anti-TNF Treatment Research Articles

Severe influenza infection is associated with inflammatory programmed cell death in infected macrophages.

Influenza A virus (IAV) is one of the leading causes of respiratory tract infections in humans, representing a major public health concern. The various types of cell death have a crucial role in IAV pathogenesis because this virus may trigger both apoptosis and necroptosis in airway epithelial cells in parallel. Macrophages play an important role in the clearance of virus particles, priming the adaptive immune response in influenza. However, the contribution of macrophage death to pathogenesis of IAV infection remains unclear. In this work, we investigated IAV-induced macrophage death, along with potential therapeutic intervention. We conducted in vitro and in vivo experiments to evaluate the mechanism and the contribution of macrophages death to the inflammatory response induced by IAV infection. We found that IAV or its surface glycoprotein hemagglutinin (HA) triggers inflammatory programmed cell death in human and murine macrophages in a Toll-like receptor-4 (TLR4)- and TNF-dependent manner. Anti-TNF treatment in vivo with the clinically approved drug etanercept prevented the engagement of the necroptotic loop and mouse mortality. Etanercept impaired the IAV-induced proinflammatory cytokine storm and lung injury. In summary, we demonstrated a positive feedback loop of events that led to necroptosis and exacerbated inflammation in IAV-infected macrophages. Our results highlight an additional mechanism involved in severe influenza that could be attenuated with clinically available therapies.

Innate lymphoid cell (ILC) subsets are enriched in the skin of patients with hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory skin disease manifested as painful inflamed lesions including deep-seated nodules, abscesses and sinus tracts. The exact aetiology of HS is unclear. Recent evidence suggests that immune dysregulation plays a crucial role in pathogenesis and disease progression. Innate lymphoid cells (ILC) are a recently identified immune cell subset involved in mediating immunity, however their role in HS has not yet been investigated. Three distinct subsets of ILC- ILC1, ILC2 and ILC3 have been described, and these are involved in skin tissue homeostasis and pathologic inflammation associated with autoimmunity and allergic diseases. In this study, we analysed by multiparameter flow cytometry the frequencies of ILC subsets in skin and peripheral blood mononuclear cells (PBMC) of HS patients and compared these to healthy control subjects and psoriasis patients. The absolute numbers of total ILC and subsets thereof were significantly reduced in the blood of HS patients relative to healthy controls. However, when patients were stratified according to treatment, this reduction was no longer observed in patients undergoing anti-TNF treatment. In HS lesional skin the absolute numbers of ILC were significantly increased relative to control skin. Furthermore, the frequencies of total ILC as well as ILC2 and ILC3 were significantly higher in non-lesional than lesional HS skin. This study analysed for the first time the presence of ILC subsets in the blood and skin of HS patients. Our findings suggest that ILC may participate in HS pathogenesis.

Children with inflammatory bowel disease already have an altered arterial pulse wave.

Adults with inflammatory bowel disease (IBD) have an increased risk for vascular events. This study aims to evaluate arterial parameters in paediatric IBD. Carotid intima-media thickness (CIMT) was measured by ultrasound, and Arteriograph was used to assess aortic pulse wave velocity (PWVao), brachial and aortic augmentation indexes (AixBrach, AixAo), central systolic blood pressure (SBPao), and heart rate (HR). A total of 161 children were included; 55 (34%) children with newly diagnosed IBD (median age 14.35 (11.88-16.31) years, 53% males), 53(33%) in remission (median age 15.62 (13.46-16.70) years, 66% males), and 53 (33%) controls (median age 14.09 (11.18-14.09) years, 55% males) were recruited into a case-control study. Compared to controls, patients with active disease and those in clinical remission had significantly lower AixBrach and AixAo (P < 0.001, P = 0.009; P < 0.001, P = 0.003). PWVao and CIMT were still normal. HR was higher in both IBD groups than in controls (P < 0.001; P = 0.006). HR positively correlated with disease duration (P = 0.001). In the ordinary least squares regression models, anti-tumour necrosis factor (TNF) α treatment predicted lower peripheral and central systolic blood pressures, in contrast to aminosalicylates and methotrexate. Aminosalicylate treatment predicted increased HR. Conclusion: Children with IBD have an increased heart rate, a lower augmentation index and, therefore, an altered pulse waveform. In paediatric IBD, arterial stiffness and CIMT are still normal, indicating the potential for adequate IBD treatment to preserve arterial health. What is Known: • Adult patients with inflammatory bowel disease (IBD) have increased carotid intima-media thickness and arterial stiffness, which positively correlates with cardiovascular risk and predicts mortality. Adequate treatment, especially anti-tumour necrosis factor (TNF) α medications, lower these risks. • Children with IBD have impaired endothelial function and reduced heart rate (HR) variability. What is New: • Children with IBD have impaired endothelial function and reduced heart rate (HR) variability. • Anti-TNFα treatment in children and adolescents with IBD lowers systolic pressure, whereas methotrexate and aminosalicylates have the opposite effect. Amiynosalyiciylate treatment also increases HR.

MIF Variant rs755622 Is Associated with Severe Crohn’s Disease and Better Response to Anti-TNF Adalimumab Therapy

Crohn's disease (CD), rheumatoid arthritis, psoriatic arthritis and other inflammatory diseases comprise a group of chronic diseases with immune-mediated pathogenesis which share common pathological pathways, as well as treatment strategies including anti-TNF biologic therapy. However, the response rate to anti-TNF therapy among those diseases varies, and approximately one third of patients do not respond. Since pharmacogenetic studies for anti-TNF therapy have been more frequent for other related diseases and are rare in CD, the aim of our study was to further explore markers associated with anti-TNF response in other inflammatory diseases in Slovenian CD patients treated with the anti-TNF drug adalimumab (ADA). We enrolled 102 CD patients on ADA, for which the response was defined after 4, 12, 20 and 30 weeks of treatment, using an IBDQ questionnaire and blood CRP value. We genotyped 41 SNPs significantly associated with response to anti-TNF treatment in other diseases. We found novel pharmacogenetic association between SNP rs755622 in the gene MIF (macrophage migration inhibitory factor) and SNP rs3740691 in the gene ARFGAP2 in CD patients treated with ADA. The strongest and most consistent association with treatment response was found for the variant rs2275913 in gene IL17A (p = 9.73 × 10-3).

Pharmacogenetic Analysis of the MIR146A rs2910164 and MIR155 rs767649 Polymorphisms and Response to Anti-TNF Treatment in Patients with Crohn's Disease and Psoriasis.

The clinical heterogeneity regarding the response profile of the antitumor necrosis factor (anti-TNF) in patients with Crohn's disease (CD) and psoriasis (PsO) is attributed, amongst others, to genetic factors that influence the regulatory mechanisms which orchestrate the inflammatory response. Here, we investigated the possible associations between the MIR146A rs2910164 and MIR155 rs767649 variants and the response to anti-TNF therapy in a Greek cohort of 103 CD and 100 PsO patients. We genotyped 103 CD patients and 100 PsO patients via the PCR-RFLP method, utilizing the de novo formation of a restriction site for the SacI enzyme considering the MIR146A rs2910164, while Tsp45I was employed for the MIR155 rs767649 variant. Additionally, we investigated the potential functional role of the rs767649 variant, exploring in silico the alteration of transcription factor binding sites (TFBSs) mapped on its genomic location. Our single-SNP analysis displayed a significant association between the rare rs767649 A allele and response to therapy (Bonferroni-corrected p value = 0.012) in patients with PsO, a result further enhanced by the alteration in the IRF2 TFBS caused by the above allele. Our results highlight the protective role of the rare rs767649 A allele in the clinical remission of PsO, implying its utilization as a pharmacogenetic biomarker.

DOP88 Understanding the molecular mechanisms of anti-TNF treatment failure: Whole blood DNA methylation changes associated with primary non-response to anti-TNF treatment in patients with Crohn’s disease

Abstract Background Anti-TNF treatment failure in patients with IBD is common and frequently related to low drug concentrations. DNA methylation sites from whole blood have been identified as effective biomarkers predicting treatment response to methotrexate and etanercept in patients with rheumatoid arthritis. We sought to define differences in DNA methylation associated with primary non-response (PNR) to anti-TNF treatment in patients with Crohn’s disease. Methods The Personalised Anti-TNF Therapy in Crohn’s disease (PANTS) study is a prospective UK-wide study investigating anti-TNF treatment failure in patients with active luminal Crohn’s disease. DNA methylation from whole blood was assessed using the Illumina EPIC Beadchip at baseline, weeks 14, 30 and 52. We compared DNA methylation profiles in a subset of adalimumab- and infliximab-treated patients who experienced PNR at week 14 and were not in remission at week 54 (infliximab = 99, adalimumab = 94) with patients who responded at week 14 and were in remission at week 54 (infliximab = 99, adalimumab = 93). Low anti-TNF drug concentration was defined as an infliximab level &amp;lt;3mg/L and adalimumab level &amp;lt;5mg/L. Epigenome-wide association (EWAS) analysis was performed using linear mixed models, where p values &amp;lt; 9 x 10-8 were considered significant. Because we observed significant changes in CD4 and CD8 T cells, B cells, NK cells, monocytes and granulocytes following anti-TNF treatment we adjusted our models for derived cell proportions (Figure 1). Results Overall, between baseline and week 14, we observed 4999 differentially methylated probes (DMPs) annotated to 2376 genes. Pathway analysis identified 108 significant gene ontology terms enriched in biological processes related to immune system processes and responses (Figure 2). EWAS analysis at baseline identified 48 DMPs annotated to 36 genes associated with PNR (Figure 3). The majority of DMPs (40/48) were hypermethylated (p &amp;lt; 0.001): of those annotated to genes, 25 were located in the gene body, 5 in the 5’ untranslated regions (UTR), 4 in transcription start sites and the remaining in 3’UTR. When EWAS analysis at baseline was stratified by anti-TNF drug concentration, 27 DMPs annotated to 17 genes were associated with PNR and low drug concentration. Of these, 11 DMPs were independently associated with low anti-TNF drug concentration at week 14 (Figure 4). We did not identify any DMPs associated with PNR with adequate drug concentration. Conclusion Our data suggests that baseline DNA methylation profiles may be used as a predictor for anti-TNF drug concentration at week 14.

P755 Impaired antibody seroconversion after COVID-19 vaccination and negative impact of immunosuppressive treatment in Inflammatory Bowel Disease. Results from a multicentre, prospective study of GETECCU (VACOVEII)

Abstract Background COVID-19 vaccination has been suggested as very effective in patients with Inflammatory Bowel Disease (IBD), but most studies assess antibody levels within a few weeks after vaccination and do not use the most recent recommendations as seroconversion cut-off. The objective of VACOVEII study is to evaluate the antibody response to vaccination at 6 months using these recommendations, the improvement after a booster dose and the effect of the immunosuppressive therapy (IST). We present the intermediate results of the study. Methods Spanish multicentre, prospective and case-control study. 18 years or older IBD patients fully vaccinated against COVID-19 were included. Those with previous COVID infection were not included, but not excluded for the next analyses if the infection was subsequent. Main outcomes were anti-SARS-CoV-2 spike protein antibody (anti S) concentrations and rate of seroconversion (defined above the protection threshold of 260 BAU/mL), measured 6 months after vaccination at a single centralized laboratory. The effect of IST on the main outcomes was analysed, adjusted by age, vaccine type and COVID infection. Groups of treatment considered for the analysis were: patients without IST (without treatment or under salicylates alone), anti-TNF in combination with immunomodulators (IMM), anti-TNF in monotherapy, IMM in monotherapy, ustekinumab and anti-integrin. Results We included 313 patients with IBD (46.5% ulcerative colitis and 52.3% Crohn’s disease, median age 49 years) vaccinated either with non-mRNA vaccines (14%) or mRNA vaccines (86%). Baseline therapy was: 124 patients without IST, 21 with anti-TNF plus IMM, 67 with anti-TNF in monotherapy, 54 with IMM in monotherapy, 28 with ustekinumab and 19 with anti-integrin. Mean anti S concentrations were significant lower in patients with anti-TNF compared with patients without IST (Figure 1). In multivariable analysis, lower antibody concentrations were independently associated with anti-TNF treatment, non-mRNA vaccines and older age. Within the patients with no COVID infection during the follow-up, we found very low rates of seroconversion in patients with anti-TNF (14.1%), ustekinumab (30.8%) and IMM in monotherapy (34.9%), compared with patients without IST (51.5%) (Table 1). In multivariable analysis, anti-TNF treatment, non-mRNA vaccines and older age were independently associated with lower rates of seroconversion, as well as ustekinumab and IMM in monotherapy (Table 2). Conclusion COVID-19 vaccine-induced antibody seroconversion in patients with IBD, measured at 6 months and according to &amp;gt;260 BAU as protection threshold, is clearly lower than previously reported, with a profound impact by some IST therapies, mainly anti-TNF, besides age and type of vaccine.

P552 Anti-TNF Treatment and Risk of Atrial Fibrillation in Inflammatory Bowel Disease Patients

Abstract Background Inflammation is thought to play a role in the development of atrial fibrillation (AF). Previous studies suggested that inflammatory bowel disease (IBD) is associated with increased risk of AF. These studies also found IBD patients receiving biologic agents were at higher risk of AF than patients not receiving them. We sought to determine the association between anti-TNF treatment and the risk of AF in IBD patients Methods In this observational cohort, we included all adult IBD patients who were registered in Rambam Medical Center, diagnosed with IBD from November 1983 to October 2021. We excluded patients who were diagnosed with AF and/or stroke prior to IBD diagnosis. Disease severity was based upon IBD treatment. Mild disease was defined as no treatment, 5-ASA, or topical steroids, while moderate-to-severe disease was defined as any immunomodulator, biologic or systemic steroid therapy. Primary outcome was AF diagnosis. We used Cox proportional hazard model to compare AF in patients receiving anti-TNF treatment to those with mild disease. We further adjusted the hazard ratio of AF development based on known AF risk factors, including age, male gender, cardiovascular disease, chronic kidney disease, pervious venous thromboembolism, hyperlipidemia, diabetes, and thyroid disease. Results Our initial cohort included 5,326 patients. After exclusion, 4,886 patients were included. Median follow-up time was 8.49 years 2,720 patients were considered as having mild IBD, while 787 patients received anti-TNF medications. During follow-up period, cumulative incidence of AF was 1.50% (n=41) and 0.89% (n=7), respectively (p=0.21). Unadjusted hazard ratio of AF occurrence in anti-TNF patients was 0.6 (95% CI; 0.27-1.3, p=0.211). After adjustment, hazard ratio of AF occurence was 1.33 (95% CI; 0.53-3.3, p=0.545). Conclusion Anti-TNF treatment was not associated with increased risk of AF among IBD patients. This provides reassurance regarding the cardiovascular safety of anti-TNFs in a real-world IBD cohort.

P591 Negative impact of high body mass index on the efficacy of anti-TNFα agents in patients with Inflammatory Bowel Disease

Abstract Background Anti-tumor necrosis factor (TNF)-α agents are a therapy of choice in the induction and maintenance treatment of inflammatory bowel disease (IBD). Unfortunately, their efficacy varies. Some IBD patients are primary non-responders and many will experience a secondary loss of response. However, we do not yet have good predictors of their efficacy. Obesity, which prevalence increases worldwide, is also increasingly found in IBD population. Some studies suggest an association between obesity and poorer response to anti-TNFα therapy in IBD patients, although with conflicting results. The aim of this study is to assess the impact of patients’ body mass index (BMI) on the efficacy of anti-TNFα agents in IBD and if there is difference according to the route of administration (intravenous (IV) vs subcutaneous (SC)) or the type of disease (Crohn’s disease (CD) vs ulcerative colitis (UC)). Methods We retrospectively collected data from 188 patients with IBD, aged ≥ 18 years, treated with a first anti-TNFα agent started in our center between January 2002 and December 2020 to avoid missing data. A lack or loss of response to anti-TNFα therapy was defined by the need to optimize or change the treatment or by the initiation of any intercurrent treatment (steroid therapy, hospitalization, or surgery). Frequency of the event and time to its occurrence were analyzed and compared according to BMI using uni- and multivariate logistic regression models and survival curves (Kaplan-Meier), represented by BMI categories (&amp;lt;18.5; 18.5-25; 25-30 and ≥ 30 kg/m²). Results In this cohort of 188 patients (143 CD, 43 UC, 2 Indeterminate Colitis), 8% were obese. We observed that the higher the patient’s BMI, the earlier the risk of optimization or change of treatment (HR=1.043, p=0.045). Association was even stronger for obese patients (HR=2.13, p=0.018). After adjustment for IBD type and administration route, association with obesity persisted. Two other characteristics - female gender (HR=1.56, p=0.012) and higher CRP (HR=1.14, p=0.021) – were associated with earlier optimization or treatment change. Similarly, analysis of survival curves showed a significant difference in time to optimization or change of treatment between BMI categories in patients with CD (p=0.02) but not in those with UC (p=0.87). No association was found between BMI and need for intercurrent treatment. Conclusion This study confirms an association between higher BMI – specifically obesity - and an earlier loss of efficacy of a first anti-TNFα treatment, regardless of IBD type or route of drug administration. Prospective studies with analysis of trough levels are required for a better understanding of the mechanisms involved in the response to anti-TNFα therapy in IBD obese patient.

P401 Concomitant azathioprine treatment effects vedolizumab treatment persistence in Crohn’s Disease but not in Ulcerative Colitis

Abstract Background Vedolizumab is a monoclonal antibody against integrin α4β7 that is being used for the treatment of moderate to severe Ulcerative Colitis (UC) and Crohn’s Disease (CD). Recent studies have shown conflicting results for the effect of concomitant azathioprine use with vedolizumab monotherapy. In this single center cohort study, we investigated the effect of concomitant azathioprine treatment on vedolizumab drug persistence in UC and CD treatment. Methods We performed a retrospective review of all adult (≥18 years) UC and CD patients started on VDZ at our infusion center. Data collection included baseline demographics, concomitant azathioprine therapy, VDZ therapy and disease activity scores using the partial Mayo score and Harvey Bradshaw Score. Data were obtained from the digital medical record. The primary outcome measure was VDZ persistence, represented in Kaplan-Meier analysis. This analysis assessed persistence on every 8 week dose regimen. Results This single center cohort included 142 VDZ treated UC (n=64) and CD (n=78) patients. All patients had a history of at least one anti-TNF treatment: Mean age 38.9±12.5 years and male gender 84 (59.2%). Median disease duration was 6±1.6 years. 6 Patients were excluded from the analysis since VDZ therapy has been stopped due to side effects. Mean duration of VDZ treatment in Crohn’s disease was 96.5±69.2 weeks and in UC was 72.1±60.5 weeks. Concomitant azathioprine therapy in CD increased VDZ persistence rate. However, in UC concomitant azathioprine therapy did not effect VDZ persistence rate. Conclusion The real-world data collected in this study demonstrate that concomitant azathioprine treatment increase the VDZ persistence rate in Crohn’s disease. However, concomitant azathioprine treatment does not effect the VDZ persistence rate in UC patients.

OP37 Is the withdrawal of anti-tumour necrosis factor in inflammatory bowel disease patients in remission feasible without increasing the risk of relapse? Results from the randomised clinical trial of GETECCU (EXIT)

Abstract Background Background: The feasibility of anti-TNF discontinuation in inflammatory bowel disease (IBD) must be proven in clinical trials including patients in clinical, endoscopic, and radiologic remission at the time of anti-TNF withdrawal to make recommendations for clinical practice. Aims Primary: to compare the rates of clinical remission at 1 year in patients who discontinue anti-TNF treatment vs. those who continue treatment. Secondary objectives: to know the effect of anti-TNF withdrawal on relapse-free time, mucosal healing and safety; and to identify predictive factors for relapse. Methods Prospective, quadruple-blind, multicentre, randomised, controlled trial. Patients with ulcerative colitis (UC) or Crohn’s disease (CD) in clinical remission for &amp;gt; 6 months were randomised to maintain anti-TNF treatment [maintenance arm (MA)] or to withdraw it [withdrawal arm (WA)]. Patients who were on infliximab (IFX) received IFX 5 mg/kg or an intravenous placebo every 8 weeks, while patients on adalimumab (ADA) received subcutaneous ADA 40 mg or placebo every other week. Patients were followed-up until month 12 or up to the time of clinical relapse, whichever came first. Inclusion and exclusion criteria, trial scheme and definitions are summarized in figures 1a, 1b and 1c. Results were analysed by intention-to-treat (ITT) and by per-protocol (PP). Local investigators were blinded to faecal calprotectin (FC) and IFX and ADA trough levels. On-site monitoring was performed to assess data quality. Results 159 patients were screened, from whom 140 were randomised and comprised the ITT cohort: 70 allocated to the MA and 70 to the WA. Fifteen patients dropped out before the end of follow-up (12 months or relapse), leaving 63 patients in the MA and 62 patients in the WA for the PP analysis. The characteristics of patients in the MA and WA were similar (figure 2). The proportions of patients who maintained clinical remission -59/70 (84%), 95% confidence interval (CI)=74-92% in the MA vs. 53/70 (76%), 95%CI=64-85% in the WA- and who remained without significant endoscopic lesions at the end of follow-up were similar between groups (figures 3a, 3b, 3c). Only the proportion of patients with FC &amp;gt;250 mg/g was higher in the WA at the end of follow-up (figure 3d). Maintenance of clinical remission was no different between groups (figure 4). The same percentage of patients in both groups had at least one adverse event (69%). The proportion of patients with serious adverse events was also similar between groups (4% in MA vs. 7% in WA). Conclusion Anti-TNF withdrawal in selected IBD patients in clinical, endoscopic, and radiologic remission could be feasible without an increase in the risk of clinical relapse. Long-term follow-up of these patients is warranted.

P643 Psoriasis induced by anti-TNF therapy in Inflammatory Bowel Disease: analysis of therapeutic management and evolution of both diseases in a nationwide cohort study

Abstract Background Some patients with Inflammatory Bowel Disease (IBD) who are treated with anti-TNFα therapy develop a drug-induced psoriasis (IP) as an adverse event. There are some therapeutic approaches, being more frequent to change the biologic therapy to ustekinumab, effective and approved for the treatment of both entities. This could be the best option, but available data are lacking and it could increase the risk of IBD relapse. Our aim is to assess the management of anti-TNF IP in IBD, and the subsequent evolution of both diseases in a large nationwide cohort of patients. Methods Retrospective, observational multicenter study from the prospectively maintained Spanish ENEIDA registry. Participants were patients with IBD and anti-TNFα IP. At baseline, psoriasis severity was classified as mild, moderate or severe, and remission was defined as the resolution of skin lesions, clinical response as an improvement without complete resolution, and no response as the absence of improvement. IBD clinical activity was defined based on Harvey-Bradshaw Index and Partial Mayo Score. All items were evaluated when available at baseline and 16, 32 and 54 weeks. Results Anti-TNFα IP was reported in 234 patients (CD: 185, UC: 46, unclassified IBD: 3). SWAP strategy was chosen in 76 patients (32.5%), most of them to ustekinumab (90.8%), 71 (30.3%) patients continued anti-TNF, 49 (20.9%) discontinued it, and in 38 (16.2%) a switch to a second anti-TNF was made. The decision to continue or not anti-TNF was associated to psoriasis severity (p&amp;lt;0.001) and baseline IBD activity (p=0.03). In mild psoriasis, anti-TNF was continued in 56.81% of patients, whereas SWAP and withdrawal of the anti-TNF were the most used in moderate and severe disease (32.3% and 36.5% respectively). SWAP strategy was also the most used in active IBD (46%). During follow-up, CD activity got worse in anti-TNF withdrawal group (p=0.003), without differences in the other groups. Regarding to psoriatic lesions, all strategies showed a significant improvement, with worse results when anti-TNF was continued (remission rate of 58%, p=0.042), and without differences between the other strategies at week 54. In multivariate analysis, male gender was associated with IBD remission (HR 0.233; IC95% 0.061-0.894). Trunk (OR 2.777; IC95% 1.120-6.889), as well as palms and soles location (OR 2.091; IC95% 1.018-4.294), and stopping anti-TNF treatment (OR 3.010; IC95% 1.110-8.159), were independently associated with remission of skin lesions. Conclusion Evaluating IBD activity and psoriasis severity is essential before modifying IBD treatment due to IP. Continuing anti-TNF treatment in mild psoriasis cases, and considering SWAP to ustekinumab in moderate-severe ones, could be a suitable strategy.

P111 Efficacy of a novel long-acting lipidated interleukin-22, alone and in combination with anti-TNF treatment, in a murine chronic DSS colitis model

Abstract Background Most current treatments and new agents in clinical development for Inflammatory Bowel Disease focus on inhibition of excessive inflammation. However, to break the ceiling on current clinical remission rates, new approaches, for example targeting mucosal healing, are needed. The cytokine interleukin-22 (IL-22) plays a key role in epithelial healing and has early proof-of-concept as a potential drug class in a phase 1 trial in Ulcerative Colitis. Here we present results from a mouse model of colitis demonstrating the efficacy of IL-22 agonism and complementarity with existing immunomodulatory treatment options. Methods Eight-week-old female C57Bl/6N mice (n=56) were subjected to a DSS-induced model of colitis; mice were given 2% (weight/volume) DSS in the drinking water for three 7-day cycles followed by 7 days of regular drinking water. Mice were treated from day 18 until the end of study with either vehicle, lipidated IL-22, an anti-murine TNF antibody at a suboptimal dose, a combination of the lipidated IL-22 and anti-TNF, and, as positive control, anti-murine TNF at an optimal dose. Colitis severity was monitored during the study and at study end endoscopic scoring was performed. Colon length and weight were measured, and histological analysis on formalin-fixed paraffin sections performed by a blinded pathologist. Results At termination, all treatment groups showed reduced body weight loss and improved DAI scores compared to vehicle treated animals, which was significant for all but the suboptimal anti-TNF group. Combination treatment resulted in an additive treatment effect compared to single treatment alone, with mean DAI improving by 13% and 48% for the anti-TNF and IL-22 groups alone versus 68% in combination. Similar effects were observed for the endoscopic and histological scores. The compositive endoscopic score improved by 21% (anti-TNF) and 55% (IL-22) versus 66% for the combination, and histological scores 22% and 52% versus 66%. These combination results likely represent the maximum response that can be achieved in the model, since the improvements obtained are the same as those for the treatment positive control for the model (68% and 62% improvements in endoscopic and histological scores, respectively). Conclusion A novel long-acting lipidated IL-22, which acts on epithelial repair mechanisms, demonstrated strong and significant improvements on all measured parameters in a chronic DSS model of colitis. Combining the IL-22 mode-of-action with an immunomodulatory agent, exemplified by a murine anti-TNF antibody, demonstrated the complementarity of IL-22 agonism to existing treatment options. Clinical trials to assess safety and tolerability of lipidated IL-22 are expected to commence at the start of 2023.

P758 Impact of co-medication on rates of endoscopic remission: post-hoc analysis of randomised non-inferiority trial of 1600 mg versus 400 mg tablets of mesalazine for the treatment of mild-to-moderate ulcerative colitis

Abstract Background Some studies reported that anti-TNF treatment in biologic-naïve elderly onset inflammatory bowel disease patients may be less effective than in non-elderly onset patients (Amano et al. Scientic Reports. 2022 12:5324). We assessed known factors as well as presence of co-morbidities and polypharmacy associated with endoscopic remission in mild-to-moderate (Mayo clinic score ≥5) adult ulcerative colitis (UC) patients treated with mesalazine. Methods In a post-hoc analysis of data from a phase 3 non-inferiority trial ( D’Haens et al. Aliment Pharmacol Ther.2017;46:292–302)we examined the strength of association between number of co-medications and comorbidities by calculating Spearman’s rho. We used multivariable logistic regression modeling to determine the associations between endoscopic remission as outcome (yes vs. no; defined as either Mayo endoscopic subscore of 0 or ≤1 according to blinded central reading) and independent variables (disease duration, Mayo endoscopic score at baseline, leucocyte concentration at baseline, Robarts Histopathologic Index at baseline, age [≤60 vs. &amp;gt;60 years of age], gender, comedications at the time of the trial [none, ≤2, ≥3], comorbidities [none, 1-2, 3-5, &amp;gt;5], body mass index, disease extent prior to the trial, smoking status [current, ex, and never] at week 8 and 38. Collinear variables were examined in separate models. P-value of &amp;lt;0.05 was considered to be statisically significant. Results We analyzed data on 774 patients (330 female, 43.5±14.3 [SD] years of age, median disease duration of 3.00 years [IQR 0.56; 7.88], 175 and 92 persons with 1-2 and ≥3 comedications, respectively) and 679 patients (289 female, 43.7±14.5 [SD] years of age, median disease duration of 2.99 years [0.57; 7.62]; 150 and 85 persons with 1-2 and ≥3 comedications, respectively) that had colonoscopy/sigmoidoscopy at 8 weeks of double-blind induction and 38 weeks open-label maintenance phases of the study, respectively. We observed a moderate association between number of comorbidities and comedications (week 8: Spearman rho=0.545, P-value of &amp;lt; 0.001; week 38: Spearman rho=0.512, P-value &amp;lt; 0.001). Patients with baseline Mayo clinic endoscopic score of 3 and increased baseline leucocyte concentration, were less likely to be in endoscopic remission irrespective of endoscopic remission definition and time post treatment (Table 1). In addition, patients with ≥3 co-medications were less likely to be in endoscopic remission of 1 at week 8 and 38 and in endoscopic remission of ≤1 at week 38 (Table 1). Conclusion The increased number of co-medications rather than the actual age may be responsible for decreased effectiveness of medications, including mesalazine, in elderly UC patients highlighting the importance of healthy aging.

P424 Do antiTNF through levels correlate with joint extraintestinal manifestations (EIM) activity in Inflammatory bowel disease (IBD) patients?

Abstract Background Inflammatory arthropathies are the most common EIM associated to IBD with a prevalence of 20-50% for axial inflammation and 5-20% for peripheral arthritis. AntiTNF is the preferred treatment in patients with axial spondiloarthritis (AxSp) intolerant or refractory to NSAIDs and has shown efficacy in peripheral arthritis (pSp) as well. Nevertheless, an optimal antiTNF through level has not been yet stablished in this clinical setting. Thus, our aims were to evaluate the correlation between antiTNF through levels and joint EIM activity in IBD patients. Methods We conducted a prospective, multicenter cohort study. IBD patients diagnosed with articular EIM (AxSp, pSp or both) under antiTNF treatment at least 6 months were included. Anti-TNF concentrations were measured using ELISA. Blood samples were obtained just before the administration of the drug (trough levels), and an simultaneous evaluation by a reumatologist was performed. Definitions: inactive AxSp = ASDAS-CRP &amp;lt;1,3 and BASDAI&amp;lt;2 , low active AxSp: ASDAS-CRP &amp;lt;2,1 and BASDAI&amp;lt;4; inactive pSp=arthritis, enthesitis and dactylitis=0, low active pSp: arthritis, enthesitis and dactylitis ≤1. IBD activity was based on partial Mayo score for ulcerative colitis (UC) patients and on Harvey-Bradshaw score for Crohn′s disease (CD) patients. Results A total of 78 patients were included: Median age 52 ±15, 45% women, 82% CD (56% ileal; 18% colic; 24% ileocolic; 2% upper gastrointestinal involvement; 22% stricturing behaviour; 16% penetrating; 14% perianal disease), 18% UC (61% extensive, 15% left-sided, 23% proctitis), 11% had another EIM. HLA B-27 was present in 26% patients. Distribution of spondiloartrhopaties was: AxSp 42%, pSp 37%, or both 20%. Among CD patients, 18,9% presented clinical activity (n=14). Mean IBD disease duration was 11± 9,7 years. Fourteen patients (18%) were also under immunosupressive treatment .Through levels distributed by joint activity are shown in table 1.Figure 1 shows distribution of adalimumab through levels by AxSp activity. Conclusion No correlation between antiTNF through levels and joint EIM activity was found in these preliminary results. However, patients with active axial Sp treated with adalimumab had lower through levels than those with inactive axial Sp.

OP11 Ileocecal resection for recently diagnosed ileocecal Crohn’s disease is associated with improved long-term outcomes compared to anti-tumor necrosis factor therapy: a population-based study

Abstract Background Early treatment of Crohn’s disease (CD) often involves biologics such as anti-tumor necrosis factor (anti-TNF) agents. Ileocecal resection (ICR), while a therapeutic option in early CD, is generally reserved for complicated CD or when medical treatment fails. We aimed to compare long-term outcomes of ICR and anti-TNF therapy as index treatment for ileocecal CD, initiated within one year of diagnosis, in the Danish nationwide cohort. Methods Using cross-linked nationwide registers, we identified all individuals who lived in Denmark and were diagnosed with ileal CD between 2003 and 2018. We included individuals who underwent ICR or received anti-TNF drugs as index treatment for ileocecal CD within one year of diagnosis. We excluded patients who did not have pathology information confirming disease in the ileocecal region. The primary outcome was a composite of CD-related hospitalization, systemic corticosteroid exposure, CD-related surgery, and perianal CD diagnosis. We conducted Cox proportional hazards regression analyses to compare outcomes in the two groups after adjusting for potential confounders. We also determined the proportion of individuals initiated on immunomodulator (IMM), anti-TNF, or no therapy at 5 years after ICR. Results Of the 16,443 individuals diagnosed with ileocecal CD between 2003 and 2018, 581 (3.5%) and 698 (4.2%) individuals with confirmed disease in the ileocecal region underwent ICR and received anti-TNF as the index treatment, respectively. The composite outcome occurred in 273 individuals (IR 110.3/100,0 person years (PY)) in the ICR group and in 318 individuals (IR 201.9/100,0 PY) in the anti-TNF group. The risk of the composite outcome was 33% lower in the ICR group compared to the anti-TNF group (aHR 0.67; 95% CI 0.54, 0.83), after adjusting for demographic and clinical variables. On analysis of individual outcomes, ICR was associated with reduced risk of systemic corticosteroid exposure and CD-related surgery, but not CD-related hospitalization or perianal CD diagnosis. Of individuals who underwent ICR, the proportion that was initiated on IMM, anti-TNF treatment or no treatment at 5 years of follow up was 47.5%, 17.1%, and 50.3%, respectively. Conclusion These data support the role of ICR as an index treatment for ileocecal CD and challenge the current paradigm of reserving surgery for complicated CD refractory or intolerant to medications. Further studies will help identify characteristics of individuals who needed no treatment after ICR.

DOP51 Mucosa-associated microbial signatures associate with objective response prior to the start of anti-TNFα but not vedolizumab or ustekinumab in Crohn’s disease patients

Abstract Background Crohn’s disease (CD) is a complex immune-mediated disease of the gastrointestinal tract where the gut microbiome plays an important role. Current biological treatment options in CD include the anti-TNFα agents adalimumab (ADA) and infliximab (IFX), vedolizumab (VDZ), and ustekinumab (USTE). Finding biomarkers to predict therapy response is still a clinical unmet need, as the majority of CD patients fail to reach endoscopic remission within 1 year of treatment. While the majority of studies focus on fecal samples, mucosa-adherent bacterial signature could bring forth stable biomarkers. In this study, we sought to identify signatures of the adherent microbiome in intestinal biopsies aimed at differentiating responders (R) from non-responders (NR), prior to the start of biological treatment. Methods We prospectively collected paired ileal and colonic biopsies (stored snapfrozen in -80 ºC) from adult CD patients scheduled to start anti-TNFα (IFX and ADA), VDZ and USTE treatment during baseline endoscopies. After 6-12 months of follow-up, patients were classified as either R or NR based on endoscopic response (≥50% reduction in SES-CD score) in combination with steroid-free clinical response (≥3 point drop in HBI or HBI ≤4) and/or biochemical response (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin or a basal CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Microbiome composition of the biopsies was determined using 16S RNA gene V3V4 amplicon sequencing. Results For the anti-TNFα cohort, we included in total 36 CD patients (21R and 18 NR), for VDZ cohort a total of 44 patients (28 R and 16 NR) and for USTE cohort a total of 40 patients (20R and 20 NR).When comparing α-diversity and β-diversity between R and NR, we did not find significant differences in ileal and colonic samples at baseline for the VDZ and USTE cohorts. Notable, for the anti-TNFα cohort (table 1), we obtained significant differences when comparing α-diversity (p=0.028) and β-diversity between R and NR. We demonstrated differences between colonic R and NR in taxa abundance for ASVs associated with the phyla Bacteroidetes, Firmicutes, Fusobacteria, Proteobacteria (figure 1). Furthermore, ASVs associated with Firmicutes, Bacteroidetes, Actinobacteria are different in abundance between ileal R and NR (figure 2). Figure 1: Differential taxa abundance colonic R vs NR anti-TNFα Figure 2: Differential taxa abundance ileal R vs NR anti-TNFα Figure 3: graphical summary Conclusion Here, we investigated the microbial signature of R and NR before the start of treatment of three separate cohorts and we demonstrated that the mucosa-associated microbiome differentiates R and NR to anti-TNFα therapy. Further analyses as part of the EPIC Pioneer study, are ongoing.

P556 Surgery in high-risk paediatric Crohn’s Disease treated with up-front anti-TNF agents and long-standing biologic therapy

Abstract Background High-risk (HR) Crohn’s Disease (CD) is associated with high surgical and progression rates. Therefore, recent ESPGHAN guidelines (GL) suggest starting an early anti-TNFα treatment to modify the natural history of the disease. The aim of our study was to evaluate the surgical rate in a population of HR-CD paediatric patients treated with up-front anti-TNFα agents and long-standing biologic therapy Methods This is a retrospective, observational, single-center study conducted at the Paediatric Gastroenterology, Hepatology, and Endoscopy Unit at Policlinico Umberto I Hospital – Sapienza University of Rome. We collected data from all patients diagnosed with CD under 18 years, with a minimum follow-up of 12 months. between June 2008 to July 2022. Patients were then stratified at the diagnosis into HR and LR, based on ESPGHAN GL criteria. Demographic, clinical, laboratory, endoscopic, and imaging data were collected at 6, 12, 24, 36, 48, and 60 months Results 130 patients were enrolled, 76 HR (58%) and 54 LR (42%) [median age 12.5 (IQR) yrs, female 45 (35%), medium follow-up 54±24 months]. The HR group included 39 patients (51%) with panenteric disease, 15 (20%) with a structuring behavior (B2), 3 (4%) with structuring/penetrating disease (B2-B3), and 26 (34%) with perianal involvement (p). Early anti-TNFα agents were started in 80% of patients &amp;lt;6 months from the diagnosis, while 15 (20%) started biological therapy between 6 and 12 months from the diagnosis. All patients continued biologic therapy throughout the study follow-up: 20 (26%) optimized anti-TNF, 25% switched biologic, 11% added an immunomodulator, and 4% combined 2 biological drugs. The surgical rate at 5 years was 29% (n=22) and 29% n=16) in HR and LR groups respectively (p-value 1,0). Eleven % (n=8) of HR patients needed surgical resection, while perianal surgery (seton drainage, fistulotomy, fistulectomy) was performed in 18% (n=14), with no significant difference with LR group [(intestinal resection 18% (10/55), perianal surgery 11% (6/55), p &amp;gt; 0.05]. Perianal disease resulted positively associated with surgical risk (p 0.002, OR 5.62 CI 1.84-17.15) while small bowel imaging at the diagnosis was a protective factor for surgery (p 0.017, OR 0.23 CI 0.07-0.77). No significant difference was found in the interval free from surgery between HR and LR, although HR children mainly needed surgery in the first 12 months after the diagnosis. Conclusion Our data suggest that paediatric patients with HR-CD treated with early anti-TNF agents and long-standing biologic therapy have a similar disease course and surgical risk to those with LR disease. At a 5-year follow-up, one-third of patients needed surgery, mainly in the first year after the diagnosis

P704 The effect of antiTNFα and anti-integrin agents on liver steatosis in inlamatory bowel disease patients with non-alcoholic fatty liver disease

Abstract Background Non-alcoholic fatty liver disease (NAFLD) has been recognized as a common condition in inflammatory bowel disease (IBD) patients and could contribute to their overall morbidity. Anti-TNFα and anti-integrin agents have been the cornerstones of IBD therapy with proven clinical efficacy, but it΄s effect on liver steatosis is still unclear. Therefore this study aimed to evaluate the impact of anti-TNFα and anti-integrin agents on liver steatosis in IBD patients with proven NAFLD. Methods A total of 32 IBD patients with NAFLD, naive to biologic agents, 21 with an established diagnosis of ulcerative colitis, and 11 with Crohn’s disease were prospectively recruited for the study. NAFLD was defined by a baseline attenuation (ATT) coefficient measured by shear-wave (SW) elastometry of 0.63 dB/cm/MHz or higher and a baseline alanine aminotransferase (ALT) of more than 40 IU/L for males and 35 IU/L for females. The exclusion criteria were alcohol use (consuming &amp;gt; 40 g alcohol/day for men and &amp;gt; 20 g/day for women in the preceding 12 months), concomitant chronic viral hepatitis, the presence of hepatic carcinoma, biliary disease, drug use, and hypothyroidism. A total of 11 patients were treated with Adalimumab, 9 patients with Infliximab, and 12 patients with Vedolizumab. The SW elastometry and laboratory exams were performed at the moment of therapy induction and after the 6-month course of therapy. Results The anti-TNFα treatment significantly reduced liver steatosis according to the ATT coefficient dynamic (0.70±0.07 vs 0.66±0.03 dB/cm/MHz, p=0.021) and ALT level dynamic came on the verge of statistical significance (44±7 vs 40±6 IU/L, p=0.058). We did not observe a significant difference between the Infliximab- and Adalimumab-treated patients. The anti-integrin agent, Vedolizumab, had no impact on liver steatosis (0.66±0.03 vs 0.67±0.04 dB/cm/MHz) and ALT level dynamic (47±4 vs 45±5, p=0.29). Both groups of agents had no impact on patients’ lipid profile dynamic. We found no correlation between liver steatosis level and CRP and fecal calprotectin dynamic. Conclusion In the short term, we observed potential beneficial effects of anti-TNFα agents on liver steatosis of IBD patients with proven NAFLD.

P649 Does serum triiodothyronine-to-thyroxine (T3/T4) ratio predict therapeutic outcome to anti-TNF therapies in biologic-naïve patients with active luminal Crohn’s disease?

Abstract Background Lower serum free triiodothyronine-to-thyroxine (fT3/fT4) ratio has been linked to non-response to treatment in a range of diseases, including in biologic-treated patients with IBD. We sought to assess whether baseline serum fT3/fT4 ratio predicted primary non-response (PNR) and non-remission to infliximab and adalimumab in patients with Crohn’s disease. Methods We included 997 adult participants from the Personalised Anti-TNF Therapy in Crohn’s Disease study (PANTS). Thyroid function tests, using the Roche Elecsys TSH immunoassay and T3 and T4 electrochemiluminescence assays, were measured on stored baseline samples (prior to biologic treatment). PNR, assessed at week 14, was defined as treatment failure (including IBD-related surgery), ongoing corticosteroid use, or both CRP failing to fall to ≤3 mg/L, or by 50% from baseline, and HBI failing to fall to ≤4, or by 3 points. Non-remission, assessed at week 54, was defined as either CRP of &amp;gt; 3mg/L or HBI of &amp;gt;4 points, ongoing corticosteroid therapy, or exit for treatment failure. Results Serum fT3, fT4 and TSH concentrations were similar in infliximab (n=549) and adalimumab treated (n=448) patients. Baseline median [IQR] fT3/fT4 ratios were lower in women than men (0.30 [0.27 - 0.34] vs 0.32 [0.28 - 0.36], p&amp;lt;0.001), in patients with more severe inflammatory disease, and in patients receiving corticosteroids (0.28 [0.25 - 0.33] vs 0.32 [0.29 - 0.36], p&amp;lt;0.001). Multivariable logistic regression analysis demonstrated that fT3/fT4 ratio was independently associated with PNR at week 14 (OR 0.51, 95% CI 0.31 – 0.85, p = 0.009), however when stratified by drug and adjusted for variables known to be associated with PNR, low fT3/fT4 ratio remained associated with PNR for adalimumab, but not infliximab. After excluding patients treated with corticosteroids at baseline, there was no difference in fT3/fT4 ratio in those who experienced PNR compared to those who did not (PNR: [128/630] 0.31 [0.28 – 0.35] vs no PNR: [502/630] 0.32 [0.29 – 0.36], p = 0.095). The optimal threshold to determine PNR was 0.31 (AUC 0.57 [95% CI 0.54 - 0.61] sensitivity 0.62 [95% CI 0.41 - 0.74], specificity 0.53 [95% CI 0.42 - 0.73]). No association was seen for baseline fT3/fT4 ratio and non-remission or changes in faecal calprotectin concentrations at week 54. Conclusion Lower baseline serum fT3/fT4 ratio was independently associated with female sex, higher inflammatory burden at baseline, and baseline corticosteroid use, and predicted PNR to anti-TNF therapy at week 14, but not non-remission or change in faecal calprotectin concentrations at week 54. Overall, however, the diagnostic accuracy of baseline fT3/fT4 ratio to predict PNR to anti-TNF treatment was modest, limiting its clinical utility.