Ustekinumab Therapy Research Articles

Long-term efficacy and survival of ustekinumab therapy in patients with inflammatory bowel disease

The article reviews data on the long-term effectiveness and survival of biological therapies for treating inflammatory bowel diseases, such as ulcerative colitis and Crohn’s disease. It highlights the shift in treatment goals, emphasizing not only induction and maintenance of remission but also long-term outcomes. The choice of therapy is becoming increasingly complex, as it must consider both clinical efficacy and endoscopic remission, which, serves as a predictor of long-term treatment effectiveness. Special attention is given to ustekinumab – antibodies targeting interleukins 12 and 23. This drug has shown high long-term effectiveness and safety in treating ulcerative colitis and Crohn’s disease. Studies indicate that ustekinumab effectively maintains clinical remission in patients, providing stable results and a low rate of serious adverse events. Long-term data also highlight its advantages over other biological agents, such as infliximab and adalimumab, in terms of therapy sustainability. The article includes data from clinical trials of ustekinumab extending up to 5 years, demonstrating good treatment sustainability, as well as various real-world practice studies confirming the prolonged effectiveness of ustekinumab in patients with ulcerative colitis and Crohn’s disease. The article evaluates and analyzes these data on long-term effectiveness and drug survival and also emphasizes the importance of an individualized approach in selecting therapy, taking into account prior treatment experience and inflammation activity.

Challenges in Managing Cytomegalovirus Colitis in a Complex Case of Ulcerative Colitis With Hyposplenism and Ustekinumab Therapy

ABSTRACT Colitis secondary to cytomegalovirus (CMV) infection is a recognized complication in patients with ulcerative colitis. This case report details a patient with a background of ulcerative colitis with resultant hyposplenism on ustekinumab therapy who presented with CMV colitis. The presence of hyposplenism with the use of ustekinumab resulted in challenges when treating the CMV infection due to the absence of immune response and required individual tailoring of therapy with higher doses of ganciclovir and valganciclovir according to trough level measurement.

Future is Brighter: New Potential Paradigm-Shifting Medications and Regimens for Diabetes and Obesity.

Diabetes is a chronic illness that can become debilitating owing to its microvascular and macrovascular complications. Its prevalence is increasing and so is its cost. Diabetes, particularly type 2, appears to have a very close relationship with obesity. While lifestyle modifications, exercises, and current therapeutics have substantially improved clinical outcomes, the need for new therapeutics and regimens continue to exist. Several new medications and regimens for diabetes, obesity, and diabesity are showing promising results in advanced clinical trials. For type 1 diabetes mellitus (T1DM), they include teplizumab, ustekinumab, jakinibs, and cell therapies, whereas for type 2 diabetes mellitus (T2DM), they include once-weakly insulin, tirzepatide, high oral dose of semaglutide, orforglipron, retatrutide, CagriSema, and survodutide. Given their structural and mechanistic diversity as well as their substantial efficacy and safety profiles, these medications and regimens are paradigm shifting and promise a brighter future. They will likely enable better disease prevention and management. This review will provide details about each of the above strategies to keep the scientific community up to date about progress in the fields of diabetes and obesity.

Comparative evaluation of Point of Care assay with ELISA techniques for quantifying serum concentrations of ustekinumab in inflammatory bowel disease patients

Objectives: to evaluate the analytical performance and clinical utility of the POC-AFIAS assay in comparison with two ELISA established assays for quantifying serum concentrations of ustekinumab.Methods: A prospective study was conducted. Consecutive serum samples from adult patients undergoing treatment with ustekinumab were collected. Three analytical techniques were compared for the quantification of ustekinumab serum concentrations: the AFIAS-10® POC assay (POC-AFIAS), the Promonitor® ELISA assay (ELISA-PRO), and the ELISA Ridascreen® assay (ELISA-RDSC).Ustekinumab concentrations were evaluated within three therapeutic ranges: <1 µg/mL, 1-4.5 µg/mL, and >4.5 µg/mL. Statistical analysis included Pearson correlation, intra-class correlation coefficient, and Bland-Altman analysis.Results: A total of 104 patients were included in the study. The median ustekinumab concentrations measured were 5.22 µg/mL (POC-AFIAS), 3.99 µg/mL (ELISA-PRO), and 4.50 µg/mL (ELISA-RDSC). Strong correlations were observed between techniques (POC-AFIAS and ELISA-PRO: r=0.921, POC-AFIAS and ELISA-RDSC: r=0.940, ELISA-PRO and ELISA-RDSC: r=0.976). The Bland-Altman analysis revealed a bias difference of 1.81 µg/mL between POC-AFIAS and ELISA-PRO, and 1.27 µg/mL between POC-AFIAS and ELISA-RDSC. Agreement rates varied by therapeutic range, with the highest agreement observed within the therapeutic range (97.3%) and lower agreement for supra-therapeutic concentrations (74.6%).Conclusion: This study demonstrated that the POC-AFIAS assay provides comparable results to established ELISA techniques for quantifying serum concentrations of ustekinumab, particularly within the therapeutic range. The findings suggest that the POC-AFIAS assay offers a rapid and effective tool for managing ustekinumab therapy in clinical practice.

S1772 Ustekinumab Therapy Is Associated with Biochemical Response in Patients with Primary Sclerosing Cholangitis and Inflammatory Bowel Disease

S1772 Ustekinumab Therapy Is Associated with Biochemical Response in Patients with Primary Sclerosing Cholangitis and Inflammatory Bowel Disease

Comparison of ustekinumab, infliximab and combination therapy in moderately to severely active ulcerative colitis - a study protocol of a randomized, multicenter, head-to-head COMBO-UC trial.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a complex etiology that affects the large intestine. Characterized by chronic, bloody diarrhea, UC can lead to severe complications, including an increased risk of colorectal cancer. Despite advancements in conservative treatment, including biologics like anti-TNF agents and ustekinumab (UST), many patients do not achieve full remission. Dual targeted therapy (DTT) combining infliximab (IFX) and UST is a promising approach to improve treatment outcomes. This prospective, randomized, multicenter, head-to-head controlled trial will evaluate the efficacy and safety of UST, IFX, and combination therapy (UST + IFX) in 172 patients with moderate to severe active UC across eight gastroenterology centers in Poland. The study includes a 14-16 week remission induction period followed by a 52-week maintenance phase. Patients will be randomly assigned to one of three treatment arms: IFX monotherapy, UST monotherapy, or IFX + UST combination therapy. Primary endpoint is clinical and endoscopic remission post-induction. Secondary endpoints include clinical response, biochemical remission, histological remission, and quality of life assessments using the Inflammatory Bowel Diseases Questionnaire and 36-Item Short Form Survey. Safety will be monitored through adverse event and serious adverse event reporting. This trial aims to determine whether combining IFX and UST can achieve higher remission rates and better long-term outcomes compared to monotherapy. The results could provide crucial insights into the optimal use of biologic agents in UC treatment, potentially establishing DTT as a standard therapy. The study's design, including extensive follow-up and robust endpoint measures, will contribute to understanding the therapeutic potential and safety profile of this combination therapy.

Comparative Efficacy and Safety of Ustekinumab and Secukinumab in the Treatment of Generalized Pustular Psoriasis: A 48-Week Retrospective Cohort Study with Genetic Background Analysis.

Recent studies have shown that novel biologics may provide significant clinical benefits for patients with generalized pustular psoriasis (GPP). Ustekinumab and secukinumab have been approved in Japan for GPP treatment in adult patients. However, the differences in efficacy and safety of these two drugs in GPP are not known. Based on the genetic background, we aimed to compare the efficacy and safety of secukinumab and ustekinumab in patients with GPP. Patients with moderate to severe GPP who were treated with ustekinumab/secukinumab at our department from July 2019 to May 2022 were included in this study and followed up for 48weeks. The difference in efficacy between ustekinumab and secukinumab was evaluated by assessing changes in body temperature, laboratory indices, recovery of skin lesions, and changes in quality of life. Additionally, we collected patients' saliva for genotyping and explored the effect of CARD14 genetic mutations on clinical efficacy. A total of 65 patients (32 adults and 33 children) with moderate to severe GPP were included in this study. 31 patients received ustekinumab therapy, and 34 patients were treated with secukinumab. Secukinumab demonstrated superiority to ustekinumab, as evidenced by a higher GPPASI 90 response at week 2. Additionally, the efficacy of ustekinumab and secukinumab was found to be independent of the presence of the CARD14 mutation. Secukinumab is superior to ustekinumab in rapidly clearing the skin and improving health-related quality of life. Moreover, the responses to ustekinumab/secukinumab in patients were not influenced by CARD14 gene mutations.

One-year Safety and Effectiveness of Ustekinumab in Patients With Crohn's Disease: The K-STAR Study.

This study investigated the safety and effectiveness of ustekinumab (UST) in Korean patients with Crohn's disease (CD). Adult patients with CD treated with UST were prospectively enrolled in the K-STAR (Post-MarKeting Surveillance for Crohn's Disease patients treated with STelARa) study between April 2018 and April 2022. Both the clinical effectiveness and adverse effects of UST therapy were analyzed. Missing data were handled using nonresponder imputation (ClinicalTrials.gov Identifier: NCT03942120). Of the 464 patients enrolled from 44 hospitals across Korea, 457 and 428 patients (Crohn's disease activity index ≥150) were included in the safety analysis and effectiveness analysis sets, respectively. At weeks 16 to 20 after initiating UST, clinical response, clinical remission, and corticosteroid-free remission rates were 75.0% (321 of 428), 64.0% (274 of 428), and 61.9% (265 of 428), respectively. At week 52 to 66, clinical response, clinical remission, and corticosteroid-free remission rates were 62.4% (267 of 428), 52.6% (225 of 428), and 50.0% (214 of 428), respectively. Combined effectiveness (clinical response + biochemical response) was achieved in 40.0% (171 of 428) and 41.6% (178 of 428) at week 16 to 20 and week 52 to 66, respectively. Biologic-naïve patients exhibited significantly higher rates of combined effectiveness than biologic-experienced patients (50.3% vs 30.7% at week 16-20, P < .001; 47.7% vs 36.0% at week 52-66, P = .014). No additional benefits were observed with the concomitant use of immunomodulators. Ileal location was independently associated with a higher probability of clinical remission compared with colonic or ileocolonic location at week 52 to 66. Adverse and serious adverse events were observed in 28.2% (129 of 457) and 12.7% (58 of 457), respectively, with no new safety signal associated with UST treatment. Ustekinumab was well-tolerated, effective, and safe as induction and maintenance therapy for CD in Korea.

AVT04: An Ustekinumab Biosimilar.

AVT04 (Uzpruvo®) is a biosimilar of the reference anti-interleukin (IL)-12 and IL-23 monoclonal antibody ustekinumab. It is approved in the EU for plaque psoriasis, paediatric plaque psoriasis, psoriatic arthritis and Crohn's disease as per the reference product. AVT04 has similar physicochemical characteristics to those of reference ustekinumab, and the pharmacokinetic similarity of the agents has been shown in healthy volunteers and patients with moderate to severe chronic plaque psoriasis. AVT04 demonstrated clinical efficacy similar to that of reference ustekinumab in patients with moderate to severe chronic plaque psoriasis, and was generally well tolerated in this population. The tolerability, safety and immunogenicity profiles of AVT04 were similar to those of reference ustekinumab, and switching from reference ustekinumab to AVT04 had no impact on efficacy, safety or immunogenicity. The role of reference ustekinumab in the management of inflammatory diseases is well established and AVT04 provides an effective biosimilar alternative for patients requiring ustekinumab therapy.

A High Visceral-to-Skeletal Muscle Area Ratio on Cross-Sectional Imaging Is Associated With Failure of Standard Ustekinumab Doses: A Multicenter Study.

Anti-interleukin 12/23 agents have shown greater durability in response compared with anti-tumor necrosis factor α agents. Data on the association between body composition (BC) or body mass index (BMI) and ustekinumab's therapeutic response is limited. We aimed to evaluate the impact of BC on time to failing standard doses of ustekinumab in patients with Crohn's disease (CD). Patients with CD aged 16 years and older from 2 tertiary centers were studied retrospectively. Included patients had abdominal imaging within 6 months of ustekinumab induction and were followed until April 30, 2022. An experienced abdominal radiologist blinded to the clinical information measured the area of visceral fat area and skeletal muscle area at the mid L3 vertebral level, with values corrected for height 2 to derive respective indices (visceral fat index [VFI], skeletal muscle index [SMI]) and the VFI:SMI ratio. Ninety-nine patients met inclusion criteria. The mean age at ustekinumab induction was 46.6 (±1.6) years. The median BMI (interquartile range) was 26.5 (22.6-30.8). Twenty-four patients (24.2%) did not respond or lost response to standard doses of ustekinumab over the follow-up duration. A younger age (hazard ratio 0.96, 95% confidence interval 0.94-0.99, P = 0.01) and a VFI:SMI ratio >1.6 (hazard ratio 4.65, 95% confidence interval 1.73-12.45, P = 0.002) were both associated with a shorter time to failing ustekinumab at standard doses on multivariate analysis. BMI, notably, had no association with the primary outcome. A high VFI:SMI ratio is associated with an increased risk of failing standard doses of ustekinumab. BC measurements derived from cross-sectional imaging at the start of ustekinumab therapy is a useful indicator for therapeutic durability.

Intestinal mRNA expression profiles associated with mucosal healing in ustekinumab-treated Crohn's disease patients: bioinformatics analysis and prospective cohort validation

BackgroundVariations exist in the response of patients with Crohn’s disease (CD) to ustekinumab (UST) treatment, but the underlying cause remains unknown. Our objective was to investigate the involvement of immune cells and identify potential biomarkers that could predict the response to interleukin (IL) 12/23 inhibitors in patients with CD.MethodsThe GSE207022 dataset, which consisted of 54 non-responders and 9 responders to UST in a CD cohort, was analyzed. Differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Least absolute shrinkage and selection operator (LASSO) regression was used to screen the most powerful hub genes. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performances of these genes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was used to estimate the proportions of immune cell types. These significantly altered genes were subjected to cluster analysis into immune cell-related infiltration. To validate the reliability of the candidates, patients prescribed UST as a first-line biologic in a prospective cohort were included as an independent validation dataset.ResultsA total of 99 DEGs were identified in the integrated dataset. GO and KEGG analyses revealed significant enrichment of immune response pathways in patients with CD. Thirteen genes (SOCS3, CD55, KDM5D, IGFBP5, LCN2, SLC15A1, XPNPEP2, HLA-DQA2, HMGCS2, DDX3Y, ITGB2, CDKN2B and HLA-DQA1), which were primarily associated with the response versus nonresponse patients, were identified and included in the LASSO analysis. These genes accurately predicted treatment response, with an area under the curve (AUC) of 0.938. T helper cell type 1 (Th1) cell polarization was comparatively strong in nonresponse individuals. Positive connections were observed between Th1 cells and the LCN2 and KDM5D genes. Furthermore, we employed an independent validation dataset and early experimental verification to validate the LCN2 and KDM5D genes as effective predictive markers.ConclusionsTh1 cell polarization is an important cause of nonresponse to UST therapy in patients with CD. LCN2 and KDM5D can be used as predictive markers to effectively identify nonresponse patients.Trial registration: Trial registration number: NCT05542459; Date of registration: 2022-09-14; URL: https://www.clinicaltrials.gov.

Baseline Assessment of Serum Cytokines Predicts Clinical and Endoscopic Response to Ustekinumab in Patients With Crohn's Disease: A Prospective Pilot Study.

No biomarkers are currently available to predict therapeutic response to ustekinumab (UST) in Crohn's disease (CD). The aim of this prospective study was to identify 1 or more cytokines able to predict mucosal healing in patients with CD treated with UST. We prospectively enrolled consecutive CD patients treated with UST. At weeks 0 (baseline), 24, and 48, a panel of serum cytokines was measured by a fluorescence assay. At the same time points, fecal calprotectin (FC) was assessed. A colonoscopy was performed at baseline and at week 48, where therapeutic outcome was evaluated in terms of mucosal healing. Out of 44 patients enrolled, 22 (50%) achieved mucosal healing at the end of follow-up. Response was associated with higher interleukin (IL)-23 levels (P < .01). Fecal calprotectin levels decreased over time in responders but did not change in nonresponders (test for the interaction between time and mucosal healing, P < .001). This pilot study showed that IL-23 and FC could be reliable biomarkers in predicting therapeutic outcome to UST therapy in CD. In particular, the correlation between baseline serum levels of IL-23 and mucosal healing at 48 weeks is particularly strong, paving the way for its use to drive therapeutic decisions.

Persistence, effectiveness and safety of ustekinumab and vedolizumab therapy for complex perianal fistula in Crohn's disease: The HEAL study from GETECCU

The efficacy of ustekinumab and vedolizumab for treating complex perianal fistula in Crohn's disease has been barely studied. We aimed to assess treatment persistence, clinical remission, and safety of these drugs in this context. Crohn's disease patients who had received ustekinumab or vedolizumab for the indication of active complex perianal fistula, were included. Clinical remission was defined according to Fistula Drainage Assessment Index (no drainage through the fistula upon gentle pressure) based on physicians' assessment. Of 155 patients, 136 received ustekinumab, and 35 vedolizumab (16 received both). Median follow-up for ustekinumab was 27 months. Among those on ustekinumab, 54 % achieved remission, and within this group, 27 % relapsed during follow-up. The incidence rate of relapse was 11 % per patient-year. Multivariate analysis found no variables associated with treatment discontinuation or relapse. Median follow-up time for patients receiving vedolizumab was 19 months. Remission was achieved in 46 % of the patients receiving vedolizumab, and among them, 20 % relapsed during follow-up. The incidence rate of relapse was 7 % per patient-year. Adverse events were mild in 6 % on ustekinumab and 8 % on vedolizumab. Ustekinumab and vedolizumab appear effective, achieving remission in around half of complex perianal fistula patients, with favorable safety profiles.

Effectiveness and Safety of Ustekinumab in Pediatric Ulcerative Colitis: A Multi-center Retrospective Study from the Pediatric IBD Porto Group of ESPGHAN.

Current data on ustekinumab therapy in children with ulcerative colitis (UC) or unclassified inflammatory bowel disease (IBDU) are limited. We aimed to evaluate the effectiveness and safety of ustekinumab in pediatric UC and IBDU. This multicenter retrospective study included 16 centers affiliated with the IBD Interest and Porto groups of ESPGHAN. Children with UC or IBDU treated with ustekinumab were enrolled. Demographic, clinical, laboratory, endoscopic, and imaging data as well as adverse events were recorded. Analyses were all based on the intention-to-treat principle. Fifty-eight children (39 UC and 19 IBDU, median age 14.5 [IQR 11.5-16.5] years) were included. All had failed biologic therapies, and 38 (66%) had failed two or more biologics. Corticosteroid-free clinical remission (CFR) was observed in 27 (47%), 33 (57%), and 37 (64%) children at 16, 26, and 52 weeks, respectively. Normalization of C-reactive protein and calprotectin <150μg/g were achieved in 60% and 52%, respectively, by 52 weeks. Endoscopic and radiologic remissions were reached in 8% and 23%, respectively. The main predictors of CFR were diagnosis of UC compared with IBDU (hazard ratio [HR] 2.2, 95% CI 1.03-4.85; p=0.041) and no prior vedolizumab therapy (HR 2.1, 95% CI 1.11-4.27; p=0.023). Ustekinumab serum levels were not associated with disease activity. Adverse events were recorded in six (10%) children, leading to discontinuation of the drug in three. Based on these findings, ustekinumab appears as an effective therapy for pediatric refractory UC and IBDU. The potential efficacy should be weighed against the risks of serious adverse events.

Ustekinumab in pediatric patients with Crohn's disease: safety, and efficacy results from a multicenter retrospective study in China.

Ustekinumab (UST) is approved as an effective therapy for Crohn's disease (CD) in adults. Off-label use is increasing in the pediatric population, more data on safety and efficacy in pediatric patients with CD is urgently needed. This study aimed to evaluate the clinical efficacy and safety of UST in children and adolescents with Crohn's disease. This multicenter retrospective study carried out at three tertiary care centers, and identified children who received their first dose of UST at 18 years old or younger and followed up for a minimum of 24 weeks. Data on demographics, disease behavior, location and activity, treatment history were collected. The primary outcomes were clinical remission at weeks 24-32 and weeks 48-56 of UST therapy. Secondary outcomes were clinical response at the same time points, endoscopic remission, changes in C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin and fecal calprotectin, improvement in growth parameters, and rate of adverse events. Sixteen patients were included, and 11/13 (84.6%) continued to receive UST after 1 year. Our data demonstrate that the clinical remission rates were 41.7% at weeks 24∼32 with the Weighted pediatric CD activity index (wPCDAI) was lower than baseline (43.8, IQR: 31.3-51.9 vs.15, IQR: 5.6-25, p < 0.001) and 75% at weeks 48-56 with wPCDAI was lower than baseline (42.5, IQR: 23.8-50 vs. 7.5, IQR: 0-13.8, p = 0.004). Five of eleven children achieved endoscopic remission. No serious adverse events were recorded during the study period. UST is efficacious and safe in pediatric patients with CD. Pediatric patients could benefit from UST as either a primary or secondary biologic therapy for the induction, or maintenance of remission of CD.

Difficult-to-treat inflammatory bowel disease: Effectiveness and safety of 4th and 5th lines of treatment.

Many patients with inflammatory bowel disease (IBD) have signs or symptoms of active disease despite multiple treatment attempts. This emerging concept is defined as difficult-to-treat IBD. The objective of this study was to investigate for the first time the treatment persistence, efficacy and safety of biologics or small molecules used in 4th or 5th line therapy. We reviewed all consecutive patients with IBD treated at the Nancy University Hospital between July 2022 and April 2023 with the 4th or 5th line treatment for at least three months. The primary outcome was to assess the persistence rate of 4th and 5th line therapy. We enrolled 82 patients with IBD (4th line: 44; 5th line: 38). On Kaplan-Meier analysis, the duration of risankizumab, ustekinumab or vedolizumab therapy did not differ significantly (p>0.05) as 4th and 5th line treatment. The restricted mean survival time analysis showed that the persistence rate of risankizumab was the highest as 4th line therapy (risankizumab vs. vedolizumab: 36.0 and 29.4weeks, respectively, p=0.008; risankizumab vs. ustekinumab: 36.0 and 32.8weeks, respectively, p=0.035). In multivariate regression, Crohn's disease diagnosis (Odd ratio 4.6; 95% confidence interval 1.7-12.4) was significantly associated with treatment persistence. In this first real-world setting, risankizumab could have a longer persistence rate as 4th line treatment for IBD than other agents. Persistence of biological agents was greater in Crohn's disease than in ulcerative colitis. More studies are needed to compare treatment efficacy in patients with difficult-to-treat IBD.

Association between Ustekinumab Trough Levels, Serum IL-22, and Oncostatin M Levels and Clinical and Biochemical Outcomes in Patients with Crohn's Disease.

Background: Ustekinumab (UST) has demonstrated effectiveness in treating patients with Crohn's disease. Monitoring treatment response can improve disease management and reduce healthcare costs. We investigated whether UST trough levels (TLs), serum IL22, and Oncostatin M (OSM) levels could be early indicators of non-response by analysing their correlation with clinical and biochemical outcomes in CD. Methods: Patients with CD initiating UST treatment from October 2018 to September 2020 were enrolled at six Italian centres for inflammatory bowel disease (IBD). Clinical and biochemical data were collected at four time points: baseline, second subcutaneous (SC) dose, fourth SC dose, and 52 weeks. TLs were measured during maintenance, at the second SC dose, and at the fourth SC dose. IL-22 and OSM serum levels were assessed at baseline and the second SC dose. We analysed whether TLs, IL22 levels, and OSM serum levels were associated with clinical response, clinical remission, biochemical remission, and endoscopic remission using the appropriate statistical tests. Results: Out of eighty-four initially enrolled patients, five were lost to follow-up, and eleven discontinued the drug before 52 weeks. At the 52-week time point, 47% achieved biochemical remission based on faecal calprotectin levels, and 61.8% achieved clinical remission. TLs at the second SC dose significantly correlated with biochemical remission at the same time point (p = 0.011). However, TLs did not correlate with clinical remission. Baseline OSM levels did not correlate with biochemical or clinical remission or response. IL22 levels notably decreased during UST therapy (p = 0.000), but its values did not correlate with biochemical or clinical remission. Conclusions: UST is an effective therapy for patients with CD. TLs measured at the second SC dose significantly correlated with biochemical remission, emphasising their potential role in treatment monitoring. Levels of OSM and IL-22, despite a significant decrease in the latter during therapy, did not exhibit correlations with clinical or biochemical outcomes in our study. Further studies are needed to confirm these findings.

A222 CLINICAL EFFECTIVENESS AND SAFETY OF USTEKINUMAB IN YOUTH WITH REFRACTORY INFLAMMATORY BOWEL DISEASE IN SAUDI ARABIA: A RETROSPECTIVE COHORT STUDY

Abstract Background Inflammatory bowel disease (IBD) incidence and prevalence have been increasing worldwide with higher disease severity observed in pediatrics. Limited data exists on the effectiveness of ustekinumab (UST) in children. Aims To describe the effectiveness and safety of UST in pediatric patients with IBD. Methods A retrospective, single-center cohort study was conducted between January 2017 and February 2022. The study included patients ≤16 years of age who were treated with off-label UST and followed up for a minimum of one year. Clinical remission was defined as a decrease in the score on the Pediatric Crohn's Disease (CD) and Pediatric Ulcerative Colitis (UC) Activity Indices to ≤10 at week 52. Results A total of 13 patients who had failed anti-TNFα therapy were included, 8 (61.5%) with CD and 5 (38.5%) with UC. The median age of the patients was 13y (IQR: 11.5 to 14). UST treatment was initiated at a median of 3y (IQR: 2.3 to 7) after diagnosis. Ten patients (76.9%) achieved clinical remission. There were no statistically significant differences in baseline characteristics between patients who achieved and did not achieve clinical remission. Biochemical remission was achieved in 6 patients (46.2%). C-reactive protein levels decreased significantly in the remission group and insignificantly in the non-remission group. No significant changes were observed in erythrocyte sedimentation rate, albumin, or hemoglobin. BMI improved (Fig 1) and the need for corticosteroids significantly decreased after UST therapy in the remission group (P = 0.014). Endoscopy conducted post-treatment in 7 patients confirmed remission in 6 patients, with one patient showing clinical remission but not endoscopic remission. Adverse events included two instances of infection and once case of headache. Conclusions UST was effective as a secondary biologic therapy for the induction and maintenance of remission in patients with anti-TNFα refractory IBD. At one year, 84% of patients remained on UST with no severe adverse reactions reported. Future prospective large-scale studies are necessary to assess the therapeutic positioning and optimal dosing regimens of UST in pediatric IBD. Figure 1. Change in BMI Z-score throughout the study (P value of interaction = 0.049). Funding Agencies None

SAFETY OF ANTI-TUMOR NECROSIS FACTOR AGENTS COMPARED TO USTEKINUMAB AND VEDOLIZUMAB IN ELDERLY PATIENTS WITH ULCERATIVE COLITIS

Abstract BACKGROUND Common first-line treatments for ulcerative colitis (UC) currently include anti-tumor necrosis factor (anti-TNF) agents, ustekinumab (interleukin-12/interleukin-23 receptor antagonist), and vedolizumab (integrin antagonist). However, there are safety concerns when prescribing biologic therapies to elderly patients. While these medications have all demonstrated general efficacy and safety in UC, this study aims to examine the long-term comparative safety of anti-TNF agents with vedolizumab and ustekinumab in elderly patients with UC. METHODS The Research Network on TriNetX database was accessed on September 26, 2023, to identify patients at least 65 old who were diagnosed with UC: the first cohort included patients prescribed anti-TNF agents (included adalimumab, certolizumab pegol, golimumab, and infliximab) and the second cohort included patients prescribed either vedolizumab or ustekinumab. Primary outcomes included mortality, corticosteroid use, subsequent colectomy, colon cancer, infections, and all-cause hospitalizations within 10 years after matching for age, sex, and race. All analyses were performed in real-time using built-in statistical algorithms on TriNetX. RESULTS After matching cohorts, 1,075 elderly patients with UC patients were included in each cohort as shown in table 1. Patients who were prescribed anti-TNF therapy had a significantly increased 10-year risk of mortality (10.7%) compared to patients on either vedolizumab or ustekinumab therapy (5.77%) (OR 1.96, 95% CI [1.42, 2.7], p &amp;lt;0.0001). Corticosteroid use was higher in the anti-TNF cohort (40.6% vs 34.9%, p= 0.007). There were no significant differences between the two cohorts when comparing the need for colectomy (3.26% vs 2.23%, p = 0.15) or colorectal cancer occurrence (1.67% vs 2.05%, p=0.52) within 10 years. However, the anti-TNF cohort had a higher risk of all-cause hospitalization (32.5 % vs 22%, p=&amp;lt;0.0001), respiratory tract infections (18.4% vs 14.5%, p=0.015), and urinary tract infections (10.4% vs 7%, p=0.005). CONCLUSION In elderly patients with UC, ustekinumab or vedolizumab are safer treatment options compared to anti-TNF therapy. Table 1 Demographics and Comparative 10-year Outcomes of Elderly Patients with UC.

P085 Tc17 cells with a distinct immune signature do not correlate with response to therapy with ustekinumab or TNF antibodies in active Crohn’s Disease

Abstract Background IL-17 producing CD8+ T cells (Tc17) expressing a specific immune signature (CD6high, CD39, CD69, PD-1, CD27low) were shown to be associated with active Crohn’s Disease (CD) and inform flare free survival. Here, we addressed the question whether Tc17 cells and their signature also correlate with response of CD patients to therapies with antibodies targeting TNFα or IL-12/23. Methods Peripheral blood mononuclear cells were longitudinally collected from CD patients prior to and up to 35 weeks after initiation of therapy with either TNF antibodies or ustekinumab and CD8+ T cells were analyzed by flow cytometry. Results were correlated with clinical outcomes. Results We analyzed dynamic changes during treatment in blood samples of 36 CD patients initiating anti-TNF (n = 14) or ustekinumab therapy (N = 22). Baseline Tc17 frequencies differed between ustekinumab and anti-TNF treatment groups, with significantly higher frequencies in the ustekinumab group. This may be due to differences in the baseline patient characteristics; while ustekinumab treated patients were all previously treated with anti-TNF-antibodies, most of the anti-TNF treated patients were naïve to biologics. Indeed, Tc17 frequencies increased during anti-TNF treatment, while Tc17 frequencies were reduced at follow up in the ustekinumab group. However, Tc17 frequencies in the peripheral blood at baseline did not correlate with response to either therapy, nor did the frequencies of Tc17 cells expressing Tc17 signature proteins. The expression of Tc17 signature proteins by IL-17A producing CD8+ T cells did not change significantly during follow up, suggesting that the Tc17 signature was preserved during anti-TNF and ustekinumab therapy. We did not observe major changes in the production of pro-inflammatory cytokines by Tc17 cells during therapy. Conclusion Our data suggest that despite playing a pathogenic role in CD, Tc17 cells with a distinct immune signature do not directly correlate with response to therapy with anti-TNF agents or ustekinumab. However, anti-TNF therapy may skew CD8 T cell differentiation towards a Tc17 phenotype, which may have an impact on long term disease outcomes and should be investigated further.