To Anti-tumor Necrosis Factor Research Articles

High Body Mass Index and Response to Anti-Tumor Necrosis Factor Therapy in Pediatric Crohn's Disease.

Obesity is common among patients with pediatric Crohn's disease (PCD). Some adult studies suggest obese patients respond less well to anti-tumor necrosis factor (TNF) treatment. This study sought compares anti-TNF response and anti-TNF levels between pediatric patients with normal and high body mass index (BMI). The COMBINE trial compared anti-TNF monotherapy with combination therapy with methotrexate in patients with PCD. In this secondary analysis, a comparison of time-to-treatment failure among patients with normal BMI vs BMI Z -score >1, adjusting for prescribed anti-TNF (infliximab [IFX] or adalimumab [ADA]), trial treatment assignment (combination vs monotherapy), and relevant covariates. Median anti-TNF levels across BMI category was also examined. Of 224 participants (162 IFX initiators and 62 ADA initiators), 111 (81%) had a normal BMI and 43 (19%) had a high BMI. High BMI was associated with treatment failure among ADA initiators (7/10 [70%] vs 12/52 [23%], hazard ratio 0.29, P = 0.007) but not IFX initiators. In addition, ADA-treated patients with a high BMI had lower ADA levels compared with those with normal BMI (median 5.8 vs 12.8 μg/mL, P = 0.02). IFX trough levels did not differ between BMI groups. Overweight and obese patients with PCD are more likely to experience ADA treatment failure than those with normal BMI. Higher BMI was associated with lower drug trough levels. Standard ADA dosing may be insufficient for overweight children with PCD. Among IFX initiators, there was no observed difference in clinical outcomes or drug levels, perhaps due to weight-based dosing and/or greater use of proactive drug monitoring.

Is the use of secukinumab after anti-TNF therapy greater than expected for the risk of developing inflammatory bowel disease?

ObjectiveIn this study, our objective was to present real-life data on the incidence of inflammatory bowel disease (IBD) among patients receiving secukinumab treatment. MethodsThe study consisted of 209 patients who had prior exposure to anti-tumor necrosis factor (TNF) or were biologically naive. Patients with a pre-existing history of IBD were excluded from the study. ResultsOf the 209 patients in the study, 176 (84.3%) had ankylosing spondylitis, while 33 (15.7%) had psoriatic arthritis. 112 (53.6%) patients had prior exposure to at least one anti-TNF treatment before initiating secukinumab. IBD developed in 10 (4.8%) of the 209 patients. The incidence of IBD among patients who initiated secukinumab as their first biologic agent was 1%. For patients who had previously received any anti-TNF treatment and subsequently transitioned to secukinumab, the incidence of IBD was 8% (p=0.018, odds ratio (OR): 8.38, 95% CI: 1.04–67.45). A mean of 3.67 months (±4.3) after anti-TNF use, whereas IBD symptoms developed in the biologically naive patient after 15 months. ConclusionOur study observed IBD incidence in 4.8% of patients using secukinumab. Patients who initiated secukinumab after previous anti-TNF treatment exhibited a significantly higher rate and risk of developing IBD. The onset of IBD occurred earlier in these patients (mean 3.67 months), whereas a single case of IBD showed a longer duration (15 months). Further studies with larger patient numbers are warranted to provide a more comprehensive understanding of our findings.

Clinical and ultrasonographic enthesitis assessment before and after anti-tumor necrosis factor treatment in patients with spondyloarthritis.

This study aimed to clinically and ultrasonographically evaluate enthesitis in patients with spondyloarthritis (SpA) and to determine enthesitis response to anti-tumor necrosis factor (TNF) treatment. Thirty-one SpA patients (22 males, 9 females; mean age: 39.4±10.9 years; range, 22 to 60 years) who started anti-TNF treatment due to their high disease activity were included in the cross-sectional prospective study between May 2017 and January 2018. Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Disease Activity Index, Ankylosing Spondylitis Quality of Life Questionnaire, Bath Ankylosing Spondylitis Functional Index, and Bath Ankylosing Spondylitis Metrology Index were recorded. Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) and Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Score were utilized for clinical enthesitis evaluation. Patients were ultrasonographically evaluated in accordance with the Madrid Sonographic Enthesitis Index (MASEI) by a blinded sonographer. Patients were clinically and ultrasonographically assessed at baseline and in the third month after the treatment. In the initial evaluation, 24 (77.42%) of the patients had clinical enthesitis, and 30 (96.77%) of the patients had ultrasonographic enthesitis. After anti-TNF treatment, MASES, SPARCC, MASEI-structure, MASEI-thickness, MASEI-bursitis, MASEI-Doppler, MASEI-inflammatory, and MASEI-total scores significantly decreased (p<0.05). There was no significant change in MASEI-damage, MASEI-erosion, and MASEI-calcification scores following the therapy (p>0.05). Anti-TNF treatment may improve clinical and ultrasonographic enthesitis, particularly inflammatory changes. Erosions and calcifications may not ameliorate after three months of anti-TNF treatment.

DOP06 Development of simplified scoring system to predict two-year clinical remission of patients with Ulcerative Colitis after treatment with vedolizumab

Abstract Background No prospective study had been conducted to demonstrate the efficacy of vedolizumab in patients with ulcerative colitis (UC). While several studies have identified predictive factors for achieving mucosal healing, a well-validated algorithm is lacking. We aimed to identify the predictive factors and develop a practical scoring system to assess the efficacy of vedolizumab in patients with UC. Methods We performed a logistic regression analysis from the data of withdrawal versus continuation of thiopurine in vedolizumab-treated patients with ulcerative colitis (VIEWS) study which is a prospective multi-center longitudinal cohort in UC patients in Australia who had clinical and endoscopic remission (Mayo score ≤ 1) at baseline and continued vedolizumab as maintenance treatment. Predictive factors of two-year steroid-free clinical remission were developed into a model that predicted the outcome of treatment. We then validated our scoring system in a separate retrospective cohort of patients with UC who received vedolizumab in routine practice during 2016-2021. Results The derivation cohort comprised 62 patients, with 48 patients (77.4%) maintaining clinical remission at 2 years. Patient characteristics are presented in table1. Independent predictive factors used in developing the model included combination of thiopurine continuation (OR 3.6, P-value 0.11), absence of exposure to anti-tumor necrosis factor (TNF) (OR 3.75, P-value 0.047), histologic remission at baseline (OR 10.79, P-value 0.002), and duration of UC &amp;lt; 5 years (OR 9.29, P-value 0.04). The final simplified score is as follows: 3x (thiopurine continuation) + 2x (absence of exposure to anti-TNF) + 3x (histologic remission at baseline) + 2x (duration of UC &amp;lt; 5 years) yielding the area under the receiver operating characteristic curve (AUROC) of 0.86 in the derivation cohort (figure 1). In the validation cohort, there were 43 UC patients who had been initiated and continued vedolizumab as maintenance treatment, with 30 patients (69.8%) remained in clinical remission at two years. The AUROC of validation cohort was 0.75 after applying simplified score. At a cut-off level of 4 points, the model can identify two-year clinical remission with 83% sensitivity and 54% specificity, respectively. Conclusion We developed the practical predictive scoring system to determine UC patients who are likely to remain in clinical remission after two years of treatment with vedolizumab. In high-risk UC patients, combination use of vedolizumab and thiopurine is strongly recommended.

Is the use of secukinumab after anti-TNF therapy greater than expected for the risk of developing inflammatory bowel disease?

ObjectiveIn this study, our objective was to present real-life data on the incidence of inflammatory bowel disease (IBD) among patients receiving secukinumab treatment. MethodsThe study consisted of 209 patients who had prior exposure to anti-tumor necrosis factor (TNF) or were biologically naive. Patients with a pre-existing history of IBD were excluded from the study. ResultsOf the 209 patients in the study, 176 (84.3%) had ankylosing spondylitis, while 33 (15.7%) had psoriatic arthritis. 112 (53.6%) patients had prior exposure to at least one anti-TNF treatment before initiating secukinumab. IBD developed in 10 (4.8%) of the 209 patients. The incidence of IBD among patients who initiated secukinumab as their first biologic agent was 1%. For patients who had previously received any anti-TNF treatment and subsequently transitioned to secukinumab, the incidence of IBD was 8% (p=0.018, odds ratio (OR): 8.38, 95% CI: 1.04–67.45). A mean of 3.67 months (±4.3) after anti-TNF use, whereas IBD symptoms developed in the biologically naive patient after 15 months. ConclusionOur study observed IBD incidence in 4.8% of patients using secukinumab. Patients who initiated secukinumab after previous anti-TNF treatment exhibited a significantly higher rate and risk of developing IBD. The onset of IBD occurred earlier in these patients (mean 3.67 months), whereas a single case of IBD showed a longer duration (15 months). Further studies with larger patient numbers are warranted to provide a more comprehensive understanding of our findings.

Hepatorenal pathologies in TNF-transgenic mouse model of rheumatoid arthritis are alleviated by anti-TNF treatment

ObjectiveTo examine and quantify liver and kidney lesions and their response to anti-tumor necrosis factor (TNF) therapy in a TNF-Tg mouse model of rheumatoid arthritis (RA).MethodsFemale TNF-Tg (Tg3647) mice were used as the animal model for chronic RA. Ultrasound, immunofluorescence, histological staining, serology tests, and real-time RT-PCR were used to examine the pathological changes in the liver and kidney.ResultsTNF-Tg mice showed a significant decrease in the body weight and a dramatic increase in the volumes of the gallbladder, knee cavity, and popliteal lymph nodes. The liver and kidneys of TNF-Tg mice showed increased chronic inflammation and accumulation of immune cells and fibrosis, compared to wild-type (WT) mice. Moreover, upregulation of inflammatory factors and impaired normal function were observed in the liver and kidneys of TNF-Tg mice. Inflammatory infiltration and fibrosis of the liver and kidneys of female TNF-Tg mice were improved after anti-TNF treatment, and better treatment effects were achieved at 4.5-month-old mice when they were received 8 weeks of intervention.ConclusionsWe found that TNF drives the development of liver and kidney pathology in female TNF-Tg mice and that there are limitations to the loss of utility of anti-TNF for the prolonged treatment of RA-associated hepatic and renal injury. This study provides a reliable and clinically relevant animal model for further studies exploring the molecular mechanisms and drug discovery for hepatorenal pathologies in RA.

Stimulation of the vagus nerve as atherapeutic principle.

Modulation of the parasympathetic tone leads to extensive physiological reactions at several levels, including the decreased production of proinflammatory cytokines. Many studies have demonstrated that chronic inflammatory diseases are associated with reduced parasympathetic and increased sympathetic activities. Moreover, it was demonstrated that a low parasympathetic and a high sympathetic activity in patients with rheumatoid arthritis (RA) predicts apoor therapeutic response to anti-tumor necrosis factor (TNF) treatment compared to RA patients with amore balanced autonomic nervous system. The autonomic equilibrium could be restored by electrical stimulation of the vagus nerve. Considering the patients who do not sufficiently respond to the available drugs, patients for whom the effectiveness of the drugs wanes over time, or have drug-related adverse events, anonpharmacological approach such as bioelectronics might be auseful supplement as an instrument in the successful extension of the therapeutic armamentarium for rheumatic diseases; however, there is a great need for further studies and the development of novel therapeutic strategies in the field of neuroimmunology.

Stimulation of the vagus nerve as a therapeutic principle. German Version

Modulation of the parasympathetic tone leads to extensive physiological reactions at several levels, including the decreased production of proinflammatory cytokines. Many studies have demonstrated that chronic inflammatory diseases are associated with reduced parasympathetic and increased sympathetic activities. Moreover, it was demonstrated that a low parasympathetic and a high sympathetic activity in patients with rheumatoid arthritis (RA) predicts apoor therapeutic response to anti-tumor necrosis factor (TNF) treatment compared to RA patients with amore balanced autonomic nervous system. The autonomic equilibrium could be restored by electrical stimulation of the vagus nerve. Considering the patients who do not sufficiently respond to the available drugs, patients for whom the effectiveness of the drugs wanes over time, or have drug-related adverse events, anonpharmacological approach such as bioelectronics might be auseful supplement as an instrument in the successful extension of the therapeutic armamentarium for rheumatic diseases; however, there is a great need for further studies and the development of novel therapeutic strategies in the field of neuroimmunology.

Evaluation of Lupus Cases Related to TNF Inhibitors in Children

Systemic lupus erythematosus (SLE) due to anti-tumor necrosis factor (TNF) agents is a rare entity. We reported three cases who developed lupus-like syndrome while receiving infliximab therapy for various reasons. All cases demonstrated clinical and laboratory findings of SLE. And all of them needed treatment. We would like to emphasize that the risk of anti-TNF-alpha-induced lupus should be kept in mind in patients receiving anti-TNF therapy for any reason.

HLA-DQA1*05 Was Not Associated With Primary Nonresponse or Loss of Response to First Anti-TNF in Real-World Inflammatory Bowel Disease Patients.

We lack predictors of response to biologics in the management of patients with inflammatory bowel disease (IBD). A recent study has shown a significant association between HLA-DQA1*05 carriers and the development of loss of response to anti-tumor necrosis factor (TNF) mediated by immunogenicity. Retrospective single-center cohort study including IBD patients who had received anti-TNF therapy as a first biologic and whose HLA-DQA1*05 had been determined. Primary nonresponse and secondary failure (assessed by survival analysis) have been evaluated as well as safety outcomes. A total of 199 IBD patients (161 [81%] with Crohn's disease and 38 [19%] with ulcerative colitis) were included. A total of 42.4% were HLA-DQA1*05 carriers and 60% received combination therapy at the start of anti-TNF treatment. Median follow-up was 24 (interquartile range, 11-66) months. No statistically significant differences were found in primary nonresponse to anti-TNF (89.3% vs 87.8%; P = .825), depending on HLA carriers and noncarriers. No differences in secondary loss of response according to HLA variant in any of the analyses performed (full cohort, according to IBD or anti-TNF type) were observed. Again, no differences were observed in patients treated with combination therapy. In terms of safety, no significant differences were found in the rate of infusion reactions or serious adverse events. In our real-life cohort of IBD patients treated for the first time with anti-TNF, being an HLA-DQA1*05 carrier did not act as a predictor of response failure, either primary or secondary. The safety of anti-TNF treatment has also not been influenced by the variant.

Comparing Patient Reported Outcomes among Anti-TNF Experienced Patients with Ulcerative Colitis Initiating Vedolizumab versus Tofacitinib

Abstract Background Primary and secondary non-response to Anti-Tumor Necrosis Factor (TNF) therapy is common in patients with ulcerative colitis (UC), yet limited research has compared the effectiveness of subsequent biological therapy. Objective We sought to compare the effectiveness of vedolizumab and tofacitinib in anti-TNF experienced patients with UC, focusing on patient-prioritized patient reported outcomes (PROs). Methods We conducted a prospective cohort study nested within the Crohn’s &amp; Colitis Foundation’s IBD Partners and SPARC IBD initiatives. We identified anti-TNF experienced patients with UC initiating vedolizumab or ustekinumab and analyzed PROs reported approximately 6 months later (minimum 4 months, maximum 10 months). Co-primary outcomes were Patient Reported Outcome Measurement Information System (PROMIS) domains of Fatigue and Pain Interference. Secondary outcomes included PRO-2, treatment persistence, and need for colectomy. Results We compared 72 vedolizumab initiators and 33 tofacitinib initiators. At follow-up, Pain Interference (P=0.04), but not Fatigue (P=0.53,) was lower among tofacitinib initiators. A trend towards higher Social Role Satisfaction was not significant. The remainder of secondary outcomes (PRO2, treatment persistence, colectomy) did not differ between treatment groups. Conclusion Among anti-TNF experienced patients with UC, Pain Interference 4-10 months after treatment initiation was lower among tofacitinib users as compared to vedolizumab users. Many, but not all, secondary endpoints and subanalyses also favored favored tofacitinib. Future studies with larger sample sizes are needed to further evaluate these findings.

Evaluation of HLA-B27 frequency in patients with ankylosing spondylitis, and its relationship with clinical symptoms in Khuzestan province

Introduction: Ankylosing spondylitis (AS) is an autoimmune disease, which causes mild to severe clinical symptoms in patients. Several inherited and acquired factors are involved in the pathogenesis of the disease. Human leukocyte antigen B27 (HLA-B27) is one of the factors, whose expression affects patients’ susceptibility to AS. Objectives: In this study, we evaluated HLA-B27 frequency in AS patients of Khuzestan province of Iran. Patients and Methods: The study population (N=114) including patients with AS. Patients were examined and confirmed by a rheumatologist based on New York modified criteria. Clinical information was extracted from patients’ documents. Furthermore, general characteristics of the patients and several clinical variables (physio-pathological, self-report, and imaging) were taken into consideration. Results: The results showed that 62.3% of the patients were HLA-B27 positive, while 37.7% of which were HLA-B27 negative. This difference was statistically significant (P &lt;0.05). The disease duration was shown to be almost equal in both groups (i.e., HLA-B27 positive and HLA-B27 negative). According to the results, various clinical symptoms (like ocular complications and peripheral arthritis) were observed in patients, and the complications of which were higher in HLA-B27 negative patients compared to HLA-B27 positive ones (P &lt;0.05). Besides, it was seen that the male patients have shown a higher physio-pathological (using polymerase chain reaction [PCR] technique) report for positive HLA-B27 and a higher magnetic resonance imaging involvement compared with females, whereas the women showed higher disease activity score i.e., higher mean Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) value. Conclusion: For the AS patients, negative HLA-B27 cases show more progressive involvement sacroiliac joints compared with the positive HLA-B27 cases. More importantly, of hundred percent of patients who responded to anti-tumor necrosis factor (TNF) treatment, 52.6% were positive for the HLA-B27 antigen, and 47.4% were negative for the HLA-B27 antigen. Overall, it can be said that HLA-B27 lonely is not involved in the pathogenesis of AS and environmental factors should be investigated and involved in the disease development.

Comparing Patient-Reported Outcomes Among Anti-TNF-Experienced Patients with Crohn's Disease Initiating Vedolizumab Versus Ustekinumab.

Primary and secondary non-response to anti-tumor necrosis factor (TNF) therapy is common in patients with Crohn's disease (CD), yet limited research has compared the effectiveness of subsequent biological therapy. We sought to compare the effectiveness of vedolizumab and ustekinumab in anti-TNF-experienced patients with CD, focusing on patient-prioritized patient-reported outcomes (PROs). We conducted a prospective, internet-based cohort study nested within IBD Partners. We identified anti-TNF-experienced patients initiating with CD vedolizumab or ustekinumab and analyzed PROs reported approximately 6months later (minimum 4months, maximum 10months). Co-primary outcomes were Patient-Reported Outcome Measurement Information System (PROMIS) domains of Fatigue and Pain Interference. Secondary outcomes included patient-reported short Crohn's disease activity index (sCDAI), treatment persistence, and corticosteroid use. Inverse probability of treatment weighting (IPTW) was used to control for a number of potential confounders and incorporated into linear and logistic regression models for continuous and categorical outcomes, respectively. Overall, 141 vedolizumab and 219 ustekinumab initiators were included in our analysis. After adjustment, we found no differences between treatment groups in our primary outcomes of Pain Interference or Fatigue or the secondary outcome of sCDAI. However, vedolizumab was associated with lower treatment persistence (OR 0.4, 95% CI 0.2-0.6) and higher corticosteroid use at follow-up assessment (OR 1.7, 95% CI 1.1-2.6). Among anti-TNF experienced patients with CD, Pain Interference or Fatigue was not significantly different 4-10months after starting ustekinumab or vedolizumab. However, reduced steroid use and increased persistence suggest superiority of ustekinumab for non-PRO outcomes.

Real-World Evidence Comparing Vedolizumab and Ustekinumab in Antitumor Necrosis Factor-Experienced Patients With Crohn's Disease.

Many patients with Crohn's disease (CD) lose response or become intolerant to antitumor necrosis factor (TNF) therapy and subsequently switch out of class. We compared the effectiveness and safety of ustekinumab to vedolizumab in a large, geographically diverse US population of TNF-experienced patients with CD. We conducted a retrospective cohort study using longitudinal claims data from a large US insurer (Anthem, Inc.). We identified patients with CD initiating vedolizumab or ustekinumab with anti-TNF treatment in the prior 6 months. Our primary outcome was treatment persistence for >52 weeks. Secondary outcomes included (i) all-cause hospitalization, (ii) hospitalization for CD with surgery, (iii) hospitalization for CD without surgery, and (iv) hospitalization for infection. Propensity score fine stratification was used to control for demographic and baseline clinical characteristics and prior treatments. Among 885 new users of ustekinumab and 490 new users of vedolizumab, we observed no difference in treatment persistence (adjusted risk ratio 1.09 [95% confidence interval 0.95-1.25]). Ustekinumab was associated with a lower rate of all-cause hospitalization (adjusted hazard ratio 0.73 [0.59-0.91]), nonsurgical CD hospitalization (adjusted hazard ratio 0.58 [0.40-0.83]), and hospitalization for infection (adjusted hazard ratio 0.56 [0.34-0.92]). This real-world comparative effectiveness study of anti-TNF-experienced patients with CD initiating vedolizumab or ustekinumab showed similar treatment persistence rates beyond 52 weeks, although secondary outcomes such as all-cause hospitalizations, nonsurgical CD hospitalizations, and hospitalizations for infection favored ustekinumab initiation. We, therefore, advocate for individualized decision making in this medically refractory population, considering patient preference and other factors such as cost and route of administration.

Landscape of sialylation patterns identify biomarkers for diagnosis and prediction of response to anti-TNF therapy in crohn's disease.

Crohn's disease (CD), a subtype of inflammatory bowel disease (IBD), causes chronic gastrointestinal tract inflammation. Thirty percent of patients do not respond to anti-tumor necrosis factor (TNF) therapy. Sialylation is involved in the pathogenesis of IBD. We aimed to identify potential biomarkers for diagnosing CD and predicting anti-TNF medication outcomes in CD. Three potential biomarkers (SERPINB2, TFPI2, and SLC9B2) were screened using bioinformatics analysis and machine learning based on sialylation-related genes. Moreover, the combined model of SERPINB2, TFPI2, and SLC9B2 showed excellent diagnostic value in both the training and validation cohorts. Importantly, a Sial-score was constructed based on the expression of SERPINB2, TFPI2, and SLC9B2. The Sial-low group showed a lower level of immune infiltration than the Sial-high group. Anti-TNF therapy was effective for 94.4% of patients in the Sial-low group but only 15.8% in the Sial-high group. The Sial-score had an outstanding ability to predict and distinguish between responders and non-responders. Our comprehensive analysis indicates that SERPINB2, TFPI2, and SLC9B2 play essential roles in pathogenesis and anti-TNF therapy resistance in CD. Furthermore, it may provide novel concepts for customizing treatment for individual patients with CD.

Surgical Management of Small Bowel Crohn's Disease.

Crohn's disease in the small bowel could present itself as an inflammatory stricture, a fibrotic stricture as penetrating disease or a combination of both. It is pertinent to differentiate the disease process as well as its extent to effectively manage the disease. Currently, a combination of medical and surgical therapies forms part of the treatment plan while the debate of which therapy is better continues. In managing the strictures, identification of the disease process through imaging plays a pivotal role as inflammatory strictures respond to anti-tumor necrosis factor (TNF) and biological agents, while fibrotic strictures require endoscopic or surgical intervention. Recent evidence suggests a larger role for surgical excision, particularly in ileocolic disease, while achieving a balance between disease clearance and bowel preservation. Several adaptations to the surgical technique, such as wide mesenteric excision, side to side or Kono-S anastomosis, and long-term metronidazole therapy, are being undertaken even though their absolute benefit is yet to be determined. Penetrating disease requires a broader multidisciplinary approach with a particular focus on nutrition, skincare, and intestinal failure management. The current guidance directs toward early surgical intervention for penetrating disease when feasible. Accurate preoperative imaging, medical management of active diseases, and surgical decision-making based on experience and evidence play a key role in success.

P450 Ustekinumab and vedolizumab for extraintestinal manifestations in inflammatory bowel disease

Abstract Background Extraintestinal manifestations (EIM) occur in up to 50 % of patients with inflammatory bowel disease (IBD) and are associated with significant morbidity and diminished quality of life. Ustekinumab (UST) and vedolizumab (VDZ) are effective for Crohn’s disease (CD) and ulcerative colitis (UC). However, their efficacy for treatment of EIM is not well established. The aim of our study was to compare the effectiveness of UST and VDZ for treatment of EIM in IBD. Methods We included IBD patients treated with VDZ or UST that are followed in the gastroenterology department of Sheba medical center between 2015 and 2021. Only patients with active EIM at the start of the treatment were included. The duration of follow- up was up to 52 weeks Results 112 patients were included. Fifty-three patients (47%) were treated with ustekinumab and 59 (53%) with vedolizumab: 62(55%) women, 88% (n-99) had CD (52% had a small bowel,29% had both small bowel and colon disease location). Twenty-four patients (21%) were naïve to anti-tumor necrosis factor (TNF) inhibitors. The most common EIM was arthralgia (95/112, 84%). Patients treated with UST were more likely to be anti TNF experienced (n=51/53 [96%] compared with n=34/59 [58%], p&amp;lt;0.0001). Only 1 UC patient (1/53, 2%) treated with UST was included compared with 12 UC patients (12/59, 20%) in the VDZ group. Clinical response of EIM at week 52 was achieved in 42% of patients treated with UST (n-20/47) and 25% of patients (n- 13/52) treated with vedolizumab, this difference was not statistically significant (p =0.08). There was no difference between UST and VDZ regarding their effect on EIM at earlier timepoints (week 6, 14, 26) (n-9/39 [23%] vs. n-17/56 [30%] p=0.8, n-9/36 [25%] vs. n-17/55 [31%], p=0.6, n-14/41 [34%] vs. n-17/55 [30%], p=0.8, respectively). The difference between groups was also not observed for specific types of EIMs Conclusion In our retrospective study, no difference was found between VDZ and UST regarding their effect on EIM in IBD patients for up to 52 weeks of follow-up.

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

POS0446 FILGOTINIB-TREATED RHEUMATOID ARTHRITIS PATIENTS WITH HIGH BASELINE NEUTROPHIL-TO-LYMPHOCYTE RATIO SHOW BETTER CLINICAL RESPONSE RATES AND PATIENT-REPORTED OUTCOMES

Background:Rheumatoid arthritis (RA) is a systemic inflammatory disease which includes increased innate and myeloid immune cell activation. Filgotinib (FIL), an oral JAK1 inhibitor, has shown safety and efficacy in three phase 3 studies (FINCH1-3) in adults with moderately-to-severely active RA. The baseline (BL) neutrophil-to-lymphocyte ratio (NLR) in RA has been associated with a positive response to anti-tumor necrosis factor (TNF) therapy1 and a negative response to DMARD triple therapy2. We previously reported a BL signature of clinical response in the FINCH2 (bDMARD-IR) population which included a neutrophil component3.Objectives:We conducted a post-hoc analysis to explore whether the BL NLR was associated with response to treatment in the FINCH studies.Methods:Clinical data of 3273 RA patients (pts) enrolled in the FINCH clinical trials (FINCH3, methotrexate (MTX)-naïve: NCT02886728; FINCH1, MTX-Inadequate Responder (IR): NCT02889796; FINCH2, bDMARD-IR: NCT02873936) were retrospectively analyzed for a relationship between the BL NLR and composite clinical endpoints (ACR-N, DAS28CRP, or CDAI) or PROs (Pain VAS, FACIT Fatigue, HAQ-DI) through week 24. Pts were classified as High or Low BL NLR using a cutpoint (2.7) identified as an independent predictor of treatment failure in a published RA study2. Adjusted clinical outcomes were estimated based on mixed effects linear regression models including geographic region and demographics covariates.Results:57% of pts enrolled in the FINCH trials were classified as BL NLR-High (Table 1) and FINCH3 NLR-High pts showed higher BL DAS28(CRP). FINCH1 and FINCH3 FIL+MTX-arm NLR-High pts demonstrated significantly better DAS28(CRP) response compared to NLR-Low pts (Figure 1). DAS28(CRP) differences between NLR-High and NLR-Low were detectable as early as Week 2 for FIL200mg + MTX and were sustained through Week 24. FINCH1 and FINCH3 FIL200mg + MTX NLR-High pts also demonstrated sustained clinical and PRO improvements over NLR-Low, including CDAI, ACR-N, Pain VAS, FACIT Fatigue, and HAQ-DI. The strength of these associations was dose-dependent; pts that received FIL100mg + MTX demonstrated weaker but directionally consistent trends in both populations. No significant association between NLR subgroup and clinical efficacy was observed in FINCH2 FIL+MTX-arm pts, FIL-monotherapy (FINCH3) pts, or adalimumab+MTX (FINCH1) pts.Conclusion:In FINCH1 (MTX-IR) and FINCH3 (MTX-naïve), FIL200mg + MTX -arm NLR-High pts demonstrate better sustained clinical response and PRO scores compared to NLR-Low pts. These data are the first to report an association between the BL NLR and therapeutic response in large randomized RA clinical trials. Future studies on pathobiologies reflected by the NLR biomarker may clarify its potential to guide RA disease management.

Oncostatin M Is a Biomarker of Diagnosis, Worse Disease Prognosis, and Therapeutic Nonresponse in Inflammatory Bowel Disease.

BackgroundOncostatin M (OSM) has been implicated in the pathogenesis of inflammatory bowel disease (IBD) and as a marker for nonresponsiveness to anti-tumor necrosis factor (TNF) therapy. We further unraveled the potential of OSM and related receptors as markers of diagnosis, prognosis, and therapy response in IBD.MethodsWe collected inflamed mucosal biopsies and serum from patients with Crohn disease (CD) and with ulcerative colitis: (1) newly diagnosed patients who were treatment-naïve, (2) patients initiating anti-TNF or (3) vedolizumab therapy, (4) postoperative patients with CD, and (5) multiple-affected families with IBD including unaffected first-degree relatives (FDRs). We measured the gene expression of mucosal OSM and its receptors OSMR/LIFR and co-receptor IL6ST, and the protein expression of serum OSM. Statistical significance was defined as P < 0.05.ResultsNewly diagnosed patients showed significantly increased mucosal OSM/OSMR compared with control patients, with the highest enrichment for OSM (fold change [FC] >17.9). Likewise, ileal OSM/OSMR were significantly upregulated in postoperative recurrent CD. Serum OSM was increased in newly diagnosed patients and postoperative patients with recurrent CD (FC ≥ 2.6). In families with IBD, higher serum levels were observed in FDRs than in control families (FC = 2.2). Furthermore, elevated colonic OSM/OSMR (but not serum OSM) were associated with the early need for biologic therapy (FC ≥ 1.9), and higher OSM was also predictive of primary nonresponse to both anti-TNF and vedolizumab therapy (FC ≥ 2.4). Immunohistochemistry highlighted mucosal OSM expression in macrophages.ConclusionsWe found that OSM is a diagnostic biomarker in the tissue and serum not only of newly diagnosed patients with IBD and postoperative patients with recurrent CD but also of their FDRs. Higher colonic OSM levels are furthermore associated with poor prognosis and with primary nonresponse to biologic therapies. Therefore, OSM could guide clinical decision-making.