Ustekinumab Therapy Research Articles

P1163 Treatment-based risk stratification of serious and opportunistic infections in IBD patients from an tertiary center in brazil: a comparison between advanced therapies and non-biologic exposure in real world setting

Abstract Background The risks of serious and opportunistic (OIs) infections associated with advanced therapies for IBD is one of the main concerns of both physicians and advanced practice clinicians in IBD care. We assessed the incidence and stratify the risk of serious infections or OIs in patients with IBD treated with advanced therapy. Methods We performed an ambispective observational study of adults patients with a diagnosis of IBD in a tertiary IBD center located in Brazil. We retrospectively analyzed the IBD patients from 2014 to 2017 and prospectively those from 2018 to 2022. Serious infections were defined as those requiring intravenous antibiotic therapy or hospitalization. The incidence (per 100 patient-years) and risks of serious and OIs associated with exposure to combination therapy (anti-TNF and thiopurines), monotherapies with anti-TNF, vedolizumab, ustekinumab or tofacitinib were compared with exposure to aminosalicylates using marginal structural Cox proportional hazard models adjusted for baseline characteristics and medications. Results Among the 504 patients, 75 serious infections and 35 OIs were observed, resulting in overall incidence rates of serious infections and OIs of 3.1 and 1.1 per 100 PY, respectively. Overall incidence rates of serious infections ranged from 0.1, 0.15, 0.13, 0.16, 1.2., and 3.1 per 100 PY in those exposed to aminosalicylates, ustekinumab, vedolizumab, tofacitinib, anti-TNF monotherapy, and combination therapy, respectively. Conversely, the overall incidence rates of OIs ranged from 0, 0.1, 0.1, 0.3, 0.9, and 2.1 per 100 PY in those exposed to aminosalicylates, ustekinumab, vedolizumab, tofacitinib, anti-TNF monotherapy, and combination therapy, respectively. OIs were mostly due to Mycobacterium tuberculosis (n=21) and herpes zoster (n=11). Compared with aminosalicylates, vedolizumab and ustekinumab therapy did not increase the risk of serious infections and OIs (HR, 0.93; 95% CI, 0.42-1.81). Conversely, tofacitinib, anti-TNF monotherapy and combination therapy were associated with increased risks of OIs (HR, 1.13; 95% CI, 1.05-2.01), HR, 2.13; 95% CI, 1.92-5.81 and HR, 32.3; 95% CI, 19.21-40.53, respectively). Conclusion Anti-TNF therapy and combotherapy were associated with an increased risk of serious infections and OIs, while vedolizumab and ustekinumab presented a insignificant risk of these infections. Tofacitinib was associated with a small increased risk of OIs. Tuberculosis was the main OI, and was associated exclusively with the use of anti-TNF monotherapy or combotherapy. In choosing advanced therapy for IBD, clinicians should consider, among other factors, the risk of serious infections and OIs and weighed against potential benefits of the various targeted therapies for IBD.

P0070 Distinct Serum Proteome Alterations Following Vedolizumab and Ustekinumab Therapy in IBD Patients

Abstract Background Inflammatory bowel disease (IBD) is a chronic intestinal disorder characterized by relapse and remission. Dysregulated cytokine networks and excessive immune activation drive intestinal inflammation. Therapies targeting cytokines (e.g., TNF, IL-12/23) and immune cell trafficking (e.g., integrin inhibitors) have been effective. However, the impact of anti-integrin (vedolizumab) and anti-IL-12/23 (ustekinumab) therapies on systemic inflammation is poorly understood. This study compares serum proteome profiles of patients treated with vedolizumab or ustekinumab to elucidate their distinct effects on inflammatory pathways. Methods This study included patients with Crohn’s disease (CD), ulcerative colitis (UC), and age- and sex-matched healthy donors (HD), who received either ustekinumab or vedolizumab treatment. The ustekinumab cohort comprised 23 CD and 10 UC patients, while the vedolizumab cohort included 7 CD and 27 UC patients. Serum samples were collected from ustekinumab-treated patients at baseline (week 0) and 8 weeks post-treatment, and from vedolizumab-treated patients at baseline (week 0) and 6 weeks post-treatment. Additionally, serum samples were collected from 32 healthy donors. Proteomic analysis was performed using the Olink Inflammation Panel, measuring 92 inflammation-related proteins. Differential protein expression analysis was conducted to compare baseline and post-treatment samples within each cohort. Results Serum proteomic analysis using the Olink Inflammation panel revealed significant alterations in the levels of 15 proteins in IBD patients compared to healthy controls. Pro-inflammatory markers, including 4E-BP1, SIRT2 and TNF were significantly upregulated, indicating immune activation in IBD. Conversely, anti-inflammatory regulators, such as LIF-R and SCF, were significantly downregulated. Ustekinumab treatment led to upregulation of IL-12B and downregulation of 4E-BP1, SIRT2. Notably, IL-12B was upregulated in both CD and UC, while 4E-BP1 and SIRT2 were downregulated in CD (week 8 vs week 0). Conversely, vedolizumab treatment induced robust proteomic changes over time. Between week 0 and week 6, majority of proteins showed significant differential expression, more than the differences observed between IBD and HD groups. Conclusion Serum proteomic profiles of IBD patients differ from healthy donors. Ustekinumab induced minimal serum changes, indicating a limited systemic effect, while vedolizumab led to substantial proteomic shifts, suggesting broader modulation of inflammation. These distinct effects highlight the differing mechanisms of ustekinumab and vedolizumab on systemic inflammation in IBD, prompting further investigation to optimize therapeutic strategies.

P1300 HLA-C*06 Genotype and Ustekinumab Therapy Persistence in Inflammatory Bowel Disease

Abstract Background Ustekinumab (UST) is an anti-IL12/23 monoclonal antibody approved for use in psoriasis and inflammatory bowel disease (IBD). HLA-C*06 allele carriage has been associated with higher rates of response to UST in psoriasis patient populations.1 The association between HLA-C*06 carriage and UST response in IBD has not been previously evaluated. We aimed to further explore HLA-C*06 carriage as a pharmacogenetic marker as a response to UST therapy in IBD patients. Methods A multi-centre retrospective study of IBD patients treated with UST in Ireland was performed. Baseline demographics of the cohort were collected. HLA-C*06 genotypes were generated by imputation from whole genome sequence using HIBAG. UST therapy persistence, was considered a proxy for treatment response, and was expressed as time to discontinuation of UST therapy. The primary endpoint was UST therapy persistence segregated by HLA-C*06 allele genotype. Statistical analysis was performed using survival analysis and multivariate cox logistic regression with effect of covariates on outcome expressed as odds ratios (OR). Results 143 IBD patients were identified and included in the study population. In this population, 32 patients (22%) carried at least one HLA-C*06 allele. There was no significant difference in median time to UST therapy discontinuation comparing HLA-C*06 carriers to non-carriers at 700-days follow-up, p=0.32 [Figure 1]. In a multivariate regression neither HLA-C*06 allele carriage (OR 1.2, p=0.5), male gender (OR 1.2, p=0.6), CD phenotype (OR 1.6, p=0.44), nor concomitant immunomodulator use (OR 1.1, p=0.8) were independently associated with time to UST therapy discontinuation. Conclusion HLA-C*06 allele carriage is not associated with increased UST therapy persistence in IBD. Larger studies of UST therapy outcome in IBD patients with characterised HLA-C*06 genotype are required to confirm this finding.

P0972 Higher vedolizumab clearance associates with poor therapeutic outcomes during maintenance therapy of vedolizumab in Crohn’s disease

Abstract Background Drug Clearance (CL) is a better pharmacokinetic (PK) metric compared to trough levels (TL) in associating with therapeutic outcome of infliximab, adalimumab and ustekinumab therapy in Crohn’s disease (CD). However, data regarding vedolizumab (VDZ) are limited. We compared the performances of VDZ CL and TL in associating with therapeutic outcomes in CD. Methods This retrospective analysis included a subset patients from the LOVE-CD trial at Amsterdam UMC. Blood samples were collected at trough during intravenous VDZ maintenance treatment and stored at -80ºC until analysis. VDZ TL were measured using homogenous mobility shift assay and CL was estimated using nonlinear mixed effect models. Therapeutic outcomes consisted of endoscopic remission (Simple Endoscopic Scoring for CD [SES-CD] <3) measured at one-year after starting treatment, and clinical and biochemical remission status (CRP <3 mg/L with CD activity index <150) at each maintenance cycle. Statistical analyses included receiver operating characteristics (ROC) curves, area under the curve (AUC) and logistic regression. Results A total of 50 patients (24 females, mean age 37 years) were evaluated in this analysis. At one year 39 patients had endoscopic data; 17/39 (44%) were in endoscopic remission. In the 50 patients, 38% of cycles (120/312, median 6 per patients) showed clinical and biochemical remission. Median TL and CL were 16.0 µg/mL (IQR: 9.5-23.8 µg/mL) and 0.154 L/day (IQR: 0.125-0.190 L/day) respectively. Anti-drug antibodies to VDZ were negligible in this cohort (2.5%, 8/323 specimens). ROC analysis yielded higher AUC with CL (AUC= 0.824 [95%CI: 0.683-0.964]) than with TL (AUC=0.606 [95%CI: 0.421- 0.790]) (difference= 0.218 95%CI: 0.074- 0.362; p=0.003) in distinguishing endoscopic remission from endoscopic active disease. Similar results were observed with the clinical and biochemical remission outcome (AUC [conc]=0.530 [95%CI: 0.466-0.595] compared to AUC[CL]=0.646 [95%CI: 0.584- 0.709]) (difference: 0.116 95%CI: 0.063- 0.169; p<0.001). Logistic regression revealed that TL were not significantly associated with either of the two outcomes (p>0.28) (Figure). In contrast, higher CL (>0.156 L/day) was associated with 9.0-fold (95%CI: 1.7,44.0) and 2.1-fold (95%CI: 1.3,3.4) lower likelihood of endoscopic and clinical & biochemical remission, respectively (p<0.01) (Table). Conclusion These data support the hypothesis that VDZ CL is better than TL in associating with outcomes of VDZ treatment in CD. Given that there was little immune response to VDZ in this study, the association between higher CL and poor outcome most likely reflects higher inflammatory burden that consumes the drug from the central compartment.

P0717 Real-world data of Mirikizumab in the induction and maintenance therapy for ulcerative colitis

Abstract Background Mirikizumab, a humanized IgG4 monoclonal antibody binding subunit p19 of interleukin 23, has been approved for the therapy of ulcerative colitis since May 2023. Phase 3 studies showed significant efficacy in both inducing and sustaining clinical remission in patients with moderate to severe active ulcerative colitis. Methods All patients with active ulcerative colitis who began induction therapy with Mirikizumab at our outpatient clinic between July 2023 and June 2024 were analyzed retrospectively with a follow-up period until October 2024. Patients with prednisolone therapy exceeding 20 mg, loperamide intake or deviation of standard clinical application period were excluded. The primary endpoints were defined as achieving clinical remission following the completion of intravenous induction (at weeks 12, 16 or 24) and the maintenance of clinical remission at any time between week 8 and week 49 following the initiation of subcutaneous application. Secondary endpoints included rates of clinical remission and relapse in patients previously treated with Ustekinumab, a monoclonal antibody targeting the p40 subunit of interleukin-12 and -23. Results A total of 40 patients started Mirikizumab induction therapy, with 23 meeting the inclusion criteria. Seventeen patients were observed in the maintenance period. After completion of induction, 20 out of 23 patients (87.0%) achieved clinical remission. Among these, 12 (60.0%) had previously been treated with Ustekinumab. During the maintenance period, 6 out of 17 patients (35.3%) experienced a relapse, of whom 5 (83.3%) had prior therapy with Ustekinumab. Within the Ustekinumab subgroup, 5 out of 10 patients (50.0%) suffered relapse after initially achieving clinical remission. Conclusion Mirikizumab is an effective therapy in patients with active ulcerative colitis, including those who had a prior loss of response to Ustekinumab therapy. Patients with prior Ustekinumab therapy exhibited a higher rate of relapse during the maintenance phase.

OP12 Therapeutic antibody clearance better predicts endoscopic outcomes than trough concentrations in patients with Crohn’s disease

Abstract Background Monitoring of monoclonal antibody (mAb) clearance has been suggested for prediction and follow-up of treatment outcomes in patients with inflammatory bowel diseases. We investigated clearance monitoring in patients with Crohn’s disease (CD) using data from clinical trials. Methods Data from patients with moderate-to-severe CD starting infliximab (n=108; TAILORIX trial [1]) and ustekinumab (n=80; a real-life cohort study [2]) therapy were repurposed. Endoscopic remission (CD Endoscopic Index of Severity <3) was assessed at week (w)12 and w54 of infliximab therapy. Endoscopic response (≥50% reduction in Simple Endoscopic Score for CD) was assessed at w24 of ustekinumab therapy. We performed Bayesian forecasting to estimate time-varying mAb clearance using measured drug concentrations, covariates, and population pharmacokinetics models (NONMEM 7.5). A novel software tool for clearance monitoring of infliximab and ustekinumab was developed using the Shiny and mapbayr packages in R. Results Baseline demographics and clinical characteristics of the patients are summarized in Table 1. Patients achieving endoscopic remission at w12 had significantly lower infliximab clearance and higher infliximab serum trough concentrations (Ctrough) at w2 and w6 of standard 5 mg/kg infliximab induction therapy, than patients without endoscopic remission (p<0.05). During infliximab maintenance therapy (with eventual dose optimisations), patients achieving endoscopic remission at w54 had significantly lower infliximab clearance (p<0.001) but not higher infliximab Ctrough (p=0.92) than patients without endoscopic remission. Moreover, infliximab clearance during maintenance had similar discriminative ability as faecal calprotectin (area under the receiver operating characteristics curve 0.63 [95% confidence interval 0.57–0.69] vs. 0.67 [0.61–0.73], respectively) (Figure 1). Ustekinumab clearance (p<0.05), but not Ctrough, was significantly different between endoscopic responders and non-responders during standard ustekinumab induction and maintenance therapy. We developed an evidence-based interactive software tool that can predict the probability of achieving endoscopic outcomes in a clinical setting based on the estimated clearance of infliximab and ustekinumab (https://lpmx.shinyapps.io/clearance_monitoring/). Conclusion While Ctrough loses its ability to predict treatment response when doses are optimised or not administered by bodyweight, mAb clearance remains a reliable predictor. Our interactive clearance monitoring tool can forecast the chance of achieving endoscopic outcomes and distinguish between exposure-driven and mechanistic failure when patients with CD are dose-optimised.

P0876 One-year effectiveness and safety of ustekinumab treatment in patients with ulcerative colitis: An Asan-Crohn’s and Colitis Association in Daegu-Gyeongbuk (CCAiD) multicentre real-world cohort study

Abstract Background The real-life data on ustekinumab (UST) for Asian patients with ulcerative colitis (UC) are limited. We aimed to assess one-year effectiveness and safety of UST for Korean patients with UC. Methods This was a multicentre retrospective study on patients with UC who received UST at 4 academic centers in Korea between January 2021 and October 2023. The primary endpoint was clinical remission defined as partial Mayo score (PMS) ≤2 and no subscore >1 at week (W) 8 of therapy. Secondary endpoints included clinical remission (W16–20 and W52–56), corticosteroid-free clinical remission (W8, W16–20, and W52–56), clinical response (W8, W16–20, and W52–56), endoscopic remission defined as Mayo endoscopic subscore (MES) 0–1 (W16–20 and W52–56), interval shortening and durability of UST therapy till W52–56, and adverse events. Results A total of 60 patients (Male, 63.3%; Median age, 44.5 years; Disease duration, 6.5 years; Previous exposure to advanced therapies, 70.0%; Extensive colitis, 65.0%; Median baseline Mayo score, 8; Concomitant use of immunomodulators, 40.0%) were included. Excluding one patient in clinical remission at baseline, 49.2% (29/59) achieved clinical remission at W8. At W16–20, and W52–56, 59.3% (35/59), and 55.9% (33/59) achieved clinical remission. The clinical response rates at W8, W16–20, and W52–56 were 67.9% (40/59), 69.5% (41/59), and 66.1% (39/59), respectively (Figure 1). Endoscopic remission rates at W16–20 and W52–56 were 55.9% (33/59) and 37.3% (22/59), respectively (Figure 1). Multivariable analysis identified factors associated with clinical remission at W52–56 (body mass index, adjusted odds ratio [aOR]: 1.26, 95% confidence interval [CI] 1.00–1.57, p<0.05; previous exposure to advanced therapies, aOR: 0.20, 95% CI 0.04–0.98, p<0.05; concomitant use of immunomodulators, aOR: 4.69, 95% CI 1.04–21.06, p=0.04; endoscopic remission at W16–20, aOR: 13.47 95% CI 2.87–63.30, p<0.01). Till W52–56, the interval shortening rate for subcutaneous UST treatment from every 12 to 8 weeks was 20% (12/60). Nine patients (15.0%) stopped UST, primarily due to a secondary loss of response (8.3%, 5/60), followed by a primary non-response (6.7%, 4/60). Adverse events occurred in 24 patients (40.0%) and serious adverse event in one patient (1.7%) (Table 1). Conclusion UST was effective with an acceptable safety profile for Korean patients with UC. Previous exposure to advanced therapies was associated with a lower probability of clinical remission at one year after UST therapy. Financial support This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (NRF-2021R1A2C2095096).

P0118 A novel subset of TNIP3+ OLR1+ AQP9+ inflammatory monocytes drives resistance to multiple biologics in ulcerative colitis

Abstract Background We previously reported that the pre-treatment mucosal enrichment of a 325-transcript-long module, TM1, predicts resistance to ustekinumab and anti-TNF therapy in moderate-to-severe ulcerative colitis (UC). Only 5% of patients with high TM1 expression achieved week 8 mucosal healing with ustekinumab and no patients with high expression had week 6 histo-endoscopic remission in two infliximab-treated cohorts. We explored which cell populations might be driving this phenomenon to guide potential therapeutic perspectives. Methods We used gene set variation analysis (GSVA) to calculate the enrichment score of TM1 in transcriptionally profiled single cells from mucosal biopsies from patients with active UC [1]. We sub-clustered cell populations of interest, which were defined based on the ranked fold changes of differentially expressed genes between these groups, and investigated their molecular phenotype. Transcriptomic signatures were defined using the top 20 markers of each population. We employed the LiANA tool to predict likely cell-cell interactions and Ingenuity Pathway Analysis upstream regulator analysis (IPA, Qiagen, US) to identify inhibitory drugs. Analyses were performed in R (v 4.2.2, Vienna) and GraphPad Prism (US, v 10.3). Results GSVA revealed that TM1 was particularly enriched in the myeloid compartment and most highly in inflammatory monocytes (IMs). Further analyses defined three subpopulations named IM0, IM1 and IM2. These were PKIB+ SNX17+ NDUFB5+, TNIP3+ OLR1+ AQP9+ and CLLU1OS+ LAD1+ CXCL5+, respectively. IM1 cells also differentially expressed TREM1 and ETS2, which have been previously associated with anti-TNF resistance and disease severity [2]. Eleven of the top 20 IM1 transcripts were present in TM1 compared to 2/20 from IM2 and 0/20 for IM0. Enrichment of IM1 marker genes in pre-treatment UC biopsy samples also correlated highly with TM1 enrichment (ρ=0.92, p<0.0001). Ligand-receptor analysis suggested that these IM sub-populations interacted with myeloid, lymphoid, mesenchymal and epithelial cells, particularly involving the IM1 receptors CD44, CD4 and LILRB2, and ligands S100A8, IL1β and S100A9. Common interactions included S100A8/9 from IM1 and IM0 binding TLR4 and CD36 on IM1s, and FN1 from mesenchymal cells stimulating PLAUR, C5AR1 and CD44 on IM1s. IPA highlighted MEK inhibitors U0126 and SB203580 as potential drugs that could counteract the effect of IM1 functions. Conclusion A population of TNIP3+ OLR1+ AQP9+ IMs appears to be involved in resistance to ustekinumab and anti-TNF medications in UC, which augments previous findings about treatment resistance. MEK inhibitors may offer a novel IBD drug class to target these cells in refractory disease.

P0879 The totality of evidence for FYB202 – an EU-approved and US-licensed biosimilar to reference ustekinumab

Abstract Background Ustekinumab is a fully human IgG1/kappa monoclonal antibody to interleukin (IL)-12/23. It is authorized for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, and active inflammatory bowel disorder. FYB202 has been approved by both EMA and FDA in September 2024 as a biosimilar to reference ustekinumab based on extensive comparative analytical characterization data and the proof of equivalence in clinical performance. Methods A full set of critical quality attributes was investigated with a comprehensive set of analytical methods. Functional comparability of FYB202 to the reference product for the main mechanism of action was assessed with IL-12 and IL-23 binding and bioassays. Equivalence in PK and efficacy as well as similarity in safety, tolerability, and immunogenicity were evaluated in clinical trials in healthy subjects and psoriasis patients. Results FYB202 was found to be analytically similar to reference ustekinumab with respect to physicochemical and biological properties, including structure, function, purity, and potency. Most relevant potency results are shown in Figure 1. A 3-arm PK study in 491 healthy volunteers demonstrated PK equivalence between FYB202 and both EU-approved and US-licensed ustekinumab and between the two reference drugs (all 90% CIs were within the predefined equivalence margin of 80 to 125% (Balser1). FYB202 was shown to be equivalent to reference ustekinumab in 392 patients with moderate-to-severe plaque psoriasis, with the mean percent improvement in PASI score from baseline to week 12 within the predefined equivalence intervals for both the EU- and US-specific analyses. The similarity in response was maintained over the whole course of the study. Transitioning from reference product to FYB202 had no clinically relevant effect on efficacy, safety, or immunogenicity (Papp2). Conclusion FYB202 has been shown to have similar physicochemical and functional properties and equivalent clinical performance was shown in clinical studies. Based on a totality of evidence approach, proof of therapeutic equivalence in the sensitive psoriasis population allows for extrapolation to other indications, with similar clinical performance of FYB202 and reference ustekinumab assumed across all approved indications. FYB202 provides a safe and effective biosimilar alternative for patients in need of ustekinumab therapy.

P0939 Efficacy of Ustekinumab-based integrated medicine therapy in patients with symptomatic stricturing Crohn’s disease: a retrospective study

Abstract Background Strictures are the most prevalent structural complication in Crohn’s disease (CD). Surgery and endoscopic balloon dilation are widely used worldwide. there is a lack of data regarding the use of ustekinumab (UST) for symptomatic stricturing CD in China. This study aims to assess the efficacy of UST in these patients and identify factors predicting treatment success. Methods This observational cohort study retrospectively included adult CD patients undergoing their first UST therapy for symptomatic strictures, confirmed via endoscopy or imaging. We defined the primary outcome as UST continuation without the prohibited treatments (corticosteroids, other biologics), endoscopic dilation, or bowel resection at week 52. Treatment effectiveness was evaluated according to the relief of symptoms, and baseline factors independently associated with success were identified using a logistic regression model. Results From June 2022 to April 2024, 73 patients were screened, of whom 54 were included in the study. Treatment success was observed in 44 out of 54 patients (81.5%) at week 52, while 10 patients required surgery or other biologics during follow-up. Regarding endoscopic stenosis remission, 11 (39%) patients could pass the colonoscope across the previously obstructed area, and the DBE-CD decreased from 3.85±0.15 to 3.04±0.24 (p=0.048). Complete resolution of prestenotic dilatations (<3.0 cm) on CT enterography was seen in 20 of 38 patients (53%). Intestinal ultrasound at 52 weeks showed an improvement (>25%) in bowel wall thickness in 23 (43%) of the 54 patients. UST reduced the International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) from 71.71±5.23 to 54.73±5.41 (p=0.036). Faecal calprotectin levels normalized in 23 (43%) patients (p=0.01), while normalization of CRP was seen in 37 (69%) patients (p=0.25). Aside from one patient (2%) reporting leukemia and two patients (4%) reporting serious infections, no other severe adverse events were observed during the study. Conclusion Ustekinumab (UST) is effective in controlling the progression of intestinal strictures in Crohn’s disease (CD) patients. The majority of patients experienced symptom remission, improved stricture morphology, and a reduction in stricture-associated inflammation.

P1143 Impact of vitamin D metabolism gene polymorphisms on therapeutic efficacy of vedolizumab and ustekinumab in Inflammatory Bowel Disease

Abstract Background Vitamin D (VD) is a crucial biological agent with immunoregulatory and anti-inflammatory properties. There is growing interest in identifying genes regulated by VD to explore its therapeutic potential in various diseases, including Inflammatory Bowel Disease (IBD). Understanding single nucleotide polymorphisms (SNPs) and genotypes of VD-associated genes is essential for predicting therapeutic outcomes of biologic treatments and personalizing IBD management. This study aimed to evaluate the role of VD-related genetics in predicting the clinical response of patients with Crohn's disease (CD) and ulcerative colitis (UC) to biologics vedolizumab (VDZ) and ustekinumab (UST) after 12 months of therapy (T12), and to assess the achievement of fecal calprotectin (FC) levels <250 mg/kg, a surrogate marker for mucosal healing. Methods A prospective study was conducted including 103 patients (67 with CD, 36 with UC) treated with VDZ (40/103) and UST (63/103). SNPs of the genes CYP24A1, GC, CYP27B1, VDR ApaI, VDR Cdx2, VDR BsmI and VDR TaqI were analyzed using polymerase chain reaction (PCR) and correlated with clinical and laboratory outcomes through contingency tables and univariate logistic regression analysis for each SNP. Results UST therapy showed a higher clinical response rate at T12 than VDZ (85.7% vs. 67.5%, OR 2.89, 95% CI 1.10-7.60, p=0.03). A significant association was observed between response at T3 and T12 (p=0.0002, OR 6.91, 95% CI: 2.48-19.30). The GC 1296 AC polymorphism was a negative predictor of response at T12, with 63.6% of non-responders carrying this genotype. Treatment stratification confirmed that in VDZ-treated patients, AC heterozygotes were less likely to achieve the primary outcome (46.7%), with an OR of 4.57 (95% CI: 1.12-18.73, p=0.04). CYP24A1 8620 AG was a statistically significant negative predictor for achieving FC levels < 250 mg/kg (p=0.045). Moreover, CYP24A1 22776 CT and VDR Cdx2 GG were associated with a higher likelihood of presenting with CD rather than UC (OR = 3.40, 95% CI: 1.35 - 8.52, p-value = 0.009 and OR = 3.74, 95% CI = 1.02-13.77, p-value = 0.047, respectively). In addition, SNPs in the CYP27B1 gene, -1260 GT and +2838 CT, were significantly associated with non-ileal CD (non-L1 CD), increasing the probability of non-L1 presentation by 3-fold (OR = 3.13, 95% CI: 0.98-10.01, p-value = 0.054) and 7-fold (OR = 7.02, 95% CI: 1.44-34.25, p-value = 0.01), respectively. Conclusion In conclusion, this study identifies associations between polymorphisms in the vitamin D pathway and clinical and laboratory responses to VDZ or UST after 12 months of therapy, IBD phenotype, and CD localization. Further research is needed to validate these findings and to develop personalized IBD treatment strategies.

Oral Microbiota Associated with Clinical Efficacy of Ustekinumab in Crohn's Disease.

Crohn's Disease (CD) is a chronic inflammatory gastrointestinal disease. Ustekinumab (UST) has been utilized as a therapeutic option for CD patients. However, approximately 40-60% of patients exhibit an inadequate response to UST. Accumulating evidence has confirmed the involvement of oral bacteria in the development of CD. Nevertheless, the relationship between oral microbiota and the efficacy of UST therapy in CD patients has remained unexplored. We recruited 28 healthy individuals and 53 CD patients, 47 of whom completed the entire UST therapy. Oral samples and clinical data were collected. The clinical response and clinical remission were defined based on the CDAI score. Oral samples were analyzed by 16S rRNA gene sequencing. The analysis of sequence data was performed by QIIME and R. We revealed the oral microbial difference between the Healthy Control (HC) group and the CD group. The enrichment of Fusobacteria, Leptotrichia, Capnocytophaga, and Campylobacter, and the diminution of Haemophilus and Rothia were observed in the CD group. Differences in oral microbiota were also identified among patients with different efficacy of UST. Compared to the response and remission groups, both the non-response and non-remission groups showed significantly higher levels of Fusobacteria and Leptotrichia. Predictive models for clinical response and clinical remission in UST were developed based on oral microbiota, with the Area Under the Curve (AUC) value of 0.944 and 0.930, respectively. Oral microbiota was relevant to the UST efficacy in patients with CD based on the predictive model. These findings suggest that oral microbiota could serve as a non-invasive prognostic biomarker for UST treatment in CD patients.

Improvement in serum eosinophilia is observed in clinical responders to ustekinumab but not adalimumab in inflammatory bowel disease.

In inflammatory bowel disease (IBD), the number of eosinophils increases in the lamina propria of the intestinal tract, but their specific patho-mechanistic role remains unclear. Elevated blood eosinophil counts in active IBD suggest their potential as biomarkers for predicting response to biological therapies. This study evaluates blood eosinophil count trends and their predictive value for clinical response and endoscopic improvement in patients with IBD receiving ustekinumab or adalimumab induction therapy. Participant-level data from phase 3 and 4 clinical trials (UNIFI, SEAVUE, VARSITY) evaluating ustekinumab and adalimumab for moderate-severe Crohn's disease (CD) and ulcerative colitis (UC) were used. The primary outcome was clinical response, defined by reductions in disease activity scores. Eosinophil counts were compared between responders and non-responders at multiple time points using t-tests. Logistic regression assessed the odds of achieving a clinical response based on baseline eosinophil counts. Among patients treated with ustekinumab for UC, responders had significantly higher baseline eosinophil counts compared to non-responders (0.21 × 109/L vs 0.18 × 109/L, P = .042). By week 8, responders showed a greater absolute (-0.07 × 109/L vs -0.01 × 109/L, P < .001) and percent decline (-33.33% vs -5.55%, P = .027) in eosinophil counts. In CD, ustekinumab responders also had higher baseline eosinophil counts and showed significant reductions by week 8. However, no significant differences in eosinophil counts were observed among CD patients treated with adalimumab or UC patients treated with vedolizumab. Eosinophil reduction was identified as a marker for early response to ustekinumab in both UC and CD, but not adalimumab. No difference was observed among UC patients treated with vedolizumab either. Targeting the IL-12/IL-23 pathway may be more effective in managing eosinophil-associated inflammation in IBD.

Impact of 5-Aminosalicylic Acid on Ustekinumab in Inflammatory Bowel Disease: A Retrospective Medical Claims Analysis.

The efficacy of 5-aminosalicylic acid (5-ASA) in combination with advanced therapies (ADTs), particularly ustekinumab (UST), for the treatment of inflammatory bowel disease (IBD) remains unclear. This retrospective cohort analysis used data from the Medical Data Vision database, including patients with ulcerative colitis (UC) and Crohn's disease (CD) who had initiated UST therapy. Cumulative UST continuation rates and factors associated with UST failure were analyzed, and post hoc subgroup analyses based on prior ADT use were conducted. A total of 1971 patients with CD and 1284 patients with UC were included. Overall, the concomitant use of 5-ASA did not significantly affect UST failure in either CD or UC. Post hoc subgroup analysis suggested a protective effect of 5-ASA in ADT-naïve patients with CD or UC who had been previously exposed to ADT. 5-ASA did not provide a significant overall benefit when used in combination with UST for CD or UC. However, post hoc subgroup analyses indicated a potential role for 5-ASA in specific subgroups. Further studies are necessary to confirm these findings and explore personalized treatment strategies.

Associations Between Polymorphisms of Genes Related to Vitamin D Pathway and the Response to Vedolizumab and Ustekinumab in Inflammatory Bowel Disease.

Background/Objectives: Vitamin D (VD) has immunoregulatory properties, generating interest in its potential to influence therapeutic outcomes in inflammatory bowel disease (IBD), other than affecting the expression of genes encoding enzymes and transporters involved in drug metabolism and transport. This study investigated VD-related single nucleotide polymorphisms (SNPs) as predictors of clinical responses in patients with Crohn's disease (CD) and ulcerative colitis (UC) treated with vedolizumab (VDZ) or ustekinumab (UST) after 3 (T3) and 12 months (T12), as well as the achievement of fecal calprotectin (FC) levels < 250 mg/kg, a marker of mucosal healing. Methods: In this prospective study, 103 patients (67 CD, 36 UC) were enrolled, 40 receiving VDZ and 63 receiving UST. SNPs in the genes CYP24A1, GC, CYP27B1, and VD receptor (VDR) were analyzed via polymerase chain reaction (PCR) and associated with clinical and laboratory outcomes. Results: UST therapy demonstrated a higher clinical response rate at T12 compared to VDZ (p = 0.03). A correlation was found between response at T3 and T12 (p = 0.0002). GC 1296 AC polymorphism negatively predicted response at T12, with 63.6% of non-responders carrying this genotype. CYP24A1 8620 AG was a negative predictor for achieving FC < 250 mg/kg (p = 0.045). CYP24A1 22776 CT and VDR Cdx2 GG increased the likelihood of presenting CD over UC (OR 3.40, p = 0.009 and OR 3.74, p = 0.047, respectively). Additionally, CYP27B1 -1260 GT and +2838 CT increased the likelihood of non-ileal CD (OR 3.13, p = 0.054; OR 7.02, p = 0.01). Conclusions: This study reveals associations between VD-SNPs, clinical response to VDZ and UST, and IBD phenotype and localization, supporting the development of personalized IBD treatment and warranting further validation.

The incidence of hepatitis B reactivation in patients receiving ustekinumab: a systematic review and proportional meta-analysis.

This meta-analysis will evaluate the risk of hepatitis B reactivation in patients treated with ustekinumab for inflammatory bowel disease and psoriasis. We aim to determine the true incidence of this adverse event, reconcile discrepancies in reported reactivation rates, and elucidate the associated risk. We conducted a rigorous systematic review adhering to established guidelines. Major databases like MEDLINE, Google Scholar, CENTRAL, and ClinicalTrials.gov were searched. Studies involving patients with documented hepatitis B infection undergoing ustekinumab therapy were included. Patients receiving concurrent antiviral medications were excluded. To account for potential underreporting, studies without reactivation events or with sample sizes ≥3 were also considered by using generalized linear mixed models and Clopper-Pearson confidence intervals. This review was prospectively registered in PROSPERO (CRD42023418130). We analyzed data from nine studies involving 104 hepatitis B virus (HBV)-infected patients. The pooled HBV reactivation (HBVr) incidence among hepatitis B surface antigen-positive patients was 10% [95% confidence interval (CI): 0-31%], with low heterogeneity (I2 = 7.13%, τ2 = 0.4) and a nonsignificant Q-statistic (Q = 5.38, P = 0.37). For the occult HBV-infected patients, the pooled HBVr incidence was 3% (95% CI: 0-11%), with no heterogeneity (I2 = 0%, τ2 = 0.0) and a nonsignificant Q-statistic (Q = 2.7, P = 0.61). The reactivation rates showed high consistency across studies, with no significant difference between the two groups. While our data suggest lower HBVr risk with ustekinumab, confirmation is needed due to limited sample size and retrospective design.

Management of patients with Crohn's disease – from history to modern approaches

Since the isolation of Crohn's disease as a separate pathology, significant progress has been made both in the diagnosis of the disease and in approaches to the treatment of patients with this pathology. The active introduction of biologics and the top-down approach into clinical practice in patients with negative prognosis factors has led to a significant improvement in treatment results and prognosis in patients. The use of the most effective anti-inflammatory therapy during the «therapeutic window of opportunity» – up to 18 months – is the key to achieving remission, or minimal activity of Crohn's disease by suppressing inflammation and preventing irreversible structural damage to the intestinal wall and, as a result, the development of complications. The article presents an excursion into the history of the discovery of this disease, which is still far from its completion. The approaches to the treatment of patients with this pathology are highlighted with an explanation of the current position based on data from meta-analyses and systematic reviews. A demonstration of a patient with a penetrating phenotype of Crohn's disease in the form of a perianal lesion and a history of oncopathology is presented. Ustekinumab therapy can be considered as an optimal management strategy for patients with Crohn's disease with unfavorable prognosis factors.

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.

Real-World Ustekinumab Experience in Ileum-Dominant Versus Colonic Crohn’s Disease

Abstract Background Crohn’s disease (CD) presents with diverse phenotypes. It remains unclear if CD location affects therapy efficacy. The aim of this study was to compare the real-world performance of ustekinumab in ileum-dominant and colonic CD. Methods We performed a single-center, IRB-approved, retrospective review of all adult CD patients who received ustekinumab. We stratified patients by ileal involvement: ileum-dominant (ileal and ileocolonic) and colonic CD. The primary outcome was the absence of ulcers on follow-up colonoscopy. The secondary outcomes included CRP, calprotectin, surgery, and hospitalization. Chi-square tests (or Fisher’s exact test) and 2-sample t-tests (or Wilcoxon’s rank-sum test) were used to compare categorical and numeric variables between groups, respectively; analyses were performed using R Computing Software versions 3.6.1. Results Eighty-four patients with ileum-dominant CD and 27 patients with colonic CD were treated with ustekinumab. The median time to follow-up endoscopy was 13 months. Follow-up colonoscopy after ustekinumab therapy was ulcer-free in 45% of ileum-dominant CD and 76% of colonic CD (P = .02). Of patients with ulcers prior to starting ustekinumab, 24% of ileum-dominant CD and 67% of colonic CD were ulcer-free (P = .01). There were similar rates of hospitalizations and surgery and no significant differences in mean calprotectin and CRP between the two groups on follow-up after ustekinumab therapy. Conclusions This real-world experience of ustekinumab demonstrates higher rates of endoscopic healing among colonic CD when compared to ileum-dominant CD. Disease location may predict endoscopic healing by ustekinumab. Further studies are necessary to expand our understanding of ustekinumab responsiveness to different CD phenotypes.