anti-TNF Monotherapy Research Articles

HLA DQA1*05 and risk of anti-TNF treatment failure and anti-drug antibody development in children with Crohn's Disease: HLA DQA1*05 and Pediatric Crohn's Disease.

HLA DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data. We analyzed banked serum from patients with CD < 21 years of age enrolled in COMBINE, a multi-center, prospective randomized trial of anti-TNF monotherapy vs. combination with methotrexate. The primary outcome was a composite of factors indicative of treatment failure. The secondary outcome was ADA development. A trend towards increased treatment failure among HLA DQA1*05 positive participants was not significant (HR 1.58, 95% CI 0.95-2.62; p=0.08). After stratification by HLA DQA1*05 and by methotrexate vs. placebo, patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05 positive patients on placebo (HR 0.31, 95% CI 0.13-0.70; p=0.005).A trend toward increased ADA development among HLA DQA1*05 positive participants was not significant (odds ratio [OR] 1.96, 95% CI 0.90-4.31, p=0.09). After further stratification, HLA DQA1*05 negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05 positive patients on placebo (OR 0.12, 95% CI 0.03-0.55; p=0.008). In a randomized trial of children with CD initiating anti-TNF, 40% were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1*05 is an important biomarker for prognosis and risk stratification.

Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease.

Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab). We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization. Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 μg/mL [P = .49]; adalimumab: 11.1 vs 10.5 μg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 μg/mL [P < .01]; adalimumab: 9.1 vs 12.3 μg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14). LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.

S1413 Impact of Race on Clinical Outcomes in IBD Patients on Anti-TNF Monotherapy and Anti-TNF Combination Therapy With Immunomodulators: A Propensity-Matched Cohort Study

S1413 Impact of Race on Clinical Outcomes in IBD Patients on Anti-TNF Monotherapy and Anti-TNF Combination Therapy With Immunomodulators: A Propensity-Matched Cohort Study

Clinical impacts of immunomodulator withdrawal from anti-tumor necrosis factor combination therapy in pediatric inflammatory bowel disease.

Combination therapy consists of both anti-tumor necrosis factor (anti-TNF) and an immunomodulator (IMM) and has been shown to improve outcomes in patients with inflammatory bowel disease (IBD). This study assesses the impacts of IMM withdrawal from combination therapy to anti-TNF monotherapy in children with IBD. This single-center retrospective cohort study included children with IBD initiated on combination therapy between 2014 and 2019 who discontinued the IMM. We evaluated whether IMM withdrawal impacts laboratory values and disease activity. Linear mixed effects models with random intercepts were used to compare differences between groups. Chi-square and Kruskal-Wallis tests were used for comparisons between patients who did and did not require subsequent escalation of therapy. One hundred and fifty-two patients discontinued the IMM which did not significantly affect disease activity. However, 18% of patients escalated therapy after IMM withdrawal, primarily due to low anti-TNF levels. Lower anti-TNF and higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels before IMM withdrawal were associated with subsequent escalation of therapy. Overall, there was no statistically significant effect on anti-TNF drug levels. Patients with Crohn's disease (CD) on infliximab (IFX) and methotrexate (MTX) who discontinued the IMM had an increase in mean ESR and CRP (p < 0.05). IMM withdrawal from anti-TNF combination therapy may be considered safe in the setting of higher anti-TNF levels and normal serum inflammatory markers. Clinicians should consider assessing anti-TNF levels and inflammatory markers after IMM withdrawal, especially in patients with CD receiving IFX who discontinued MTX.

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.

IMPROVEMENT IN GROWTH AND NUTRITION STATUS AFTER ANTI-TNF THERAPY INITIATION AMONG PATIENTS WITH PEDIATRIC CROHN’S DISEASE: RESULTS FROM THE COMBINE TRIAL

Abstract BACKGROUND Growth failure impacts 15-40% of children with Crohn’s disease (CD). Potential causes of growth failure include chronic inflammation, malabsorption, and poor nutritional intake. Control of inflammation is key to improving growth outcomes. Anti-TNF therapy has been associated with improved growth and nutritional status in affected children. Large studies of serial outcomes of growth after anti-TNF therapy initiation are limited. OBJECTIVE We sought to 1) describe baseline weight, height, and BMI status at anti-TNF initiation in children with CD in a large, multicenter clinical trial, 2) compare the demographic and clinical characteristics of children with and without weight, height, and BMI disturbance, and 3) describe follow-up anthropometric parameters at approximately 12 and 24 months after anti-TNF initiation. METHODS We analyzed data from the COMBINE trial, a multicenter study comparing infliximab or adalimumab in combination with oral methotrexate to anti-TNF monotherapy for children with CD. We obtained demographic, clinical, and anthropometric data at time of enrollment and after 12 and 24 months. Weight, height, and BMI Z-scores were dichotomized as normal (≥ -1) versus disturbance (&amp;lt; -1) at each time point. We used standard descriptive statistics to summarize the distribution of Z-scores and bivariate statistics to compare demographic, clinical, and treatment characteristics among participants with versus without growth disturbance at baseline. RESULTS Our study population included 199 children (25% female, 83% white, mean age 12 years). Of these, 53 (26.6%) had a weight disturbance at baseline (Table 1). Of 188 children with height data available at baseline, 52 (27.7%) had a height disturbance and 37 (19.7%) had a BMI disturbance. The mean short pediatric CD activity index (sPCDAI) was higher in those defined with weight, height, and BMI disturbance at baseline compared to those with normal parameters (Table 2). Gender, race, ethnicity, and age at time of anti-TNF initiation were not different between groups with and without weight, height, or BMI disturbances. Approximately 12 months after enrollment, the proportion of patients with height disturbance was 6.1% with a continued decrease to 0.9% at 24 months. BMI disturbance was observed in 7.5% of participants at 12 months and 2.8% at 24 months. Weight disturbance was observed among 5.7% and 0.8% of participants at 12 and 24 months respectively. DISCUSSION A substantial proportion of children with CD had weight, height, and BMI disturbance at time of anti-TNF initiation. These proportions decreased at approximately 12 months and 24 months, demonstrating significant improvement in growth disturbances after anti-TNF therapy. Table 1 % of children with weight, height, and BMI disturbance (Z-score &amp;lt;-1) at time of enrollment in addition to 12 and 24 months after anti-TNF therapy initiation. Table 2 Mean short pediatric Crohn’s disease activity index (sPCDAI) for BMI, weight, and height at time of anti-TNF initiation.

P883 Impaired long-term quantitative cellular response to SARS-COV-2 vaccine in thiopurine-treated IBD patients

Abstract Background SARS-CoV-2 mRNA vaccine induces a robust immune response in most patients with inflammatory bowel disease (IBD). However, humoral short-term response appears to be reduced in patients receiving anti-TNF agents or tofacitinib, even after booster doses. Data on long-term immune response is limited. We aimed to assess short and long-term humoral and T-cell response to SARS-CoV-2 mRNA vaccine in IBD patients receiving anti-TNF and/or thiopurines. Methods A prospective, longitudinal study was carried out in IBD patients receiving thiopurines, anti-TNF mono, or combo therapy. Patients had received between 2 and 4 doses of mRNA SARS-CoV-2 vaccine. Cellular and humoral response to the vaccine was assessed by serum interferon-gamma release assay (IGRA) and antibody SARS-CoV-2, respectively. We defined short-term response as humoral and T-cell response six weeks after the second vaccine and long-term response 6 to 12 months after that. Primary outcome was to determine if T-cell immune response differs in IBD patients receiving anti-TNF versus thiopurines. Results We recruited 148 IBD patients, 57 treated with anti-TNF monotherapy, 53 with anti-TNF combo, and 38 with thiopurines. Short-term T-cell and humoral responses were similar between the three groups. However, long-term T-cell concentration was reduced in thiopurine-treated (median 0.7 UI/mL [0.26-2.35]; p&amp;lt;0.05) and anti-TNF-combo-treated patients (median 0.4 UI/mL [0.22-1.13]; p&amp;lt;0.01) when compared to anti-TNF monotherapy (median 2.2 UI/mL [1-4.15]). Multivariate analysis showed that anti-TNF monotherapy (-0.93, p&amp;lt;0.05) and decreased time between vaccination and T-cell response measurement (0.04 [.00005-.078] p=0.05) were associated with increased T-cell concentration long-term when compared to the other groups of patients. Conclusion We found a diminished long-term quantitative cellular response in our cohort of IBD patients vaccinated for SARS-CoV-2 treated with thiopurines or combo therapy compared with anti-TNF monotherapy. These findings highlight the recommendation to receive booster doses in IBD patients, specially those receiving thiopurines.

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.

P556 Immunomodulator and advanced therapies for Induction of clinical remission and response in Crohn’s disease: A systematic review and network meta-analysis

Abstract Background Several effective advanced therapies have been approved for the treatment of Crohn’s disease (CD) in the past two decades. Many have used synthesis techniques to study this area, but these rarely consider both advanced and immunomodulator therapy together in the same analysis. Network meta-analysis enables the direct and indirect comparison of these different therapeutic agents, aiding in determining their relative positioning within the treatment algorithm. Methods We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials between inception and October 2023 for randomised controlled trials (RCTs). The outcomes included were clinical remission and response, adverse events (AE), withdrawal due to AE, total and serious AE. We performed random-effects meta-analysis and network meta-analysis (frequentist approach), and estimated relative risk (RRs), 95%CI values. We used GRADE to ascertain certainty of evidence. Results A total of 83 RCTs comprising 19214 patients were eligible. A total of 28 interventions were included in the analysis. Combination of anti-tumor necrosis factor (TNF) and immunomodulators, anti-TNF monotherapy (adalimumab [ADA], infliximab [IFX], BI695501), IL-23 antagonists (ustekinumab [UST], guselkumab, risankizumab [RIS], mirikizumab), anti-integrins (vedolizumab, natalizumab) and upadacitinib were effective in inducing clinical remission compared to placebo (Figure 1). There was moderate certainty of evidence for combination of ADA and azathioprine (AZA) (RR 3.1, 95%CI [2.0-4.8]; risk difference [RD]: 40.1%), IFX+AZA (RR 2.5, 95%CI [1.7-3.8]; RD: 28.9%), ADA (RR 2.5, 95%CI [1.8-3.5]; RD:28.5%), and UST (RR 2.0 95%CI, [1.6-2.5]; RD: 19.2%) in induction of clinical remission compared to placebo. For induction of clinical response, there was moderate certainty of evidence for IFX+AZA (RR 2.8, 95%CI [1.6-4.8]), ADA (RR 2.5, 95%CI [1.7-3.9]), IFX (RR 2.8, 95%CI [1.6-4.8]), RIS (RR 1.9, 95%CI [1.3-2.6]). On analysis of serious adverse events all therapies were of no difference to placebo (very low certainty). On sensitivity analysis, the impact of concomitant immunomodulator use and the biological naivety of patients had little effect on these results. Conclusion On network meta-analysis, combination of anti-TNFs and immunomodulators followed by anti-TNF monotherapy had large effect size with moderate certainty for the induction of clinical remission. More novel therapies appear to have examples of similarly important effect sizes, but are currently limited due to the imprecision of the limited evidence base at present and future research should target these therapies in study.

P1043 Immunomodulator and advanced therapies for prevention of clinical relapse and loss of response during maintenance phase in Crohn’s disease: A systematic review and network meta-analysis

Abstract Background Several effective advanced therapies have been approved for the treatment of Crohn’s disease (CD) in the past two decades. Given lack of adequate head-to head clinical trials it is challenging to position these therapies in the management algorithm. Therefore we performed this network meta-analysis to inform therapeutic decisions. Methods We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials between inception and October 2023 for randomised controlled trials (RCTs). Outcomes assessed were clinical relapse (loss of clinical remission), loss of clinical response, adverse events (AE), withdrawal due to AE, and serious AE. We performed random-effects meta-analysis and network meta-analysis (using a frequentist approach), and estimated relative risk (RRs), 95%CI values. We used GRADE to ascertain certainty of evidence. Results A total of 32 RCTs comprising 10,924 patients were included in the analysis. On network meta-analysis of 15 interventions based on prevention of clinical relapse, combination of infliximab (IFX) and azathioprine (AZA) (RR 0.31, 95%CI [0.17-0.56]), IFX (RR 0.62, 95%CI [0.5-0.76], moderate certainty), and adalimumab (RR 0.68, 95%CI [0.55-0.84], moderate certainty) were the only agents that were effective compared to placebo (Figure 1). Methotrexate (RR 0.57, 95%CI [0.32-1.03], low certainty) and azathioprine (RR 0.82, 95%CI [0.62-1.1]), very low certainty) were not effective. On analysis based on prevention of clinical response for nine interventions, there was high certainty evidence for ustekinumab (RR 0.73, 95%CI [0.61-0.86]), upadacitinib (RR 0.64, 95%CI [0.57-0.72]), and moderate certainty of evidence for infliximab (RR 0.71, 95%CI [0.59-0.84]), adalimumab (RR 0.68, 95%CI [0.61-0.75]), certolizumab (RR 0.57, 95%CI [0.47-0.7]), CTP13 (RR 0.46, 95%CI [0.38-0.57]), vedolizumab (RR 0.82, 95%CI [0.68-0.99]), natalizumab (RR 0.54, 95%CI [0.43-0.68]). Tofacitinib was not effective and there was no data available for immunomodulators and combination therapies for this outcome. On analysis of serious adverse events advanced therapies were of no difference to placebo (very low certainty). Conclusion On network meta-analysis immunomodulators and advanced therapies for maintenance phase, combination of anti-TNFs and immunomodulators followed by anti-TNF monotherapy had large effect size with moderate certainty for prevention of clinical relapse. There was moderate to high certainty evidence to suggest newer advanced therapies are effective in prevention of loss of clinical response.

P714 Immunogenicity and safety of adjuvated recombinant zoster vaccine in IBD patients on different immunosuppressive therapies

Abstract Background Aberrant immune regulation and the use of immunosuppressive therapy make IBD patients more susceptible to complications of primary Varicella Zoster Virus (VZV) infection and significantly increase the risk of Herpes Zoster (HZ). HZ can be prevented by vaccination and RZV is the first HZ vaccine approved for immunocompromised persons. Limited data on immunogenicity and safety of RZV in immunosuppressed IBD patients are available. We investigated humoral and cell-mediated response and safety of RVZ vaccination in IBD patients under different immunosoppressive therapies. Methods In this prospective single centre study, adult IBD patients were enrolled and vaccinated with 2 doses of RZV between May and July 2022. Different immunosuppressive regimens (anti-metabolites, anti-TNF mono and combination therapy; ustekinumab and vedolizumab monotherapy; mofetyl mycofenolate/steroid combination therapy) were not discontinued and the administration schedule maintained. Immunogenicity was evaluated by quantitative detection of serum IgG anti-VZV antibodies and anti-VZV glycoprotein E (gE) antibodies before and 1 month after vaccination completion using ELISA. Reactogenicity was evaluated by diary cards reporting adverse events for 7 days after each dose. Events were graded from 1 (mild, not interfering with everyday activities) to 3 (severe, preventing normal everyday activities). Disease activity was assessed by SCCAI and HBI before vaccination, 7 and 30 days after each dose. Results Vaccination was completed in 104 (98.1%) out of 106 enrolled patients (median age 49.7 years, 59.4% male; 55.7% UC, 44.3% CD). Humoral response was observed in all patients, with a significant increase of anti-VZV antibodies (median UTI 23.8; IQR: 20.2-26.2 vs median UTI 419; IQR: 20.2-26.2, 376-458, p&amp;lt;0.001, median 17.8 fold increase, figure 1) and anti-gE antibody concentration compared to baseline (median OD 0.24; IQR: 0.21-0.26 vs OD 0.53; IQR:0.4-0.6, median 2.3 fold increase, p&amp;lt;0.001, figure 1). Imunosuppressive agents, either in mono or combination therapy, did not influence anti-VZV titre, anti-gE concentration and CMI response. Local and systemic solicited reactions after any dose were reported in 96.2% (grade 3=24.8%) and 88.6% (grade 3=33.3%) of patients respectively, with higher grade of intensity after the second dose. No severe adverse events related to vaccination were observed; 2 patients (1.9%) reported a disease flare. Conclusion RZV vaccine is able to induce a robust gE-specific humoral immune response. The type and intensity of immunosuppressive regimens did not influence humoral immunogenicity. RZV vaccination was safe and well tolerated in terms of both reactogenicity and exacerbation of disease.

Tumor Necrosis Factor Inhibitors in Inflammatory Bowel Disease and Risk of Immune Mediated Inflammatory Diseases

Tumor necrosis factor inhibitors (anti-TNF) are effective therapies for several immune-mediated inflammatory diseases (IMIDs). However, case reports have identified the paradoxical occurrence of IMIDs in patients treated with anti-TNF. We studied the risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa after the initiation of anti-TNF therapy for inflammatory bowel disease (IBD). We conducted 2 nationwide cohort studies comprising all patients with IBD in Denmark (2005-2018) and France (2008-2018). We obtained individual-level information on exposure to anti-TNF, diagnoses of IMIDs including rheumatoid arthritis, psoriasis, and hidradenitis suppurativa, and potential confounders from healthcare registers in the respective countries. We used Cox models to estimate hazard ratios (HRs) for the association between anti-TNF exposure and IMIDs and then pooled the estimates from the 2 cohorts. To test the robustness of our results, we performed an active comparator analysis of anti-TNF monotherapy vs azathioprine monotherapy. The Danish and French cohorts comprised 18,258 and 88,786 subjects with IBD, respectively, contributing a total of 516,055 person-years of follow-up. Anti-TNF was associated with an increased risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa in both the Danish (HR, 1.66; 95% confidence interval [CI], 1.34-2.07) and the French cohort (HR, 1.78; 95% CI, 1.63-1.94), with a pooled HR of 1.76 (95% CI, 1.63-1.91). Anti-TNF was also associated with an increased risk of the outcomes when compared with azathioprine (pooled HR, 2.94; 95% CI, 2.33-3.70). In 2 nationwide cohorts of IBD patients, anti-TNF therapy was associated with an increased risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa.

Impact of Holding Immunosuppressive Therapy in Patients with Inflammatory Bowel Disease Around mRNA COVID-19 Vaccine Administration on Humoral Immune Response and Development of COVID-19 Infection.

The BNT162b2 and mRNA-1273 COVID-19 vaccines are efficacious in patients with inflammatory bowel disease; but there are a lack of data examining if holding immunosuppressive therapy around vaccination improves immune response. We studied the effect of holding IBD medications around the time of vaccination on antibody response and breakthrough COVID-19 infection. Partnership to Report Effectiveness of Vaccination in populations Excluded from iNitial Trials of COVID is a prospective cohort of individuals with IBD receiving COVID-19 vaccination. Quantitative measurement of anti-receptor binding domain IgG antibodies to SARS-CoV-2 was performed 8 weeks after completing a vaccination series. 1,854 patients were included; 59% were on anti-TNF (10% of these on combination therapy), 11% on vedolizumab, and 14% on ustekinumab. 11% of participants held therapy before or after vaccine administration for at least 2 weeks. Antibody levels were similar in participants continuing versus holding anti-TNF monotherapy before or after the second vaccine (BNT162b2: 10 μg/mL vs 8.9 μg/mL, mRNA-1273: 17.5 μg/mL vs 14.5 μg/mL). Comparable results were seen in those on combination therapy. Antibody titers in those on ustekinumab or vedolizumab were higher compared to anti-TNF users, but there was no significant difference if drug was held or continued (BNT162b2: 22.5 μg/mL vs 23 μg/mL, mRNA-1273: 88 μg/mL vs 51 μg/mL). Holding therapy was not associated with decreased rate of COVID-19 infection compared to those not holding therapy (BNT162b2: 28% vs 29%; mRNA-1273 19% vs 31%). We recommend continuing IBD medications while receiving mRNA COVID-19 vaccination without interruption.

Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn’s Disease: A Pragmatic Randomized Trial

Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn's disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. Patients with pediatric Crohn's disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. Among adalimumab but not infliximab initiators, patients with pediatric Crohn's disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. gov, Number: NCT02772965.

A195 DURABILITY OF SEROLOGICAL RESPONSES AFTER SECOND, THIRD AND FOURTH DOSE OF SARS-COV-2 VACCINATION IN INFLAMMATORY BOWEL DISEASE: A PROSPECTIVE COHORT STUDY

Abstract Background Adequate serological responses following two-dose regimens and additional doses of SARS-CoV-2 vaccination have been demonstrated for the vast majority of those with IBD. However, antibody levels following 2nd, 3rd, and 4th dose SARS-CoV-2 vaccination may decrease over time in the IBD population. Purpose We assessed the durability of serological responses to 2nd, 3rd, and 4th dose SARS-CoV-2 vaccination over time in a cohort of IBD patients. Method Adults with IBD who received at least one dose of a SARS-CoV-2 vaccine (n=559) were evaluated for serological response to the spike protein of SARS-CoV-2 using the Abbott IgG II Quant assay with a seroconversion threshold of ≥ 50 AU/mL. The geometric mean titer (GMT) with 95% confidence intervals (CI) were calculated and stratified by weeks (1–8, 8–16, 16–24, 24+ weeks) after each vaccine dose. We compared stratified GMTs with Mann–Whitney U tests using a significance level of 0.05. Result(s) Our cohort (n=559) comprised the following patient characteristics: 82.8% were 18–65 years-old (n = 463), 53.1% were female (n =297), and 71.6% had Crohn’s disease (n =400). IBD medications were classified in the following mutually exclusive groups: No immunosuppressives 10.5% (n = 59), anti-TNF monotherapy 35.8% (n = 200), immunomodulatory monotherapy 2.1% (n =12 ), vedolizumab 11.8% (n =66 ), ustekinumab 20.4% (n =114 ), tofacitinib 1.2% (n =7 ), combination therapy 15.9% (n = 89), and prednisone 2.1% (n =12). For vaccine type, 85.6% and 82.3% had Pfizer for 3rd and 4th dose, respectively, while the remainder had Moderna. Seroconversion rates 1–8 weeks after 3rd and 4th dose were both 99.9%. Figure 1 compares GMTs with 95% CI by weeks after each vaccine dose. GMTs are highest 1–8 weeks after 2nd dose (4053 AU/mL; 95% CI: 3468, 4737 AU/mL; n=337), 3rd dose (12116 AU/mL; 10413, 14098 AU/mL; n=256), and 4th dose (14337 AU/mL; 10429, 19710 AU/mL; n=67). Subsequently, antibody levels decay from 1–8 weeks to 8–16 weeks (p&amp;lt;0.001) for 2nd dose (mean difference: –2224 AU/mL), 3rd dose (mean difference: –7526 AU/mL), and 4th dose (mean difference: –9715 AU/mL). Compared to 16–24 weeks after 2nd dose, antibody levels 24+ weeks after were similar (GMTs: 795 AU/mL vs. 1043 AU/mL, p=0.52). For third dose, antibody levels 8–16 weeks and 16–24 weeks after vaccination were similar (4590 AU/mL vs. 4073 AU/mL, p=0.73) along with 16–24 weeks compared to 24+ weeks after vaccination (4073 AU/mL vs. 5876 AU/mL, p=0.18). Image Conclusion(s) Within 1–8 weeks after each dose of vaccine, serological responses spikes with each subsequent dose yielding a higher GMT. While antibody levels decay 8–16 weeks after each dose, similar GMT levels beyond 16 weeks may indicate durability of antibody levels over a longer duration of time. Disclosure of Interest None Declared

P654 Controversies in the management of anti-TNF therapy in Crohn’s disease patients. A Delphi consensus

Abstract Background Over the last years significant advances have arisen in CD. New therapies with different mechanisms of action have been approved for the management of Crohn’s disease (CD). However, there is limited evidence on optimal positioning of agents as first-or second-line therapies due to the lack of head-to-head robust comparative data. Our aim was to establish feasible and practical recommendations for the management of patients with moderate to severe CD with the use of anti-tumour necrosis factor (TNF) drugs, with special focus on controversial areas. Methods A group of 9 expert gastroenterologists identified current relevant clinical controversies in the management of CD with anti-TNF therapies. A comprehensive literature review was performed to analyze them and a survey was launched to examine current clinical practice. This was a structured survey organized in 2 main sections that included several questions: 1) Sociodemographic and practice related questions; 2) Opinion and attitude in daily practice related to: the use of anti-TNFs, vedolizumab or ustekinumab in naïve and refractory patients, the role of HLA-DQA105, or monitoring of drug levels. An invitation to participate was emailed to a representative number of 244 IBD treating physicians all over the country. The results of the literature review and survey were discussed in a nominal group meeting, and a set of statements were proposed for a Delphi process. The participants of the survey were also invited to the Delphi. Agreement was defined if at least 70% of the participants voted ≥7 (from 1, totally disagree to 10, totally agree). For each statement, the level of evidence and grade of recommendation was established based on the Oxford Evidence Based Medicine categorization. Results A total of 14 statements were generated (table 1 depicts the statements and the results of the Delphi). All but two achieved required level of agreement. The statements cover the following areas: 1) use of first-line non-anti-TNF biologic therapy; 2) role of HLA-DQA1*05 in daily practice; 3) attitudes in primary nonresponse and loss of response to anti-TNF therapy due to immunogenicity; 4) ustekinumab or vedolizumab if a change of mechanism of action is considered; 5) anti-TNF drug levels monitoring during induction; 6) combined therapy with an immunomodulator and anti-TNF monotherapy. Conclusion This document sought to pull together the experts’ attitudes when dealing with different clinical scenarios of patients with CD on anti-TNF.

P759 Perianal Crohn’s disease – therapeutic response and anal cancer risk - a single centre retrospective cohort

Abstract Background Perianal manifestations of Crohn’s disease (CD) occur in up to 43% of CD patients, and are strongly associated with colonic and rectal involvement. They have negative effects on patients’ quality of life and the risk of anal cancer (AC) is two to three times higher than the general population. The management of perianal disease (pCD) often includes a local approach but also a systemic therapeutic escalation. Methods Aim: to evaluate the response to therapy and the incidence of AC in patients with pCD. Retrospective single-centre study, recruiting all adult patients with pCD. We analysed the population demography, extraintestinal manifestations, the presence of perianal disease at diagnosis, the subtype of pCD, PDAI score, baseline treatment and the need for readjustment. We evaluated the clinical and MRI response atsix months, further therapeutic changes required, the incidence of anal and rectal cancer and the status at last follow-up. Results 174 patients with CD, 50 with pCD (29%) – from these: 59% Male; Age 22-77 (median 51); Extraintestinal manifestations 16 (31%); pCD at the diagnosis of CD 29 (57%). pCD characterization: fistula 46 (92%) (simple 6; complex 40); abscess 27 (54%); fissure 12 (24%). PDAI score: 1-17 (median 7,5). Approach: fistulotomy 25 (49%); seton placement 13 (25%); protective stoma 5 (9,8%). Antibiotics in 43 (86%). Therapeutic change 40 (84%) -started: corticosteroid course 9 (18%) (all with rectal disease activity), anti-TNF 28 (55%), thiopurine 23 (45%) 13 of them in monotherapy. At 6 months: global clinical improvement 41 (81%); healed PD 18 (35%). Follow up 2-49 years (mean 20); Subsequent treatment change during follow up: 28 (55%). At last follow-up: luminal CD in clinical remission 44 (86%); pCD improvement 43 (84%) and deep remission in 32 (64%). By univariate analysis there was no significant association between starting anti-TNF therapy or monotherapy with thiopurine and clinical response at 6 months, or at last follow up, with MRI improvement. During follow up, 3 patients (6%) develop AC (2 perianal fistula-related cancer; 1 adenocarcinoma). There was no significant association with the use of anti-TNF (p 0,356) or thiopurine (p 0,312) but there was an association with absence of clinical response at 6 months (p 0,050) and lack of MRI improvement (p 0,057). There were no rectal cancer cases. Conclusion Most patients with pCD required therapeutic changes, the majority of them initiating anti-TNF – this resulted in luminal disease remission and at least pCD improvement in more than 80% of patients. The small sample size limited our results, but AC seemed to be more common in patients with chronically active pCD.

P747 The impact of COVID-19 on patients with Inflammatory Bowel Disease: A population-based study using artificial intelligence

Abstract Background Coronavirus disease 2019 (COVID-19) has been a pandemic that is still very prevalent. Patients with Inflammatory Bowel Disease (IBD) represent a special population considering their already altered immune system and their exposure to several immunosuppressive therapies. We pretend to study the impact of COVID-19 on IBD patients in our community, Castilla-La Mancha (a region in central Spain). Methods Retrospective observational study using an artificial intelligence with natural language processing capability, the SAVANA manager, we analyzed data from 1 808 010 patients with Electronic Medical Records (EMR) within the public health system of Castilla-La Mancha from March 1st 2020 to January 1st 2021. Data on demographic characteristics, hospitalization, ICU admission and mortality were collected. We compared COVID outcomes between IBD and non-IBD patients. We compared COVID outcomes in IBD patients according to their treatment (comparing each treatment group to those IBD patients with no treatment); we considered: immunomodulators (azathioprine, mercaptopurine, methotrexate), antiTNF alone or combined with immunomodulator, vedolizumab, ustekinumab and tofacitinib; mesalazine and corticosteroids were not analyzed. Results 2 243 patients with IBD suffered COVID-19, compared to COVID-19 cases without IBD there were less females, they suffered more arterial hypertension, diabetes mellitus, dyslipidemia, obesity, or tabacco use (TABLE 1). And yet, despite these being proven risk factors for worse outcomes for COVID-19, no differences were appreciated in hospitalization rate, ICU admission, or mortality between those with or without IBD (TABLE 2). COVID-19 was more frequent in IBD patients (32.59 vs 13.28%). Comparing IBD patients with COVID-19 according to their treatments (TABLE 3), vedolizumab is the only treatment with a higher risk for COVID-19 infection, however the hospitalization risk for vedolizumab is lower than for those without it. Immunomodulators do also have a lower hospitalization risk both alone or in combination with antiTNF, no differences were found for antiTNF monotherapy, ustekinumab or tofacitinib. ICU rate and mortality are no different between treatments, except for tofacitinib (0.00% ICU rate, 10.00% mortality), however the small number of patients using this treatment may bias this result. Conclusion COVID-19 in IBD patients is no different in hospitalization, ICU admission or mortality compared to non-IBD population. IBD patients exposed to immunomodulators and vedolizumab have less hospitalization risk than those not exposed, no differences were found for antiTNF alone or ustekinumab. The impact of tofacitinib in COVID outcomes requires further investigation.

Retreatment with anti-tumor necrosis factor therapy in combination with an immunomodulator for recurrence of Crohn's disease after ileocecal resection results in prolonged continuation as compared to anti-tumor necrosis factor monotherapy.

A considerable proportion of Crohn's disease patients that undergo ileocecal resection (ICR) have failed anti-tumor necrosis factor (TNF) therapy preoperatively. This study aimed to assess the effectiveness of retreatment of anti-TNF therapy in patients with postoperative recurrence. A real-world cohort study was performed on Crohn's disease patients who underwent primary ICR after anti-TNF therapy failure, and who were retreated with anti-TNF therapy for postoperative symptomatic Crohn's disease. The primary outcome was treatment failure (the need for (re)introduction of corticosteroids, immunosuppressants, or biologicals or the need for re-resection). Sub-analyses were performed on the nature of preoperative anti-TNF failure (primary non-response, secondary loss of response, intolerance), indication for ICR (refractory, stricturing, penetrating disease), combination therapy with immunomodulators, retreatment with the same anti-TNF agent and preoperative exposure to 1 vs. >1 anti-TNF agents. In total, 66 of 364 patients retreated with anti-TNF therapy following ICR. Cumulative rates of treatment failure at 1 and 2 years were 28% and 47%. Treatment failure rate at 2 years was significantly lower in patients receiving combination therapy as compared to anti-TNF monotherapy (30% vs. 49%, P = 0.02). No difference in treatment failure was found with regards to the nature of preoperative anti-TNF failure (P = 0.76), indication for ICR (P = 0.88) switch of anti-TNF agent (P = 0.55) agent, and preoperative exposure to 1 vs. >1 anti-TNF agents (P = 0.88). Retreatment with anti-TNF therapy for postoperative Crohn's disease recurrence is a valid strategy after preoperative failure. Combination therapy is associated with a lower rate of treatment failure.

Low Risk of Lymphoma in Pediatric Patients Treated for Inflammatory Bowel Disease.

Despite the effectiveness of immune-suppressing therapies in treating pediatric inflammatory bowel diseases (IBDs), concerns of lymphoma may limit their use. We used a large administrative claims database to evaluate the risk of lymphoma in pediatric IBD and conducted a case series analysis of medication exposure in children diagnosed with lymphoma. We analyzed administrative claims from the 2007 to 2018 IQVIA database and identified pediatric (≤18 years) patients with Crohn's disease or ulcerative colitis using International Classification of Diseases, 9th or 10th Revision codes and pharmacy claims. Lymphoma cases were identified by diagnosis codes and confirmed by independent claim-by-claim review by a pediatric oncologist and gastroenterologist. We calculated incidence rates for lymphoma among patients with and without pharmacy claims for treatment followed by treatment description among those who developed lymphoma during follow-up. A total of 10,777 pediatric patients with IBD received ≥1 IBD therapy (median age 15 years [12-17], 45% female and 61% diagnosed with Crohn's disease) during 28,292 patient-years of follow-up. Among treated patients, 5 lymphoma cases were identified (incidence rate 17.7/100,000 patient-years; 95% confidence interval 6.5-39.2). Of these, 4 were treated with a thiopurine before lymphoma diagnosis, and none received anti-tumor necrosis factor-α (anti-TNF) monotherapy. The overall lymphoma incidence was low among our cohort of treated pediatric patients with IBD. We observed no cases of lymphoma among patients prescribed anti-TNF monotherapy. These findings reinforce the relative safety of anti-TNF monotherapy for the treatment of pediatric IBD.