Anti-tumor Necrosis Factor Therapy Research Articles

Infliximab modifies CD74-mediated lymphatic abnormalities and adipose tissue alterations in creeping fat of Crohn's disease.

Lymphatic abnormalities are essential for pathophysiologic changes of creeping fat (CrF) in Crohn's disease (CD). Anti-tumor necrosis factor (TNF) therapy has been proved to alleviate CrF lesions, however, whether it achieves these by remodeling lymphatics is unknown. CD74 expression was detected in CrF and uninvolved mesentery of CD patients. Lymphatic functions in vitro were evaluated and lymphatic endothelium barrier were checked by transendothelial electrical resistance (TEER) and FITC-Dextran permeability. Protein level of tight junction and signaling pathways were detected by western blotting. CD74 was upregulated in LECs of CrF and positively correlated with TNF-α synthesis. This was suppressed by IFX administration. In vitro, TNF-α stimulated LECs to express CD74 through NF-κB signaling pathway, and this was rescued by IFX. CD74 downregulation suppressed the abilities of LECs in proliferation, migration and tube formation. Interaction of CD74-MIF impaired LECs' barrier via reducing tight junction proteins in an ERK1/2-dependent manner, which was reversed by CD74 downregulation. Consistently, the CD patients receiving IFX therapy displayed decreased lymphangiogenesis and improved mesenteric lymphatic endothelium barrier, companied with reduced adipocyte size and adipokine levels in CrF. Anti-TNF therapy could modify pathological changes in CrF by alleviating CD74-mediated lymphatic abnormalities.

Prevalence, incidence, and treatment patterns of fistulizing Crohn disease: A US population-based cohort study.

Population-based studies for patients with fistulizing Crohn disease (CD), a severe complication of CD, are limited. To report estimates of the prevalence and incidence rates of fistulizing CD in the United States and examine associated treatment patterns among incident cases. This retrospective, observational cohort study used a US administrative claims database from January 1, 2016, to December 31, 2019, with at least 365 days' continuous insurance enrollment. The prevalent patient population comprised patients with incident or existing cases of fistulizing CD. Crude, age, and sex-adjusted prevalence and incidence rates of fistulizing CD were estimated. Baseline characteristics, comorbidities, and CD-related medications and medical procedures were examined for patients with fistulizing CD. The overall crude prevalence (prevalent cases: n = 5,082) and incidence rates (incident cases: n = 2,399) between 2017 and 2019 were 25.2 (95% CI = 24.5-25.9) per 100,000 persons and 6.9 (95% CI = 6.6-7.1) per 100,000 person-years, respectively. Age- and sex-adjusted prevalence and incidence rates were 24.9 (95% CI = 24.2-25.6) per 100,000 persons and 7.0 (95% CI = 6.7-7.3) per 100,000 person-years, respectively. Approximately half of all patients with incident fistulizing CD were prescribed biologic therapies within 1 year of an incident fistula diagnosis, with anti-tumor necrosis factor therapies the most widely prescribed biologic class; antibiotic and corticosteroid use was also common. Among the incident cases, approximately one-third of patients required surgery during the follow-up period, most of which occurred within 3 months of the index date. This study reports age- and sex-adjusted prevalence and incidence rates for fistulizing CD of 24.9 per 100,000 persons and 7.0 per 100,000 person-years, respectively. As a concerning complication of CD, first-year treatment of fistulas in the United States commonly includes anti-tumor necrosis factor therapy, and there is a considerable surgical burden.

Anti–Tumor Necrosis Factor Therapy and Risk of Kidney Function Decline and Mortality in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is associated with adverse clinical outcomes, including chronic kidney disease and mortality, due in part to chronic inflammation. Little is known about the effects of anti-tumor necrosis factor (TNF) therapy on kidney disease progression and mortality among patients with new-onset IBD. To examine the association of incident use of TNF inhibitors with subsequent decline in kidney function and risk of all-cause mortality. This retrospective cohort study used data from the US Department of Veterans Affairs health care system. Participants were US veterans with new-onset IBD enrolled from October 1, 2004, through September 30, 2019. Data were analyzed from December 2022 to February 2024. Incident use of TNF inhibitors. The main outcomes were at least 30% decline in estimated glomerular filtration rate (eGFR) and all-cause mortality. Among 10 689 patients (mean [SD] age, 67.4 [12.3] years; 9999 [93.5%] male) with incident IBD, 3353 (31.4%) had diabetes, the mean (SD) baseline eGFR was 77.2 (19.2) mL/min/1.73 m2, and 1515 (14.2%) were newly initiated on anti-TNF therapy. During a median (IQR) follow-up of 4.1 (1.9-7.0) years, 3367 patients experienced at least 30% decline in eGFR, and over a median (IQR) follow-up of 5.0 (2.5-8.0) years, 2502 patients died. After multivariable adjustments, incident use (vs nonuse) of TNF inhibitors was significantly associated with higher risk of decline in eGFR (adjusted hazard ratio [HR], 1.34 [95% CI, 1.18-1.52]) but was not associated with risk of all-cause mortality (adjusted HR, 1.02 [95% CI, 0.86-1.21]). Similar results were observed in sensitivity analyses. In this cohort study of US veterans with incident IBD, incident use (vs nonuse) of TNF inhibitors was independently associated with higher risk of progressive eGFR decline but was not associated with risk of all-cause mortality. Further studies are needed to elucidate potentially distinct pathophysiologic contributions of TNF inhibitor use to kidney and nonkidney outcomes in patients with IBD.

Antibiotics influence the risk of anti-drug antibody formation during anti-TNF therapy in Chinese inflammatory bowel disease patients.

Aims: The formation of anti-drug antibodies (ADAs) during anti-tumor necrosis factor (anti-TNF) therapy is reported to lead to reducing serum drug levels, which may bring about a loss of response to treatment. Previous research has suggested an association between specific antibiotic classes and ADA formation during anti-TNF therapy. However, there are few studies specifically examining this association in Chinese inflammatory bowel disease (IBD) patients. Therefore, our study aimed to evaluate the possible effect of antibiotic use on ADA formation to anti-TNF therapy in Chinese patients with IBD. Methods: A total of 166 patients with IBD, including 149 with Crohn's disease (CD) and 17 with ulcerative colitis (UC), were included in this retrospective analysis. These patients were initially treated with anti-TNF therapy (infliximab or adalimumab) after January 2018 and reviewed with available ADA levels before October 2023. After univariable analysis of all the variables, a multivariate Cox proportional hazards model was used to assess the association between antibiotic use and ADA development. Results: Among 166 IBD patients treated with infliximab (108/166, 65.1%) or adalimumab (58/166, 34.9%), 31 patients (18.7%) were measured as positive ADA levels. Cox proportional hazard model demonstrated an increased risk of ADA formation in IBD patients who used β-lactam-β-lactamase inhibitor combinations (BL-BLIs) (HR = 5.143, 95%CI 1.136-23.270, p = 0.033), or nitroimidazoles (HR = 4.635, 95%CI 1.641-13.089, p = 0.004) during 12months before the ADA test. On the contrary, a reduced risk was noted in patients treated with fluoroquinolones (HR = 0.258, 95% CI 0.072-0.924, p = 0.037). Moreover, the median serum infliximab or adalimumab concentration in patients with positive ADA levels was significantly lower than that in patients with negative ADA levels (infliximab: 0.30 vs. 1.85μg/mL, p < 0.0001; adalimumab: 0.45 vs. 7.55μg/mL, p = 0.0121). Conclusion: ADA development is associated with various antibiotic classes. BL-BLIs and nitroimidazoles might increase the risk of ADA formation during anti-TNF therapy in Chinese IBD patients, while the treatment with fluoroquinolones could probably reduce such risk. There were certain limitations in the retrospective analysis of the study, therefore, the results are just for reference, and other studies are needed to further confirm our findings.

Demographic and Clinical Features and Factors Affecting the Quality of Life of Patients With Hidradenitis Suppurativa: A Cross-sectional Study.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disorder with well-known adverse effects on quality of life (QoL). Improving patients' QoL has become an important objective of treatment. The purpose of this study was to evaluate the demographic and clinical characteristics and factors affecting the QoL of patients with HS. One hundred seventy-six patients with HS aged between 18 and 65 years were included in the study. The patients' demographic and clinical characteristics, treatments, and comorbidities were recorded. The disease stage was determined based on the Hurley staging system. The Dermatology Life Quality Index (DLQI) was used to evaluate QoL. Mean DLQI scores were significantly higher in patients with advanced Hurley stages, lesions in the gluteal region and legs, and with more than 2 affected areas (p < .001). Correlations between patient-reported treatment outcomes and clinical characteristics of the patients were assessed. Findings of this study indicate the existence of a potential "window of opportunity" for laser epilation and wide local surgical excision, similar to anti-tumor necrosis factor therapy. Timely and appropriate treatment can only be provided for patients with HS by evaluating objective disease severity measures and subjective patient data in combination.

Higher and Sustained Cell-Mediated Immune Responses After 3 Doses of mRNA COVID-19 Vaccine in Patients With Inflammatory Bowel Disease on Anti-Tumor Necrosis Factor Therapy.

Studies suggest that the generation of durable T-cell immunity following coronavirus disease 2019 (COVID-19) vaccination protects against severe disease. The aim of this study was to measure cell-mediated immune response (CMIR) 1-2 months and 6 months after a third dose of a COVID-19 mRNA vaccine. This prospective study (HumoRal and CellULar initial and Sustained immunogenicity in patients with inflammatory bowel disease [IBD]) evaluated CMIR at 28-65 days (t 1 ) after dose 2, 28-65 days (t 2 ) (n = 183) and 6 months (±45 days) (t 3 ) (n = 167) after a third dose of an mRNA COVID-19 vaccine. A small cohort had blood sample available 28-65 days (t 4 ) (n = 55) after a fourth dose. Primary outcomes were CMIR at (t 2 ) and (t 3 ). Secondary outcomes included the effect of immunosuppressing IBD medications on CMIR and response at (t 4 ). All patients had measurable CMIR at all time points. CMIR increased at t 2 compared with that at t 1 (median 1,467 responding cells per million (interquartile range [IQR] 410-5,971) vs 313 (94-960) P < 0.001). There was no significant waning in t 2 vs t 3 or significant boosting at t 4 . Those on anti-tumor necrosis factor monotherapy had a higher CMIR compared with those not on this therapy at t 2 (4,132 [IQR 1,136-8,795] vs 869 [IQR 343-3,221] P < 0.001) and t 3 (2,843 [IQR 596-6,459] vs 654 [IQR 143-2,067] P < 0.001). In univariable analysis, anti-tumor necrosis factor monotherapy was associated with a higher CMIR at t 2 ( P < 0.001) and t 3 ( P < 0.001) and confirmed in a multivariable model ( P < 0.001). A third dose of a COVID-19 vaccine boosts CMIR, and the response is sustained in patients with IBD.

Effect of anti-tumor necrosis factor therapy on the efficacy of aerobic exercise in patients with ankylosing spondylitis

Background: This study aims to evaluate the effects of aerobic exercise on ankylosing spondylitis (AS) patients' clinical outcomes when combined with anti-tumor necrosis factor (TNF) treatments. Methods: Fifty patients diagnosed with AS participate in the study, with 25 on anti-TNF treatment and 25 off anti-TNF treatment. Patients' age, education, body mass index, smoking habits, symptom duration, date of diagnosis, medication use, comorbidities, and surgical history were assessed. Patients receive instructions to walk for 30 minutes, three times per week for twelve weeks and receive evaluation at weeks 0, 6, and 12. Disease activity is evaluated using Visual Analog Scale (VAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), while sleep quality is assessed by the Pittsburgh Sleep Quality Index (PSQI). The Ankylosing Spondylitis Life Quality (ASQoL) is used to measure the quality of life and physical activity is measured by the International Physical Activity Questionnaire (IPAQ). Results: During week 6, VAS, BASDAI, PSQI, and IPAQ scores were significantly lower in both groups, one taking anti-TNF and the other anti-TNF-free, in comparison to baseline and week 12 scores. After undergoing six weeks of aerobic exercise treatment, those taking anti-TNF displayed greater improvements in ASQoL scores in contrast to those who were not taking anti-TNF. Conclusion: Aerobic exercise is an effective intervention for enhancing disease activity, quality of life, sleep quality, and physical activity in patients with AS. Additionally, anti-TNF treatment appears to amplify the clinical benefits associated with exercise and facilitate patients' physical activity.

High Body Mass Index and Response to Anti-Tumor Necrosis Factor Therapy in Pediatric Crohn's Disease.

Obesity is common among patients with pediatric Crohn's disease (PCD). Some adult studies suggest obese patients respond less well to anti-tumor necrosis factor (TNF) treatment. This study sought compares anti-TNF response and anti-TNF levels between pediatric patients with normal and high body mass index (BMI). The COMBINE trial compared anti-TNF monotherapy with combination therapy with methotrexate in patients with PCD. In this secondary analysis, a comparison of time-to-treatment failure among patients with normal BMI vs BMI Z -score >1, adjusting for prescribed anti-TNF (infliximab [IFX] or adalimumab [ADA]), trial treatment assignment (combination vs monotherapy), and relevant covariates. Median anti-TNF levels across BMI category was also examined. Of 224 participants (162 IFX initiators and 62 ADA initiators), 111 (81%) had a normal BMI and 43 (19%) had a high BMI. High BMI was associated with treatment failure among ADA initiators (7/10 [70%] vs 12/52 [23%], hazard ratio 0.29, P = 0.007) but not IFX initiators. In addition, ADA-treated patients with a high BMI had lower ADA levels compared with those with normal BMI (median 5.8 vs 12.8 μg/mL, P = 0.02). IFX trough levels did not differ between BMI groups. Overweight and obese patients with PCD are more likely to experience ADA treatment failure than those with normal BMI. Higher BMI was associated with lower drug trough levels. Standard ADA dosing may be insufficient for overweight children with PCD. Among IFX initiators, there was no observed difference in clinical outcomes or drug levels, perhaps due to weight-based dosing and/or greater use of proactive drug monitoring.

An atypical presentation of axial spondyloarthritis with severe acute low back pain: A case report

Axial spondyloarthritis (axSpA) represents a chronic inflammatory condition primarily impacting axial joints, characterized by sacroiliitis and spondylitis. In axSpA patients, low back pain (LBP) typically assumes a chronic and inflammatory nature, where diagnostic delays can precipitate disability. However, atypical axSpA presentations pose challenges for early diagnosis and management. In the current study, we detail the case of a 39-year-old male presenting with acute, severe LBP and bilateral sacroiliitis. Initial treatment with non-steroidal anti-inflammatory drugs (NSAIDs), the standard first-line therapy, was discontinued due to severe gastrointestinal bleeding. Following a bone biopsy that excluded alternative etiologies, axSpA was confirmed based on diagnostic criteria. Elevated inflammatory markers, contraindications to NSAIDs, and magnetic resonance imaging findings prompted the initiation of anti-tumor necrosis factor (TNF) therapy. Remarkably, a marked improvement was observed in less than six weeks post anti-TNF therapy commencement. This case underscores the significance of recognizing atypical axSpA presentations and underscores the potential for swift and robust responses to anti-TNF agents. Optimal patient outcomes hinge upon effective disease pattern recognition and treatment selection.

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

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. 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. 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. 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.

Bartonella Henselae Related Unilateral Anterior Uveitis and Subsequent Multifocal Retinitis in a Case Under Certolizumab Treatment.

A case of ocular bartonellosis under anti-tumour necrosis factor treatment is described. A 29-year-old woman with psoriasis who had been on certolizumab treatment was examined with a left visual deterioration following a fever bout, malaise, and placoid erythematous rashes on her neck. As there was acute anterior uveitis in her left eye, it was recommended to stop certolizumab treatment for a possible infectious aetiology. However, her physician elected to continue the certolizumab treatment. Ten days later, the patient noticed further visual decline despite the topical steroid treatment. This time, there were scattered yellow-white small retinitis foci at the left posterior pole. Infectious agents were searched and while Bartonella henselae antibodies were negative for immunoglobulin M, the immunoglobulin G titre was 1/80. Clinical findings were improved with the systemic treatment of oral trimethoprim-sulfamethoxazole (160/800 mg twice daily for six weeks) and azithromycin (500 mg once daily for two weeks). Though extremely rare, ocular bartonellosis should be kept in mind in patients on anti-tumour necrosis factor treatment as rapid and accurate diagnosis may end up with an excellent visual outcome and full recovery. Anti-tumour necrosis factor treatment is fraught with several ocular side effects including myositis, corneal infiltrates, scleritis, uveitis, optic neuritis, retinal vasculitis and ophthalmoplegia.When a new uveitis episode occurs in cases undergoing anti-tumour necrosis factor therapy, its cause poses a diagnostic challenge as it can have either an infectious or a non-infectious nature.Though very rare, ocular bartonellosis may also occur in immunocompromised individuals and a prompt diagnosis and appropriate treatment can lead to an excellent visual recovery.

Therapeutic drug monitoring of vedolizumab therapy in inflammatory bowel disease.

Therapeutic drug monitoring is effective for optimizing anti-tumor necrosis factor therapies in inflammatory bowel disease, but for vedolizumab, a gut-selective leucocyte migration inhibitor, data are scarce. Observational cohort study including 116 bio-experienced inflammatory bowel disease patients treated with vedolizumab for active luminal disease. Biobanked trough blood samples (n=676) covering 96% of patients were analyzed using a drug-binding immunofluorometric assay. Steroid-free treatment outcomes were classified by clinical disease activity indices and objective findings, primarily endoscopy. Patients with clinical remission to vedolizumab induction therapy (37%) had significantly higher trough levels than those without at weeks 6 (mean 34.1 vs 28.0μg/mL, P=0.03) and 10 (34.8 vs 27.5μg/mL, P=0.01). Optimal thresholds for discrimination were 32.4μg/mL (AUCROC 0.66, P=0.04) and 23.5 (AUCROC 0.67, P=0.01), respectively. This positive association persisted during maintenance phase with 11.9μg/mL (AUCROC 0.69, P<0.01) associated with clinical remission (37%) and 15.3 (AUCROC 0.74, P<0.001) for objective remission (46%). Stratification by temporal evolution of treatment effects revealed higher induction and maintenance vedolizumab levels in persistent and slow responders as compared to secondary or persistent failures. Pharmacokinetics was influenced by rare formation of anti-vedolizumab antibodies (2%), and to a lesser extent gender and albumin during induction, but not disease severity, concomitant steroids, or thiopurine metabolites. Switching to subcutaneous administrations resulted in 2.3-fold increase in steady-state trough levels. Our study supports maintaining adequate drug exposure being essential for sustained positive outcomes of vedolizumab and emphasizes individualized, therapeutic drug monitoring-based treatment regimens. Controlled trials and pharmacokinetic modeling are, however, needed.

Real-world effectiveness of a single conventional disease-modifying anti-rheumatic drug (cDMARD) plus an anti-TNF agent versus multiple cDMARDs in rheumatoid arthritis: a prospective observational study.

The objective of this prospective, observational multicenter study (NCT03264703) was to compare the effectiveness of single conventional disease-modifying anti-rheumatic drug (cDMARD) plus anti-tumor necrosis factor (TNF) therapy versus multiple cDMARD treatments in patients with moderate-to-severe rheumatoid arthritis (RA) following cDMARD failure in the real-world setting in South Korea. At the treating physicians' discretion, patients received single cDMARD plus anti-TNF therapy or multiple cDMARDs. Changes from baseline in disease activity score 28-joint count with erythrocyte sedimentation rate (DAS28-ESR), corticosteroid use, and Korean Health Assessment Questionnaire (KHAQ-20) scores were evaluated at 3, 6, and 12 months. Of 207 enrollees, the final analysis included 45 of 73 cDMARD plus anti-TNF and 91 of 134 multiple-cDMARD recipients. There were no significant between-group differences (BGDs) in ANCOVA-adjusted changes from baseline in DAS28-ESR at 3, 6 (primary endpoint), and 12 months (BGDs -0.18, -0.38, and -0.03, respectively). More cDMARD plus anti-TNF than multiple-cDMARD recipients achieved a >50% reduction from baseline in corticosteroid dosage at 12 months (35.7% vs 14.6%; p=0.007). Changes from baseline in KHAQ-20 scores at 3, 6, and 12 months were significantly better with cDMARD plus anti-TNF therapy than with multiple cDMARDs (BGD -0.18, -0.19, and -0.19 points, respectively; all p≤0.024). In the real-world setting, relative to multiple cDMARDs, single cDMARD plus anti-TNF therapy significantly improved quality-of-life scores and reduced corticosteroid use, with no significant BGD in disease activity, in RA patients in whom previous cDMARD therapy had failed.

MAINTENANCE EFFICACY OF ORAL INDIGO NATURALIS FOR ULCERATIVE COLITIS: A SINGLE-CENTER, OPEN-LABEL, RANDOMIZED, CONTROLLED STUDY

Abstract BACKGROUND Indigo naturalis (IN) is one of the herbal medicines in Chinese medicine. Recent reports have demonstrated a strong remission induction efficacy of oral IN in induction therapy for ulcerative colitis (UC), but the efficacy of IN in maintenance therapy for UC is unknown. OBJECTIVES We aimed to clarify the maintenance effect of IN. METHODS A single-center, open-label, randomized, controlled trial was conducted from August 2017 to August 2020. Patients with UC who received induction therapy with IN and maintenance therapy with IN for at least 1 year were enrolled. Patients with endoscopically confirmed mucosal healing (Mayo endoscopic subscore 0 or 1) were randomized. Patients were randomized to continue or discontinue IN. The primary endpoint was the remission rate at 52 weeks after discontinuation. Patients who relapsed during the observation period were given additional therapy, and remission rates were examined for patients who received an increased dose of IN or resumed oral therapy. The study was registered in the University Hospital Medical Information Network Center Trials registry, UMIN000028574. RESULTS A total of 20 patients participated in this study, 10 in the IN-continued group and 10 in the IN-discontinued group. The median age was 32.5 years and 33.5 years in the IN-continued group and IN-discontinued group, respectively, and 6 and 5 patients were male. Two patients in the IN-continued group and three patients in the IN-discontinued group were treated with azathioprine. One patient in the IN-continued group and three patients in the IN-discontinued group were treated with anti-tumor necrosis factor therapy. The remission rates at 52 weeks were 90% (9/10) of patients in the IN-continued group and 20% (2/10) in the IN-discontinued group. The remission rate was significantly higher in the IN-continued group (p = 0.0055). Of the 9 patients who relapsed, 7 were treated with increased or resumed oral IN, and all patients were induced remission again. No serious adverse events were observed during the observation period. CONCLUSIONS IN appears to be very effective in maintaining remission; the high efficacy of reintroduction in patients who relapsed after discontinuation of IN suggests that discontinuation of IN in cases of remission may be an option.

DOP18 Efficacy of risankizumab versus ustekinumab by baseline Crohn’s Disease location: post-hoc analysis of the SEQUENCE head-to-head trial

Abstract Background In Crohn’s disease (CD), disease location may impact treatment effect. This post-hoc analysis of the SEQUENCE head-to-head trial (NCT04524611) compared the efficacy of risankizumab (RZB), an interleukin (IL)-23 p19 inhibitor, versus ustekinumab (UST), an IL-12/23 p40 inhibitor, by CD location. Methods SEQUENCE was an open-label, efficacy assessment-blinded, randomized controlled trial, which enrolled patients (pts) with moderate to severe CD who previously failed ≥1 anti-tumor necrosis factor (TNF) therapy. Pts included in the primary efficacy analysis were randomised 1:1 to receive RZB (selected dosing: intravenous 600 mg induction dose administered at weeks (wks) 0, 4, and 8, followed by subcutaneous 360 mg maintenance dose every 8 wks starting at wk 12) or UST (a single weight-based induction dose administered at wk 0, followed by subcutaneous 90 mg maintenance dose every 8 wks starting at wk 8. A mandatory steroid taper began at wk 2. The primary endpoints were clinical remission (CD Activity Index &amp;lt;150) at wk 24 and endoscopic remission (Simple Endoscopic Score for CD ≤4 and at least a 2-point reduction versus baseline and no subscore &amp;gt;1 in any individual variable, as scored by a central reviewer blinded to treatment allocation) at wk 48. In this post-hoc analysis, both endpoints were evaluated in 100% of pts included in the primary efficacy analysis, stratified by baseline CD location subgroups (ileal only, colonic only, ileal-colonic). Nominal P-values were reported for treatment differences within subgroups. Results At baseline, majority of pts had either ileal-colonic (225 [43.3%]) or colonic (208 [40%]) CD; 87 (16.7%) pts had isolated ileal disease. At wk 24, numerically greater proportions of pts achieved clinical remission with RZB versus UST, regardless of disease location (treatment difference [95% confidence interval], P-value: ileal only, Δ0.8 [-20.1, 21.7], P=0.941; colonic only, Δ22.4 [9.2, 35.5], P=0.001; ileal-colonic, Δ18.2 [5.3, 31.0], P=0.007) (Figure). Pts randomized to RZB with colonic only disease had numerically higher rates of clinical remission relative to pts with ileal only or ileo-colonic disease. At wk 48, RZB-treated pts demonstrated numerically higher rates of endoscopic remission than UST-treated pts (ileal only, Δ22.5 [4.4, 40.6], P=0.017; colonic only, Δ18.3 [6.6, 30.0], P=0.003; ileal-colonic, Δ10.3 [-0.2, 20.9], P=0.057) (Figure). Endoscopic remission rates in the RZB-treated pts were generally similar between ileal only and colonic only CD. Conclusion In pts who have failed ≥1 anti-TNF therapy, RZB demonstrated greater rates of endoscopic remission compared to UST regardless of CD location, and greater rates of clinical remission in ileo-colonic and colonic CD.

P755 Long-term need for restart of biologics after withdrawal in patients with Inflammatory Bowel Disease in mucosal healing

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

P994 Single center assessment of intravenous ustekinumab maintenance in Crohn’s disease

Abstract Background Ustekinumab (UST) is usually employed in Crohn’s disease (CD) after anti-tumor necrosis factor (TNF) therapy failure or if anti-TNF therapy is contraindicated. Higher UST trough levels have been associated with better clinical/endoscopic outcomes, so dose escalation (reducing dosing intervals or reinduction) is widely used. Intravenous (iv) maintenance has been proposed, but it has been barely assessed. Methods Single center, retrospective case series. All patients with CD starting treatment with UST and receiving at least one dose were eligible. Subjects started on UST in other centers or those prescribed for any indication different than IBD were excluded. Dose escalation to iv maintenance was performed in case of lack or loss of response or persisting significant inflammation in laboratory tests, imaging or endoscopy. Following dose escalation, Harvey Bradshaw Index (HBI), fecal calprotectin and C reactive protein (CRP) were checked at each visit. UST trough levels were also assessed. Primary outcomes were clinical remission (HBI&amp;lt;5) and biochemical remission (fecal calprotectin &amp;lt;250 mg/kg). Adverse events, and treatment persistence were also assessed. Results A total of 131 patients treated between May 2017 and August 2023 were included. Sixty (45.8%) patients were escalated to iv UST maintenance after a median of 14.1 (IQR: 8-50.4) weeks of UST treatment. Baseline characteristics are shown in table 1. Patients were started on iv UST maintenance due to persistent inflammatory activity in imaging/endoscopic procedures in 21 (35%), clinical response without remission in 17 (28.3%), low trough concentrations in 16 (26.7%) and primary non-response in 6 (10%). Thirty-three (55%) were receiving sc UST every 4 weeks and 23 (38.3%) started iv maintenance directly after UST induction. At initiation of iv maintenance, patients presented a median HBI index of 4 (IQR: 2-7), a fecal calprotectin of 514 (IQR: 213-1078) mg/kg and UST trough levels of 4.8 (IQR: 3-7.3) μg/mL. Following iv maintenance, UST trough levels increased to 10.9 (IQR: 8-17.4). Clinical remission rates increased from baseline (48.3%) at weeks 8 (79.6%, p=0.001), 24 (72%, p=0.01) and 48 (74.4%, p=0.01). However, the 10-13% increase observed in the biochemical remission rates was not statistically significant (figure 1). Treatment persistence 2 years after starting UST iv maintenance was 72.2% (95% CI: 54.7-83.8%). Only 2 infectious adverse events were observed in the whole cohort (2/131, 1.6%), both in patients receiving sc maintenance. Conclusion UST iv maintenance in bio-experienced patients is safe and increases clinical remission rates, although it did not achieve a relevant improvement in biochemical remission rates.

P611 Relation between AntiTNF levels during the induction and clinical and radiological outcomes in perianal Crohn´s disease

Abstract Background Perianal Crohn's disease(PCD) significantly impacts quality of life with poor long-term prognosis. Anti-tumor necrosis factor(anti-TNF) therapy improves fistula closure rates. However, achieving permanent closure remains challenging. Our aim is to evaluate the relation between antiTNF(infliximab (IFX) and adalimumab(ADA) serum concentrations at induction(w2 and 6), and clinical and radiological outcomes at w24 and w52 Methods We conducted a single tertiary center, retrospective, cohort study including patients with an established diagnosis of PCD treated with antiTNF because of perianal activity. Variables related to their PCD(phenotype, location, fistulas type) were collected. Regarding treatment, we collected serum levels at week 2,6,24 and 52, concomitant treatment and setons presence. We defined clinical response as the absence of drainage on physical examination and clinical remission as the absence of external fistula openings. Radiological response was defined as the absence of T2 hypersignal, gadolinium enhancement, abscess and proctitis in pelvic MRI Results 65 patients were included, baseline characteristics are in Table1. None of the demographic characteristics collected were statistically significant related to clinical or radiological response although non smokers(p=0.01), ileal(p=0.02) and non-stricturing disease(p=0.01) had statistically significant higher drug levels. Taking into account the clinical response at w52, IFX mean levels at w2 were 25.8µg/mL(SD 4.1) in non responders and 30.9µg/mL(SD 14) in responders(p=0.39). At w6 they were 17.2µg/mL(SD 12.2) and 19.4µg/mL(SD 13.8) respectively(p=0.7). ADA mean levels at w2 were 13.3µg/mL(SD 7.7) in non responders and 14µg/mL(SD 6.3) in responders(p=0.87). At w6 they were 10.1µg/mL(SD 3.3) and 12µg/mL(SD 6.1) respectively(p= 0.59). For radiological response at w52 IFX mean levels at w2 were 27µg/mL(SD 15.3) in non responders and 32.7µg/mL(SD 14.5) in responders(p=0.45). At w6 the mean levels were 15.9µg/mL(SD 6.7) and 23.7µg/mL(SD 14.8) respectively(p=0.27). In ADA group the mean levels at w2 were 14.8µg/mL(SD 7.6) in responders and only one patient did not respond. At w6 ADA mean levels were 12.3µg/mL(SD 5.9) in non responders and 12.7µg/mL(SD 6.2) in responders(p=0.94). Early response at w24 was related with a long-term response at w52, 89.9% of the patients who responded at w52, had already responded at w24. Conclusion In our study we observed that almost 90% of the patients who had an early response also responded at w52, so trying to achieve an early response should be an aim in clinical practice. Despite the limited number of patients, our study shows a trend in the relationship between higher antiTNF levels and clinical and radiological response rates

P530 Early Intestinal Ultrasound changes to predict treatment response to anti-TNF therapy in paediatric Inflammatory Bowel Disease; a pilot study

Abstract Background In paediatric Inflammatory Bowel Disease (IBD) selecting the right treatment in the early stages of disease is key to prevent disease progression and to prevent unnecessary exposure to ineffective treatment. Intestinal ultrasound (IUS) is increasingly used to monitor disease activity in response to therapy. However, little is known about the early transmural changes during anti-tumour necrosis factor (anti-TNF) therapy in paediatric IBD. The aim of this study is to assess the early changes in IUS parameters and to evaluate the very early predictive value of IUS for therapy response in paediatric IBD treated with anti-TNF-α therapy. Methods In this pilot study children (aged 3-18 years) starting with anti-TNF therapy (infliximab or adalimumab) were enrolled prospectively if ultrasound at baseline showed bowel wall thickness (BWT) ≥ 2,5mm. IUS was performed at baseline and the most affected bowel segment was identified. Subsequently IUS was repeated in this segment at week 2 and week 13. Response to therapy was determined at week 13. Response and remission was defined as follows. - Therapy response: a ≥50% decrease in faecal calprotectin (FCP) in combination with a decrease in PUCAI (≥20 points or normalisation) /PCDAI (≥12.5 points or normalisation), or normalisation of FCP (&amp;lt;250mg/kg)) - IUS response: decrease in BWT by 25% OR decrease in BWT by &amp;gt;2.0 mm of the most severely affected segment compared to baseline - IUS remission/Transmural healing: BWT&amp;lt;2.0 mm and no Doppler signal(Limberg score) and no mesenteric fat proliferation Results Eleven IBD patients (aged 7 to 12 years; 64% female) were enrolled. IUS response was observed in 5/11 patients at week 2 (decrease in BWT -25% in all). Doppler signal decreased in 3/11(one point in Limberg score in all). After 13 weeks 4/11 patients showed therapy response and 3/11 showed IUS remission. Conclusion Transmural changes were detected by IUS as early as 2 weeks after initiating anti-TNF therapy. This pilot study observed mainly reactivity in BWT, in contrast with previous studies that initially noted changes in Doppler signal. IUS has the potential to predict therapy response at an early stage. A larger sample size is needed to accurately assess its predictive value at week 2 for treatment response.

P323 Defining Normal Bowel Wall Thickness on Intestinal Ultrasound in an International Multicenter Cohort of Children with Inflammatory Bowel Disease in Sustained Deep Remission

Abstract Background Intestinal ultrasound (IUS) is a non-invasive, patient-centric tool for detecting and monitoring activity in patients with inflammatory bowel disease (IBD). Bowel wall thickness (BWT) is the most important parameter for assessing IBD activity, however, normal values are extrapolated from adults. We aimed to define normal BWT in children with IBD who achieved sustained deep remission. Methods International, multicentre, retrospective, pediatric IUS database including IBD patients (&amp;lt; 18 years) without a prior history of surgery or complications who underwent IUS after achieving sustained deep remission: absence of ulcerations on ileocolonoscopy and/or transmural healing on magnetic resonance enterography or computed tomography enterography and steroid-free clinical remission from 2020-2023. Descriptive statistics summarized data as percentages for categorical variables and median [IQR] for continuous variables. Primary outcome was median BWT by segment: sigmoid colon (SC), descending colon (DC), transverse colon (TC), ascending colon (AC), and terminal ileum (TI), assessed using Kruskall Wallis. Secondary outcomes included univariate association of BWT and age, sex, disease duration, diagnosis (Crohn’s disease (CD) vs. ulcerative colitis (UC)/IBD-unspecified (IBD-U) and medication exposure. Results 80 patients (33 (41%) female; 51 (64%) CD:26 (33%)UC:3 (4%)IBD-U, median age 15.2 [14-16.6] years) with 400 bowel segments were included. Forty (50%) received anti-tumor necrosis factor therapy (anti-TNF), 18 (23%) ustekinumab (UST), 10 (12%) mesalamine(5-ASA), 6 (8%) vedolizumab (VDZ), 5 (6%) immunomodulator monotherapy (IM), and 1 (1%) upadacitinib (UPA) (Table 1). Median BWT was 1.3 [1.0-1.6]mm for SC, 1.3 [1.1-1.7]mm for DC, 1.3 [1.0-1.6] mm for TC, 1.3 [1.0-1.6]mm for AC, and 1.3 [1.1-1.5]mm for TI (Figure 1). There was no difference in BWT between segments (p=0.7952), age (p=0.1952) or sex (p=0.781). BWT was negatively associated with disease duration (p&amp;lt;0.05). UC patients had a 0.16 mm thinner BWT than CD (p&amp;lt;0.05). Mean BWT in patients on VDZ was thinner than those on anti-TNF monotherapy (-0.19mm, p&amp;lt;0.05). BWT in patients on anti-TNF combination therapy was thicker than patients on anti-TNF monotherapy (0.21mm, p&amp;lt;0.05). There was no BWT difference between patients on IM, 5-ASA and UST compared to anti-TNF (p&amp;gt;0.05). Conclusion Normal BWT for children with IBD in deep remission is less than adults, and unaffected by age, sex and bowel segment. BWT may be affected by disease duration, phenotype and medication exposure. These findings are crucial to the standardized assessment of transmural healing in children with IBD.