Targeting Immune Cell Wiring in Ulcerative Colitis.

The cytokine TNF is thought to play a major role in the immunopathogenesis of ulcerative colitis, and anti-TNF antibodies are considered as cornerstones of clinical therapy. Two clinical trials published in The New England Journal of Medicine now challenge this paradigm and suggest new avenues for research.

Using Computer Vision to Improve Endoscopic Disease Quantification in Therapeutic Clinical Trials of Ulcerative Colitis.

BACKGROUND & AIMS: Endoscopic assessment of ulcerative colitis (UC) typically reports only the maximum severity observed. Computer vision methods may better quantify mucosal injury detail, which varies among patients. METHODS: Endoscopic video from the UNIFI clinical trial (A Study to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Participants With Moderately to Severely Active Ulcerative Colitis) comparing ustekinumab and placebo for UC were processed in a computer vision analysis that spatially mapped Mayo Endoscopic Score (MES) to generate the Cumulative Disease Score (CDS). CDS was compared with the MES for differentiating ustekinumab vs placebo treatment response and agreement with symptomatic remission at week 44. Statistical power, effect, and estimated sample sizes for detecting endoscopic differences between treatments were calculated using both CDS and MES measures. Endoscopic video from a separate phase 2 clinical trial replication cohort was performed for validation of CDS performance. RESULTS: Among 748 induction and 348 maintenance patients, CDS was lower in ustekinumab vs placebo users at week 8 (141.9 vs 184.3; P < .0001) and week 44 (78.2 vs 151.5; P < .0001). CDS was correlated with the MES (P < .0001) and all clinical components of the partial Mayo score (P < .0001). Stratification by pretreatment CDS revealed ustekinumab was more effective than placebo (P < .0001) with increasing effect in severe vs mild disease (-85.0 vs -55.4; P < .0001). Compared with the MES, CDS was more sensitive to change, requiring 50% fewer participants to demonstrate endoscopic differences between ustekinumab and placebo (Hedges' g = 0.743 vs 0.460). CDS performance in the JAK-UC replication cohort was similar to UNIFI. CONCLUSIONS: As an automated and quantitative measure of global endoscopic disease severity, the CDS offers artificial intelligence enhancement of traditional MES capability to better evaluate UC in clinical trials and potentially practice.

Emerging biologic therapies for systemic lupus erythematosus.

PURPOSE OF REVIEW: The approval of belimumab and anifrolumab has expanded the scope of treatment for systemic lupus erythematosus (SLE) patients. However, many patients remain refractory to currently available therapies and suffer from drug toxicities. This review will discuss approved and target-specific therapeutics in development that bring hope for better SLE treatments. RECENT FINDINGS: Since the last review on this subject in the journal, the FDA has approved anifrolumab and belimumab for SLE and lupus nephritis (LN), respectively. A fully humanized anti-CD20, obinutuzumab, met the primary end point in a phase II trial in LN. A Tyk2 inhibitor, deucravacitinib, and an antibody targeting plasmacytoid dendritic cells, litifilimab, met the primary end point in phase II trials in SLE and cutaneous lupus erythematosus (CLE). Ustekinumab and baricitinib met the primary end point in phase II but not in phase III trials. SUMMARY: While many drug candidates which met the end points in phase II trials have failed phase III trials, the number of target-specific therapies for SLE has continued to expand.

Evolution of Symptoms After Ustekinumab Induction Therapy in Patients With Crohn's Disease.

BACKGROUND & AIMS: Ustekinumab is an effective treatment of Crohn's disease (CD). Of interest to patients is knowing how soon symptoms may improve. We analyzed ustekinumab response dynamics from the ustekinumab CD trials. METHODS: Patients with CD received intravenous induction with ustekinumab ∼6 mg/kg (n = 458) or placebo (n = 457). Week 8 ustekinumab responders received subcutaneous ustekinumab 90 mg as the first maintenance dose or as an extended induction dose for nonresponders. Patient-reported symptom changes (stool frequency, abdominal pain, general well-being) within the first 14 days and clinical outcomes through week 44 were evaluated using the CD Activity Index. RESULTS: After ustekinumab infusion, stool frequency improvement was significantly (P < .05) greater than placebo on day 1 and for all patient-reported symptoms by day 10. In patients with no history of biologic failure or intolerance, cumulative clinical remission rates increased from 23.0% at week 3 to 55.5% at week 16 after the subcutaneous dose at week 8. Corresponding cumulative rates for patients with a history of biologic failure or intolerance increased from 12.9% to 24.1%. Neither change from baseline in CD Activity Index score nor week 8 ustekinumab pharmacokinetics were associated with week 16 response. Among all patients who received subcutaneous ustekinumab 90 mg q8w, up to 66.7% were in clinical response at week 44. CONCLUSIONS: Ustekinumab induction provided symptom relief by day 1 post-infusion. Following ustekinumab infusion and a subcutaneous 90 mg injection, clinical outcomes continued to increase through week 16 and up to week 44. Regardless of week 8 clinical status or ustekinumab pharmacokinetics, patients should receive additional treatment at week 8. CLINICALTRIALS: gov numbers, NCT01369329, NCT01369342, and NCT01369355.

Comparative Effectiveness of Biologic Therapies in Preventing Penetrating Complications in Patients With Crohn's Disease.

BACKGROUND & AIMS: Comparative effectiveness of biologics in preventing penetrating disease (PD) in Crohn's disease (CD) is not well established. We compared the risk of developing luminal and perianal PD (LPD and PPD) between biologics used as first-line therapies. METHODS: Adults (>17 years) with CD who initiated their first biologic (anti-tumor necrosis factor [anti-TNF], ustekinumab [UST], or vedolizumab [VDZ]) were identified from Merative Commercial Database (2006 and 2020). We excluded preexisting PD using a minimum look-back period of 1 year. Cohorts were balanced by inverse probability of treatment weighting based on age, sex, comorbidities, prior CD surgery, and CD severity. Pairwise comparisons were performed by Cox proportional hazards models, adjusted for immunomodulator exposure, and with biologic exposure treated as a time-dependent variable based on a medication possession ratio of 0.8. RESULTS: Our analysis included 40,693 patients: 93% anti-TNF, 3% UST, and 4% VDZ. After inverse probability of treatment weighting all comparisons were well balanced. Anti-TNF was protective against LPD (hazard ratio, 0.66; 95% confidence interval, 0.55-0.78; P < .0001) and PPD (hazard ratio, 0.88; 95% confidence interval, 0.80-0.96; P = .0045) compared with VDZ and LPD (hazard ratio, 0.37; 95% confidence interval, 0.30-0.46; P < .0001) compared with UST. There were no significant differences in the risk of LPD and PPD between VDZ and UST. These results were similar after limiting the study period to after 2016. CONCLUSIONS: Anti-TNF therapy was associated with a lower risk of LPD and PPD compared with VDZ, and lower risk of LPD compared with UST. Further studies are needed to validate these findings and to determine potential reasons for these differences.

Risk of Cancer Recurrence in Patients With Immune-Mediated Diseases With Use of Immunosuppressive Therapies: An Updated Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: There are limited data on the safety of immunosuppressive therapy use in individuals with immune-mediated diseases with a history of malignancy, particularly with newer biologic and small-molecule treatments. METHODS: We performed a systematic search of PubMed and Embase databases to identify studies examining the impact of immunosuppressive therapies on cancer recurrence across several immune-mediated diseases. Studies were pooled together using random-effects meta-analysis and stratified by type of treatment. Primary outcome was occurrence of incident cancers, defined as new or recurrent. RESULTS: Our meta-analysis included 31 studies (17 inflammatory bowel disease, 14 rheumatoid arthritis, 2 psoriasis, and 1 ankylosing spondylitis) contributing 24,328 persons and 85,784 person-years (p-y) of follow-up evaluation. Rates of cancer recurrence were similar among individuals not on immunosuppression (IS) (1627 incident cancers, 43,765 p-y; 35 per 1000 p-y; 95% CI, 27-43), receiving an anti-tumor necrosis factor (571 incident cancers, 17,772 p-y; 32 per 1000 p-y; 95% CI, 25-38), immunomodulators (1104 incident cancers, 17,018 p-y; 46 per 1000 p-y; 95% CI, 31-61), combination immunosuppression (179 incident cancers, 2659 p-y; 56 per 1000 p-y; 95% CI, 31-81). Patients receiving ustekinumab (5 incident cancers, 213 p-y; 21 per 1000 p-y; 95% CI, 0-44) and vedolizumab (37 incident cancers, 1951 p-y; 16 per 1000 p-y; 95% CI, 5-26) had numerically lower rates of cancer. There were no studies on Janus kinase inhibitors. Stratification of studies by timing of immunosuppression initiation did not reveal a medication effect based on early (<5 years) or delayed treatment initiation. CONCLUSIONS: In patients with immune-mediated diseases and a history of malignancy, we observed similar rates of cancer recurrence in those on no immunosuppression compared with different immunosuppressive treatments.

Single-cell analysis of Crohn's disease: Unveiling heterogeneity and evaluating ustekinumab outcomes.

BACKGROUND: The present study aimed to dissect the cellular complexity of Crohn's disease (CD) using single-cell RNA sequencing, focusing on identifying key cell populations and their transcriptional profiles in inflamed tissue. METHODS: We applied scRNA-sequencing to compare the cellular composition of CD patients with healthy controls, utilizing Seurat for clustering and annotation. Differential gene expression analysis and protein-protein interaction networks were constructed to identify crucial genes and pathways. RESULTS: Our study identified eight distinct cell types in CD, highlighting crucial fibroblast and T cell interactions. The analysis revealed key cellular communications and identified significant genes and pathways involved in the disease's pathology. The role of fibroblasts was underscored by elevated expression in diseased samples, offering insights into disease mechanisms and potential therapeutic targets, including responses to ustekinumab treatment, thus enriching our understanding of CD at a molecular level. CONCLUSIONS: Our findings highlight the complex cellular and molecular interplay in CD, suggesting new biomarkers and therapeutic targets, offering insights into disease mechanisms and treatment implications.

Delayed Ustekinumab and Adalimumab Responders Have Similar Outcomes as Early Responders in Biologic-Naïve Crohn's Disease.

INTRODUCTION: Differences in 1-year outcomes among early and delayed responders have been demonstrated with some therapies in ulcerative colitis. However, it is unclear whether similar differences exist in patients with Crohn's disease (CD) treated with biologic therapies. METHODS: This was a post hoc analysis of patient-level data from the SEAVUE clinical trial program. Ustekinumab-treated and adalimumab-treated patients with clinical response at week 8, defined as a reduction in Crohn's Disease Activity Index (CDAI) score of at least 100 points from baseline or CDAI score <150, were deemed early responders and their outcomes were compared with delayed responders (week 8 nonresponders who subsequently responded at week 16) and nonresponders (no response at week 8 or 16). The primary outcome assessed was clinical remission at week 56, defined as CDAI <150. RESULTS: A total of 373 participants (187 treated with ustekinumab and 186 treated with adalimumab) were included in this analysis. The overall rate of delayed clinical response was low in the SEAVUE clinical trial program (13.1%). No differences were observed for week 56 clinical remission among early vs delayed responders to ustekinumab or adalimumab nor were there significant differences for secondary outcomes assessed. Delayed responders to ustekinumab and adalimumab had a significant decline in C-reactive protein by week 8 when compared with nonresponders. DISCUSSION: Among patients with moderate-to-severe CD, early and delayed responders to adalimumab and ustekinumab have similar 1-year clinical outcomes. Biomarker decline can be observed through the initial 8 weeks of therapy in patients who will eventually be delayed responders, which may help differentiate from nonresponders.

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

BACKGROUND: Variations 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. METHODS: The 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. RESULTS: A 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. CONCLUSIONS: Th1 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 .

Dose escalation of biologic treatment in patients with moderate-to-severe psoriasis in Japan.

Patients receiving interleukin (IL)-inhibiting biologics for moderate-to-severe psoriasis (PsO) may be treated with escalated doses to optimize outcomes. This study evaluated escalation prevalence in a Japanese claims analysis of patients with PsO diagnosis preceding IL-inhibiting biologic treatment and ≥1 post-induction maintenance claim (index date) with sufficient data availability from January 2014 to May 2022. Patients with non-persistence were excluded. Expected daily dose (EDD) was calculated as the recommended maintenance dose divided by the treatment interval. Dose escalation was defined as ≥2 claims showing a ≥20% increase in the observed average daily dose (ADD) over the EDD (with sensitivities requiring ≥1 claim and ≥30%). Significant differences were tested using multivariable regressions. The study included 982 unique patients treated with brodalumab (BRO; n = 104), guselkumab (GUS; n = 207), ixekizumab (IXE; n = 159), risankizumab (RIS; n = 135), secukinumab (SEC; n = 215) and ustekinumab (UST; n = 196). Within 12 months, dose escalation was observed for all IL-inhibiting biologics other than GUS and RIS: 44.4% for UST, 37.2% for IXE, 3.4% for SEC and 1.4% for BRO. In multivariable-adjusted analyses, odds of dose escalation were significantly lower for all products relative to UST. In sensitivities, escalation was observed for all products except RIS.

The association of age at psoriasis onset and HLA-C*06:02 with biologic survival in patients with moderate-to-severe psoriasis: a cohort study from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR).

BACKGROUND: Few studies have used real-world data to investigate the association between biologic therapy survival and age at psoriasis onset or HLA-C*06:02 status in patients with moderate-to-severe psoriasis. The robustness of these studies is limited by small sample size, short follow-up and diverse safety and effectiveness measures. OBJECTIVES: To describe biologic survival and explore whether the response to biologics is modified by age at psoriasis onset or HLA-C*06:02 status in patients with moderate-to-severe psoriasis. METHODS: Data from patients in the UK and the Republic of Ireland registered in the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) from 2007 to 2022 on a first course of adalimumab, etanercept, secukinumab or ustekinumab with at least 6 months' follow-up and a subset of BADBIR patients with available HLA-C*06:02 information registered to Biomarkers and Stratification To Optimise outcomes in Psoriasis (BSTOP) were analysed. Patients aged ≥ 50 years at treatment initiation were classified into early-onset psoriasis (EOP) (presenting in patients ≤ 40 years of age) and late-onset psoriasis (LOP) (presenting in patients > 40 years of age). BADBIR patients with available information in BSTOP were categorized as HLA-C*06:02- or HLA-C*06:02 + . Biologic survival was defined as treatment discontinuation associated with ineffectiveness or occurrence of adverse events (AEs). Adjusted survival function and hazard ratio (aHR) with 95% confidence interval (CI) were estimated using a flexible parametric model to compare discontinuing therapy between age at psoriasis onset and HLA-C*06:02 groups. Each model included exposure (biologics), effect modifier (age at onset or HLA-C*06:02 status), interaction terms and several baseline demographic, clinical and disease severity covariates. RESULTS: Final analytical cohorts included 4250 patients in the age at psoriasis onset group [2929 EOP (69%) vs. 1321 LOP (31%)] and 3094 patients in the HLA-C*06:02 status group [1603 HLA-C*06:02+ (52%) vs. 1491 HLA-C*06:02- (48%)]. There was no significant difference between EOP and LOP in drug survival associated with ineffectiveness or AEs for any biologics. However, compared with patients who were HLA-C*06:02-, patients who were HLA-C*06:02 + were less likely to discontinue ustekinumab for reasons associated with ineffectiveness (aHR 0.56, 95% CI 0.42-0.75). CONCLUSIONS: HLA-C*06:02, but not age at psoriasis onset, is a predictive biomarker for biologic survival in patients with psoriasis. Findings from this large cohort provide further, important information to aid clinicians using biologic therapies to manage patients with psoriasis.

Selection strategy of second-line biologic therapies in adult patients with ulcerative colitis following prior biologic treatment failure: Systematic review and meta-analysis.

BACKGROUND: Optimizing second-line biologic therapies for adult ulcerative colitis (UC) post first-line failure is essential. OBJECTIVE: Compare second-line biologic therapy efficacy in adult UC patients with prior treatment failure. METHODS: A comprehensive search of electronic databases up to May 2023 was conducted to assess second-line biologic therapy efficacy using a random effects model. Parameters analyzed included clinical remission rate, clinical response rate, mucosal healing rate, annual discontinuation rate, and colectomy rates. RESULTS: Forty-three research papers were analyzed. Clinical remission rates for second-line biologics were ranked at 6-14 weeks: Infliximab (30%) was followed by Vedolizumab (29%), Ustekinumab (27%), and Adalimumab (19%). At 52-54 weeks, the order shifted, with Vedolizumab (35%) followed by Infliximab (32%), Ustekinumab (31%), and Adalimumab (26%). The mucosal healing rate was 21%, ranked as: Infliximab (31%), Vedolizumab (21%), Adalimumab (21%), and Ustekinumab (14%). The annual discontinuation rate stood at 20%, with Adalimumab (25%), Vedolizumab (18%), Infliximab (17%), and Ustekinumab (16%). Discontinuation rates due to primary failure (PF), secondary failure (SF), and adverse events (AE) were 6%, 12%, and 3%, respectively. The annual colectomy rate was 9%, with Adalimumab (15%) followed by Vedolizumab (10%), Ustekinumab (9%), and Infliximab (5%), and colectomy rates of 10% due to PF, 12% due to SF, and 4% due to AE. CONCLUSION: For UC patients with first-line treatment failure, it is recommended to prioritize infliximab or vedolizumab as second-line biologic therapies, while avoiding adalimumab as the primary choice. Further clinical trials are necessary to assess ustekinumab efficacy accurately.

Use of Biologics for the Treatment of Inflammatory Conditions of the Pouch: A Systematic Review.

BACKGROUND: Patients with medically-refractory ulcerative colitis or advanced neoplasia are often offered an ileal-pouch-anal anastomosis to restore bowel continuity. However, up to 50% of patients can suffer from inflammatory conditions of the pouch, some of which require biological therapy to treat. The aim of this study was to determine the efficacy of each biological agent for the treatment of inflammatory conditions of the pouch. MATERIALS AND METHODS: A comprehensive literature search was performed in the major databases from inception through February 11, 2020, for studies assessing the efficacy of biologics in chronic antibiotic-refractory pouchitis (CARP) and Crohn's disease (CD) of the pouch. Both prospective and retrospective studies were included. The primary outcomes of interest were complete and partial responses were defined within each study. χ 2 test was used to compare variables. RESULTS: Thirty-four studies were included in the systematic review and meta-analysis. Sixteen studies (N=247) evaluated the use of infliximab (IFX), showing complete response in 50.7% and partial response in 28.1% for CARP, and complete response in 66.7% and partial response in 20% for CD of the pouch. Seven studies (n=107) assessed the efficacy of adalimumab. For CARP, 33.3% of patients had a complete response, and 38.1% had a partial response, whereas for CD of the pouch, 47.7% experienced a complete response, and 24.6% had a partial response. Three studies (n=78) reported outcomes with the use of ustekinumab, showing 50% complete response and 3.8% partial response for CARP. For the CD of the pouch, 5.8% had a complete response and 78.8% had a partial response. Seven studies (n=151) reported the efficacy of vedolizumab, showing 28.4% complete response and 43.2% partial response in patients with CARP, whereas 63% of patients experienced partial response in CD of the pouch. IFX had higher rates of complete response in CARP compared with adalimumab ( P =0.04) and compared with vedolizumab ( P =0.005), but not compared with ustekinumab ( P =0.95). There were no new safety signals reported in any of the studies. CONCLUSIONS: Biologics are safe and efficacious in the treatment of chronic, refractory inflammatory conditions of the pouch. IFX seems to be more efficacious than adalimumab and vedolizumab for CARP. Further prospective, head-to-head evaluations are needed to compare biological therapies in the treatment of CARP and CD of the pouch.

Real-world long-term effectiveness of ustekinumab in ulcerative colitis: results from a spanish open-label cohort.

OBJECTIVE: Ustekinumab was recently approved for the treatment of moderate-to-severe ulcerative colitis (UC). Although data from the UNIFI clinical trial are encouraging, real-world data assessing effectiveness and safety are scarce. The aim of this study was to assess the effectiveness, safety and pharmacokinetics of ustekinumab in a large cohort of refractory UC patients. METHODS: Multicenter observational study of UC patients who received ustekinumab for active disease. The Partial Mayo Score (PMS), endoscopic activity, C-reactive protein (CRP) and faecal calprotectin (FC) were recorded at baseline and at different time points. Demographic and clinical data, adverse events (AEs) and surgeries were documented. RESULTS: A total of 108 patients were analyzed from 4 referral Spanish hospitals. The clinical remission rates were 59%, 56.5%, 57% and 69% of patients at weeks 8, 16, 24 and 52, respectively. Normalization of FC was achieved in 39.6%, 41% and 51% at weeks 8, 24 and 52, respectively. CRP normalization was observed in 79%, 75% and 76.5% of patients at weeks 8, 24 and 52, respectively. Fewer previous anti-TNF agents and loss of response to anti-TNF were associated with clinical response and normalization of FC, respectively. AEs were observed in 5 patients, and 9 underwent colectomy. Ustekinumab persistence rates were 91%, 83% and 81% at 24, 48 and 96 weeks, respectively. CONCLUSIONS: Ustekinumab demonstrated, in the real-world setting, long-term effectiveness and a favorable safety profile in a cohort of refractory UC patients.

Real-world effectiveness of ustekinumab and vedolizumab in TNF-exposed pediatric patients with ulcerative colitis.

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.

Combination biologic therapy in pediatric inflammatory bowel disease: Safety and efficacy over a minimum 12-month follow-up period.

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.

Clinical Update on the Prevention and Management of Postoperative Crohn's Disease Recurrence.

PURPOSE OF REVIEW: Despite advances in therapeutics, a significant portion of patients with Crohn's disease still require surgical management. In this article, we present updates to the natural history, prognostication and postoperative monitoring, and novel therapeutics in the prevention and treatment of postoperative Crohn's disease recurrence. RECENT FINDINGS: Clinical risk factors have been associated with higher rates of postoperative recurrence (POR), and in recent studies demonstrate an increased cumulative risk with presence of additional risk factors. Additional novel clinical, histologic, and "-omic" risk factors for recurrence have recently been elucidated, including the role of the mesentery on recurrence and perioperative intraabdominal septic complications. High-risk patients benefit most from medical prophylaxis, including anti-TNF with or without immunomodulator therapy to prevent recurrence. New biologics such as vedolizumab and ustekinumab have emerging evidence in the use of prophylaxis, especially with recent REPREVIO trial data. Non-invasive disease monitoring, such as cross-sectional enterography, intestinal ultrasound, and fecal calprotectin, have been validated against ileocolonoscopy. Recent advances in the prediction, prevention, and monitoring algorithms of postoperative Crohn's disease may be leading to a reduction in postoperative recurrence. Ongoing trials will help determine optimal monitoring and management strategies for this at-risk population.

Dual-Targeted Therapy with Upadacitinib and Ustekinumab in Medically Complex Crohn's Disease.

BACKGROUND AND AIMS: Ongoing efforts to break the therapeutic ceiling in inflammatory bowel disease include combination therapy approaches. Dual-targeted therapy (DTT) has been reported in case reports and small case series. This report describes our experience with ustekinumab (UST) and upadacitinib (UPA) as DTT in patients with Crohn's disease (CD). METHODS: In this retrospective, observational study, we reviewed medical records of patients with CD treated with combined UST and UPA between April 2021 and July 2022. Clinical remission was defined as Harvey-Bradshaw Index (HBI) ≤ 4, and clinical response was defined as decrease in HBI ≥ 3 or physician's assessment of clinical response. RESULTS: We identified 10 CD patients treated with UST/UPA, with median follow-up period of 10 months (interquartile range (IQR) 7.3-12). Median age was 35.5 years (IQR 28.3-43.8) and median number of prior biologic treatment exposures was 4 (IQR 4-5). Indications for UST/UPA were active CD (n = 6), extraintestinal manifestations (EIM) (n = 2), and both active CD and EIM (n = 2). Five of six patients with active CD achieved clinical remission with UST/UPA. Two patients with active EIM (joint pain) achieved resolution of their symptoms. One patient exhibited improvement in both conditions. Three patients developed mild respiratory symptoms and one experienced bowel obstruction. Two patients developed nausea resulting in de-escalation of treatment interval or discontinuation altogether. CONCLUSION: Based on our case series, combination therapy with UST and UPA may be effective and appears safe in refractory Crohn's disease and for patients with co-existing extraintestinal manifestations.

Comparison of the Effectiveness of Vedolizumab and Ustekinumab in Crohn's Disease Patients Who Failed Anti-tumor Necrosis Factor-α Treatment in Japan: An Observational Study Utilizing Claims Database.

This study aimed to investigate whether the approved sequence of vedolizumab and ustekinumab impacts the results of previous observational studies conducted in the European Union (EU), comparing the effectiveness of these drugs in Crohn's disease (CD) patients who failed anti-tumor necrosis factor-α (TNFα) treatment. We conducted this study in Japan, where the approved sequence of drugs is different from that of the EU. We extracted 256 patients diagnosed with CD, who had a history of anti-TNFα treatment and were prescribed either vedolizumab or ustekinumab, from JMDC claims database. The patients' backgrounds were adjusted by inverse probability of treatment weighting using propensity score. The primary outcome was treatment persistence. Secondary outcomes were a steroid-free period, time to hospitalization, and time to CD-related surgery. The hazard ratios (HR) for survival times were estimated using the Cox proportional hazard model. The treatment persistence (primary endpoint) was significantly longer for ustekinumab than vedolizumab (HR, 0.32; 95% confidence interval (CI), 0.15-0.72). The results of the secondary endpoints were as follows: steroid-free period (HR, 0.38; 95% CI, 0.10-1.48), time to hospitalization (HR, 1.07; 95% CI, 0.60-1.91), or time to CD-related surgery (HR, 0.33; 95% CI, 0.11-0.97). There were no outcomes indicating the superiority of vedolizumab. Our findings suggest that ustekinumab is a more effective treatment option than vedolizumab for CD patients who failed to anti-TNFα treatment, and this finding remains consistent across both Japan and the EU.

Comparison of SB17 and reference ustekinumab in healthy adults: A randomized, double-blind, single-dose, phase I study.

OBJECTIVE: This study compared the pharmacokinetic (PK) characteristics of SB17 (Samsung Bioepis, Incheon, Republic of Korea), a proposed biosimilar of ustekinumab (UST) against reference UST (Stelara, Janssen Biotech, Horsham, PA, USA). MATERIALS AND METHODS: This double-blind, three-arm, parallel-group, single-dose study randomized 201 healthy adult subjects 1 : 1 : 1 to receive 45 mg of SB17, European Union-sourced UST (EU-UST) or United States of America-sourced UST (US-UST) via subcutaneous (SC) injection. Primary endpoints were area under the concentration-time curve from time zero to infinity (AUCinf) and maximum serum concentration (Cmax). Safety, tolerability, and immunogenicity were investigated. RESULTS: All 90% confidence intervals (CIs) for the ratios of AUCinf and Cmax between groups were within the predefined bioequivalence margin of 0.8 - 1.25. The geometric LSMeans ratios of AUCinf and Cmax were 0.99 and 0.90 for SB17/EU-UST, 1.01 and 0.94 for SB17/US-UST, and 1.02 and 1.05 for EU-UST/US-UST, respectively. The proportion of subjects with treatment-emergent adverse events (TEAEs) was comparable between SB17, EU-UST, and US-UST (68.7, 58.2, and 65.7%). No deaths, serious adverse events (SAEs), or severe TEAEs were reported. The incidence of subjects testing positive for post-dose anti-drug antibodies (ADAs) was 26.9%, 34.3%, and 34.3% in the SB17, EU-UST, and US-UST groups, respectively. Among the subjects with a positive ADA result at day 99/end of study, 53.8% (SB17 n = 5, EU-UST n = 12, and US-UST n = 11) were positive for neutralizing antibodies (NAbs). CONCLUSION: This study demonstrated bioequivalence of SB17, EU-UST, and US-UST in terms of PK. Safety, tolerability, and immunogenicity were also comparable between all groups.