anti-TNF Research Articles

Should Histoplasmosis be Screened for Before Initiation of Tumour Necrosis Factor Alpha Inhibitors?

Histoplasmosis is associated with ANCA positivity.Despite the negative investigations for histoplasmosis and criteria for GPA being met, patients should be closely monitored for possible clinical worsening after the initiation of immunosuppressive therapy, especially TNF-alpha inhibitors.Current guidelines are not recommending routine screening or pre-emptive therapy for histoplasmosis before initiation of TNF-alpha inhibitors.

Effective Inhibition of TNF-α/mTOR Axis-Mediated Liver Inflammation and Fibrosis Induced by TAA Using a Combination of Metformin and Resveratrol in Association with the Inhibition of the Profibrotic Gene and Protein Expression

Effective Inhibition of TNF-α/mTOR Axis-Mediated Liver Inflammation and Fibrosis Induced by TAA Using a Combination of Metformin and Resveratrol in Association with the Inhibition of the Profibrotic Gene and Protein Expression

Dose reduction of biologics in patients with plaque psoriasis: a review.

Dose reduction (DR) of first-generation biologics for plaque psoriasis (TNF-alpha inhibitors (i) and interleukin (IL)-12/23i) has been described in a previous scoping review. The literature on the DR of the newest generation of biologics (IL-17/23i) was scarce. The current review provides a literature update on the previous scoping review on the DR of all biologics, including the newest generation, with a focus on the uptake and implementation of DR in practice. The current literature search on DR revealed 14 new articles in addition to those in the previous review. Four of the newly found articles tested DR strategies, mostly focusing on first-generation biologics; only guselkumab (IL-23i) was included in one study. The other 10 studies showed data on regaining response after failure of DR, safety, cost-effectiveness, and uptake and implementation, as well as information about IL-17/23i. The eligibility criteria to start DR included both absolute and relative Psoriasis Area and Severity Index (PASI) scores (PASI ≤3/≤5/PASI 75-100) and/or Dermatology Life Quality Index (DLQI) ≤3/≤5, or BSA ≤1/≤2, or Physician Global Assessment (PGA) ≤1/0-2 during a period ranging from 12 weeks to ≥1 year. Most studies used PASI ≤5 and/or DLQI ≤5 or PGA ≤1 for ≥6 months. DR strategies were mostly performed by stepwise interval prolongation in two steps (to 67% of the standard dose, followed by 50%). Some studies of IL-17/23i reduced the dose to ±25%. The tested DR strategies on stepwise or fixed DR on TNF-αi and IL-12/23i (three studies), as well as one "on-demand" dosing study on IL-23i guselkumab, were successful. In the case of relapse of DR on TNF-αi and IL-12/23i, clinical effectiveness was regained by retreatment with the standard dose. All studies showed substantial cost savings with the biologic DR of TNF-αi and IL-12/23i. The identified barriers against the implementation of DR were mainly a lack of guidelines and scientific evidence on effectiveness and safety, and a lack of time and (technical) support. The identified facilitators were mainly clear guidelines, feasible protocols, adequate education of patients and physicians, and cost reduction. In conclusion, DR seems promising, but a research gap still exists in randomized, prospective studies testing DR strategies, especially of IL-17/23i, hampering the completion of guidelines on DR. Taking into account the identified barriers and facilitators most likely results in a more successful implementation of biologic DR in practice.

Biological Therapy for Psoriasis in Cancer Patients: An 8-Year Retrospective Real-Life Study.

Background: It is now recognized that psoriasis plays a key role in the development of several comorbidities, such as cardiovascular disease, and metabolic syndrome. Some authors have hypothesized that patients with psoriasis may have an increased risk of developing certain types of cancer. The efficacy and safety of biologic drugs are well-documented in clinical trials and in real-life studies. However, there is limited evidence on the safety of the use of biologic treatments in cancer patients with psoriasis, and the use of this therapeutic class in patients with a pre-existing or concomitant malignancy is still debated. Methods: We have conducted a retrospective observational study of a group of oncology patients with moderate-to-severe psoriasis treated with biologic therapy at the Dermatology Clinic of the University of Naples Federico II, during the period from 2016 to 2024. We included 20 adult patients; in 15 of them the diagnosis of neoplasm preceded the start of treatment biologic, while four of these patients had been diagnosed with cancer during the course of therapy biologics. Results: The most represented neoplasms in our population were breast carcinoma, prostate carcinoma, thyroid carcinoma, and chronic lymphatic leukemia. Anti-IL17 drugs were the most frequently prescribed (47.7%), followed by anti-IL23p19 (36.8%), anti-IL-12/23 (10.5%) and anti-TNF alpha (5.26%). All patients showed improvement of psoriasis after starting the therapy. Conclusions: Our experience supports the effectiveness and safety of biological therapy for psoriasis in patients with a history of cancer or recent onset neoplasia.

Abstract 2753: Muc4 is a biomarker of metastasis in TNBC and its downregulation by blocking soluble TNF prevents metastasis in combination with immunotherapy

Abstract Triple negative breast cancer (TNBC) accounts for about 10-15% of all breast cancers and has the worst survival rate. Immunotherapy is a new treatment option but resistance is frequent. We have demonstrated that TNF induces trastuzumab resistance through mucin 4 (MUC4) upregulation and it is an independent biomarker of poor response to therapy in HER2+ breast cancer. MUC4 is a transmembrane glycoprotein involved in metastasis (MTS) dissemination. Here, we evaluated the impact of the axis TNF/MUC4 on the invasive capacity of TNBC cell lines and in a preclinical model of spontaneous MTS. Finally, we assessed the clinical impact of MUC4 expression in TNBC patients. TNF blockade was achieved with etanercept (E), which blocks the soluble (sTNF) and transmembrane isoform of TNF, or with the dominant negative protein INB03 (DN) which neutralizes only sTNF. BT-549 and MDA-MB-231 human TNBC cell lines treated with E or DN exhibit a decrease in MUC4 expression. To assess the impact of TNF blockade on tumor cells and its effect on the tumor microenvironment, we collected conditioned media (CM) from MDA-MB-231 and BT-549 cells treated with E or DN which were used to evaluate the invasive capacity of the TNBC cell lines. The invasion of BT-549 and MDA-MB-231 was impaired with CM-Eta (p≤0.01) and CM-DN (p≤0.01 and p≤0.05, respectively). Female BALB/c mice bearing the TNBC LMM3 tumors were treated with IgG, DN, anti-PD-1 antibodies or DN+anti-PD-1 for two weeks. After the treatments we performed surgery to remove the primary tumor and the animals were sacrificed 2 weeks later. No effect on tumor growth was observed. However, the DN+anti-PD-1 group was the only one with less of 3 MTS per lung (p≤0.05). We obtained tumor extracts and found that the tumors of the animals treated with DN or DN+anti-PD-1 had decreased MUC4 expression measured by Western blot. We determined the presence of TILs by H & E and the expression of MUC4, Ki67, PD-L1 (SP142), androgen receptor (AR) and cytokeratin 5 by immunohistochemistry in a cohort of 56 early TNBC patients. MUC4 expression was inversely correlated with TILs presence (p=0.0003). Since TILs are associated with good prognosis, we evaluated the effect of BT-549-CM and MDA-MB-231-CM on T cell migration. CM-DN from both cell lines increased T cell migration compared to control CM (p≤0.01). MUC4 expression was inversely correlated with Ki67 (≥30%, p=0.036), PD-L1 (p=0.001) and AR (p=0.047) in our cohort. Moreover, MUC4 proved to be an independent predictor of poor overall survival (p=0.02), and is associated with a higher MTS risk (p=0.005). MUC4 is associated with poorly-infiltrated TNBC, and sTNF blockade downregulates its expression decreasing MTS when combined with anti-PD-1. We propose the TNF as a new target for the treatment of TNBC, and MUC4 as a predictive biomarker to guide a combined treatment of TNF blockers with immunotherapy. Citation Format: Florencia Luciana Mauro, Sofia Bruni, Agustina Dupont, Gloria Inurrigarro, Silvina Figurelli, Sabrina Barchuk, Daniel Lopez Della Vecchia, Rosalia Cordo Russo, Ernesto Gil Deza, Maria Florencia Mercogliano, Roxana Schillaci. Muc4 is a biomarker of metastasis in TNBC and its downregulation by blocking soluble TNF prevents metastasis in combination with immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2753.

Retracted: In Silico Characterization of Growth Differentiation Factors as Inhibitors of TNF-Alpha and IL-6 in Immune-Mediated Inflammatory Disease Rheumatoid Arthritis.

[This retracts the article DOI: 10.1155/2021/5538535.].

Natural Autoantibodies in Biologic-Treated Rheumatoid Arthritis and Ankylosing Spondylitis Patients: Associations with Vascular Pathophysiology.

Cardiovascular (CV) morbidity and mortality have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Natural autoantibodies (nAAb) are involved in innate immunity, as well as autoimmunity, inflammation, and atherosclerosis. There have not been any studies assessing the effects of biologics on nAAbs in RA and AS, also in relation to vascular pathophysiology. Fifty-three anti-TNF-treated RA and AS patients were included in a 12-month follow-up study. Anti-citrate synthase (CS) and anti-topoisomerase I fragment 4 (TOPO-F4) IgM and IgG levels were determined by ELISA. Ultrasonography was performed to assess brachial artery flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT), and arterial pulse-wave velocity (PWV). Other variables were also evaluated at baseline and 6 and 12 months after treatment initiation. Anti-TNF therapy improved FMD in RA and PWV in AS and stabilized ccIMT. TNF inhibition increased anti-CS IgM and IgG, and possibly also anti-TOPO-F4 IgG levels. Various correlation analyses revealed that nAAbs might be independently involved in autoimmunity as well as changes in inflammation and vascular pathology over time in biologic-treated patients (p < 0.05). We also found associations between anti-TOPO-F4 IgG and anti-Hsp60 IgG (p < 0.05). Baseline nAAb levels or nAAb level changes might determine changes in CRP, disease activity, FMD, PWV, and ccIMT over time (p < 0.05). The interplay between arthritis and inflammatory atherosclerosis, as well as the effects of anti-TNF biologics on these pathologies, might independently involve nAAbs.

Full Guidelines—From the Medical Board of the National Psoriasis Foundation: Perioperative management of systemic immunomodulatory agents in patients with psoriasis and psoriatic arthritis

BackgroundSystemic immunomodulatory agents are indicated in the treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis. Perioperative use of these medications may increase the risk of surgical site infection and complication. ObjectiveTo evaluate the risk of surgical site infection and complication in patients with chronic autoimmune inflammatory disease receiving immunomodulatory agents (tumor necrosis factor-alpha inhibitors, interleukin [IL]-12/23 inhibitor, IL-17 inhibitors, IL-23 inhibitors, cytotoxic T-lymphocyte–associated antigen-4 co-stimulator, phosphodiesterase-4 inhibitor, Janus kinase inhibitors, tyrosine kinase 2 inhibitor, cyclosporine, and methotrexate) undergoing surgery. MethodsWe performed a search of the MEDLINE PubMed database of patients with chronic autoimmune inflammatory disease on immune therapy undergoing surgery. ResultsWe examined 48 new or previously unreviewed studies; the majority were retrospective studies in patients with rheumatoid arthritis and inflammatory bowel disease. ConclusionFor low-risk procedures, TNF-alpha inhibitors, IL-17 inhibitors, IL-23 inhibitors, ustekinumab, abatacept, methotrexate, cyclosporine, and apremilast can safely be continued. For intermediate- and high-risk surgery, methotrexate, cyclosporine, apremilast, abatacept, IL-17 inhibitors, IL-23 inhibitors, and ustekinumab are likely safe to continue; however, a case-by-case approach is advised. Acitretin can be continued for any surgery. There is insufficient evidence to make firm recommendations on tofacitinib, upadacitinib, and deucravacitinib.

Effects of tumor necrosis factor-alpha inhibitors on lipid profiles in patients with psoriasis: a systematic review and meta-analysis.

There is no consensus on the effect of tumor necrosis factor-alpha (TNF-alpha) inhibitors on lipid profiles in patients with psoriasis. This study aimed to investigate the effects of TNF-alpha inhibitors on lipid profiles (triglycerides, total cholesterol, low-density lipoprotein, or high-density lipoprotein) in patients with psoriasis. We searched PubMed, Embase, and Cochrane Library databases for articles published before October 17, 2023. Four TNF-alpha inhibitors (infliximab, etanercept, adalimumab, and certolizumab) were included in our study. (PROSPERO ID: CRD42023469703). A total of twenty trials were included. Overall results revealed that TNF-alpha inhibitors elevated high-density lipoprotein levels in patients with psoriasis (WMD = 2.31; 95% CI: 0.96, 3.67; P = 0.001), which was supported by the results of sensitivity analyses excluding the effect of lipid-lowering drugs. Subgroup analyses indicated that high-density lipoprotein levels were significantly increased in the less than or equal to 3 months group (WMD = 2.88; 95% CI: 1.37, 4.4; P < 0.001), the etanercept group (WMD = 3.4; 95% CI = 1.71, 5.09, P < 0.001), and the psoriasis group (WMD = 2.52; 95% CI = 0.57, 4.48, P = 0.011). Triglyceride levels were significantly increased in the 3 to 6-month group (WMD = 4.98; 95% CI = 1.97, 7.99, P = 0.001) and significantly decreased in the 6-month and older group (WMD = -19.84; 95% CI = -23.97, -15.7, P < 0.001). Additionally, Triglyceride levels were significantly increased in the psoriasis group (WMD = 5.22; 95% CI = 2.23, 8.21, P = 0.001). Our results revealed that TNF-alpha inhibitors might temporarily increase high-density lipoprotein levels in patients with psoriasis. However, changes in triglycerides were not consistent among the different durations of treatment, with significant increases after 3 to 6 months of treatment. Future prospective trials with long-term follow-up contribute to confirming and extending our findings. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023469703.

Circulating Tfh cells are differentially modified by abatacept or TNF blockers, and predict treatment response in Rheumatoid Arthritis.

CD4+CXCR5+PD-1hi follicular helper T (Tfh) cells dwell in the germinal centers (GCs) of lymphoid organs and participate in Rheumatoid Arthritis (RA) pathogenesis; the frequency of their circulating counterparts (cTfh-frequency) is expanded in RA and correlates with the pool of GC Tfh cells. Our objective was to study the effect of abatacept (ABT) or TNF blockers (TNFb) on the cTfh-frequency in RA. Peripheral blood was drawn from seropositive-longstanding RA patients chronically receiving csDMARDS (n = 45), TNFb (n = 59), or ABT (n = 34), and healthy controls (HC) (n = 137). Also, patients with an incomplete response to csDMARDS (n = 41) who initiated TNFb (n = 19) or ABT (n = 22), were studied at 0 and 12 months. The cTfh-frequency was examined by cytometry. As compared with HC, an increased cTfh-frequency was seen in seropositive-longstanding RA chronically receiving csDMARDs or TNFb but not ABT. After escalating from csDMARDs, the cTfh-frequency did not vary in patients who were given TNFb but decreased to HC levels in those given ABT. In the ABT group, the baseline cTfh-frequency was higher for patients who attained 12M remission (12Mr), vs those who remained active (12Ma): 0m cutoff for remission >0.38% (Sens. 92%, Sp. 90%), OR 25.3. Conversely, in the TNFb group, the baseline cTfh-frequency was lower for 12Mr vs 12Ma: 0m cutoff for non-remission >0.44% (Sens. 67%, Sp. 90%), OR 8.5. ABT but not TNFb, is able to curtail the cTfh-frequency in RA. A higher baseline cTfh-frequency predicts a good response to ABT but a poor response to TNFb.

Therapeutic Drug Monitoring for Biologic and Small-Molecule Therapies for Inflammatory Bowel Disease.

Background: Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, necessitates long-term medical therapy to manage symptoms and prevent complications. Therapeutic drug monitoring (TDM) has emerged as a strategy to optimize treatment efficacy, particularly with anti-tumour necrosis factor (anti-TNF) alpha drugs. This review explores the role of TDM for non-anti-TNF advanced therapies in IBD, focusing on vedolizumab, ustekinumab, tofacitinib, upadacitinib, risankizumab and ozanimod. Methods: The literature search, conducted through OVID (Medline) and PubMed, delves into proactive versus reactive TDM, timing of monitoring and methods for measuring drug levels and anti-drug antibodies. Results: While ustekinumab and vedolizumab exhibit exposure-response relationships, consensus on target levels and the role of TDM adjustments remains elusive. Limited data on risankizumab suggest a dose-dependent response, while for small molecule therapies (janus kinase inhibitors and ozanimod), the absence of real-world data and commercially available TDM tools pose challenges. Conclusion: At present, with the available data, there is a limited role for TDM in non-anti-TNF biologic and small-molecule therapies. This review underscores the need for further research to delineate the utility of TDM in guiding treatment decisions for these agents.

P892 Do anti TNF alpha drugs reduce cardiovascular risk in Crohn's disease ?

Abstract Background We now know that Crohn's disease (CD) is characterised by a higher cardiovascular risk, despite the low frequency of traditional risk factors. Arterial stiffness (AS) and its relationship with chronic inflammation seem to explain this paradox. Given that inflammation plays an important role in AS, reducing it should make it possible to reduce this stiffness. This led us to evaluate the effect of anti TNF alpha on AS Methods This was a prospective observational study involving 118 patients with CD, 63 of whom were taking anti TNF alpha (Adalimumab, Infliximab). AS was assessed by pulse wave measurement (aPWV) using a validated Sphingmocor Syndney device at the time of recruitment and during patient follow-up. Statistical analysis was performed using SPSS statistical software and Student's t-test for paired samples. Results The mean age was 37 years [19-67], sex ratio = 1.5, 22.2% were active smokers, 62.9% of patients were in a flare and 43.3% had had at least two relapses in the year prior to recruitment, median duration of disease was 30 months. The mean duration of follow-up was 9 months [6-24]. The reduction in aPWV was highly significant for patients on anti-TNF alpha therapy, whether with flexible or rigid arteries: the mean aPWV was 7.67+/-1.4 vs 7.08+/-1.07 for patients on anti-TNF alpha therapy, with a p=2*10-5. The aPWV was 8.49+/-1.07 vs 7.42+/- 0.44 for patients with rigid arteries with a p= 3*10-4. Conclusion Treatment with Anti TNF alpha appears to slow down aPWV in Crohn's disease, and may therefore be a good way of reducing the cardiovascular risk and the risk of developing cardiovascular disease in Crohn's disease.

P803 iGenoMed-MTT: A prospective multiomic study of response to molecularly targeted therapies in IBD

Abstract Background No tools exist to individualize treatment selection in Inflammatory bowel disease (IBD) to optimize outcomes. We prospectively recruited patients prior to initiation of molecularly targeted (advanced) therapy (MTT) to identify predictive biomarkers of response and define pathways impacted by successful treatment. Methods Serum was collected before initiation of treatment in all patients, and at visit 1 (V1~16 wks) for a subset of patients. Serum samples were analyzed for &amp;gt;140 protein biomarkers (OLINK) and &amp;gt;1200 lipid metabolites. Whole exome sequencing and GWAS data was generated for all participants. Initial data outline proteomic data. Results Of the first 166 IBD patients analyzed, therapies initiated included TNF antagonists (n=85), ustekinumab (n=43), vedolizumab (n=28) and janus kinase inhibitors (n=10). Bio-naïve (n=96) and patients using baseline corticosteroids (n=77) were included. Sixty-three patients achieved remission. In TNF-antagonist initiations, serum TNF concentrations increased between baseline and V1 (p=4E-3), while it decreased for other MTTs (p=0.07). In bio-naïve patients, serum TNF concentration had a strong correlation with CXCL10 (r=0.58, P=3E-10). From the Principal Component Analysis of analytes correlated to TNF in bio-naïve patients, we built a proxy for the level of active TNF. At baseline, compared to TNF antagonist naïve patients, significantly higher serum TNF concentrations existed in patients with prior TNF-antagonist exposure &amp;gt;1-month post-cessation and a markedly high TNF concentration with cessation &amp;lt;1 month prior to baseline (p&amp;lt; 2E-16). In patients with prior TNF-antagonist exposure, serum TNF concentrations did not correlate with other cytokines (incl. CXCL10). In these patients, elevated serum TNF were found at V1, suggesting accumulation of inactive (complexed) TNF with treatment. A similar pattern was observed for IL-12 after ustekinumab treatment (elevated serum IL-12 with recent ustekinumab (p= 8E-13), large increase in IL-12 after ustekinumab (p=9E-5)). Reduced IL-12 concentrations existed in current corticosteroid users, compared to previous users and those who never used (p=4E-8). In baseline samples in bio-naive patients prior to therapy initiation, serum concentrations of six analytes provided a discriminant model of corticosteroid use, whith an area under (AUC) the receiver operation characteristic (ROC) curve showed excellent discrimination (AUC=0.91). Conclusion These data uniquely characterize proteomic data in patients with various advanced therapies and will enable development of predictive panels. Unique availability of multiple therapies linked to longitudinal proteomic data may allow personalized panels for treatment selection.

P762 Risk of Infection After Acute Severe Ulcerative Colitis in East Asia and Australia/New Zealand: AOCC and ANZIBDC collaboration study

Abstract Background Infection is one of the concerns in the treatment of inflammatory bowel disease, and advanced age and immunosuppressants are known to be risk factors for infection. However, there has been no studies on infection after acute severe ulcerative colitis (ASUC) and its associated factors. The aim of this study was to investigate infection and associated factors in ASUC patients, as well as differences in infection risk between regions of East Asia and Australia/New Zealand (ANZ). Methods We retrospectively analyzed patients with ASUC diagnosed according to Truelove Witt criteria from January 2015 to September 2022. We identified the overall incidence of infection and related risk factors, and then analyzed the differences by two regions. Results A total of 676 ASUC patients (329 in East ASIA, 347 in ANZ) were enrolled. Overall infections within 1 year after ASUC occurred in 65 patients (9.6%). Clostridioides difficile (C. diff) infection (17/65, 26%), CMV colitis (14/65, 21%), and pneumonia (7/65, 10%) were most common infections. Risk factor associated with infection was combination therapy with anti-TNF agent and thiopurine at discharge (hazard ratio [HR] 5.225, 95% confidential interval [CI] 2.469-11.059, P&amp;lt;0.001). The group with infections exhibited worse outcomes, including a higher readmission rate (39.3% vs. 92.2%, p &amp;lt; 0.001), readmission due to ulcerative colitis (UC) (16.3% vs. 31.3%, p = 0.004), UC-related mortality (0.9% vs. 9.6%, p &amp;lt; 0.001), and overall mortality during the follow-up period (1.1% vs. 13.8%, p &amp;lt; 0.001, Table 1). In comparative analysis between East Asia and ANZ, there was no difference in the incidence of infection (7.6% vs 11.5%, p=0.083) and infection related mortality (1% vs 0.3%, p=1.000) within 1 year after ASUC. CMV colitis (10/25, 40%) and C. difficile infection (6/25, 24%) were common in East Asia while C.difficile infection (11/40, 27%) and skin infections (7/40 17%) occurred frequently in ANZ. The risk factors for infection in East Asia were anti TNF at discharge (HR 3.684, 95% CI 1.434-9.465, P=0.007) and CMV infection (HR 3.587, 95% CI 1.136-11.333, P=0.03), but the risk factors for infection in ANZ were combination therapy with anti TNF and thiopurine at discharge. (HR 7.911, 95% CI 3.397-11.333, P=&amp;lt;0.001, Figure 1). Conclusion The incidence of infection within 1 year after ASUC is 9.6%, and combination therapy of anti-TNF and thiopurine at discharge is a risk factor. Infections were associated with poor prognosis including mortality. There was no difference in the incidence and mortality rates of infections between East Asia and ANZ while the types of infections and related risk factors were different.

P1197 ERAP2 genetic variant rs2248374 is linked to paradoxical skin reactions induced by TNF-alpha inhibitors in Romanian patients with Inflammatory Bowel Diseases

Abstract Background The endoplasmic reticulum aminopeptidases (ERAPs) are responsible for trimming protein residues to optimal length for major histocompatibility complex class-1 mediated antigen presentation process. Genome-wide association studies have shown the influence of ERAP1 and ERAP2 genetic variants in disease susceptibility for autoimmune disorders. Their role in inflammatory bowel diseases (IBD) however remains obscure due to literature data paucity. The aim of this study was to evaluate the role of a single nucleotide polymorphism (SNP) rs2248374 (G/A) of ERAP2 gene in disease susceptibility and response to treatment in Romanian population with IBD. This SNP is of particular importance because the G allele produces a truncated ERAP2 transcript undergoing nonsense-mediated decay and therefore individuals with GG genotype have no functional ERAP2 enzyme. Methods The study involved 186 IBD patients (87/99 UC/CD, 91M/69F) and 150 healthy controls (77M/73F) all unrelated and of Romanian ethnicity. Extraintestinal manifestations (EIM) were documented in 43 IBD patients (19UC/24BC). Among patients with biological treatment against TNF-alpha (N=113) there were 31 (27.4%) primary non-responders and 13 (11.5%) with paradoxical skin reactions. All subjects were genotyped for ERAP2 rs2248374 (G/A) using TaqMan Allelic Discrimination Assay (C_25649529_10 Real-Time PCR System, Applied Biosystems by Thermo Fisher Scientific, USA). Association tests were performed with OpenEpi online software using Two by Two Table statistics. P-values (2-tail from Mid-P exact test) were considered significant if &amp;lt;0.05. Results Controls and patients were in Hardy-Weinberg equilibrium for the investigated SNP. No significant differences were observed in relation with the risk of disease or with the therapy response. The minor allele A frequency was significantly lower in IBD patients with paradoxical skin reactions (27%) versus patients without these manifestations (50%, p=0.02, OR 0.36). The genotype AA, responsible for full ERAP2 expression, had 0% frequency in the group with adverse skin reactions compared with 23.2% in patients without (p=0.04, OR 0.0). The GG genotype which is related with no ERAP2 protein expression was more frequent in the subgroup of patients with EIM (41.8%) than in patients without EIM (26.7%), showing a marginal association (p=0.06, OR 1.97). Conclusion Our results point to the fact that ERAP2 rs2248374 AA genotype exerts a protective effect over paradoxical skin reaction induced by TNF antagonist agents, and GG genotype shows marginal association with the presence of EIM in Romanian patients with IBD. We consider these results worthy of replication in larger cohorts of patients.

How to translate genetic findings into clinical applications in spondyloarthritis?

Spondyloarthritis (SpA) is characterized by a strong genetic predisposition evidenced by the identification of up to 50 susceptibility loci, in addition to HLA-B27, the major genetic factor associated with the disease. These loci have not only deepened our understanding of disease pathogenesis but also offer the potential to improve disease management. Diagnostic delay is a major issue in SpA. HLA-B27 testing is widely used as diagnostic biomarker in SpA but its predictive value is limited. Several attempts have been made to develop more sophisticated polygenic risk score (PRS). However, these scores currently offer very little improvement as compared to HLA-B27 and are still difficult to implement in clinical routine. Genetics might also help to predict disease outcome including treatment response. Several genetic variants have been reported to be associated with radiographic damage or with poor response to TNF blockers, unfortunately with lack of coherence across studies. Large-scale studies should be conducted to obtain more robust findings. Genetic and genomic evidence in complex diseases can be further used to support the identification of new drug targets and to repurpose existing drugs. Although not fully driven by genetics, development of IL-17 blockers has been facilitated by the discovery of the association between IL23R variants and SpA. Development of recent approaches combining GWAS findings with functional genomics will help to prioritize new drug targets in the future. Although very promising, translational genetics in SpA remains challenging and will require a multidisciplinary approach that integrates genetics, genomics, immunology, and clinical research.

P602 Risankizumab levels but not IL22 are significantly correlated and predictive of clinical and biochemical remission in Crohn's disease

Abstract Background Risankizumab (RZB) is an anti-IL23 monoclonal antibody blocking the p19 subunit, whose recent Phase 3 trial demonstrated its efficacy in CD. Compassionate use has been possible since December 2019. The aim of this study was to investigate whether RZB and IL22 levels correlated with deep remission. Methods Any CD patient receiving RZB (compassionate use) was eligible for the study. All patients were treated with a regimen of RZB (600mg W0, W4 and W8) followed by 360 mg/sc every 8 weeks from W12. Patients with other dosing regimens were excluded. Before each infusion or SC injection, fecal calprotectin, CRP, RZB levels (ELISA ; Theradiag) and IL-22 levels (ELLA automated system; Biotechne). Clinical and biochemical remission was defined by a clinical score (CDAI) &amp;lt; 150 with fecal calprotectin &amp;lt; 250 µg/ml and CRP &amp;lt; 5 mg/l. Results 28 patients on failure to anti TNF, vedolizumab and ustekinumab (mean age: 44 years, sex ratio M/F: 1.3) with 95 RZB maintenance samples (360mg/sc every 8 weeks) were eligible. For 44 RZB samples (46%), patients were in clinical and biochemical remission . Patients with clinical and biochemical remission had higher mean RZB levels than patients without clinical and biochemical remission (21.6 +/-13.3 versus 7.4+/-6.4 µg/ml; p=0.001). Biochemical and clinical remission rates were significantly higher in the highest RZB quartiles (p=0.01) (Figure 1). Area under the curve analysis (AUC: 0.93; p&amp;lt;0.001) isolated a RZB threshold significantly associated with clinical and biochemical remission: 11.5 µg/mL (sensitivity: 81.8%, specificity: 80.3%, PPV: 78.2%, NPV: 83.6%, accuracy: 81%.) . The progression-free survival curves towards loss of clinical and biochemical remission were significantly more favorable in the group of patients with RZB levels &amp;gt; 11.5µg/mL (p=0.03) . In univariate and multivariate analysis, only RZB level was isolated as a factor associated with clinical and biochemical remission: HR: 1.36 (CI95: 1.05-1.35), p=0.001). Conversely, albumin, CRP, albumin and other patient variables were not significantly associated with deep remission. The IL22 levels are not statistically significantly different between clinical and biochemical remission or not (respectively, 10.4 pg/mL (4.2-17.2) vs 8.6 pg/mL (4.3-16.2); p = 0.73) Conclusion RZB levels are significantly higher in clinical and biochemical remission CD. A threshold of 11.5µg/mL predicts clinical and biochemical remission in CD and is associated with significantly better progression-free survival. Conversely, IL22 levels are not associated with clinical and biochemical remission. However, these results are in a limited patient population of those receiving compassionate use therapy.

N22 Compliance with Anti-TNF Alpha Treatment and Quality of Life of Inflammatory Bowel Patients: A Descriptive and Correlational Study

Abstract Background Today, anti-TNF agents are often preferred in the treatment of inflammatory bowel diseases. During this long-term treatment, patients' compliance with the treatment is very important. This study aims to determine the relationship between compliance with anti-TNF alpha treatment and quality of life in inflammatory bowel patients. Methods This study is currently being carried out at Gazi Hospital Gastroenterology Department, Inflammatory Bowel Diseases Outpatient Clinic. The study will be carried out between November and February 2024. Data are collected using the "Patient Information Form", "Inflammatory Bowel Diseases Quality of Life Scale", "Anti-TNF Alpha Treatment Compliance Scale". Whether the variables were suitable for normal distribution was determined by the Kolmogorov-Smirnov test. Since parametric test assumptions were not met, Mann-Whitney U test, Kruskal Wallis test and Sperman correlation analysis were used in the analysis of scale scores. Statistical significance value was accepted as p&amp;lt;0.05. Results In this section, the pilot results of the study are presented and its implementation is ongoing (Number of patients reached: 117). The mean age of the patients participating in the study was determined to be 38.99±13.73 (minimum=18, maximum=68). It was determined that 53.7% of the patients were male, 57.3% were married and 42.7 of them had no children. The diagnosis of 65% of patients is Crohn's disease. The rate of patients being diagnosed with inflammatory bowel disease for 3-5 years was found to be 29.9%. The total score of the Inflammatory Bowel Diseases Quality of Life Scale was found to be 160.04±32.24 (minimum=88.00, maximum=224.00). The total score of the Anti-TNF Alpha Treatment Compliance Scale was found to be 2.36±0.72 (minimum=1.00, maximum=4.58). It was determined that there was a strong negative relationship between the total scores of the scales (p= &amp;lt;0.001). Conclusion It can be said that the treatment compliance of the patients is at a moderate level and their quality of life is at a good level. The relationship between patients' treatment compliance and their quality of life is also negative.

P604 Exploring the role of chest X-ray in latent tuberculosis screening in Inflammatory Bowel Disease

Abstract Background Patients being treated with biologics or JAK inhibitors have an increased reactivation risk of latent tuberculosis infection (LTBI), and this is associated with a more severe infective course. Current ECCO guidance recommends the screening for LTBI by a combination of patient clinical data and epidemiological factors, chest X-ray (CXR), and tuberculin skin test or interferon-gamma release assay (IGRA) prior to starting immunosuppressive treatment. The evidence supporting CXR is categorized at evidence level 5, and information on its use in screening for LTBI originates from two decades ago. Apart from radiation exposure, a single posterior-anterior view has limited diagnostic capabilities. This study aims to determine the relation between CXR findings and IGRA test results in patients undergoing LTBI screening before commencing immunosuppressive therapy for Inflammatory bowel disease (IBD) patients in a low-risk population. Methods This is a retrospective analysis whereby IBD patients (≥16 years) on biologics or JAK inhibitors were identified from our local database. The clinical data, epidemiological, CXR and IGRA result were then analysed from the electronic case records. The IGRA test used was the QuantiFERON-TB Gold. Results A total of 356 patients were included in the study, with 58.7% (n=209) being male. Among these patients, the majority had Crohn's disease (66.6%, n=236), 30.1% (n=109) had ulcerative colitis, and the remaining 2.8% were classified as having IBD-unclassified. Most patients (97.1%) had been exposed to anti-TNF alpha medications and 13.2% were exposed to multiple biologicals. The mean age of IBD diagnosis was 30.3 years (SD+/-15.7). None of the patients had any clinical suggestion nor any evidence for exposure to TB. None of the CXRs performed revealed any radiological signs of prior TB infection. 93.8% (n=334) of the IGRA results were negative and 4.2% (n=15) were categorized as indeterminate. Among those with indeterminate results, 66.7% (n=10) were undergoing corticosteroid treatment for active disease. The remaining 2.0% (n=7) had a positive IGRA test and were treated for LTBI.None of these patients had TB reactivation when then treated with biologicals. Conclusion This research highlights that performing routinely a CXR in individuals with a negative IGRA offers little to no benefit, and subjects patients to unnecessary radiation. It also demonstrates the importance of conducting the IGRA test early, before initiating any immunosuppressive treatment. Furthermore, in patients with a negative IGRA, if chest imaging is required for screening purposes, opting for an ultra-low dose CT might be more prudent than a CXR, as it visualises the lungs better and the radiation exposure is not substantially different.

Evolution and Prognosis of Digestif Fistulas in Crohn's Disease (CD) Other Than Ano-Perineal Manifestations (APM)

Background and Objectives: Crohn's disease (CD) is a chronic inflammatory disease of the intestine. It can evaluate by the occurrence of intestinal complications in particular fistulas whose management can be medical or surgical. The objective of our work is to specify the evolutionary modalities, as well as the predictive factors of bad prognosis. Patients and Methods: this is a monocentric, descriptive and analytical retrospective study conducted in a hepato gastroenterology department including patients with fistulizing Crohn's disease, outside ano perineal fistulas from 1990 to 2023. Statistical analysis was performed using SPSS22.0 software. Results: Of a total of 960 patients, 38 had fistulizing CD. 65% of our patients were classified as A3 according to the Montreal classification, and 34% as A2. They were 24 women with a sex ratio of 1.71 F/H. The type of fistula was Greco-Greatic in 4 patients (10.5%), Greco-Colic in 5 patients (13%), Entero-Cutaneous in 12 patients (31.5%), Gastro-Colic in 3 patients (7.9%), Interdigestive and Entero-Cutaneous in 10 patients (26%), Interdigestive and Greco-Vesical in 2 patients. All our patients had benefited from a bi-antibiotic therapy, 33 had benefited from surgical resection. Postoperative treatments were based on therapeutic abstention in 5 patients (13.1%), immunosuppressive treatment in 18 patients (47%), anti TNF treatment in 7 patients (18%). The endoscopic recurrence rate 6 months after treatment was 32.5%. In univariate analysis, the factors influencing the evolution of fistulizing crohn's disease were the number of fistulas and age with p values lower than 0.05 (respectively 0.022 and 0.009). Conclusion: Digestive fistulas represent a complication during CD, which pose a problem of medical-surgical management and have an impact on the quality of life of the patients. Our study showed that age (p=0.022) and the number of fistulas (p=0.009) represent the factors influencing the natural history of fistulizing CD.