anti-TNF Treatment Research Articles

P645 Ileocecal resection in paediatric Crohn’s disease based on the Hungarian Paediatric IBD Registry

Abstract Background Despite optimized treatment, almost one-third of the patients with IBD develop complications such as fistulae, strictures, and abscesses, thus need surgical treatment within 5 years of diagnosis. In paediatric Crohn’s disease surgery may be considered when a patient has active disease despite optimized medical treatment. The aim of our study was to evaluate the practice of surgical interventions in paediatric Crohn’s disease regarding indications, postoperative therapy and follow-up endoscopy in Hungary. Methods We performed a retrospective analysis based on the database of the Hungarian Paediatric IBD Registry (HUPIR). The HUPIR is a prospective, nationwide registry launched in 2007. Data of patients who underwent ileocecal resections between January 2010 and December 2019 were included in the analysis. We applied descriptive statistical methods to characterise the cumulative incidence of surgical resections, the urgency of the interventions, postoperative complications and follow-up endoscopies. Results Altogether 943 newly diagnosed CD patients were reported between 2010 and 2019, among them 55 (6%) had ileocecal resection of 99 children with CD who underwent (10%) surgical interventions within 2.15 years mean follow-up period. Surgical data of ileocecal resections were available in 47 (85%) cases (mean age: 14.5 years, male:20). Disease localization at diagnosis was ileocecal in 38% and ileocolonic in 40.2%. The mean time between diagnosis and surgical intervention was 21.2 months (0–62). The ileocecal resection was elective in 37 (78.7%), and laparoscopic resection was performed in 17 cases (36%). Frequency of early postoperative complication was 8.5% (4/47), which was not associated with the urgency of the intervention, the technique, preoperative corticosteroid or anti-TNF treatment. Only the third of the patients (17/47, 36%) had colonoscopy within 6 months after resection. Conclusion Based on the HUPIR the number of surgical ICR is lower than in earlier reports reflecting a different approach. The early complication rate was low despite the low number of interventions. In a middle-income country, it is a question why surgical intervention are lower compared to international. Paediatric gastroenterologists seem to prefer conservative therapy probably due to the lack of experienced paediatric IBD surgeons.

P580 Early intestinal ultrasound assessment predicts endoscopic response and remission on anti-TNF treatment in Crohn’s Disease – a prospective longitudinal cohort study

Abstract Background In the assessment of treatment response in Crohn’s Disease (CD) objective measures are superior to clinical improvement. Intestinal ultrasound (IUS) is an emerging modality with high accuracy to detect CD disease activity. Less is known about early transmural changes at IUS in treatment follow-up. Therefore, we aimed to investigate conventional IUS and contrast-enhanced ultrasound (CEUS) parameters and how they are associated with endoscopic treatment response. Methods In this longitudinal prospective cohort study, consecutive patients with active CD according to the simplified endoscopic score (SES-CD≥3) starting anti-TNF-α treatment were included. We recorded clinical, biochemical, IUS and CEUS parameters at baseline (T0), after 4–8 weeks (T1) and at 12–34 weeks (T2). IUS parameters were scored as previously established1. The SES-CD was scored per segment by a gastroenterologist immediately after endoscopy. The bowel segment with highest SES-CD score and thickest wall on IUS was identified. At T2, endoscopic response (decrease SES-CD≥50%) and endoscopic remission (SES-CD=0) were scored per segment. IUS and CEUS were scored blindly by two readers using recorded videos. Results 40 patients were included (Table 1) with 23 completing follow-up. The other 17 patients had side-effects and stopped treatment (n=9), underwent bowel surgery (n=5) or were lost to follow-up (n=3). At T2, 14 reached endoscopic remission, 17 had endoscopic response. The absolute decrease in BWT at T1 and T2 paralleled endoscopic response (Figure 1). Decrease in BWT of 18% at T1 (Fig 2) predicted endoscopic response accurately (OR: 10.8, 95%CI: 1.7–69.0, p=0.012). For T2, 29% decrease in BWT (Fig 2) was most accurate to determine endoscopic response (OR: 37.5, 95%CI: 2.8–507.5, p=0.006). At T2, a BWT of 3.2 mm was most accurate (AUROC: 0.940, 95%CI: 0.862–1.000, p<0.0001, sensitivity: 92%, specificity: 85%) to determine endoscopic remission (OR: 39.4, 95%CI: 7.7–202.6, p<0.0001). Normalization of Colour Doppler Signal (CDS) (no signal or single vessel) (OR: 13.8, 95%CI: 1.3–147.8, p=0.03) or Wash-out Rate (WoR) at CEUS (1 dB increase: OR: 0.8, 95%CI: 0.60–0.96, p=0.019) added significantly to BWT to determine endoscopic remission at T2. Conclusion Decrease of BWT 4–8 weeks after treatment initiation predicted endoscopic response later during follow-up. In addition, we have provided accurate cut-off values for (Δ)BWT associated with endoscopic response and remission at different time-points. CDS or WoR were both of additional value to determine endoscopic remission after 12–34 weeks. As CEUS is time consuming, CDS might be sufficient in the close follow-up of CD patients. Reference 1. Novak et al, JCC 2021

DOP30 Long-term outcomes of Crohn’s perianal fistulas treatment: anti-TNF with surgical closure versus anti-TNF alone (PISA-II) - A patient preference RCT

Abstract Background The PISA-II trial showed that anti-TNF induction combined with surgical closure induces MRI healing more frequently than anti-TNF alone at 18 months follow-up (FU) and that this was associated with no recurrences at the time. The aim of this study was to compare long-term outcomes of both treatment arms. Methods In this FU study, data were collected from patients who participated in the PISA-II trial, a multicentre, international patient preference randomised controlled trial that compared anti-TNF induction combined with surgical closure to anti-TNF therapy alone as treatment for Crohn’s perianal fistulas. FU data were collected from the time of enrolment in the PISA-II trial until November 2021. Primary outcome was radiological healing at MRI and secondary outcomes included long-term clinical closure, recurrences, anti-TNF trough levels (suboptimal level was defined as infliximab <5.0ug/ml, adalimumab <5.9ug/ml), incontinence (improved, decreased or never had), and a decisional regret scale. Results Long-term FU data were collected from 88 out of 94 patients included in the PISA-II trial, 35/38 in the surgical closure arm and 53/56 in the anti-TNF treatment arm. Median FU was 5 years (IQR 4–7). During long-term FU radiological healing occurred in significantly more patients in the surgical closure arm (40% vs 17%; P=0.018). Long-term clinical closure occurred in 71% in the surgical closure arm and in 60% in the anti-TNF treatment arm (P=0.533). Recurrences occurred in 20% in the surgical closure arm and in 36% in the anti-TNF treatment arm (P=0.111). One patient with radiological healing developed a recurrence (4.3%) vs 12/57 (21.1%) patients with clinical closure. Trough levels were available in 32/53 patients treated with anti-TNF. Around the time of recurrence a suboptimal anti-TNF serum trough level occurred in 6/10. In the surgical closure arm, 6 patients had more and 6 patients had less incontinence problems after treatment, comparable to the 5 patient in the anti-TNF treatment arm with more and 8 with less incontinence problems. All patients in the surgical closure arm who completed the questionnaire (strongly) agreed that undergoing surgery was the right decision and 79% of the patients in the anti-TNF arm (strongly) agreed, 14% neither agreed nor disagreed and 7% disagreed that anti-TNF treatment was the right decision. Conclusion This study further supports the previous finding that anti-TNF induction combined with surgical closure should be considered in patients with Crohn’s perianal fistulas as long-term outcomes are favourable. Interestingly, surgical closure does not seem to be correlated to decreased continence, and all patients agreed that surgery was the right decision.

P515 Inflammatory bowel disease and malignancy – the outcome of patients with malignancy diagnosed before IBD diagnosis or IBD-targeted therapy

Abstract Background The treatment strategy in IBD patients with previous malignancy is not well defined, and the available literature is scarce.The main aim of this study was to describe the outcome of IBD patients with previous malignancy or before exposure to IBD-related treatment. Methods The study cohort included IBD patients with at least one malignancy diagnosed before IBD or before initiation of IBD-related treatment (excluding 5-ASA/corticosteroids). All patients were followed at the department of gastroenterology in Sheba medical center between 2010 and 2021. Clinical and demographic data were extracted from the patients’ medical records. The main outcome of interest was a relapse of previous malignancy or the development of a second malignancy. Results From our IBD database comprising 3811 patients, we identified 86 patients with malignancy before IBD-related treatment: 38 diagnosed with malignancy 6 years before IBD (median time, IQR=3–12) and 48 - after (15 years (IQR7-22) IBD diagnosis but before exposure to IBD treatment. The most common malignancy preceding IBD was breast cancer found in 9/38 (24%) patients. Other malignancies before IBD diagnosis included: lymphoma 7/38 patients (18%), melanoma in 6 patients (16%), and leukemia in 4 patients (11%). After a diagnosis of IBD, 38/86 (44%) patients were treated with thiopurines, 28/86 (32%) with vedolizumab (VDZ), and 26/86 (30%) with anti-TNFs. 10/86 (9%) patients were further diagnosed with second primary malignancy. The median time from first to second malignancy was 7 years (IQR=16-6); 7/10 patients (70%) were exposed to thiopurines, 6/10 (60%) to anti-TNFs, and 6/10 (60%) to VDZ. The only clinical variable associated with second malignancy was female gender (9/40 (22.5%) vs. 1/46 (2.2%), p=0.005). 20/86 patients (23%) had a recurrence of malignancy (median- 3 years (IQR=3–9). The most common recurrent malignancies were non-melanotic skin cancer (NMSC) In 9 patients (45%) and melanoma in 3 patients (20%). Of patients with recurrence, 11 patients (55%) were exposed to thiopurines, 10 patients (50%) were exposed to anti-TNFs, and 5 patients (25%) were exposed to vedolizumab. Treatment with anti-TNFs was associated with recurrence of NMSC (6/25 (24%) vs. 2/52 (3.7%), p=0.047). Conclusion In our retrospective tertiary center cohort, recurrence of malignancies in IBD patients with previous neoplasia was uncommon. However, most recurrent malignancies were solid and hematopoietic malignancies. Female gender was associated with an increased risk of second malignancy, while anti-TNF treatment was associated with an increased risk of NMSC recurrence. Our findings underline the importance of rigorous dermatological follow-up in IBD patients with previous NMSC treated with anti-TNFs

P314 Elderly onset is associated with low efficacy of anti-TNF treatment in Bio-naïve IBD patients: A multicenter cohort study by the Osaka Gut Forum

Abstract Background The number of elderly patients with inflammatory bowel disease (IBD) is increasing, but the outcomes of patients with elderly onset (EO) IBD treated with anti-tumor necrosis factor (TNF) remains uncertain. The present study evaluated the efficacy and safety of anti-TNF treatment for bio-naïve EO-IBD. Methods This was a multicenter retrospective observational study including bio-naïve patients with IBD who started anti-TNF treatment from, 2010 to, 2019 at, 18 hospitals of the Osaka Gut Forum. Elderly patients were defined as those, 60 years and older, and elderly patients with IBD were further divided into those with EO (Elderly-EO) and those with non-elderly onset (Elderly-NEO). The clinical symptoms were evaluated by partial Mayo score (pMayo) for UC and Harvey-Bradshaw index (HBI) for CD, and the clinical remission rate at, 52 weeks after the start of treatment was analyzed retrospectively. Clinical remission was defined as pMayo ≤, 2 and each subscore ≤, 1 for UC and HBI ≤, 4 for CD. Results A total of, 432 patients were enrolled, comprising, 55 with Elderly-EO (12.7%), 25 with Elderly-NEO (5.8%), and, 352 under age, 60 (Non-elderly, 81.5%). After, 52 weeks of anti-TNF treatment, clinical and steroid-free remission rates were significantly lower in Elderly-EO than in Non-elderly (37.7% and, 60.8%; P = 0.001, and, 35.9% and, 57.8%; P = 0.003, respectively), and comparable between Elderly-NEO and Non-elderly. Multivariate analysis revealed that elderly onset was a significant factor for both clinical remission [Odds ratio (OR), 0.49, 95% confidence interval (CI), 0.25–0.96] and steroid-free remission [OR, 0.51, 95%CI, 0.26–0.99] after, 52 weeks of anti-TNF treatment. The rate of cumulative severe adverse events was significantly lower in Elderly-EO than in Non-elderly (P = 0.007), but comparable between Elderly-NEO and Non-elderly. Conclusion Anti-TNF treatment is less effective for bio-naïve EO-IBD than for elderly patients with younger onset and non-elderly, and may raise safety concerns in this group of patients.

P362 Influence of HLA DQA1*05 genotype in patients with inflammatory bowel disease and Anti-TNF treatment with proactive therapeutic drug monitoring

Abstract Background The HLADQA1*05 variant increases the risk of developing antibodies against infliximab and adalimumab. Whether proactive therapeutic drug monitoring (PTDM) could overcome this immunogenicity remains unknown. The primary aim was to evaluate the influence of the allele HLADQA1*05 on treatment persistence. Methods We performed a single centre retrospective cohort study. IBD patients starting anti-TNF therapy between January, 2017 and March, 2021 were included. HLA DQA1*05 genotype screening was performed during, 2021. PTDM was defined as periodic drug level measurement (≥2 determinations during the first year of treatment and ≥1/annual determination during the following years), regardless of clinical condition, with according dose optimization. Patients not fulfilling these criteria were excluded. Target concentration during induction:, 25–30 mcg/ml (week, 2) and, 20 mcg/ml (week, 6) for Infliximab and >, 10 mcg/ml (week, 2 and, 4) for Adalimumab. During maintenance:, 3–10 mcg/ml for Infliximab and, 8–12 mcg/ml for Adalimumab. Clinical remission was defined as HBI <5 or pMS ≤, 2 without any item >1 and biochemical remission as a fecal calprotectin<250 mg/kg. Variables associated with treatment persistence were assessed with multivariable Cox regression analysis. Results 126 patients started anti-TNF therapy during the study period. Fourteen were excluded (8 lacked PTDM and, 6 declined the HLA DQA1*05 genotype), thus including, 112 patients with a median follow-up of, 73.9 (IQR:, 35.4–133.1) weeks, 52 (46.4%) HLADQA1*05 positive. Figure, 1 presents baseline characteristics. Combination therapy with thiopurines was more frequent among HLADQA1*05 negative patients (28 (46.7%) vs, 12 (23.1%), p=0.01). During their first year, patients underwent a median of, 3 (IQR, 2–4) drug level measurements. We performed, 497 determinations (4/patient (IQR:3–6);, 149 (30%), drove to dose modifications, 63 (42.3%) among symptomatic patients and, 86 (57.7%) among asymptomatic ones. Primary nonresponses were higher (8.1% vs, 0, p=0.06) among HLADQA1*05 negative patients. The HLADQA1*05 positive presented non-significant higher clinical remission rates at week, 14 (77.9% vs, 73.9%, p=0.69) and, 56 (73.2% vs, 68.4%, p=0.64) (figure 2). Figures, 3 and, 4 presents drug persistence, which was higher among HLADQA1*05 positive patients (HR:, 0.32, 95% CI:, 0.14–0.71, p=0.01). Multivariable Cox regression analysis identified systemic steroids at anti-TNF initiation (Hazard ratio (HR):, 4, 95% CI, 1.7–9.7) as a risk factor and a positive HLA DQA1*05 genotype (HR:0.31 (0.12–0.81)) as a protective factor of treatment cessation. Fig.1 Fig. 2. Fig.3 Fig.4. Conclusion: When PTDM is performed, a positive HLA DQA1*05 genotype does not associate a higher risk of treatment cessation.

P029 Expression of miR-21 in mucosal biopsies give clues to anti-TNF treatment non-response in IBD children and adults

Abstract Background The use of anti-tumor necrosis factor (TNF) treatment has improved the treatment of IBD patients. However, approximately 30% of patients fail to respond to TNF inhibitors, and up to 50% of the patients who initially benefited from treatment with TNF inhibitors lose the response over time. Thus, identifying predictors of non-response and deciding on a treatment strategy according to biomarker profiles could enhance overall IBD disease management. MicroRNA-21 (miR-21) has been found to confer drug resistance to e.g. trastuzumab, 5-fluorouracil, and cisplatin. In this study, we hypothesized that miR-21 may play a role in anti-TNF drug resistance and therefore, miR-21 levels may be a predictive biomarker of anti TNF response in IBD. Methods Archived formalin-fixed, paraffin-embedded (FFPE) mucosal biopsies of IBD patients (30 adults and 27 children) were used in this study. All biopsies were collected at the time of initiation of biologics. Patients were stratified into three groups according to treatment response: Responders, Primary non-responders (PNR), and Secondary non-responders (SNR). Responders were treated with anti-TNF for a minimum of 3 years and did not experience loss of response thereafter. PNRs lost response during the first year of treatment. SNRs were treated for a minimum of 3 years with subsequent loss of response. MiR-21 expressions were quantified using Quantitative Real-Time PCR (miRCURY LNA RT Kit, Qiagen). Expression of miR-27a was used as the endogenous reference microRNA based on previous studies. Results In adults, responders had less miR-21 expression compared to PNRs and SNRs (relative median of miR-21 expression in folds [IQR]: 3.45[3.36 - 4.2], 5.05 [3.61 - 6.88], and 7.58 [6.21 - 8.2] in responders, PNRs, and SNRs respectively, p=0.04 and p=<0.01). In children, however, responders had an increased miR-21 expression compared to PNRs and SNRs (relative median of miR-21 expression in folds [IQR]: 19.94[15.88–24.59], 9.79[7.69– 14.44], and 10.58[5.66–12.91] in responders, PNRs, and SNRs respectively, p=0.03 and p=0.01). Expression of MiR-21 was found to be higher in children than adults (relative median of miR-21 expression in folds [IQR]: 4.65[3.45–7.21], and 13.6[8.37–19.05], respectively, p=<0.01). Conclusion Higher miR-21 expression indicates a higher response rate in children, whereas higher miR-21 expression could predict resistance to anti-TNF treatment in adults. MiR-21 expression could potentially be used as a predictive biomarker for anti-TNF treatment response in IBD patients with varying measures for children and adults.

P385 Tailoring induction treatment for children with Crohn’s disease

Abstract Background Multiple clinical studies in children with Crohn’s disease (CD) have demonstrated the high efficacy of nutritional therapy with exclusive enteral nutrition (EEN) to induce remission and even to promote mucosal healing. However, EEN as inductive treatment may be not tolerated or inefficient and we are well aware of the paramount importance of a well conducted induction treatment for paediatric CD with the goal of an individualized induction treatment to improve the prognosis and the quality of life of inflammatory bowel disease (IBD) children. Methods A retrospective multicentre study including newly diagnosed children with CD treated with EEN as induction therapy was designed. The primary aim of the study was to study predictive factors of non- adherence to treatment. The secondary endpoint were predictive factors of clinical non-remission at the end of induction treatment. Those data together were analysed with the ultimate goal of trying to define an individualized induction treatment for children with CD. Results 376 CD children from, 14 IBD paediatric referral centres were enrolled in the study. The rate of EEN adherence was, 89 %. Colonic involvement and FC >, 600 μg/g at diagnosis were found associated with a reduced EEN adherence in univariate and multivariate analysis. The remission rate of those who completed induction treatment was, 67%. A multivariate analysis showed that factor determining lower remission rate were age >, 15 years and PCDAI >, 50. With those results we were able to create a decisional algorithm which is provided in figure 1. Conclusion EEN administered for, 8 weeks is effective for inducing clinical remission. The rate of adherence is high but there is a group of patients (colonic involvement + hight FC) which are at risk of non-adherence and thus may be candidate for alternative dietary induction regimens. Moreover, older patients with moderate to severe active disease (PCDAI>40), are at higher risk of failing clinical remission achievement after EEN and may benefit from an early anti-TNF alpha treatment. Personalized treatment strategies should be proposed weighing the benefits and risks based on each patient’s disease location, phenotype and disease activity with the overall aim of obtaining rapid control of inflammation to reduce long-term bowel damage.

P604 Infection Risk in Elderly Patients with Inflammatory Bowel Disease under anti-TNF, ustekinumab or vedolizumab biologic therapies: A Prospective Multicenter observational One-Year follow-up comparative study

Abstract Background The emergence of biologics has significantly improved the course of inflammatory bowel diseases (IBD) despite a potential higher risk of infections. Use of biologics in the elderly population remains a challenge since elderly patients are at higher risk of infection. Anti-tumor necrosis factor (anti-TNF), vedolizumab and ustekinumab are all potentially susceptible to increase the risk of infection. We conducted a one-year, prospective, multicenter, observational study comparing the respective infectious risk under anti-TNF, vedolizumab or ustekinumab in elderly patients with IBD. Methods All IBD patients over 65 years, from six medical centers and receiving anti-TNF (first group), vedolizumab or ustekinumab (second group, defined as new biologics) treatment were included. The primary endpoint was the prevalence of at least one infection during follow-up. The cumulative risk of severe infection requiring hospitalization was recorded. Results The study included 207 consecutive patients, 113 under anti-TNF and 94 patients under vedolizumab or ustekinumab (median age 71 years, 112 with Crohn’s disease and 95 with ulcerative colitis). There was no difference concerning combination therapy, steroids use and the Charlson index between the two groups. The prevalence of infections was similar in patients under anti-TNF (29%) and in those under vedolizumab and ustekinumab (28%) (p=0.81). There was no difference in terms of type of infection, infection-related hospitalization (7% vs 6.4%), antibiotic prescription and treatment efficacy between the two groups. In patients over 75 years of age (n=50), the prevalence of infections was comparable in both groups. Conclusion Around 30 % of elderly patients with IBD under biologics experienced at least one infection during the one-year study period. The risk does not differ between patients treated with anti-TNF and those under vedolizumab or ustekinumab.

P328 In silico evaluation and pre-clinical efficacy of anti-TNF and anti-IL-23 combination therapy in Inflammatory Bowel Disease

Abstract Background Despite advances in the treatment of inflammatory bowel diseases (IBD), fewer than, 40% of patients reach clinical remission, suggesting that improved response rates may require targeting of multiple pathogenic pathways through combination therapy. However, the rational selection of combination therapies based on patient and pre-clinical data remains a significant challenge. Methods Here, we used Crohn’s disease (CD) patient-derived molecular networks as a platform for bridging pre-clinical animal models of combination therapy to human disease. Intestinal transcriptional signatures of anti-TNF, anti-IL-23 or combination treatments were generated from the anti-CD40 agonistic antibody murine colitis model and the murine genes mapped to their human orthologues. Humanized gene signatures were intersected with human disease networks to generate treatment subnetworks and enrichment analyses performed. Results The anti-TNF subnetwork was enriched in genes expressed in myeloid cells, chemokine signaling and NFkB signaling, while the anti-IL-23 subnetwork was enriched in genes expressed in the intestinal epithelium, IL-17 signaling, and cell adhesion. The intersection of these two therapeutic gene signature subnetworks was significantly enriched in IBD GWAS loci genes and human CD inflammatory gene signatures, suggesting that the molecular mechanisms reflected in the pre-clinical model faithfully captures aspects of the human disease. Simultaneous inhibition of these two pathways could result in enhanced efficacy through targeting shared inflammatory pathways and complementary biology in myeloid and epithelial cells to reduce colitis. To test this hypothesis, mice were treated with varying doses of anti-IL-23, anti-TNF, or the combination of both. A synergistic response to combination therapy was observed both in reduction of systemic weight loss and inhibition of local colonic tissue inflammation by histopathology. A set of genes uniquely significantly modulated by the combination therapy compared to either monotherapy was mapped to our human IBD network. Upregulated gene networks in the combination therapy enriched in stromal cells, epithelial mesenchymal transition and extracellular matrix pathways, and adhesion pathways while downregulated gene networks were enriched in IBD disease signatures, M1 macrophages, neutrophils and IFN-γ signaling. Conclusion These results provide a novel, data-driven approach to predict effective combination therapies for inflammatory diseases and suggest that anti-TNF and anti-IL-23 combination therapy may drive more patients into deep remission through impacts on both shared and unique molecular pathways involved in IBD pathogenesis.

P611 Serological biomarkers of type VI and XXII collagen formation predict and monitor infliximab treatment response in patients with Crohn’s disease

Abstract Background Crohn’s disease (CD) is a chronic inflammatory disease of the gastrointestinal (GI) tract characterized by excessive protease activity and extracellular matrix (ECM) remodeling. Although biologics such as TNF-α antibodies have improved the management of disease, up to 30–50% of patients still experience non-response to treatment. Biomarkers may be useful to improve therapeutic decision-making and monitor treatment response, thereby optimizing biological therapy and decreasing the risk of surgical intervention. This study assessed whether serological biomarkers of ECM turnover could monitor or predict response to TNF-α-antagonists in patients with and without surgical history. Methods Using protein fingerprint technology, serum biomarkers of type VI (PRO-C6) and XXII (PRO-C22) collagen formation were measured in 63 patients with CD undergoing infliximab (IFX) induction therapy. Disease activity was defined by a composite of the Harvey-Bradshaw Index (HBI) and physician’s global assessments (PGA). Response to treatment was defined as steroid-free remission (HBI<5) at week 14. Patients were stratified according to history of prior surgery. Patients with history of prior surgery (n=18) were 10 responders and 8 non-responders. Patients without history of prior surgery (n=45) were 40 responders and 5 non-responders. Differences in marker levels between groups were determined using Mann-Whitney U-tests. Area under the curve (AUC) values were generated using receiver operating characteristics (ROC) statistics. Results In patients with history of prior surgery, PRO-C22 was higher at baseline in responders than non-responders (P=0.004). At week 14, responders had higher levels of PRO-C6 than non-responders (P<0.05). Biomarkers PRO-C6 and PRO-C22 demonstrated predictive value at baseline (AUC [95% CI]: PRO-C6 0.78 [0.55–1.0], P=0.012; PRO-C22 0.90 [0.73–1.0], P<0.001). At week 14, PRO-C6 was also able to discriminate between responders and non-responders (AUC [95% CI]: 0.82 [0.54–1.0], P<0.01). No significant differences were observed in patients without history of prior surgery (Figure 1). Conclusion In patients with a history of prior surgery, higher baseline levels of PRO-C22 predict treatment response to IFX, whereas PRO-C6 levels were higher at week 14 after treatment initiation. These biomarkers demonstrated promising results in predicting response to anti-TNFα treatment, as well as separating responders from non-responders at week 14. Together, these markers could be used to predict and monitor treatment response to IFX in patients with CD with surgical history and may shed light on different profiles of ECM turnover. Future studies are warranted to further validate the potential utility of these biomarkers in larger patient cohorts.

P297 Treatment of patients with complex perianal Crohn’s disease with darvadstrocel: a single-institution real life experience

Abstract Background Complex perianal disease in patients with Crohn’s disease (CD) represents a therapeutic challenge since, despite biological treatment, half of the patients do not achieve an adequate response. Treatment with allogenic expanded adipose-derived mesenchymal stem cells (Darvadstrocel) has proven to be an innovative treatment in patients refractory to treatment with immunomodulators and anti-TNF antibodies. Methods To assess the efficacy of Darvadstrocel treatment in clinical practice in patients with CD and complex perianal fistula. Method: We performed a prospective descriptive study in patients with CD and complex perianal fistula (high intersphincteric, transsphincteric, extrasphincteric or suprasphincteric; presence or ≥ 2 external opening or abscesses), refractory to antiTNF treatment, treated consecutively with Darvadstrocel at our Crohn’s and Colitis Attention Unit. Each patient was treated with 120 million stem cells (half of the dose was injected along the tract walls and the other half around the internal opening/s). Response to treatment was assessed as combined remission according to the criteria of the ADMIRE study (clinical assessment of closure of all treated external openings that drained before treatment and absence of collections> 2 cm confirmed by MRI). Results From July 2020 to October 2021 12 patients (10M / 2H) have been treated with Darvadstrocel. All patients were in clinical remission (luminal disease) and had perianal disease refractory to anti-TNF treatment. In addition, 7/12 patients were also refractory to ustekinumab. The patients had previously been treated with a mean of 5.7 perianal surgeries (1–16), most of them curettage and seton placement or replacement. One patient had previously been treated with mesenchymal stem cells in 2014 (ADMIRE participant). All fistulas were complex, 5 with a single tract, 2 with a branched tract and 5 with a double tract; 7 were transsphincteric, 1 intersphincteric (double), 1 supraelevator, 1 suprasphincteric, and 2 extrasphincteric. 6/10 patients underwent a previous conditioning surgery (cleaning, curettage and seton placement) two weeks before cell administration. Six of the 10 patients with a follow-up of at least 6 months had combined remission (60%). Two of the three patients with a 1-year follow-up presented combined remission. Regarding safety, no relevant adverse effects have been observed: 2 patients presented abscesses in the immediate postoperative period (self-drained without subsequent recurrence). Conclusion In real-life clinical practice, treatment with Darvadstrocel can be an effective and safe therapy in patients with CD and complex perianal disease refractory to biological treatment.

DOP74 Comparative effectiveness of vedolizumab and ustekinumab in Crohn’s Disease patients who failed anti-TNF treatment: Interrogating 1019 patients from the UK IBD BioResource

Abstract Background Ustekinumab (UST) and vedolizumab (VDZ) are widely used to treat patients with Crohn’s disease (CD). However, limited data exist regarding comparative effectiveness of these agents for patients with CD who have failed anti-TNF treatment. We aimed to compare the efficacy of UST and VDZ utilizing the largest cohort of CD patients who failed anti-TNF in real world clinical practice. Methods We conducted a retrospective cohort analysis using data retrieved from the UK IBD BioResource, capturing 34,148 subjects. We identified patients with CD, who failed anti-TNF and were subsequently treated with UST or VDZ as second or third-line therapy. Inverse probability of treatment weighting (IPTW) was used to balance groups using a propensity score-weighting approach accounting for baseline patient or disease related characteristics. Persistence on therapy with clinician assessment of treatment success, without the need for treatment change or surgery was used to estimate the response to treatment. We compared treatment survival curves before and after IPTW and used a log rank test for differences between groups Results 654 CD patients received VDZ, either as second line (51%) or third line (49%) therapy. 365 patients received UST, 52% as a second line and 48% as a third line therapy. All patients received either infliximab or adalimumab as first and/or second biologic therapy. Baseline characteristics are detailed in table 1. Following IPTW, variables were well balanced. Patients receiving VDZ showed similar rates of treatment success compared to UST as second- and third-line biologic agent after anti TNF failure (before IPTW adjustment, log rank p 0.241; after IPTW, log rank p 0.154). Outcomes for UST were similar between 2nd and 3rd line usage (p 0.81), but outcomes for VDZ were significantly worse when used 3rd line compared to 2nd line (p <0.0001).Subgroup analysis of unadjusted survival data showed significantly better outcomes for patients with ileal disease distributiontreated with UST compared to VDZ (p=0.043) but no significant differences in outcomes for subgroups with colonic or ileocolonic disease.We estimate persistence on UST and VDZ to be 67%, 54%, 49% and 49% at 1, 2, 3 and 5 years respectively. Conclusion Using data from a multi-institutional cohort of patients with CD with larger number of participants and longer follow-up than previous cohorts, we demonstrate no difference between UST and VDZ used as second and/or third line biologic therapy, after anti-TNF failure. Subgroup analysis reveals some patient characteristics predictive of differential treatment response.

P196 Pre-treatment antibodies to infliximab and adalimumab are common but are not associated with anti-TNF treatment failure

Abstract Background Anti-TNF treatment failure is common. Primary non-response and loss of response are frequently caused by low anti-TNF drug levels mediated, principally, by the formation of anti-drug antibodies which can be mitigated by concomitant immunomodulator use. Previous small studies in patients with IBD suggest that antibodies formed prior to treatment can bind drug and impair the pharmacokinetics, efficacy and safety of the anti-TNF drugs. We sought to determine the prevalence, neutralising capacity and clinical relevance of pre-treatment antibodies to infliximab and adalimumab in in anti-TNF-naïve patients with active luminal Crohn’s disease. Methods The Personalised Anti-TNF Therapy in Crohn’s Disease study (PANTS) is a UK-wide, multicentre, prospective observational cohort reporting treatment failure rates of the anti-TNF drugs infliximab and adalimumab in Crohn’s disease. The prevalence of antibodies to infliximab and adalimumab at baseline in all patients were measured using IDKmonitor ELISA assays and neutralising capacity in positive cases was determined using the iLite™ cell-based assays. Associations between baseline antibody status, subsequent immunogenicity and drug levels, and response status were assessed using Mann-Whitney U tests and chi-squared analyses, respectively. Results In the PANTS cohort, at baseline, pre-treatment anti-TNF antibodies were detected in 7.3% (112/1525) patients. Pre-treatment antibodies to infliximab were more common (6.3% 96/1525 vs 2.4% 36/1525, p<0.01) and of higher levels (median (IQR) infliximab: 23.9 (14.2 – 55.2) AU/ml vs adalimumab: 7.2 (6.3 – 10.4) AU/ml, p<0.0001) than adalimumab. A minority (1.3% (20/1525)) of patients had anti-drug antibody reactivity to both drugs. None of the detected anti-drug antibodies had demonstrable anti-TNF neutralising capacity detected by our iLite™ cell-based assay. No associations were seen between baseline antibody reactivity, subsequent immunogenicity, drug levels or response status at week 14 or week 52. Conclusion Pre-treatment anti-drug antibodies are common. However, they do not neutralise anti-TNF drug activity invitro, promote drug clearance or influence clinical response to anti-TNF drugs. Further work is required to understand this cross-reactivity and to determine the exact nature of the antibodies detected in drug naïve individuals.

P626 Anti-TNF monotherapy is associated with an adverse clinical outcome in female Inflammatory Bowel Disease patients who stop Anti-TNF treatment during the third trimester of pregnancy

Abstract Background Anti-TNF drugs are safe during pregnancy in inflammatory bowel disease (IBD), but they cross the placenta most actively in the third trimester, and some guidelines still recommend stopping them during this period. There few data that examines the impact of anti-TNF discontinuation on the clinical course of IBD, so we aimed to explore the clinical outcomes of IBD pregnant patients who stopped anti-TNF at the third trimester. Methods We performed a retrospective, longitudinal study on female IBD patients receiving anti-TNF agents at our IBD clinic. We included IBD pregnant patients who discontinued the anti-TNF in the third trimester of pregnancy, and we matched these cases in a 1:1 ratio with non-pregnant female IBD patients by age, type of IBD, type of anti-TNF, duration of treatment, location, and behavior of IBD. Demographic and clinical variables were collected from 18 months before anti-TNF discontinuation and 12 months after discontinuation, and when available endoscopic indices (SES CD and UC). We determined whether subjects presented any adverse clinical outcome during the follow-up defined as development of disease flare, corticosteroid use, hospital admission, need for surgery, biologic dose escalation, or switch. Results We included 34 pregnant patients and 34 controls. Patients who stopped anti-TNF more frequently presented an adverse clinical outcome during the follow-up year when compared to the control group (47.1% vs. 23.5% p = 0.04) and flare activity (35, 3 vs. 11.8%, p = 0.02). We found no differences in escalation or biologic switch, hospital admission, or surgery between the subjects. We also found an association between the development of an adverse clinical outcome and anti-TNF monotherapy (p=0.009) and a higher SESCD in the previous year (p=0.017). In the multivariate analysis, anti-TNF monotherapy was the only independent factor for developing an adverse clinical outcome up to 1 year after anti-TNF discontinuation (OR: 3.47, CI 95%: 1.16–10.4, p=0.026). Conclusion In our cohort of female IBD patients on anti-TNF, monotherapy was independently associated with an adverse clinical outcome in the following year after anti-TNF discontinuation.

DOP75 Effectiveness and Safety of tofacitinib versus vedolizumab in Patients with Ulcerative Colitis; A Nationwide, ICC Registry study

Abstract Background Clinicians face difficulty in positioning biologics and JAK inhibitors in anti-TNF refractory ulcerative colitis (UC) patients. Head-to-head trials comparing the efficacy of vedolizumab and tofacitinib in UC patients are lacking. We aimed to compare the effectiveness and safety of vedolizumab and tofacitinib in anti-TNF experienced UC patients in our prospective, nationwide registry using a propensity score weighted cohort. Methods UC patients who failed anti-TNF treatment (with or without thiopurine) and initiated vedolizumab or tofacitinib treatment subsequently, were identified in the observational prospective Initiative on Crohn and Colitis (ICC) Registry. We selected patients with both clinical (Simple Clinical Colitis Activity Index (SCCAI) >2) and biochemical (C-reactive protein (CRP) >5mg/L or faecal calprotectin (FC) >250 µg/g) or endoscopic disease activity (endoscopic MAYO score ≥ 1) at initiation of therapy. Patients previously treated with vedolizumab or tofacitinib were excluded. Corticosteroid-free clinical remission (SCCAI<2), biochemical remission (CRP ≤5 mg/L and/or FC ≤250 µg/g) and safety outcomes were compared after 52 weeks of treatment. Inverse propensity scores weighted comparison was used to adjust for confounding and selection bias. Results Overall, 83 vedolizumab and 65 tofacitinib treated patients were included (table 1). Propensity score weighted analysis showed that tofacitinib treated patients were more likely to achieve corticosteroid-free clinical remission at week 12, 24 and 52 compared to vedolizumab treated patients (OR: 5.87, 95%CI:3.55–9.70, P<0.01, OR: 2.96, 95%CI: 1.85–4.73, P<0.01 and OR 2.96, 95%CI: 1.85–4.73, P<0.01, respectively) (table 2). In addition, tofacitinib treated patients were more likely to achieve biochemical remission at week 12 and week 24, remaining only statistically borderline at week 52 (OR: 2.96, 95%CI: 1.85–4.73, P<0.01, OR: 2.96, 95%CI: 1.85–4.73, P<0.01 and OR 1.68, 95%CI: 0.99–2.86, P=0.05, respectively) (table 2). There was no difference in infection rate (OR:1.057, 95%CI: 0.60–1.86, p=0.85) or severe adverse events (OR: 0.39, 95%CI: 0.03–4.33, P=0.44). No thromboembolic events were observed. Most common reason for treatment discontinuation was loss of response (table 3). Conclusion In tofacitinib treated, anti-TNF experienced, UC patients, we observed that a higher proportion of patients achieved corticosteroid-free remission after 12, 24 and 52 weeks compared to vedolizumab treated patients. In addition, more tofacitinib treated patients achieved biochemical remission at week 12 and 24. There was no statistically significant difference in severe adverse events.

The impact of anti-TNF treatment on Wnt signaling, noggin, and cytokine levels in axial spondyloarthritis.

Anti-tumor necrosis factor (anti-TNF) agents are commonly used in treatment of axial spondyloarthritis (axSpA), but clinical and radiological improvement is not achieved in all patients. We aimed to investigate the impact of anti-TNFs on inflammatory and noninflammatory parameters in patients with axSpA. In this longitudinal study, 30 biologic naïve axSpA patients with high disease activity and 30 healthy controls were enrolled. All patients were treated with anti-TNF agents for 6months. ASDAS-CRP, BASDAI, BASFI, BASMI, patient and physician global assessments were evaluated. C-reactive protein, COX2, TNF-α IL-6, IL-17, IL-22, IL-23, IL-33, sclerostin, dickkopf-1, and noggin levels were evaluated at baseline and at 6months of anti-TNF treatment. At baseline, axSpA patients had significantly higher median (IQR) TNF-α levels, 34.4 (31.4-37.03) vs. 18.1 (12.1-28.4) pg/ml (p < 0.001), and lower DKK1, 446.7 (356.9-529.3) vs. 1088.7 (951.7-1244.4) pg/ml, and sclerostin, 312.4 (140.8-412.7) vs. 412.3 (295.4-512.8) pg/ml, compared to healthy controls (all p < 0.001). The median (IQR) serum levels of IL-17, IL-22, and IL-33 increased significantly after 6months of anti-TNF treatment, from 93.3 (85.1-104.8) to 102.1 (86.6-114.6) pg/ml (p = 0.026), 159.2 (151.9-178.4) to 183.5 (156.3-304.6) pg/ml (p = 0.033), and 127.8 (106.6-186.1) to 147.06 (128.5-213.4) pg/ml (p = 0.016), respectively. Sclerostin and DKK-1 levels increased significantly after anti-TNF treatment from 312.4 (140.8-412.7) to 405.1 (276.3-452.5) pg/ml (p = 0.018) and 446.7 (356.9-529.3) to 881.3 (663.1-972.2) pg/ml (p < 0.001), while there was no significant change in noggin level. Many inflammatory cytokines increase after anti-TNF treatment and noggin is not affected by anti-TNF treatment in AxSpA. Noggin might be a therapeutic target in patients with axSpA. • Anti-TNF therapy is not sufficient for complete blockage of the inflammatory process in axial spondyloarthritis. • The increase in IL-17, IL-22, and IL-33 may decrease the efficiency of anti-TNF therapy. • Noggin might be a therapeutic target as a complementary or alternative approach to anti-TNF therapy in axial spondyloarthritis.

THE USE OF IMMUNOSTAINING IN BIOPSIES TO EVALUATE EXPRESSION PATTERN AND PATHOPHYSIOLOGY ROLES OF ONCOSTATIN M AND ITS RECEPTOR BETA IN PEDIATRIC INFLAMMATORY BOWEL DISEASE

The mRNA expression of oncostatin M (OSM) in colonic tissue is raised in inflammatory bowel disease (IBD) and is mplicated in anti-TNF treatment resistance. OSM has multiple homeostatic functions with both pathogenic and protective roles. Still, its function in IBD continues to be enigmatic. The aim of this study is to evaluate protein expression of OSM and its receptor-β (OSMR) using immunohistochemical staining, along with the tight junction protein occludin and immune cell marker CD45, to understand the possible mechanisms behind its pathogenic effects in inflammatory process.

Effect of Anti-TNF Treatment on Mooren’s Ulcer: A Case Series and Review of the Literature

ABSTRACT We present our experience with five patients treated with anti-tumor necrosis factor alpha (TNF-α) agents who were unresponsive to conventional treatment. Additionally, we summarize the current experience with biological disease-modifying anti-rheumatic drugs (bDMARDs) in Mooren’s ulcer. Purpose To report the efficacy of systemic anti-TNF agents in Mooren’s ulcer. Design Retrospective, consecutive case series. Methods We report on clinical characteristics and outcome of five patients with Mooren’s ulcer with anti-TNF treatment. Results During a mean follow-up of 30 months, relief of symptoms and arrest of corneal melting were observed in all eyes. Systemic corticosteroid treatment could be discontinued or reduced to threshold levels. No patient experienced adverse effects on bDMARDs. Conclusions Our results suggest that bDMARDs are effective in Mooren’s ulcer unresponsive to conventional treatment. This is in line with accumulating evidence in the current literature. Therefore, more targeted immunomodulatory approaches might be an effective first-line therapy in the future.

Serum granulocyte-macrophage colony-stimulating factor (GM-CSF) is increased in patients with active radiographic axial spondyloarthritis and persists despite anti-TNF treatment

BackgroundAccumulating evidence supports the role of monocytes and neutrophils in radiographic axSpA (r-axSpA). Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a growth factor for both leukocyte lineages and a pro-inflammatory cytokine activating myeloid cells and promoting osteoclastogenesis. It acts through the JAK-STAT pathway. We measured serum GM-CSF and markers of bone metabolism in patients with r-axSpA before and after anti-TNF treatment.MethodsPatients with active r-axSpA despite treatment with NSAIDs, all eligible for treatment with a biologic agent, were recruited. Healthy donors were sampled as controls. Serum was collected before (baseline) and after 4–6 months (follow-up) of anti-TNF treatment and the following molecules were measured with ELISA: GM-CSF, sclerostin (SOST), and dickkopf-1 (Dkk-1).ResultsTwelve r-axSpA patients (7 males, 5 females, median age 37 years) with a median disease duration of 1 year and 16 age- and sex-matched controls were included. At baseline, patients had mean BASDAI 6.3±2 and ASDAS 3.2±0.7, which decreased to 4.1±1.7 and 2.2±0.6 at follow-up, respectively. At baseline, r-axSpA patients had significantly higher mean serum levels of GM-CSF (150 vs 62pg/ml, p=0.049), significantly lower Dkk-1 (1228 vs 3052pg/ml, p=0.001), but similar levels of SOST (369 vs 544pg/ml, p=0.144) compared to controls. Anti-TNF treatment did not affect GM-CSF, Dkk-1, or SOST levels. Spearman correlation analysis showed that GM-CSF correlated positively with ASDAS at baseline (r=0.61, p=0.039), while no correlations were identified between bone markers (Dkk-1, SOST) on one hand and GM-CSF or disease activity indices on the other.ConclusionsGM-CSF is increased in patients with active AS and strongly correlates with disease activity. TNF inhibition does not affect GM-SCF levels, despite improving disease activity. GM-CSF may represent an important pathway responsible for residual inflammation during TNF blockade, but also a potential target of JAK inhibitors, explaining their efficacy in r-axSpA.