapies. There is limited data on the effectiveness of HBV vaccination in patients with IBD receiving different types of IBD medications. This study intends to compare the effectiveness of HBV vaccine in patients with ulcerative colitis (UC) on Infliximab (IFX) compared to those on 5-aminosalicylic acid (5-ASA). Patients with UC aged between 18-85 years were prospectively enrolled in the study. The patients were divided into two groups: group 1 ( patients with UC on 5-ASA) and group 2 (patients with UC on IFX). HBV vaccination was administered (20 mcg) following the standard regimen, and Hepatitis B serum antibody (HbsAb) titres were assessed three months after the final dose. The response to HBV vaccines was categorized as 'adequate' immune response (≥10 IU/L) and 'effective' immune response (≥100 IU/L). In our final analysis of 118 patients with UC, 54.2% were male, and 52.5% had extensive disease. HBsAb titer levels were significantly higher in the 5ASA group (126.7 ± 37.5) compared to the IFX group (55.5 ± 29.4). Stratifying HBsAb levels into two categories (≥10-99 IU/L and ≥100 IU/L) revealed a significantly greater proportion of subjects in the 5-ASA group with levels ≥100 IU/L (76.7%) compared to the IFX group (12.1%). Conversely, the IFX group showed a higher percentage of subjects with levels between 10-99 IU/L (87.9%) relative to the 5-ASA group (23.3%). Logistic regression analysis demonstrated that patients with UC receiving 5-ASA were 23.94 times more likely to exhibit HBsAb levels ≥100 compared to those on IFX (OR 23.94, 95% CI 8.89-64.49). Immune response to hepatitis B vaccination in patient with ulcerative colitis on infliximab is attenuated compared to those on 5-ASA. Therefore emphasizing the importance of HBV vaccination for patients with IBD before starting anti-TNF therapy, especially infliximab, and advocating for screening is imperative in high risk countries.

The diagnostic accuracy of detecting active ulcerative colitis (UC) by transabdominal intestinal ultrasonography (IUS) is well described. However, the value of repeated IUS measurements in tight monitoring during treatment remains to be established. The aim of the study is to evaluate the utility of IUS for monitoring biologic therapy in UC. Additionally, to establish the correlations between IUS findings and the endoscopic Mayo score (EMS), as well as clinical and biochemical severity indices. In a prospective open-label study, individuals with moderate to severe ulcerative colitis who were initiating infliximab therapy were included, excluding those with proctitis. Patients were evaluated at baseline and after 3 months of biologics induction by means of clinical, biochemical, endoscopic mayo score, and IUS assessments. A Paired Wilcoxon analysis was conducted to compare data before and after therapy induction. The correlation between bowel wall thickness (BWT) and the endoscopic mayo score (EMS), C-reactive protein (CRP), calprotectin, and the Simple Clinical Colitis Activity Index (SCCAI) was analyzed across both visits. Thirty-two patients were enrolled and completed baseline evaluations and 21 completed follow-up assessments. The median age was 38 years (IQR 29-60), with 53% male, a median disease duration of 7 years (6-9), 41% having left-sided colitis, and 59% with pancolitis. All patients were treated with infliximab. No significant differences were observed at both time points in terms of BWT, EMS, CRP, and calprotectin (5.5 vs 4.4, p=0.2; 2 (2-3) vs 2 (1-3), p=0.4; 9.4 vs 9.6, p=0.4; 979 vs 394, p= 0.1, respectively). The only significant improvement was in terms of SCCAI (7 (4.8-8) vs 3 (1-5), p=0.009). BWT showed significant correlations with EMS (r= 0.43, p= 0.0015) (figure 1), CRP (r= 0.40, p= 0.007), and SCCAI (r= 0.28, p= 0.03), while no correlation was found with calprotectin (r= 0.19, p= 0.25). Intestinal ultrasonography could serve as a substitute for lower endoscopy in evaluating disease activity.

Abstract Background and Aims Acute severe ulcerative colitis [ASUC] is a medical emergency treated with intravenous steroids followed by infliximab or cyclosporin in the case of steroid failure with emergent colectomy required in refractory or severe cases. Case series have reported on the effectiveness of tofacitinib for refractory disease, but data regarding the effectiveness of upadacitinib in this setting have not been previously reported. We describe the use of upadacitinib therapy for steroid-refractory ASUC in patients with prior loss of response to infliximab. Methods Six patients who received upadacitinib for steroid-refractory ASUC were identified at two Australian tertiary inflammatory bowel disease centres. Patients were followed for up to 16 weeks after discharge with clinical, biochemical and intestinal ultrasound [IUS] outcomes. Results All six patients demonstrated clinical response to upadacitinib induction during their inpatient admission. Four patients achieved corticosteroid-free clinical remission by week 8, including complete resolution of rectal bleeding and transmural healing assessed by IUS, and sustained clinical remission at week 16. One patient proceeded to colectomy at week 15 due to refractory disease. No adverse events directly attributable to upadacitinib were identified. Conclusions Upadacitinib may have a role as a safe and effective salvage therapy for steroid-refractory ASUC in patients who have previously failed to respond to infliximab therapy. Prospective studies are required to determine the safety and efficacy of upadacitinib use in this setting before routine use can be recommended.

CT-P13 subcutaneous (SC) infliximab formulation was developed to provide patients with a convenient option for treatment. Previous studies have shown efficacy and safety of CT-P13 SC comparable to CT-P13 intravenous (IV) in inflammatory bowel disease (IBD)1 and rheumatoid arthritis2. This study aimed to demonstrate superiority of CT-P13 SC over placebo in maintenance therapy after induction therapy of CT-P13 IV in patients with ulcerative colitis (UC). Patients with moderately to severely active UC (modified Mayo score 5 to 9 with endoscopic subscore of ≥ 2 points) were enrolled LIBERTY-UC (NCT04205643) and treated with open label CT-P13 IV 5 mg/kg at Weeks 0, 2 and 6 as induction therapy. At Week 10, patients who had a clinical response, defined as decrease in modified Mayo score from baseline of at least 2 points and at least 30%, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1 point, were randomised in a 2:1 ratio to receive either CT-P13 SC 120 mg (CT-P13 SC) or placebo SC arms every 2 weeks up to Week 54. The primary endpoint was clinical remission at Week 54. The key secondary endpoints of clinical response, endoscopic-histologic mucosal improvement, and corticosteroid-free remission were assessed at Week 54. Safety was evaluated up to Week 54. A total of 548 patients were enrolled. Among them, 438 patients (79.9%) responded to CT-P13 IV induction dosing and were randomised (294 in CT-P13 SC arm and 144 in placebo arm, respectively) at Week 10. The rate of clinical remission at Week 54 was significantly greater in CT P13 SC (43.2%) compared to placebo (20.8%) (P<0.0001). Clinical response, endoscopic-histologic mucosal improvement and corticosteroid-free remission also showed statistically greater improvement with CT-P13 SC treatment group, compared to placebo treatment group (Table 1). The safety profile during maintenance phase was generally comparable between CT-P13 SC and placebo arms (table 2). No deaths were reported. CT-P13 SC was more effective than placebo for clinical remission, clinical response, endoscopic histologic mucosal improvement, and corticosteroid-free remission at Week 54 in patients with moderately to severely active UC. No new safety concerns were identified. These results demonstrate that the CT-P13 SC provides both a robust clinical benefit and the convenience of SC administration to patient with moderately to severely active UC. 1 Schreiber et al., 2021. Gastroenterology 2021;160:2340–23 2 Westhovens et al., 2020. Rheumatology 2020;00:1

Background: Ulcerative colitis (UC) in pediatric patients often results in corticosteroid (CS) dependency, with many individuals developing resistance to conventional treatments such as anti-TNF agents. Vedolizumab, a monoclonal antibody targeting α4β7 integrin, has shown promise in adult populations, but data on its efficacy and safety in children and adolescents are limited. Objectives: This systematic review aims to assess the effectiveness and safety of vedolizumab in treating UC in pediatric patients. Design, data sources, and methods: The PRISMA statement’s guidelines were followed in conducting this systematic review. Up until December 2024, a thorough search was carried out using keywords associated with inflammatory bowel disease (IBD), vedolizumab, and pediatric populations in the Cochrane Library, EMBASE, and PubMed. Case series of children and adolescents (less than 18 years old) with UC or unclassified IBD who were treated with vedolizumab were included in the research. Data on clinical response, mucosal healing, corticosteroid-free remission, clinical remission, and adverse events were extracted. Descriptive statistics were used in the statistical analysis. Results: A total of 14 papers were considered in the current evaluation of the effectiveness and safety of vedolizumab. Nearly one-third (36%) of patients with UC/IBD-U experienced clinical remission at 6 weeks, half of the patients at 14 weeks (50%), and 48% and 53% of patients at 22 weeks, respectively. Forty-five percent of patients maintained clinical remission after 1 year. Less than 8% of UC/IBD-U patients experienced serious side effects, while 15%–34% of patients experienced mucosal healing. Conclusion: Vedolizumab exhibits promising efficacy and a favorable safety profile in treating pediatric UC, with a sizable portion of patients achieving both clinical and corticosteroid-free remission. However, due to the limited sample sizes and lack of investigations, more randomized controlled trials and long-term research are needed to confirm these findings and develop more reliable clinical guidelines for its use in children and adolescents with UC. This means that even if the initial findings are promising, additional and better testing is required to ensure that vedolizumab is both effective and safe for young patients with UC. Trial registration: The PROSPERO registration number for this systematic review is CRD420250651513. Plain language summary Vedolizumab for children and teenagers with ulcerative colitis: what the research shows Ulcerative colitis (UC) is a long-term condition that causes inflammation in the large intestine, leading to symptoms such as diarrhea, abdominal pain, and fatigue. It can be especially challenging to treat in children and teenagers. Many young patients become dependent on steroid medications or stop responding to standard treatments over time. Vedolizumab is a newer type of medication known as a biologic. It works by targeting the inflammation specifically in the gut, rather than affecting the entire immune system. This focused action may help reduce side effects and improve treatment outcomes. Researchers reviewed 14 studies involving children and teens with UC or IBD-unclassified who were treated with Vedolizumab. Their goal was to understand how well the medicine worked and how safe it was for younger patients. The findings showed that about 1 in 3 children improved within the first 6 weeks of treatment. By week 14, almost half of the patients were experiencing better disease control, and around 45% maintained these improvements after one year. Endoscopic healing—when the gut lining looks healthier on a scope—was seen in 15% to 34% of patients. Serious side effects were uncommon, occurring in fewer than 8% of cases. These results suggest that Vedolizumab may be a safe and effective option for treating children and teenagers with UC, especially when other treatments are not working well. However, more large and long-term studies are needed to confirm how best to use this medicine in young people.

OBJECTIVES Vedolizumab (VDZ) and ustekinumab (UST) are second-line treatments in pediatric patients with ulcerative colitis (UC) refractory to antitumor necrosis factor (anti-TNF) therapy. Pediatric studies comparing the effectiveness of these medications are lacking. Using a registry from ImproveCareNow (ICN), a global research network in pediatric inflammatory bowel disease, we compared the effectiveness of UST and VDZ in anti-TNF refractory UC. METHODS We performed a propensity-score weighted regression analysis to compare corticosteroid-free clinical remission (CFCR) at 6 months from starting second-line therapy. Sensitivity analyses tested the robustness of our findings to different ways of handling missing outcome data. Secondary analyses evaluated alternative proxies of response and infection risk. RESULTS Our cohort included 262 patients on VDZ and 74 patients on UST. At baseline, the two groups differed on their mean pediatric UC activity index (PUCAI) (p = 0.03) but were otherwise similar. At Month 6, 28.3% of patients on VDZ and 25.8% of those on UST achieved CFCR (p = 0.76). Our primary model showed no difference in CFCR (odds ratio: 0.81; 95% confidence interval [CI]: 0.41-1.59) (p = 0.54). The time to biologic discontinuation was similar in both groups (hazard ratio: 1.26; 95% CI: 0.76-2.08) (p = 0.36), with the reference group being VDZ, and we found no differences in clinical response, growth parameters, hospitalizations, surgeries, infections, or malignancy risk. Sensitivity analyses supported these findings of similar effectiveness. CONCLUSIONS UST and VDZ are similarly effective for inducing clinical remission in anti-TNF refractory UC in pediatric patients. Providers should consider safety, tolerability, cost, and comorbidities when deciding between these therapies.

BACKGROUND Data on upadacitinib therapy for pediatric acute severe ulcerative colitis (ASC) are scarce. We aimed to evaluate the effectiveness and safety of upadacitinib as a salvage therapy in pediatric ASC. METHODS Children and adolescents with ASC who were treated with upadacitinib for the induction of remission were enrolled in this retrospective multicenter study. Demographic, clinical, and laboratory data as well as adverse events (AEs) were recorded after the 8-week induction period and throughout 26 weeks of therapy. Analyses were based on the intention-to-treat principal. RESULTS Twenty-two patients were included (median age 15.7 [interquartile range 13.5-16.6] years, 12 hospitalized), all with anti-tumor necrosis factor (TNF) therapy refractory disease. Ten patients were treated with corticosteroids at baseline, and upadacitinib was added to an ongoing biologic therapy in five patients. At week 8 of therapy, 11 (50%) patients of the cohort remained colectomy-free and in corticosteroid-free clinical remission (CFR), and 17 (77%) patients remained colectomy-free. Normal C-reactive protein (CRP) was achieved in 9 of 11 (82%) patients who were in CFR, and fecal calprotectin <150 mcg/g in 4 of 6 (67%) patients with available data. By week 26, 14 (64%) were in CFR and 16 (73%) patients remained colectomy-free. All these patients had normal CRP levels, and 4 of 7 patients with available data had fecal calprotectin <150 mcg/g. Twelve patients reported AEs, including two serious AEs of an appendiceal neuroendocrine tumor and cytomegalovirus colitis. CONCLUSION Upadacitinib is an effective induction therapy for children and adolescents with ASC after failing anti-TNF.

Ulcerative colitis (UC) is a disabling disease, characterized by chronic inflammation of the colon, with a rising prevalence worldwide in the pediatric age group. Although UC presents in children with varying severity, disease extent, and comorbidities, initial treatment is essentially uniform, consisting of 5-aminosalicylate drugs with corticosteroid induction for those with moderately to severely active disease. With the advent of anti-tumor necrosis factor (TNF) biologic therapy and several new biologics and small-molecule drugs for UC, precision medicine approaches to treatment are needed to more rapidly achieve sustained remission, restore quality of life, normalize development, and limit exposure to toxic corticosteroids in children with UC. Here, we review available data on clinical, biochemical, histopathologic, and molecular predictors of treatment response in UC. We also address known predictors and special treatment considerations in specific relevant scenarios such as very-early-onset UC, acute severe UC, ileal pouch anal anastomosis, and UC with concomitant primary sclerosing cholangitis. The review concludes with a prediction of how machine learning will integrate multimodal patient data to bring precision medicine to the bedside of children with UC in the future.

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INTRODUCTION There are no studies on efficacy of tofacitinib for moderate-severe ulcerative colitis (UC) in pediatric patients in Latin America. The aim of this study was to describe the efficacy and safety, in real world, treated with tofacitinib in our setting. MATERIALS AND METHODS Case series of pediatric patients with UC who received treatment with tofacitinib in induction phase for 8 weeks and then maintenance therapy between November 2021 and February 2023. RESULTS 4 female patients, median age 14.5 (SD 2.1; RIQ12.5-16.5) years, all with prior biologic exposure, all 4 with prior use of anti-TNF, and 2/4 with prior use of anti-integrin. Clinical, biochemical and endoscopic remission was obtained in 3/4 at induction. Information was obtained from 3 patients in 6-month maintenance, 2/3 remained in clinical, biochemical and endoscopic remission and 1/3 has not achieved biochemical or endoscopic remission. Information was obtained from 1 patient in 12-month maintenance, achieving clinical and biochemical remission, however, endoscopic remission has not been achieved. One patient was initiated for severe acute UC with risk of colectomy, with significant improvement after 7 days, reaching therapeutic objectives at induction. No serious adverse events were reported in any of the cases. CONCLUSIONS Efficacy and safety are demonstrated with tofacitinib in pediatric patients. With high percentage of response in induction treatment, sustained over time, and safe. In the context of severe acute hospitalized UC, it has a role as a potential rescue therapy due to its rapid action.

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Vedolizumab is an anti‐α4β7 integrin antibody that has been used successfully in the treatment of adult‐onset inflammatory bowel diseases (IBDs: Crohn disease [CD] and ulcerative colitis [UC]). Its off‐label use in the pediatric IBD (PIBD) population is increasing, but knowledge on durability beyond 6 months of treatment is limited.

Significance: Eosinophilic esophagitis (EoE) is an inflammatory condition characterized by T helper-2 (TH2) cytokines. Ulcerative colitis (UC) and Crohn disease (CD) are inflammatory conditions with different clinical presentations and immune profiles. UC is associated with TH2 cytokines and CD with TH1 cytokines. We investigated potential differences in the association of EoE with UC and CD because of these different immune profiles. Methods: We utilized ICD-9 and ICD-10 codes to find patients with inflammatory bowel disease (IBD) and EoE. We defined EoE as any esophageal biopsy with >15 eosinophils. We collected demographic, clinical, laboratory, endoscopic, and histological data. Results: Thirty patients had both EoE and IBD. 14.9% of UC patients had EoE and 5.7% of CD patients had EoE. 64.7% of UC patients presented with UC and EoE at the same time, whereas 76.9% of CD patients presented with EoE at follow up. Ten of 13 CD patients were on anti-tumor necrosis factor (TNF) at EoE diagnosis. No UC patients were on anti-TNF at EoE diagnosis. Eighty-three percent of CD patients had mild disease or were in remission, whereas 50% of UC patients had moderate to severe disease at the time of EoE diagnosis. Conclusion: A higher percentage of UC than CD patients had EoE. EoE was more likely to be present at the initial diagnosis of UC than CD. EoE was more likely after diagnosis and treatment of CD with anti-TNF, when CD activity was mild or in remission. The difference in presentation suggests that anti-TNF or it’s impact on inflammation may differentially impact the association of EoE with CD and UC.

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Background and Aims Use of anti-TNF therapies varies internationally. As an initiative of the international Pediatric IBD Network (PIBDNet), we compared global pediatric IBD anti-TNF practice patterns. Methods Physicians were surveyed about anti-TNF use in Crohn's disease (CD) and ulcerative colitis (UC). Chi-squared, independent samples Mann–Whitney U, or related samples Wilcoxon signed rank tests were used to compare groups. Results 344 physicians treating pediatric IBD responded from 43 countries (54% North America, 29% Europe, 6% Oceania, 6% Asia, 3% Africa, and 2% South America). Respondents treated a median 40 IBD patients. CD was more commonly treated with anti-TNF than UC (40% vs. 10%, p<0.001). North Americans more often used anti-TNF (median 50% vs. 30%, p<0.001) and before immunomodulator (80% vs. 35% CD, p<0.001; 76% vs. 43% steroid-dependent UC, p<0.001). Anti-TNF monotherapy was more common in North America. Anti-TNF in combination with methotrexate, instead of thiopurine, characterized North American practices. North Americans more often continued immunomodulator indefinitely and less often adhered to standard infliximab induction dosing. Access limitations were more common outside North America and Europe for both CD (67% vs. 31%, p<0.001) and UC (62% vs. 33%, p<0.001). Conclusions Anti-TNF use in North America varies significantly from elsewhere.

Objectives: Colectomy rates following acute severe ulcerative colitis have plateaued around 20% despite intravenous corticosteroid and intensified anti-tumor necrosis factor (TNF) biologic dosing. Recent studies have shown tofacitinib to provide additional benefit in further decreasing colectomy rates among hospitalized adult patients with corticosteroid- and anti-TNF-nonresponsive ulcerative colitis. Pediatric data describing the effectiveness of tofacitinib for this indication does not yet exist. We aimed to describe the treatment courses and colectomy-free survival among pediatric patients treated with tofacitinib while hospitalized for refractory ulcerative colitis. Methods: We performed a retrospective single-center cohort study of consecutive hospitalized pediatric patients initiating tofacitinib for refractory ulcerative colitis from 2018 to 2021. The primary outcome was 90-day colectomy-free survival. Secondary outcomes included colectomy-free clinical remission, corticosteroid independence, colectomy-free tofacitinib drug-persistence, tofacitinib-related adverse events, and postoperative complications. Baseline characteristics and details of the timing and positioning of therapies utilized during hospitalization were described. Outcomes were described using counts, percentages, and Kaplan-Meier curves. Results: Eleven patients met inclusion criteria. All patients demonstrated nonresponse to both intravenous corticosteroids and anti-TNF therapy prior to tofacitinib initiation. Median hospitalization length was 22 days and mean maximum pediatric ulcerative colitis activity index during hospitalization was 68. Eight of 11 patients remained colectomy-free at 90 days following hospital admission and 6 remained colectomy-free over median 182-day follow-up, including 4 of whom remained on tofacitinib. Conclusions: Tofacitinib may represent a new treatment option for hospitalized pediatric patients with corticosteroid- and anti-TNF-nonresponsive ulcerative colitis. Future research is essential in determining the optimal positioning of these therapies.

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ABSTRACT Introduction Anti-tumor necrosis factor (TNF) antibodies play a major role in treating inflammatory bowel disease (IBD), both in adult and pediatric patients. While there is a large number of studies on efficacy and safety of infliximab in treating children and adolescents with ulcerative colitis (UC), data on adalimumab (ADA) are scarce. Areas covered Here, we review published case reports, cohort and real-time data, as well as the first randomized trial, ENVISION I, using ADA for treating pediatric UC. Available evidence confirms good efficacy in inducing and maintaining remission in children and adolescents with UC, with even higher response rates compared to adult UC. ENVISION I showed that in UC patients responding to ADA induction therapy, almost half of the patients remained in remission after 52 weeks of therapy on high-dosing ADA (weekly administration). As already well experienced with other biologics, dosing schemes are different between pediatric and adult patients, with children often requiring higher dosing. Expert opinion Further data are required to better understand how to optimize ADA therapy. The present and still-growing evidence places subcutaneous (sc.) anti-TNF-medication as alternative first-line therapy also for pediatric UC. This is also reflected by the preference for sc. medication of adolescent patients allowing less frequent and autonomous drug administration.

Patient: Female, 12-year-old Final Diagnosis: Ulcerative Symptoms: Bloody diarrhea Medication:— Clinical Procedure: — Specialty: Gastroenterology and Hepatology Objective: Rare disease Background: Ulcerative colitis (UC) is a chronic autoimmune inflammatory disease of the colon that infrequently affects children. The disease requires immunosuppressive therapy to achieve remission and keep the disease in remission. Currently, many therapies are approved for use in pediatric patients with UC, including steroid, 5-aminosalicylic acid (5-ASA), azathioprine, and biologic therapy with anti-tumor necrosis factor (TNF) inhibitors. Despite their efficacy, many patients have refractory severe disease that fails therapy and may require surgical interventions. Recently, the small molecule Janus Kinase (JAK) inhibitor tofacitinib has been approved for moderate to severe UC that fails biologic therapy in adults. However, the safety and efficacy of this drug has not been tested in pediatric UC patients. Case Report: We describe a case of a 13-year-old girl with 2-year history of severe UC who had secondary loss response to both infliximab and adalimumab over 2 years, despite adequate trough serum drug levels and the concomitant use of azathioprine. She was also dependent on steroid to control her disease. Infectious work-ups were always negative for infectious organisms. She was then successfully treated with tofacitinib 5 mg orally twice daily. She went into complete clinical, endoscopic, and steroid-free remission. Conclusions: This case report highlights the safety and efficacy of tofacitinib in pediatric patients with severe refractory UC, potentially avoiding proctocolectomy in this young patient population. Future research should study the role of tofacitinib in patients with moderate to severe UC in children.

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Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis (UC), remains a clinically complex condition in children and adults. This study is a systematic analysis of key developments in the treatment of inflammatory bowel diseases, as well as their efficacy and safety over time. Early diagnosis of pediatric IBD is very important since it affects growth and development in children. New therapeutic approaches like biological agents, small molecules, and gene or targeted drugs have given the medical fraternity new treatment protocols. There is a trend towards more selective therapies for adult IBD, especially for anti-tumor necrosis factor (anti-TNF) biologics, integrin antagonists, and interleukin-12/23 (IL-12/23) inhibitors. This review emphasizes the need for patient management where early intervention leading to mucosal healing has been identified to predict durable outcomes. Systematic analysis of existing literature comparing childhood and adult populations shows that morbidity, pathophysiology, therapeutic outcome, as well as the potential for adverse outcomes are dissimilar, which supports the need for differentiated therapy. This work also looks at long-term consequences of the intervention course, the avoidance of surgery, and an improvement in the quality and stability of life as well as reduction in further development of malignant transformation. The new developing strategy of gut microbiome modification and nutrition support for maintaining remission is also argued. Despite these progresses, issues still persist concerning the effectiveness of treatments, side effects, and patients’ compliance. These recommendations give this review a prospective outlook of treatment regimens likely to define the future of IBD management for all age groups.

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Since many biological drug patents have expired, biosimilar agents (BIOs) have been developed; however, there are still some reservations in their use, especially in childhood. The aim of the current study is to evaluate the efficacy and safety of tumor necrosis factor (TNF) inhibitors BIOs as treatment for pediatric non-infectious uveitis (NIU). Data from pediatric patients with NIU treated with TNF inhibitors BIOs were drawn from the international AutoInflammatory Disease Alliance (AIDA) registries dedicated to uveitis and Behçet's disease. The effectiveness and safety of BIOs were assessed in terms of frequency of relapses, risk for developing ocular flares, best-corrected visual acuity (BCVA), glucocorticoids (GCs)-sparing effect, drug survival, frequency of ocular complications, and adverse drug event (AE). Forty-seven patients (77 affected eyes) were enrolled. The BIOs employed were adalimumab (ADA) (89.4%), etanercept (ETA) (5.3%), and infliximab (IFX) (5.3%). The number of relapses 12 months prior to BIOs and at last follow-up was 282.14 and 52.43 per 100 patients/year. The relative risk of developing ocular flares before BIOs introduction compared to the period following the start of BIOs was 4.49 (95% confidence interval [CI] 3.38–5.98, p = 0.004). The number needed to treat (NNT) for ocular flares was 3.53. Median BCVA was maintained during the whole BIOs treatment (p = 0.92). A significant GCs-sparing effect was observed throughout the treatment period (p = 0.002). The estimated drug retention rate (DRR) at 12-, 24-, and 36-month follow-up were 92.7, 83.3, and 70.8%, respectively. The risk rate for developing structural ocular complications was 89.9/100 patients/year before starting BIOs and 12.7/100 patients/year during BIOs treatment, with a risk ratio of new ocular complications without BIOs of 7.1 (CI 3.4–14.9, p = 0.0003). Three minor AEs were reported. TNF inhibitors BIOs are effective in reducing the number of ocular uveitis relapses, preserving visual acuity, allowing a significant GCs-sparing effect, and preventing structural ocular complications. ClinicalTrials.gov ID NCT05200715.

Purpose: Management of uveitis displays a particular challenge in childhood. This study aims to compare the efficacy and safety of infliximab (IFX) and adalimumab (ADA) in pediatric noninfectious uveitis that were refractory to conventional immunosuppresives. Methods: This retrospective single-center study included 33 patients who were treated with anti-tumor necrosis factor (TNF) agents (16 with IFX and 17 with ADA). Patients had diverse etiologies, including juvenile idiopathic arthritis, idiopathic uveitis, and Behçet's disease. Demographic characteristics, systemic diagnosis, findings of the ophthalmological examination, control of ocular inflammation, response to treatment, and the rate of clinical remission were studied. Results: Fourteen (87.5%) patients receiving IFX and 10 (58.8%) patients receiving ADA achieved response to treatment during the follow-up (P = 0.118). The agents were discontinued with complete clinical remission in 6 (37.5%) patients receiving IFX and in 2 (11.8%) patients receiving ADA (P = 0.118). Baseline visual acuities and parameters of inflammation improved significantly in both groups after anti-TNF therapy. Conclusion: Both IFX and ADA are safe and effective for pediatric noninfectious uveitis.

Background: The management of pediatric inflammatory bowel disease (PIBD) has evolved significantly over the past two decades, transitioning from corticosteroids and immunomodulators to biologic and small-molecule therapies. These advances have aimed not only to control inflammation but also to promote mucosal healing, improve growth, and enhance long-term quality of life. Objectives: This narrative review summarizes current evidence on the efficacy, safety, and clinical applications of biologic and novel small-molecule therapies in PIBD, highlighting emerging trends in personalized and precision-based management. Methods: A literature search was performed across PubMed, Embase, and the Cochrane Library, focusing on studies published within the last five years. Additional data were retrieved from key guidelines and position papers issued by ECCO–ESPGHAN, SIGENP, the FDA, and the EMA. Results: Anti–tumor necrosis factor (TNF) agents such as infliximab and adalimumab remain first-line biologics with proven efficacy in remission induction and maintenance. Newer biologics—vedolizumab, ustekinumab, risankizumab, and mirikizumab—offer alternatives for anti-TNF-refractory cases, showing encouraging short-term results and favorable safety profiles. Although many are approved only for adults with limited pediatric evidence, emerging small molecules—including Janus kinase (JAK) inhibitors (tofacitinib, upadacitinib) and sphingosine-1-phosphate (S1P) modulators (etrasimod)—provide oral, rapidly acting, and non-immunogenic treatment options for refractory disease. Furthermore, the gut microbiome is increasingly recognized as an emerging therapeutic target in PIBD, with growing evidence that host–microbiome interactions can influence both the efficacy and safety of biologics and small-molecule therapies. Conclusions: While biologics and small molecules have transformed PIBD management, challenges remain, including high treatment costs, limited pediatric trial data, and variable access worldwide. Future directions include multicenter pediatric studies, integration of pharmacogenomics, and biomarker-guided precision medicine to optimize early, individualized treatment and improve long-term outcomes.

Biological therapies, especially blocking tumor necrosis factor-α (TNFα) agents have radically changed the therapeutic approach and disease course of pediatric inflammatory bowel disease (IBD). In particular, drugs such as infliximab (IFX) and adalimumab (ADA) have been demonstrated to be effective in inducing and maintaining corticosteroid-free remission in both adult and pediatric patients with Crohns Disease (CD) and Ulcerative colitis (UC). Biosimilar biological (BioS) therapy is increasingly being used in pediatric age even though most knowledge on the safety and efficacy of these agents is based on IFX in adult IBD data. Studies show high rates of clinical response and remission in both IFX naïve patients and in patients switched from originator to BioS with similar risks of adverse events (AEs) as those reported with IFX originator. In the present review indications, efficacy and AEs of biological therapy in pediatric IBD will be discussed, as well as the role of other biological agents such as Golimumab, Vedolizumab and Ustekinumab, the role of BioS biological therapy and utility of therapeutic drug monitoring in clinical practice.

Abstract Rationale: Ustekinumab is effective in the treatment of adult Crohn disease (CD) and ulcerative colitis (UC). However, data on its efficacy and safety in pediatric CD and UC are limited. To the best of our knowledge, there are no reports of Japanese children with UC treated with ustekinumab in the long-term. Patient concerns: A 14-year-old man with diarrhea and bloody stools was referred to our hospital. Colonoscopy revealed total colitis-type UC. His pediatric UC activity index score was 50, indicating moderately active UC. Diagnoses: Ulcerative colitis. Interventions: Infliximab was introduced because of steroid-resistant refractory UC; however, secondary ineffectiveness was observed 17 months later. Therefore, ustekinumab was administered along with prednisolone (16 years of age). Outcomes: The patient achieved UC remission after ustekinumab treatment, leading to maintained remission without side effects. Lessons: To the best of our knowledge, this is the first pediatric case of moderately active UC successfully treated with ustekinumab in Japan. Ustekinumab combined with steroids is an effective and safe induction therapy for UC.

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Background: Sulfasalazine (SZ) is commonly used to treat pediatric ulcerative colitis (UC). SZ can be compounded into a suspension form which is beneficial for children with difficulty swallowing a pill. Despite being utilized for over 40 years, there is a lack of published data on the efficacy and safety of SZ suspension in children with UC. Recently, third-party payors have begun refusing to pay for SZ suspension due to lack of data. Methods: In this retrospective study, we reviewed the electronic medical records of patients ages <18 years diagnosed with UC from June 1999 to December 2019 at Boston Children’s Hospital and treated with SZ suspension as a first-line agent. We obtained demographics, clinical, and endoscopic data to measure outcomes at 1 year and long term. Results: Of 57 patients treated with SZ suspension, 52 (91%) had a follow-up and 26 of 52 (50%) remained in steroid-free remission at 1 year. Two patients were switched to SZ tablets due to nonmedical reasons and 11 (21%) required rescue treatment (2 infliximab, 1 tacrolimus, 8 6-mercaptopurine/azathioprine) within a year. Three required colectomy within a year and 5 in long term. Four (8%) developed nonserious adverse reactions and switched to 5-aminosalicylates (5-ASA) by 1 year. The median duration of long-term follow-up was 36 months (range, 2–205 months) with 28 requiring treatment escalation in long term. Conclusions: SZ suspension is a safe and effective treatment for UC in children with difficulty swallowing a pill. The 1-year remission rate on this treatment is comparable to 5-ASA utilized in children.

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No abstract available

Objective. To evaluate the efficacy and safety of vedolizumab in children with inflammatory bowel disease (IBD) and to supplement existing data on experience with its use in pediatric patients. Patients and methods. The efficacy of vedolizumab therapy in children with IBD was assessed by analyzing observational data of 37 patients aged 6 to 17 years (29 children with ulcerative colitis (UC), 8 children with Crohn’s disease (CD)) for the period 2019–2023. The mean age at initiation of therapy was 13 years. Prior treatment in all patients included the use of anti-TNF (tumor necrosis factor) agents. Clinical and endoscopic indices of disease activity, anthropometric and laboratory characteristics at 0–14–26–52 weeks for UC and 0–52 weeks for CD were recorded. Results. During one year of therapy, 29 patients with UC whose mean age at initiation of vedolizumab was 12.3 years and who had a history of anti-TNF therapy (100% infliximab, 48.3% adalimumab) achieved a significant improvement in PUCAI and UCEIS scores, normalization of hemoglobin and iron concentrations, regression of thrombocytosis, and a decrease in calprotectin levels; there was also a reduction in the number of patients with a BMI-for-age and length-for-age Z-scores <2. Eight patients with CD whose mean age at initiation of vedolizumab was 14.8 years and who had a history of anti-TNF therapy (62.5% infliximab, 75% adalimumab) achieved a statistically significant improvement in PCDAI and SES-CD scores, resolution of thrombocytosis, increasing hemoglobin and iron concentrations, and decreasing calprotectin levels 52 weeks after therapy initiation. In the group of patients receiving prednisolone at the time of therapy initiation, 50% of children with UC achieved steroid-free remission by week 14, while 28.5% and 60% of children with UC and CD, respectively, achieved remission by week 52. Clinical remission was established by week 14 in 16/29 (55.2%) children with UC (of whom 31% did not receive steroids), by week 52 in 20/29 (68%) children with UC and in 4/8 (50%) with CD. Conclusion. Vedolizumab demonstrated its efficacy and safety for successful use in pediatric patients with IBD. Within a year, most children with UC and CD showed improvement in anthropometric, clinical, laboratory, and endoscopic parameters. Key words: children, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, biologic therapy, vedolizuma

CT-P13 subcutaneous (SC) infliximab formulation demonstrated superiority over placebo in maintenance therapy in Crohn's disease (CD) and Ulcerative Colitis (UC) patients in two parallel 54 weeks studies (LIBERTY-CD and LIBERTY-UC). We performed a post-hoc subgroup analysis comparing patients treated with CT-P13 SC with and without combination immunosuppressants (IS) at baseline in CD and UC. Patients with moderately to severely active CD and UC who responded at W10 to CT-P13 intravenous infliximab 5mg/kg (Weeks 0, 2 and 6) were randomized (2:1) to receive CT-P13 SC 120 mg (CT-P13 SC) or placebo every 2 weeks until W54 as maintenance therapy. IS (azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]) were allowed if patients maintained stable doses at least 8 weeks prior to W0, and stable doses were maintained up to W54. 231 CD and 294 UC patients were randomized to receive CT-P13 SC maintenance therapy. Among them, 71 (30.7%) and 65 (22.1%) patients received CT-P13 SC with IS in CD and UC, respectively (In CD; 63, 4 and 4 patients of AZA, 6-MP, MTX, respectively, In UC; 63, 2 and 0 patients of AZA, 6-MP, MTX, respectively). There were no meaningful differences in efficacy outcomes at Week 54 by CT-P13 concentration tertiles at Week 54 between monotherapy and combination therapy groups in both studies (Table 1). In combined analysis of CD and UC patients, no statistically significant differences were seen in safety profile between monotherapy and combination therapy groups in the maintenance period except for infection rate (Table 2). In combined analysis of CD and UC patients, rate of anti-drug antibody [ADA] positive conversion up to W54 was statistically lower in combination therapy group (70.2% monotherapy vs 47.8% combination therapy [p<0.0001]). No meaningful differences in efficacy outcomes at W54 were observed between monotherapy and combination therapy of CT-P13 SC in CD and UC patients. Concomitant IS use was associated with less ADA formation, whereas more infections are seen for combination therapy during maintenance period in CD and UC patients. The overall safety profile during maintenance period was otherwise comparable between monotherapy and combination therapy in CD and UC patients. This post-hoc analysis suggests limited benefit of concomitant IS with CT-P13 SC but a higher infection risk. Notably, patients were not randomized according to IS use nor were the studies ‘powered’ to demonstrate differences. Proportion of patients achieving efficacy outcomes at W54 by tertile of Serum concentrations of Infliximab (ng/mL) at W54 (Pharmacokinetic population) Safety results in maintenance period (Safety population)

No abstract available

Relapsing-remitting inflammatory bowel disorders are chronic. Biologic therapy has expedited inflammatory bowel disease (IBD) treatment. Infliximab, a tumor necrosis factor (TNF)-alpha-targeting chimeric antibody, induces and maintains illness remission. Remsima and other biosimilars seek to cut medical expenses and increase medicine affordability. The aim of study is to compare the clinical efficacy, endoscopic changes, and safety of Remsima vs. Remicade in patients with IBD. From April 1, 2019, to April 1, 2020, Baghdad Medical City’s Gastroenterology and Hepatology Hospital performed this investigation. Remsima and Remicade were given to 13 ulcerative colitis (UC) and 13 Crohn’s disease patients, respectively. Disease activity was measured using Mayo Score in UC and Crohn disease activity index and simple endoscopic score for Crohn’s disease (SES-CD) in CD initially and followed up 6 months after first dose of Remsima prospectively and retrospectively for Remicade by clinical data and endoscopic findings. After 6 months of therapy, UC and CD Mayo scores decreased from 10.07 to 4.92 and 9.84 to 5.00 by Remsima and Remicade, respectively. Remsima and Remicade decreased CD mean from 436.07 to 212.84 and 428.30 to 199.53. Remsima and Remicade decreased CD SES scores from 15.15 to 6.92 and 12.69 to 5.00, respectively. 3 (23.1%) Remsima patients in both conditions had side symptoms, whereas 4 (30.8%) Remicade patients in UC and 5 (38.5%) in CD did. Groups gained weight significantly. Both medications were equally effective and safe ( P > 0.05). Remsima and Remicade are a tolerable effective treatment with no significant adverse effects in IBD patients with moderate–severe disease.

In a previous meta-analysis on randomized controlled trials (RCT) in patients with moderate-to-severe Crohn’s disease (CD) and ulcerative colitis (UC), infliximab (IFX) showed better efficacy in the induction phase and comparable efficacy during the maintenance phase and an overall similar safety profile as compared to vedolizumab (VDZ).1 The objective of this study is to indirectly compare the 1-year efficacy and safety results between subcutaneous IFX (SC IFX) and VDZ as maintenance therapies in moderate-to-severe CD and UC patients. This analysis incorporates data from three recently published clinical trials: LIBERTY-CD2, LIBERTY-UC3, and VISIBLE24. Separate pooled analyses were conducted for patients with CD and UC, combining data for predefined efficacy and safety outcomes. These outcomes included the proportions of patients achieving clinical remission (CD: absolute CDAI score of <150; UC: Total Mayo score ≤2 with no individual sub-score >1; or partial Mayo score of ≤1 point), clinical responses (CD: decrease in CDAI score of ≥100 from baseline; UC: a decrease in total Mayo score from baseline of ≥3 points and ≥30%; or a decrease in partial Mayo score from baseline of ≥2 points), and the proportions of patients experiencing adverse events (AEs), serious AEs, serious infections, or discontinuation due to AEs during the 1-year maintenance phase. Data were pooled using a random-effect model. The heterogeneity between studies was examined. A total of 2,028 patients (IFX SC, n=655; VDZ, n=1,373) were included in this pooled analysis. In CD patients, a higher proportion of patients treated with SC IFX achieved clinical remission and CDAI-100 response, with non-overlapping 95% CI during the maintenance phase compared to patients treated with VDZ (Fig.1A, B). In UC, the proportion of patients achieving clinical remission and clinical response during the maintenance phase was similar between the two treatment groups, with overlapping 95% CIs (Fig.1C, D). Safety profiles were generally similar for both indications (Fig.2). In this indirect comparison, patients treated with SC IFX achieved better efficacy in terms of clinical remission and response compared to those treated with VDZ during 1-year maintenance therapy in CD, and similar rates in UC. Subcutaneous IFX showed a similar safety profile to VDZ, with limitations in duration of follow-up and number of patients. These findings align with the results of a network meta-analysis5 showing that SC IFX ranks highest among biologics for achieving clinical remission during maintenance therapy. 1. Peyrin-Biroulet et al., BMC Gastroenterol 2022;22(1):291 2. Colombel J F et al., JCC 2023;17(S1):i161-i162 3. Sands B E et al., JCC 2023;17(S1):i623-i624 4. Severine Vermeire et al., JCC 2022;16(1):27-38 5. Peyrin-Biroulet L et al., JCC 2023:17(S1):i574–i576

Inflammatory bowel disease (IBD), consists of two primary types: Ulcerative Colitis (UC) and Crohn’s Disease (CD). Infliximab (IFX) and Adalimumab (ADA) are frequently utilized in the management of moderate to severe cases of IBD. This study aimed to assess the efficacy and safety of IFX and ADA in individuals diagnosed with moderate to severe IBD. This study is a prospective open-labeled randomized parallel study that included moderate to severe IBD patients treated with either IFX or ADA. A total of 56 patients participated, with 34 patients received IFX and 22 patients received ADA. Various measures, including Crohn’s Disease Activity Index (CDAI), Mayo Score/ Disease Activity Index (DAI), and C-reactive protein (CRP) levels, were taken at baseline and week 14 to assess the efficacy of the treatments. In addition, the levels of drugs and sTREM-1 were measured at 14 weeks. Patient safety was monitored throughout the study period. In the group received IFX, there was a notable decrease in CDAI (P = 0.045), DAI (P = 0.026), and CRP (P = 0.023 for CD, and P = 0.021 for UC) levels. In addition, the group received ADA experienced a significant reduction in CDAI (P = 0.001), DAI (P = 0.032), and CRP (P < 0.018 for CD and P = 0.003 for UC) levels. Responders had higher drug concentrations than non-responders, notably IFX concentration was higher in responders with CD (P = 0.001) and UC (P < 0.001). ADA concentration was higher in UC (P <= 0.001) and all CD patients responded to the treatment. The same trend was observed for sTREM-1 levels in CD and UC patients (P = 0.042, and P = 0.015, respectively) in the IFX group. In UC patients treated with ADA, the level of sTREM-1 was significantly low (P = 0.002). Both IFX and ADA have a good safety profile and deliver a beneficial clinical and laboratory response in moderate-severe IBD patients. This study is registered on ClinicalTrials.gov under the identifier NCT05291039. (You can access the study at https://clinicaltrials.gov/study/NCT05291039 (First Posted: March 22, 2022).

Background While indirect comparison of infliximab (IFX) and vedolizumab (VDZ) in adults with Crohn’s disease (CD) or ulcerative colitis (UC) shows that IFX has better effectiveness during induction, and comparable efficacy during maintenance treatment, comparative data specific to subcutaneous (SC) IFX (i.e., CT-P13 SC) versus VDZ are limited. Aim Pooled analysis of randomised studies to compare efficacy and safety with IFX SC and VDZ in moderate-to-severe inflammatory bowel disease. Methods Parallel-group, randomised studies evaluating IFX SC and VDZ in patients with moderate-to-severe CD or UC were identified. Eligible studies reported ≥ 1 prespecified outcome of interest at Week 6 (reflecting treatment during the induction phase) and/or at 1 year (Weeks 50-54; reflecting treatment during the maintenance phase). Prespecified efficacy and safety outcomes considered in this pooled analysis included the proportions of patients achieving disease-specific clinical responses, clinical remission, or discontinuing due to lack of efficacy, and the proportions of patients experiencing adverse events (AEs), serious AEs, infections, serious infections, or discontinuing due to AEs. Data from multiple studies or study arms were extracted and pooled using a random-effect model; comparative analyses were performed separately for patients with CD and UC. Results We identified three eligible CD trials and four eligible UC trials that assigned over 1200 participants per disease cohort to either IFX SC or VDZ. In patients with CD, intravenous induction therapy with IFX demonstrated better efficacy (non-overlapping 95% confidence intervals [CIs]) compared with VDZ; during the maintenance phase, IFX SC showed numerically better efficacy (overlapping 95% CIs) than VDZ. A lower proportion of IFX SC-treated patients discontinued therapy due to lack of efficacy over 1 year. In patients with UC, efficacy profiles were similar with IFX SC and VDZ during the induction and maintenance phases, and a lower proportion of IFX SC-treated patients discontinued therapy due to lack of efficacy over 1 year. In both cohorts, safety profiles for IFX SC and VDZ were generally comparable during 1 year. Conclusion IFX SC demonstrated better efficacy than VDZ in patients with CD, and similar efficacy to VDZ in patients with UC; 1-year safety was comparable with IFX SC and VDZ.

Ulcerative colitis (UC) is an inflammatory disorder affecting the colon, and typically, during the disease course, the condition may exacerbate, relapse, and remit. One of the most successful lines for inducing and maintaining clinical remission in subjects with UC is biological therapy with anti-tumor necrosis factor α (anti-TNF) agents, including adalimumab (ADA) and infliximab (IFX). This meta-analysis is an attempt to obtain complementary information driven by real-world experience (RWE) concerning the efficacy and safety of two of the most popular anti-TNFs in treating UC. This is a systematic review and meta-analysis of RWE studies comparing ADA and IFX as naïve anti-TNF agents for the treatment of subjects with UC. Studies were obtained by searching Scopus, Google Scholar, the Cochrane Central Register of Controlled Trials, Embase, and the PubMed Central databases. Patients treated with IFX showed significantly higher induction responses. No statistically significant difference was found in the comparison of response in the maintenance treatment period. Higher overall adverse events were related to IFX treatment, with serious adverse events that were nonsignificantly higher in the ADA-treated group. In conclusion, IFX demonstrated significantly higher induction responses compared to ADA in patients with moderate-to-severe UC. IFX was associated with higher overall adverse events, whereas serious adverse events were non-significantly higher in the ADA-treated group. IFX may be favored as a first-line agent for its induction efficacy, and the choice between IFX and ADA should be individualized based on comprehensive clinical evaluation.

Background Evidence on the effectiveness, long-term safety and longevity of biologic therapies in pediatric psoriasis patients is sparse. Objective This study aims to compares the efficacy, safety and drug survival (DS) rates of etanercept (ETA), adalimumab (ADA), infliximab (INF), ustekinumab (UST), secukinumab (SEC) and ixekizumab (IXE) in pediatric and adult psoriasis patients. Methods 293 biologic treatment cycles of 198 patients (62 pediatric and 136 adult) from three academic psoriasis referral centres were analysed. Results The following were the Psoriasis Area and Severity Index 90 response scores of pediatric and adult psoriasis patients, respectively: ETA, 42.3% vs. 34.6%; ADA, 53.8% vs. 59.8%; INF, 33.3% vs. 33.3%; UST, 76.5% vs. 56.8%; SEC, 60% vs. 60%; and IXE, 50% vs. 87.5%. The differences of responses between the two groups were statistically insignificant (p>0.05). ETA had the longest mean DS time in the pediatric group but it was related to a significantly shorter DS in pediatric patients than in adults (pediatrics: 30.58 [18.64–42.52] months vs. adults: 72.34 [54.70–89.99] months; p=0.025). ADA had the longest mean DS time in the adult group with 101.28 [84.88–117.68] months. All treatments had favorable safety profiles. No specific severe adverse effects necessitating treatment discontinuation were observed in pediatric patients. Conclusion Although responses to ETA and UST were numerically better among children, the difference was insignificant. The DS rates in each group were comparable, and no specific safety signals, limiting the long-term use of these agents, were detected in the pediatric group.

PURPOSE To assess the efficacy and safety of adalimumab (ADA) injections (Group 1), infliximab (IFX) (Group 2), and tocilizumab (TCZ) (Group 3) infusions in pediatric non-infectious retinal vasculitis (RV). DESIGN Retrospective interventional case series. METHODS Pediatric patients who were diagnosed with non-infectious RV and treated with biologics (ADA, IFX, TCZ) for ≥6 months were included. Chart review of 11 patients (18 eyes), 17 patients (30 eyes), and 7 patients (11 eyes) in Group 1, 2 and 3, respectively, was performed to assess clinical characteristics, central subfield thickness (CST), and fluorescein angiography (FA) score using the Angiographic Scoring for the Uveitis Working Group (ASUWOG) system. RESULTS Mean age was 13.5±4.3 years in Group 1, 11.8±2.5 years in Group 2, and 13.9±4.1 years in Group 3 (p=0.332). Eight patients (72.7%, 13 eyes) in Group 1, and 14 patients (82.4%, 24 eyes) in Group 2 were biologic-naïve, whereas in Group 3 all patients were treated with ADA and/or IFX prior to TCZ. Mean FA scores were significantly reduced from 6.8±2.6, 13.4±4.8, and 12.8±4.0 at baseline to 0.9±2.3, 3.6±4.6, and 4.4±3.9 at final visit in Group 1, 2, and 3, respectively (p<0.05). Complete RV resolution was observed in 12 (66.7%), 13 (43.3%), and 1 (9.1%) eyes; mean time to complete resolution was 11.0±5.0, 13.3±5.8, and 23 months in Group 1, 2, and 3, respectively. No significant adverse events were observed in any group, except hair loss in one patient which led to discontinuation of IFX infusions after 20 cycles of therapy. CONCLUSION ADA, IFZ, and TCZ are effective and safe treatment options for pediatric non-infectious RV as objectively shown by FA scoring. TCZ appears as an effective therapy for patients with JIA-associated RV or those who failed TNF-α inhibitors.

patients with Acute Severe Ulcerative Colitis (ASUC). This study aims to evaluate real-world e ffi cacy & safety outcomes of Upa compared to in fl iximab (IFX) in hospitalized UC patients. Methods: This retrospective cohort study used data from the TriNetX platform, comprising 64 healthcare organizations within the US Collaborative Network including 130 million patients. Two cohorts were identi fi ed: patients with ASUC treated with IFX (Cohort 1, n 5 3466) & ASUC patients treated with Upa (Cohort 2, n 5 178). Primary exposure was de fi ned as the fi rst occurrence of either treatment, with outcomes measured over a 5-year period post-exposure. One to 1 propensity score matching (PSM) balanced baseline characteristics between the cohorts including age, gender, race, laboratory values & comorbid conditions. Primary outcome analyzed was incidence of colectomy & secondary outcomes included rates of transfusion, IV steroid use, colon perforation, rectal bleeding and infection. Results: The IFX group consisted of 3,466 patients & the Upa group consisted of 180 patients before PSM. After PSM, 177 patients were included in each cohort. Notably more patients in the Upa group were previously treated with adalimumab(20.3%) and ustekinumab (25.4%); P , 0.001 with 44.1% of patients also previously on In fl iximab . No signi fi cant di ff erence was found in colectomy rates between the 2 cohorts. Furthermore,no signi fi cant di ff erences were found regarding future steroid use or rectal bleeding. A decreased incidence of colon perforation was noted in theUpa group compared to the IFX group ( P 5 0.001). Adverse events were also comparable in both groups as was the incidence of mortality (Table 1). Conclusion

Introduction: Ulcerative colitis (UC), an inflammatory Bowel Disease (IBD), is a chronic illness of unknown mechanism affecting the colonic mucosa, mainly causing diarrhea and bleeding. It can potentially disrupt the quality of life. Tofacitinib, a Janus Kinase inhibitor, showed a promising effect in inducing remission in IBD patients. In this study, we aim to assess the efficacy and safety of Tofacitinib in treating children with ulcerative colitis. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA), we searched four electronic databases (PubMed, Scopus, Cochrane Library, Embase, and Web of Science) to identify eligible studies reported up to July 2024. We reported outcomes as frequencies and proportions in our study. Results: We identified five studies encompassing 83 children diagnosed with IBD, of which 57 children had ulcerative colitis. The proportion of patients achieving a clinical response across one included study was 66.67%. The proportion of patients achieving clinical remission was 38.46%. Also, the proportion of patients achieving steroid-free remission across the three studies was 48.57%. The rate for serious adverse events was 25.53% across the three included studies. Conclusion: Tofacitinib could be useful in achieving clinical remission in children with UC and reducing colectomy rates. Also, a low infection rate and the incidence of serious adverse events were observed. Future randomized controlled trials with larger samples and longer follow-up periods are needed to support these findings.

Ustekinumab and vedolizumab are approved biologicals to treat adults with inflammatory bowel disease (IBD) but currently administered off-label for children. Aims: (1) assess safety and adverse events during treatment with ustekinumab or vedolizumab in pediatric IBD and (2) assess steroid free clinical remission and mucosal healing at 6 months and 1 year. Retrospective chart review of pediatric patients (<22 years) with IBD treated at an academic hospital and two affiliated practices. Inclusion: Patients with IBD who received either ustekinumab or vedolizumab between January 2015 to June 2022 with minimum of 6 months follow up. Clinical remission assessed by Pediatric Ulcerative Colitis Activity Index (PUCAI) < 10 and short Pediatric Crohn’s Disease Activity Index (shPCDAI) <15, and mucosal healing by fecal calprotectin <250 mcg/gram. Fifty-eight patients received vedolizumab and 55 patients received ustekinumab. Patients with ulcerative colitis (UC) or IBD unclassified (IBDU) on vedolizumab were more likely to be in remission at 6 months (58% vs. 42%, p = 0.3, Table 1) and significantly higher at achieving 1-year steroid free remission (64% vs. 27%, p = 0.019) compared to ustekinumab. Over two thirds of biologic naïve and about half of biologic exposed patients who received vedolizumab achieved 1-year steroid free remission (78% vs. 58%, Figure 1). All patients who received ustekinumab were biologic exposed. In Crohn’s disease (CD), no significant difference was seen in children receiving vedolizumab compared to ustekinumab at 6 months remission (57% vs. 63%, p = 0.7) or 1-year steroid free remission (70% vs. 70%, p >0.9). All biologic naïve patients and half of biologic exposed patients who received vedolizumab achieved 1 year steroid free remission. Both bionaive and two thirds of biologic exposed patients who received ustekinumab achieved 1-year steroid free remission (100% vs. 67%). When comparing vedolizumab and ustekinumab, no significant difference was observed in 6 month remission (73% vs. 59%, p = 0.2) and 1-year steroid free remission based on calprotectin (61% vs. 66%, p = 0.7). Similar to clinical remission rates, biologic naïve patients tended to have higher remission rates based on calprotectin. Five patients each had minor adverse events with ustekinumab and vedolizumab, and 20 were hospitalized mostly for IBD flare. Both biologicals were safe and effective in achieving clinical remission at 6 months and 1 year. They were more effective when used in bionaive patients, although numbers were very low for ustekinumab. The superior efficacy of vedolizumab in UC and IBDU at 1-year may be attributed to larger cohort of bionaive patients. Larger multicenter prospective studies are needed to validate these findings regarding efficacy and safety of vedolizumab and ustekinumab in pediatric IBD. Table 1 Remission on Vedolizumab and Ustekinumab Figure 1 Remission on Vedolizumab vs. Ustekinumab Stratified by Biologic Exposure

OBJECTIVES Mucosal healing (MH) is a key therapeutic target in Crohn's disease (CD) and is associated with improved outcomes. While adult studies indicate a positive correlation between serum anti-tumor necrosis factor (TNF) levels and MH, data in pediatric patients is limited. We aimed to define the association of serum anti-TNF levels with MH in pediatric patients with CD during maintenance therapy. METHODS Retrospective data (2014-2023) was collected from pediatric CD patients treated with infliximab or adalimumab who performed an ileocolonoscopy at least 26 weeks after initiating therapy. Serum anti-TNF levels around endoscopic time were compared with endoscopic findings. MH was defined as complete absence of inflammatory or ulcerative lesions across all segments of the gastrointestinal tract. Univariable and multivariable logistic regression analysis was conducted to identify factors associated with MH. RESULTS Data were obtained from 107 patients (41 infliximab and 66 adalimumab), with a median age at diagnosis of 12.6 (9.9-14.0) years. Median time until ileocolonoscopy following anti-TNF initiation was 89.0 (56.3-152.3) weeks. MH was identified in 31 (29.0%) patients. Anti-TNF serum levels were comparable in the MH and non-MH groups (9.5 [4.9-13.9] vs. 9.3 [6.4-15.7] µg/mL; p = 0.73), without differences in patients treated with infliximab or adalimumab. In multivariable analysis, diagnosis weight Z-score (odds ratio [OR] = 2.860, 95% confidence interval [CI] = 1.005-8.138; p = 0.049), along with C-reactive protein (OR = 0.037, 95% CI = 0.002-0.687; p = 0.027) and fecal calprotectin (OR = 0.995, 95% CI = 0.990-1.000; p = 0.037) at time of ileocolonoscopy were significantly associated with MH. CONCLUSIONS In our cohort, anti-TNF levels during maintenance were not associated with MH in pediatric CD.

Over the past few years, mucosal healing (MH) has emerged as a promising goal in the treatment of pediatric patients with Crohnʼs disease (CD). We aimed to assess whether combination therapy with infliximab (IFX) + azathioprine (AZA) was more effective than AZA therapy alone in achieving mucosal healing in pediatric patients with CD.

Infliximab (IFX), a monoclonal antibody targeting tumour necrosis factor-α, is utilised as a rescue therapy in acute severe ulcerative colitis (ASUC). The relationships between IFX concentrations in serum and colonic mucosa and the pharmacodynamic changes underlying mucosal healing are not well defined. We conducted an open-label, prospective, observational study in hospitalised patients with ASUC requiring rescue IFX to characterise the pharmacokinetics (PK) of IFX in serum and colonic mucosa, and to assess the relationships between IFX exposure, molecular signatures, and treatment response. Patients were followed for up to 22 weeks (wks), with longitudinal collection of serum samples (wks 0-22) and biopsies (day 2 and between wk 1622). Serum and tissue IFX concentrations were compared between endoscopic remitters (ERs; Mayo endoscopic subscore of 0 or 1 at wk 22 without an interim UC-related hospitalisation or colectomy) and non-remitters (NRs). RNA sequencing was performed on colonic biopsies to analyse differential gene expression and pathways between ERs and NRs. 14 patients (7 ERs and 7 NRs) completed the study. PK analysis demonstrated that ERs maintained significantly higher median dose-normalised serum IFX area under the curve than NRs during early induction (wk 0-2: 0.943 vs 0.402 µg*day/mL/mg, p = 0.007), induction (wk 014: 2.053 vs 1.223, p = 0.007), and maintenance therapy (wk 15-22: 0.823 vs 0.188, p = 0.007) (Figure 1A). In contrast, tissue IFX concentrations were similar, regardless of inflammation status or response outcome (Figure 1B). Transcriptomic profiling showed similar gene expression on day 2 between ERs and NRs. However, at end of study, profound transcriptional changes were observed in ERs, with 382 genes upregulated and 2,536 genes downregulated (Figure 2A). NRs showed only 1 end-of-study differentially expressed gene (DEG) compared to day 2 (Figure 2B). Pathway analysis of the DEGs in ERs indicated a significant decrease in both innate and adaptive immune responses. This was accompanied by a concomitant upregulation of metabolic processes, reflecting the molecular hallmarks associated with mucosal healing. Endoscopic remission in ASUC was strongly associated with high systemic IFX exposure across all treatment phases. Transcriptomic profiling showed a profound molecular differentiation, characterised by widespread suppression of inflammatory pathways and upregulation of metabolism in ERs, despite similar tissue IFX concentrations to NRs. Our study was the first to demonstrate the tissue transcriptional pharmacodynamics of IFX in ASUC while controlling for colonic drug exposure. Conflict of interest: Battat, Robert: Speaker/consulting/moderator: Bristol Myers Squibb, Johnson and Johnson Innovative Medicine, AbbVie, Takeda, Ferring, Celltrion, Pfizer, Merck, Eli Lilly Advisory boards: Celltrion, AbbVie, Pfizer, Janssen, Bristol Myers Squibb, Takeda, Merck, Eli Lilly Educational grants and educational sponsorships: Abbvie, Johnson and Johnson Innovative Medicine, Pfizer, Eli Lilly, Amgen, Pendopharm, Kye Pharma, Merck, Celltrion, Organon, Takeda Travel support: Pfizer, Celltrion, Johnson and Johnson Innovative Medicine, Abbvie. Massimino, Luca: Employee of Alimentiv Inc. Lefevre, Pavine: Employee of Alimentiv Inc. Ahmed, Waseem: No conflict of interest Charilaou, Paris: Advisory board fees from AbbVie and consulting fees from Prometheus Biosciences Boland, Brigid: consulting fees and participation on advisory board from Celltrion, Sanofi, Abbvie, Merck and has grant funding from Merck, Mirador, Prometheus, SRT Therapeutics and Gilead. Singh, Siddharth: No conflict of interest Dulai, Parambir: Grant: Takeda, Bristol Meyer Squibb, Merck, Genentech, Geneoscopy Personal Fees: Abbvie, Abivax, Alimentiv, Bristol Meyer Squibb, Boehringer Ingelheim, Celltrion, Cristcot, Genentech, Geneoscopy, Janssen, Lilly, Merck, Pfizer, Sanofi, Takeda Duijvestein, Marjolijn: Speaking fee from Bristol Meyers Squibb, Takeda, Galapagos, Janssen, Dr. Falk advisory board fees from Abbvie, Bristol Meyers Squibb, Celltrion, Galapagos/Alfasigma, Janssen, Takeda and grant/research support: Pfizer, Bristol Meyers Squibb, Galapagos Alfasigma, Janssen, MSD, Eli Lilly Eckmann, Lars: No conflict of interest Silverberg, Mark: Speaker for Abbvie, Janssen, Takeda, Pfizer, Ferring, Novartis, and Lilly. Advisor for Abbvie, Janssen, Takeda, Pfizer, Ferring, Gilead, Amgen, Merck, and Lilly. Research for Abbvie, Janssen, Takeda, Pfizer, and Gilead. Consults for Abbvie, Janssen, Takeda, Pfizer, and Lilly. Longman, Randy: Grant: Grant support from Boeringer Ingelheim. Personal Fees: Consultant for Pfizer, Sanofi, CJ Biosciences, Ancilia, Lukin, Dana: Consulting: Abbvie, Altrubio, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Palatin, Pfizer, Prime, PSI, Takeda, Vedanta. Grants: Boehringer Ingelheim, Johnson & Johnson Speaking: Abbvie, Johnson & Johnson Scherl, Ellen: Grant/research support from Abbott (AbbVie), AstraZeneca, CCFA, Janssen Research &Development, Johns Hopkins University, National Institute of Diabetes and Digestive and Kidney (NIDDK), National Institute of Health (NIH), New York Crohn’s Foundation, Pfizer, UCB, UCSF–CCFA Clinical Research Alliance, Genentech, Seres Therapeutics, Celgene Corporation. Consulting fees are reported for AbbVie, Crohn’s and Colitis Foundation of America (CCFA), Entera Health, Evidera, GI Health Foundation, Janssen, Protagonist Therapeutics, Seres Health, Takeda Pharmaceuticals, Bristol Myers Squibb. Stock shareholder of Gilead, and honoraria of GIHealth Foundation for non-branded speaker’s bureau, Janssen for non-branded speaker’s bureau. Rueffer, Matthew: Employee of Alimentiv Inc. Smith, Michelle: Employee of Alimentiv Inc. Filice, Melissa: Employee of Alimentiv Inc. Teft, Wendy: Employee of Alimentiv Inc Feagan, Brian G.: Consulting Fees: AbbVie, Abivax, Adaxion, Adiso, AgomAB Therapeutics, Akros, Alira Health, Ally Bridge Group, Apini Therapeutics, Argenx, Attovia Tx, Avoro Capital Advisors, Belmore Law, Biora Therapeutics, Blackbird Laboratories, Boehringer-Ingelheim, BMS, Boxer Capital, Celgene/BMS, Clarivate, Connect Biopharm, EcoR1, Eli Lilly, Ensho Therapeutics, Equillium, Evida, Enveda, Evommune Inc. Faes Farma, First Wave, Forbion, Galapagos, Genentech/Roche, General Atlantic, Genesis Therapeutics, Gerson Lehrman Group, Gilead, Guidepoint, Imhotex, ImiDomics, Immunic Therapeutics, Janssen, Japan Tobacco Inc., LifeMine Therapeutics, Mage Biologics, Merck, Mirador Therapeutics, Mobius Care, Monte Rosa Tx, Morphic Therapeutics, Nimbus Therapeutics, Novartis, Nxera, OncoC3, Palisade Bio, Pendopharm, Pfizer,Q32 Bio, REDX, Roche, Sanofi, Sobi, Sorriso, Spyre Therapeutics, Sun Pharma, Surrozen Inc., Synedgen, Takeda, Tegus Inc., Teva, Tillotts, Trex Bio, TR1X Inc. TVM Lifesciences, Ventyx Biosciences, Versant Ventures, Vida Ventures, Ysios Capital, Zagbio Stock Shareholder: Connect Biopharm, EnGene, Evida, SRT, Imidomics, Enveda Sandborn, William: Grant: Abbvie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, Glaxo Smith Kline, Janssen, Lilly, Pfizer, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda, Theravance Biopharma Personal Fees: Abbvie, Abivax, Admirx, Alfasigma, Alimentiv (Robarts Clinical Trials, owned by Health Academic Research Trust [HART]), Alivio Therapeutics, Allakos, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Bausch Health (Salix), Beigene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Meyers Squibb, Celgene, Celltrion, Cellularity, Cosmo Pharmaceuticals, Escalier Biosciences, Equillium, Forbion, Genentech/Roche, Gilead Sciences, Glenmark Pharmaceuticals, Gossamer Bio, Immunic (Vital Therapies), Index Pharmaceuticals, Intact Therapeutics, Janssen, Kyverna Therapeutics, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pandion Therapeutics, Pfizer, Progenity, Prometheus Biosciences, Protagonists Therapeutics, Provention Bio, Reistone Biopharma, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, Tillotts Pharma, UCB, Vendata Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences, Zealand Pharma Other: Allakos, BeiGene, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences, Progenity, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivreon Biosciences Jairath, Vipul: Consulting Fees: Abbvie, Alimentiv, Amgen, Anaptys Bio, Asahi Kasei, Asieris, Astra Zeneca, Attovia, Blackbird Labs, BMS, Boehringer Ingleheim, Biomebank, Caldera, Calluna, Catalytic Health, Celltrion, Ensho, Enthera, Exeliome Biosciences, Ferring, Fresenius Kabi, Gilead, Granite Bio, GSK, Janssen, Lilly, Merck, Mountainfield, MRM Health, Nxera, Organon, OSE Immunotherapeutics, Pendopharm, Pioneering Medicine, Pfizer, Prometheus, Roche/Genentech, Sanofi, SCOPE, Shattuck Labs, Sorriso, Spyre, Synedgen, Takeda, Teva, Tillotts, Union Therapeutics, Ventus, Ventyx, Vividion, Xencor, Zealand Pharma. Vande Casteele, Niels: Grant: Takeda, UCB Pharma, R-Biopharm Personal Fees: Janssen, Pfizer, Boehringer Ingelheim, Progenity, Prometheus, Takeda, UCB Pharma