anti-TNF Treatment Research Articles

Predictors of drug survival: A cohort study comparing anti-tumour necrosis factor agents using the Swedish inflammatory bowel disease quality register.

Whether long-term effectiveness differs between anti-tumour necrosis factor (anti-TNF) agents is unknown. To examine drug survival of first-line anti-TNF agents and identify predictors of discontinuation. To reduce channelling bias, we also compared drug survival of the second anti-TNF. Biologic-naïve patients (N=955) recorded in the Swedish IBD Quality Register (SWIBREG) were examined. We used propensity score matching, comparing drug survival over up to three years of follow-up. Cox regression estimated adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs). In Crohn's disease, discontinuation because of lack/loss of response was 32% [95%CI=26%-38%] for infliximab versus 16% [95%CI=11%-21%] for adalimumab. Infliximab [vs adalimumab; aHR=1.96; 95%CI=1.20-3.21] and colonic disease (L2) [vs no L2; aHR=2.17; 95% CI=1.26-3.75] were associated with higher discontinuation rates, whereas normalised CRP at three months [aHR=0.40; 95% CI=0.19-0.81] with a lower rate. Consistently, patients who switched from adalimumab to infliximab (vs infliximab to adalimumab) had earlier discontinuation (P=0.04). Concomitant use of immunomodulators was associated with a lower adverse drug reaction-mediated discontinuation rate [aHR=0.46; 95% CI=0.28-0.77], in part explained by fewer infusion reactions [aHR=0.27; 95% CI=0.08-0.89]. In ulcerative colitis, the probability of discontinuation because of lack/loss of response was 40% [95% CI=33%-47%] for infliximab versus 37% [95% CI=21%-53%] for adalimumab. Disease duration ≥10years [aHR=0.25; 95% CI=0.10-0.58] and normalised CRP after three months [aHR=0.39; 95% CI=0.18-0.84] were associated with lower discontinuation rates. Clinical characterisation of patients may aid decision-making on anti-TNF treatment. The consistently shorter drug survival for infliximab (vs adalimumab) in Crohn's disease, suggests a potential difference between the two drugs.

Disease Differentiation and Monitoring of Anti-TNF Treatment in Rheumatoid Arthritis and Spondyloarthropathies.

Rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) are comprehensive immunological disorders. The treatment of these disorders is limited to ameliorating the symptoms and improving the quality of life of patients. In this study, serum samples from RA, AS, and PsA patients were analyzed with metabolomic tools employing the 1H NMR method in combination with univariate and multivariate analyses. The results obtained in this study showed that the changes in metabolites were the highest for AS > RA > PsA. The study demonstrated that the time until remission or until low disease activity is achieved is shortest (approximately three months) for AS, longer for RA and longest for PsA. The statistically common metabolite that was found to be negatively correlated with the healing processes of these disorders is ethanol, which may indicate the involvement of the gut microflora and/or the breakdown of malondialdehyde as a cell membrane lipid peroxide product.

Difficultés diagnostiques de la maladie de Whipple au cours des rhumatismes inflammatoires chroniques : trois observations

IntroductionWhipple's disease (WD) can mimic chronic inflammatory rheumatism leading to incorrect prescription of tumor necrosis factor inhibitors (TNFI). Several complicated cases of WD have been reported during TNFI treatment which is strongly suspected to modify the host-pathogen relationship. Tropheryma whipplei asymptomatic carriage is high in the general population, making the diagnosis of WD more difficult face to unexplained arthritis. ObservationsWe report three observations that illustrate situations for which the detection of T. whipplei might be valuable to investigate the differential diagnosis of inflammatory rheumatism. ConclusionThe decision to check for T. whipplei infection should rely on individual clinical assessment. It should be considered in the absence of clinical response or in case of worsening of an inflammatory rheumatism under TNFI treatment, especially in front of atypical features. A systematic screening for T. whipplei before anti-TNF treatment seems unjustified since asymptomatic carriers are frequent.

Remission of Recalcitrant Psoriasis on Combined Biologic Therapy With Infliximab and Ustekinumab

Introduction: Anti-TNF treatment is effective for inflammatory bowel disease (IBD), however it also has the potential to cause paradoxical psoriasis which can be challenging to manage. Discontinuation of anti-TNF agents may improve psoriatic lesions but may worsen IBD. Combining biologic therapies, though not yet commonly practiced, may be a useful approach to the treatment of both conditions. Case Presentation: We describe a case of paradoxical palmoplantar psoriasis in a 48-year-old woman with ulcerative colitis (UC). Her UC was well-managed on infliximab. Following trials of several other topical and systemic therapies for her psoriatic lesions, she ultimately received relief on combined ustekinumab and infliximab therapy without flare of her IBD. Discussion: While other publications report success using ustekinumab for paradoxical psoriasis following cessation of infliximab, this case report highlights successful treatment using a combination of ustekinumab and infliximab with no reported adverse effects at 3 months. Conclusion: Discontinuation of the anti-TNF agent and use of a single biologic that may treat both IBD and psoriasis is a treatment option. Additionally, combining biologic therapies, though not yet commonly practiced, may be a useful, albeit costly, approach to prevent potential flares of IBD that may accompany cessation of some biologics. Further studies may be beneficial to assess for long term adverse effects.

Immunohistochemical Detection of Tumor Necrosis Factor Alpha in Ileocolonic Biopsies of Patients with Inflammatory Bowel Disease

Background: Tumor necrosis factor alpha (TNF-α) is a major proinflammatory cytokine playing paramount role in the pathophysiology of inflammatory bowel disease (IBD). The identification of predictive biomarkers to establish response to treatment is intuitive and still unresolved need. A biomarker of TNF-α sensitivity would avoid unnecessary exposure of the patient to the drug and to its side effects. Objective: To investigate the relationship between immunohistochemical expression of TNF-α in the biopsies of ileocolonic segments in patients with activity of both ulcerative colitis (UC) and Crohn's disease (CD) and the clinicopathologic parameters and the response to treatment. Patients and methods: The study was conducted on 41 naive patients diagnosed as IBD (UC and CD) and 15 normal subjects as a control group. All patients and control underwent full history taking (age, gender and clinical data as weight loss, diarrhea, bleeding, and duration of the disease), complete physical examination, laboratory investigation (Complete blood count (CBC), ESR, C-reactive protein (CRP), fecal calprotectin (FC)), colonoscopy disease localization, upper endoscope with upper GIT symptoms. Biopsies from the terminal ileum and different colon segments were taken for histopathological evaluation and immunohistochemistry was done according to published protocols to all cases and control. Results: Percentage and H-score for TNF-α significantly correlated with clinical severity and need to give additional treatment besides conventional therapy as anti-TNF therapy. Increased TNF-α expression is significantly associated with better response to anti-TNF treatment. Conclusion: Increased expression of TNF-α in the tissues is associated with the need to give additional treatment besides conventional therapy as anti-TNF therapy and also increased TNF expression is associated with better response to anti-TNF treatment.

Iron-dependent apoptosis causes embryotoxicity in inflamed and obese pregnancy

Iron is essential for a healthy pregnancy, and iron supplementation is nearly universally recommended, regardless of maternal iron status. A signal of potential harm is the U-shaped association between maternal ferritin, a marker of iron stores, and risk of adverse pregnancy outcomes. However, ferritin is also induced by inflammation and may overestimate iron stores during inflammation or infection. In this study, we use mouse models to determine whether maternal iron loading, inflammation, or their interaction cause poor pregnancy outcomes. Only maternal exposure to both iron excess and inflammation, but not either condition alone, causes embryo malformations and demise. Maternal iron excess potentiates embryo injury during both LPS-induced acute inflammation and obesity-induced chronic mild inflammation. The adverse interaction depends on TNFα signaling, causes apoptosis of placental and embryo endothelium, and is prevented by anti-TNFα or antioxidant treatment. Our findings raise important questions about the safety of indiscriminate iron supplementation during pregnancy.

Early prediction of clinical response to anti-TNF treatment using multi-omics and machine learning in rheumatoid arthritis.

ObjectivesAdvances in immunotherapy by blocking TNF have remarkably improved treatment outcomes for Rheumatoid arthritis (RA) patients. Although treatment specifically targets TNF, the downstream mechanisms of immune suppression are not completely understood. The aim of this study was to detect biomarkers and expression signatures of treatment response to TNF inhibition.MethodsPeripheral blood mononuclear cells (PBMCs) from 39 female patients were collected before anti-TNF treatment initiation (day 0) and after 3 months. The study cohort included patients previously treated with MTX who failed to respond adequately. Response to treatment was defined based on the EULAR criteria and classified 23 patients as responders and 16 as non-responders. We investigated differences in gene expression in PBMCs, the proportion of cell types and cell phenotypes in peripheral blood using flow cytometry and the level of proteins in plasma. Finally, we used machine learning models to predict non-response to anti-TNF treatment.ResultsThe gene expression analysis in baseline samples revealed notably higher expression of the gene EPPK1 in future responders. We detected the suppression of genes and proteins following treatment, including suppressed expression of the T cell inhibitor gene CHI3L1 and its protein YKL-40. The gene expression results were replicated in an independent cohort. Finally, machine learning models mainly based on transcriptomic data showed high predictive utility in classifying non-response to anti-TNF treatment in RA.ConclusionsOur integrative multi-omics analyses identified new biomarkers for the prediction of response, found pathways influenced by treatment and suggested new predictive models of anti-TNF treatment in RA patients.

Prevalence of latent tuberculosis before biotherapy initiation in rheumatoid arthritis and spondyloarthritis: data from the Moroccan biotherapy registry.

Before the initiation of biotherapy in the treatment of rheumatic diseases, it is highly recommended for the patients to be screened for latent tuberculosis infection (LTBI). The objective of this study is to identify the prevalence of LTBI among patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) before the initiation of biologic therapy in the Moroccan biotherapy registry (RBSMR). A cross sectional study was conducted using the baseline data of the Moroccan biotherapy registry. Tuberculin skin test or IGRA test or both tests were done before starting anti-TNF treatment for screening LTBI. The comparisons between positive and negative LTBI patients according to rheumatic disease were examined using categorical comparisons. 259 patients were included in this study.94 patients had RA and 165 had SpA. The mean age of the RA patients was 50.49 ± 11.82years with a majority of females (84%). The mean age for the SpA patients was 36 ± 13.7years with a majority of males (67.3%). The prevalence of LTBI in the RBSMR was 21.6%. This prevalence was at 24.8% in SpA patients, while it was at 15.9% for RA patients. After the comparison between positive and negative LTBI patients according to rheumatic disease, no demographic, clinical, or therapeutic characteristics were statistically associated with LTBI. This study found that in an endemic TB country like Morocco, a high prevalence of patients with SpA and RA had LTBI, and that RA patients had a lower prevalence than SpA patients.

Anti-TNF treatment corrects IFN-γ–dependent proinflammatory signatures in Blau syndrome patient–derived macrophages

Blau syndrome (BS) is an autoinflammatory disease associated with mutations in nucleotide-binding oligomerization domain 2. Although treatments with anti-TNF agents have been reported to be effective, the underlying molecular mechanisms remain unclear. We aimed to elucidate the mechanisms of autoinflammation in patients with BS and to clarify how anti-TNF treatment controls the disease phenotype at the cellular level in clinical samples. Macrophages were differentiated from monocytes of 7 BS patients, and global transcriptional profiles of 5 patients were analyzed with or without IFN-γ stimulation. Macrophages were also generated from BS-specific induced pluripotent stem cells (iPSCs), and their transcriptome was examined for comparison. Aberrant inflammatory responses were observed upon IFN-γ stimulation in macrophages from untreated BS patients, but not in those from patients treated with anti-TNF. iPSC-derived macrophages carrying a disease-associated mutation also showed IFN-γ-dependent accelerated inflammatory responses. Comparisons of peripheral blood- and iPSC-derived macrophages revealed the upregulation of nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) targets in unstimulated macrophages as a common feature. IFN-γ stimulation is one of the key signals driving aberrant inflammatory responses in BS-associated macrophages. However, long-term treatment with anti-TNF agents ameliorates such abnormalities even in the presence of IFN-γ stimulation. Our data thus suggest that preexposure to TNF or functionally similar cytokines inducing NF-κB-driven proinflammatory signaling during macrophage development is a prerequisite for accelerated inflammatory responses upon IFN-γ stimulation in BS.

Gp130 Signaling in NOD2-Driven Crohn’s Disease: A Key Player in Fibrosis and a Novel Target for Refractory Patients

Gp130 Signaling in NOD2-Driven Crohn’s Disease: A Key Player in Fibrosis and a Novel Target for Refractory Patients

High Anti-Infliximab Antibody Titers Do Not Impact Response to Subsequent Adalimumab Treatment in Inflammatory Bowel Diseases

While the role of anti-drug antibodies in mediating loss of response to infliximab (IFX) is known, it is possible that there are different clinical implications for high compared to low titers of antibodies to infliximab (ATI). The impact of ATI titer on efficacy of subsequent anti-TNF treatment has not been established previously. This is a multicenter retrospective cohort study of individuals with IBD who discontinued infliximab due to development of ATI and were subsequently switched to adalimumab therapy. IFX anti-drug antibody titer level was measured using Mayo or Esoterix assays. We examined clinical and endoscopic response to adalimumab at 3months, 12months, and 2years. Our study included 90 patients (69 CD, 17 UC, 4 CD of the ileoanal pouch) with IBD. The median antibody titer levels for the Esoterix (208 u/mL) or Mayo clinic laboratory (236 u/mL) were similar (p > 0. 50). Patients with high ATI titers (median 824 u/ml, IQR 405-1250 u/ml) were as likely to respond to adalimumab as those with low titers (median 76u/ml, IQR 41-129 u/ml). At 3months and 12months, the rates of clinical response/remission to adalimumab therapy were 78% and 77%, respectively, among those with high ATI titers and 81% and 84% among those with low ATI titers (p = 0.81 and 0.62, respectively). In patients who initiated a different therapeutic mechanism after adalimumab, the response rates were similar to that observed with adalimumab. The presence of high titers of anti-drug antibodies to IFX is not predictive of treatment failure with adalimumab.

IL-33 Gene Polymorphisms as Potential Biomarkers of Disease Susceptibility and Response to TNF Inhibitors in Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients.

ObjectiveRheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) belong to inflammatory rheumatic diseases, the group of conditions of unknown etiology. However, a strong genetic component in their pathogenesis has been well established. A dysregulation of cytokine networks plays an important role in the development of inflammatory arthritis. Interleukin 33 (IL-33) is a recently identified member of the IL-1 family. To date, the significance of IL-33 in inflammatory arthritis has been poorly studied. This research aimed to investigate the potential of IL-33 gene polymorphisms to serve as biomarkers for disease susceptibility and TNF inhibitor response in RA, AS, and PsA patients.Materials and MethodsIn total, 735 patients diagnosed with RA, AS, and PsA and 229 healthy individuals were enrolled in the study. Genotyping for three single nucleotide polymorphisms (SNPs) within the IL-33 gene, namely, rs16924159 (A/G), rs10975519 (T/C), and rs7044343 (C/T), was performed using polymerase chain reaction amplification employing LightSNiP assays.ResultsIn the present study, the IL-33 rs10975519 CC genotype was associated with a decreased risk of developing RA in females, while the IL-33 rs16924159 polymorphism was associated with the efficacy of anti-TNF therapy and clinical parameters for RA and AS patients. The IL-33 rs16924159 AA genotype correlated with higher disease activity and worse clinical outcomes in RA patients treated with TNF inhibitors, and AS patients carrying the IL-33 rs16924159 AA genotype had higher disease activity and a worse response to anti-TNF therapy. That indicates a deleterious role of the IL-33 rs16924159 AA genotype in the context of RA, as well as AS.ConclusionsThe obtained results suggest that IL-33 gene polymorphisms might be potential candidate biomarkers of disease susceptibility and anti-TNF treatment response in patients with inflammatory rheumatic diseases.

Gp130 blockade to NOD off Crohn’s disease

In a recent publication, Nayar et al. uncover specific inflammatory cell populations associated with Crohn's disease (CD) pathogenesis, and a gp130-STAT3 signaling axis linked to disease in anti-TNF antibody treatment-refractory patients. Therefore, gp130 blockade might represent a potential CD therapy approach, perhaps in conjunction with existing anti-TNF treatment regimes.

Effects of Anti-Inflammatory Treatment and Surgical Intervention on Endothelial Glycocalyx, Peripheral and Coronary Microcirculatory Function and Myocardial Deformation in Inflammatory Bowel Disease Patients: A Two-Arms Two-Stage Clinical Trial.

Sixty inflammatory bowel disease (IBD) patients (45 Crohn disease and 15 ulcerative colitis, 40 ± 13 years, 53% male) were examined at baseline and 4 months after intervention (surgical (35 patients) or anti-TNFa treatment (25 patients)). IBD severity, using Mayo score, Harvey–Bradshaw Index (HBI) and biomarkers, was correlated with cardiovascular markers. At baseline, the disease severity, the white blood cells (WBC) values and the reducing power (RP) were significantly correlated with the aortic pulse wave velocity (PWV) (r = 0.4, r = 0.44 and r = 0.48, p < 0.05) and the lateral mitral E’ velocity (r = 0.35, p < 0.05 and r = 0.3, p < 0.05). Four months after intervention, there was a reduction of WBC (1962.8/mm3 ± 0.425/mm3, p < 0.001), C-reactive protein (CRP) (8.1 mg/L ± 1.7 mg/L, p < 0.001), malondialdehyde (MDA) (0.81 nmol/mg ± 0.37, p < 0.05) and glycocalyx perfused boundary region (PBR 5-25) (0.24 μm ± 0.05 μm, p < 0.01). Moreover, the brachial flow mediated dilatation (FMD), the coronary flow reserve (CFR) and the left ventricle global longitudinal strain (LV GLS) were significantly improved for both groups (4.5% ± 0.9%, 0.55 ± 0.08, 1.4% ± 0.35%, p < 0.01), while a more significant improvement of PWV/GLS was noticed in the anti-TNFa group. IBD severity is associated with vascular endothelial, cardiac diastolic, and coronary microcirculatory dysfunction. The systemic inflammatory inhibition and the local surgical intervention lead to significant improvement in endothelial function, coronary microcirculation and myocardial deformation.

P674 Definition of a microbial signature as a predictor of anti-TNFα treatment response

Abstract Background Crohn’s disease (CD) and ulcerative colitis (UC) evolve with alternate outbreaks and remissions of variable duration. Tumour necrosis factor α antagonists (anti-TNFα) have enhanced the treatment of patients with inflammatory bowel disease (IBD), improving the patient’s quality of life by reducing the number of surgeries and hospitalizations. Despite these advances, about 10–30% of patients do not respond to the treatment after the induction period. Recent studies have pointed, on one hand, gut microbiota can play a role in the anti-TNFα treatment response as gram-positive bacteria can modulate the response of NOD proteins and, on the other hand, gram-negative bacteria can stimulate TLR4 receptors causing activation of NFkß. This study aimed to define a microbial signature that could be used to predict the response of patients with CD and UC to anti-TNFα treatment. Methods This observational study consisted of obtaining a stool sample from 38 IBD patients before starting an anti-TNFα treatment. Patients were recruited at Hospital Universitari Dr. Josep Trueta (Girona) and Hospital Universitari de Bellvitge (l’Hospitalet de Llobregat). During the one-year follow-up period, disease activity levels, faecal calprotectin evolution, and anti-TNFα antibody levels were analysed to assess response to treatment, differentiating 2 groups: responders and non-responders. From each sample, DNA was purified and used in a qPCR for the quantification of the following markers: F. prausnitzii (Fpra) and its phylogroups (PHG-I and PHG-II), E. coli (Eco), A. muciniphila (Akk), Ruminococcus sp. (Rum), Bacteroidetes (Bac), M. smithii (Msm), and the total bacterial load (Eub). Results In this proof of concept, the predictive ability to identify anti-TNFα treatment responders was analysed. Individually, none of biomarkers demonstrated the ability to differentiate between groups with high sensitivity and specificity. However, an algorithm consisting of the combination of 5 microbial markers (Msm, Fpra, PHGII, Rum, and Eub) showed a high capacity to discriminate between responders and non-responders. The algorithm proved high sensitivity and specificity reporting values ​​of 93.33% and 100%, respectively, with a positive predictive value of 100% and a negative predictive value of 75% for predicting response to biologic treatment. Conclusion A specific microbial signature could beneficiate patients with IBD by predicting the therapeutic effectiveness of an anti-TNFα treatment, which could lead to a personalized therapy, improving the patients’ quality of life, saving costs, and gaining time in patient recovery.A larger prospective study will be needed to validate these results.

P507 Vulvar Crohn’s disease: A challenging diagnosis

Abstract Background Crohn’s disease is an inflammatory bowel disorder with several well-known extraintestinal manifestations, such as erythema nodosum, uveitis, and arthritis. Less commonly observed are cutaneous, so-called metastatic lesions of the vulva, which represent a diagnostic and therapeutic dilemma and require a multidisciplinary approach. The objective of this study was to report a case series of patients with vulvar Crohn’s disease (VCD), describe its clinical features, histopathologic characteristics and therapeutic management. Methods In this retrospective study, we reviewed all cases of VCD seen in our department between 2008 and 2016. Data concerning age at diagnosis of VCD, vulval symptoms at presentation, histologic findings, and different treatment modalities were recorded. Only patients with both clinical features of VCD [knife-cut fissures, edema, ulceration] and histologic confirmation were included. A total of 3 cases were identified among 106 female patients with CD. Results Case 1: A 58-year-old patient, presented with a 4-year history of vulvar pain and itching. She had no bowel complaints. Clinical examination revealed hypertrophic exophytic lesions associated with linear ulcearations involving the vulva. A biopsy from the lesional skin showed non caseating gigantocellular granuloma. In view of the clinical and histopathological features, a diagnosis of Crohn’s disease of the vulva was made. Anti TNF treatment with adalimumab was started, resulting in a significant regression of the lesions. Case 2: A 47-year-old patient presented to our department with complaints of painful, persisting vulvar ulcers, and resulting dysperunia for 2 years. On clinical examination she had unilateral vulvar oedema with multiple “knife-cut” linear ulcers. A skin biopsy was done which revealed dense inflammatory lymphocytic infiltrate with non caseating granulomas. Treatment with adalimumab was initiated. An improvement of symptoms was noted. Case 3: A 16-year-old patient with no remarkable medical history, presented with a 2-year- history of persistent cheilitis and vulvar pain. Clinical examination of the external genitalia revealed ‘knife-cut’ vulvar fissures with important bilateral labial swelling and multiple papules on the surrounding skin. Histological analysis showed chronic inflammatory infiltrate with noncaseating tuberculoid granulomas. Anti-TNF treatment with infliximab was started with partial regression of lesions. Conclusion Our findings highlight the importance of keeping VCD on the differential diagnosis when faced with a range of vulvar symptoms. Anti-TNF agents seem to be an efficient treatment strategy for this particular localization.

P012 Low frequencies of circulating inhibitory TIGIT+CD38+ effector T cells identify an immunologically distinct subgroup of pediatric patients with severe Crohn’s disease

Abstract Background Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a T cell driven intestinal inflammation. Current T cell suppressive therapeutic regimens are moderately successful due to a large clinical heterogeneity amongst patients. Detailed understanding of aberrant inflammatory and inhibitory T-cell responses in individual patients is lacking. Previously, we have shown that, in healthy individuals, 40% of peripheral blood CD38+ (CD62LnegCD4+) effector T cells, which are enriched for intestinal antigen specificity, express the inhibitory molecule T cell immunoglobulin and ITIM domain (TIGIT). TIGIT+CD38+ effector T cells have a regulatory function, produce IL-10 and express multiple co-inhibitory receptors. Conversely, TIGITnegCD38+ effector T cells are enriched in inflammatory IFN-γ producing cells. In a small cohort of pediatric-onset IBD patients, low frequencies of TIGIT+CD38+ effector T cells were associated with a reduced duration of clinical remission. We hypothesize that a subgroup of IBD patients has reduced frequencies of circulating inhibitory TIGIT+CD38+ effector T cells, reflecting a distinct pathogenesis associated with a more severe disease course. Methods In the Rotterdam PIBD-SETQuality cohort of newly diagnosed pediatric IBD patients (CD: n=37; UC: n=16), patients with suspicion of IBD but negative diagnosis (n=12) and age-matched healthy controls (n=22), we monitored TIGIT+ and TIGITnegCD38+ effector T cells in peripheral blood and collected plasma at diagnosis and during immunosuppressive therapy. Results At diagnosis, approximately 50% of CD patients had strongly reduced frequencies of inhibitory TIGIT+CD38+ effector T cells compared to UC patients and age-matched controls. CD patients with low frequencies of TIGIT+CD38+ effector T cells at diagnosis needed earlier anti-TNF treatment with 73% of patients receiving anti-TNF treatment within 1 year versus 38% for patients with normal frequencies of TIGIT+CD38+ effector T cells. Inflammatory TIGITnegCD38+ effector T cells were enriched in Ki67, reflecting recent proliferation, and expressed chemokine receptors associated with inflammatory non-classical T-helper-1 IFN-γ hiIL-17lo producing cells. High frequencies of TIGITnegCD38+ effector T cells correlated with high plasma IFN-γ concentrations. Conclusion These results demonstrate that reduced frequencies of circulating inhibitory TIGIT+CD38+ effector T cells discriminate a subgroup of pediatric CD patients with high frequencies of inflammatory IFN-γ hiIL-17lo producing cells, high plasma IFN-γ concentrations, and in need of early anti-TNF treatment, possibly indicative of a distinct pathogenesis with a more severe disease course.

P475 Real world data on treatment success and drug persistence in anti-TNF therapy for ulcerative colitis

Abstract Background The efficacy and safety of anti-TNF treatment for ulcerative colitis (UC) have been well documented in clinical trials. More data are required to increase knowledge on treatment success in a real world setting. This study reports real world data on treatment success, drug persistence and safety of anti-TNF treatment in patients with UC. Methods Patients with UC starting anti-TNF treatment with infliximab (IFX) or adalimumab (ADA) between January 2014 and December 2019 at Oslo University Hospital in Norway were included in a retrospective review of medical records. Eligible patients were biologically naïve adults (≥18 years) with no history of UC-related surgery. Follow-up was 12 months. Drug persistence was defined as the proportion of patients still receiving first-line anti-TNF treatment without addition of a second biologic agent. Remission was defined as i) clinical remission (six-point Mayo Score &amp;lt;2), ii) biochemical remission (fecal calprotectin &amp;lt;250 and CRP &amp;lt;5) or iii) a combination of the two. Treatment success was defined as drug persistence and remission. Serious adverse events (SAEs) were defined according to Good Clinical Practice guidelines. Results In total, 116 patients were included (mean age 35.5 ±13.9 years (SD), 58% male), of which 95 received IFX treatment and 21 ADA. Drug persistence was 74%. Treatment success by different definitions of remission and remission rates for drug persistent patients according to these definitions are reported in the table. SAEs were recorded on 18 occasions (four immediate infusion reactions, two colectomies, five infections and seven other events). Conclusion Treatment success by the strictest definition of remission was 40%. Of drug persistent patients, 44% were not in remission when applying the same definition. Whether these results reflect inadequacies in definitions of remission, a tendency for clinicians to let other variables guide treatment or a delay in drug switching warrants further investigation.

P251 Antiphospholipid antibodies in Crohn’s disease: Results of a prospective single-center study

Abstract Background Assess the prevalence of antiphospholipid antibodies (APL) and their association with disease phenotype and activity in patients with Crohn disease (CD). Methods This is a prospective study involving 30 patients with CD over a period of 2016 to 2020. Family and personal history of thromboembolic disease and fetal loss as well as their delay in relation to the date of the sample were taken from from the interrogation. Disease-related data such as age at the time of diagnosis, location and phenotype of the disease as well as treatment medical received were identified from the medical records. Disease activity was evaluated according to the CDAI (Crohn Disease Activity Index) score calculated time of inclusion. The serum of the patients was tested on anti-β2-glycoprotein-I (anti-β2-GPI Ig M / G), anti-cardiolipin (ACA Ig M / G) by method enzyme immunoassay (ELISA). This test was considered positive if the rate of anti-cardiolipin antibody was&amp;gt; 12U / mL and the level of anti-β2- glycoprotein-1&amp;gt; 8U / mL. The occurrence of thromboembolic events was noted during follow-up. Results The average age was 47.3 ± 10.8 years (29 men and 21 women). A family history of thromboembolic disease has been noted in 2 patients. A patient developed a pulmonary embolism 37 months before his inclusion in postoperative context. A history of fetal loss was reported in 7 women (16%) with a delay ranging from 5 to 432 months (in mean 181.6 ± 146) before their inclusion in the study. The average age at time of diagnosis was 37.9 ± 11.7 years. Colonic localization of the disease was noted in 12 patients (41.4%) and the inflammatory phenotype was the more common (62.1%). The disease was active in 13 patients (44.8%) with a mean CDAI score of 149.2 ± 111.7 (23–469). A patient has presented a mesenteric infarction during his follow-up 35 months after his inclusion. Positive anti-β2-glycoprotein-1 antibody levels IgG type with levels negative anti-cardiolipin antibodies were found in 2 patients (6%). No patient had positive anti-cardiolipin antibodies. No difference was found for the prevalence of anti-β2-GPI in patients patients in remission compared to those with active disease (p = 0.22) and in patients with severe acute colitis compared to the rest of the patients (p = 0.2). The frequency of β2-GP1 was not higher in patients with CRP greater than 6 mg / L compared to those with a normal CRP (p = 0.4). Anti-TNF treatment was started in 5 patients and no association was found between anti-TNF treatment and the prevalence of anti-β2-GP1 (p = 0.7). APL status was not associated with phenotype and localization of disease or thrombotic events. Conclusion The present study did not demonstrate an association between APL antibodies and disease phenotype or activity.

OP18 Treatment of perianal fistulas in Crohn’s Disease: Surgical closure after anti-TNF induction treatment versus anti-TNF without surgery (PISA II) - A patient preference RCT

Abstract Background Current guidelines on Crohn’s perianal fistulas recommend anti-TNF treatment and suggest to consider surgical closure in amendable patients. However, long-term outcome of both treatments have not been directly compared. The aim of this study was to assess MRI healing in a patient preference RCT comparing both treatment modalities. Methods This multicentre, international trial compared surgical closure following anti-TNF induction (4 months) to anti-TNF therapy without surgery. Patients were counselled for both treatment arms and randomised if there was no preference. Due to the combination of a preference and randomised cohort, the appropriate sample size to detect a clinically relevant increase of 25% closure (from 15% to 40%) was flexible and adjusted for a possible skewed distribution (86 patients in case of 1:1 treatment allocation). All Crohn’s patients ≥ 18 years with a (re)active high perianal fistula and a single internal opening were eligible. Exclusion criteria were previous failure of anti-TNF, recto-vaginal fistula, proctitis, or stoma. Patients received seton placement prior to treatment. Primary outcome was MRI healing after 18 months (defined as a complete fibrotic fistula or MAGNIFI-CD score of 0–5). Secondary outcomes included clinical healing, re-interventions and fistula recurrence. Results Between September 2013 and December 2019, 7 hospitals in the Netherlands and Italy included 93 patients (59% females, median age 34 years) of which 32 were randomised. Thirty-seven patients were treated in the surgical closure group and 56 in the anti-TNF group, with comparable baseline characteristics. After 18 months, MRI healing was significantly higher after surgical closure (41% vs 11%; P=0.002). Although a trend was seen in favour of surgical closure, clinical healing rates and surgical re-interventions were not significantly different between groups (65% vs 45%, P=0.07 and 19% vs 34%, P=0.1). After median 38 months follow-up, 12 patients in the anti-TNF group crossed over to surgical closure. Both long-term MRI healing and clinical closure in the per protocol analysis remained significantly higher for the surgical closure group (46% vs 11%, P=0.002 and 65% vs 29%, P=0.006). One patient (4%) with a MAGNIFI-CD score ≤5 developed a recurrent fistula after 46 months, whereas recurrences occurred in 37% of patients with MAGNIFI-CD score &amp;gt;5 (P=0.004). Conclusion These results demonstrate that surgical closure following anti-TNF induction treatment induces MRI healing more frequently than anti-TNF alone. This is associated with increased long-term clinical closure and reduced recurrences. These data suggest that Crohn’s perianal fistula patients amendable for surgical closure should be counselled for this therapeutic approach.