Prior Anti-tumor Necrosis Factor Research Articles

Vedolizumab versus ustekinumab in Crohn's disease with prior anti-tumor necrosis factor failure: an updated meta-analysis.

Ustekinumab and vedolizumab are key treatment options for Crohn's disease patients who fail anti-tumor necrosis factor (TNF) therapy. This updated meta-analysis aims to compare the efficacy and safety of these two drugs. We performed a systematic review in PubMed, Embase , and Cochrane databases searching for randomized and nonrandomized studies comparing vedolizumab versus ustekinumab in patients with Crohn's disease with previous anti-TNF failure or intolerance. The primary outcome was steroid-free clinical remission (SFR) at the pos-induction (12-16 weeks) and maintenance period (48-52 weeks). The odds ratio (OR) was used for binary outcomes with their respective 95% confidence interval (CI). Heterogeneity was assessed using the Cochran Q test and I2 statistics. This meta-analysis included 11 studies and 2724 patients. There was a significant difference favoring ustekinumab in SFR at pos-induction (OR, 1.44; 95% CI, 1.11-1.88; P = 0.006; I2 = 27%) and maintenance periods (OR, 1.86; 95% CI, 1.23-2.82; P = 0.003; I2 = 80%), in clinical remission at pos-induction period (OR, 2.04; 95% CI, 1.58-2.63; P < 0.001; I2 = 3%), and in treatment discontinuation due to adverse events (OR, 0.31; 95% CI, 0.16-0.60; P < 0.001; I2 = 0%). In patients with Crohn's disease with prior anti-TNF failure, ustekinumab showed higher SFR during both the pos-induction and maintenance period and a lower rate of treatment discontinuation due to adverse events.

Short-term efficacy of vedolizumab in patients with inflammatory bowel disease in real-life settings in Bosnia and Herzegovina.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), necessitates effective management strategies. This study aims to evaluate the real-world efficacy of vedolizumab, a newer biological therapy, in treating IBD in Bosnia and Herzegovina. A retrospective observational study was conducted across six medical centers, involving 139 IBD patients, 76 with UC and 63 with CD. Patients were assessed for clinical remission and other outcomes at the 26-week mark post vedolizumab treatment initiation. At 26 weeks, clinical remission was achieved in 82.9% of UC patients and 85.7% of CD patients. Mucosal healing was observed in 38.1% of CD patients. The efficacy of vedolizumab did not significantly differ based on prior anti-tumor necrosis factor (anti-TNF) exposure. Notably, the clinical scoring tools for predicting vedolizumab response showed limited applicability in this cohort. Vedolizumab demonstrated high efficacy in treating both UC and CD in real-world settings in Bosnia and Herzegovina, underscoring its potential as a significant therapeutic option in IBD management.

Effectiveness and Persistency of Ustekinumab Treatment for Ulcerative Colitis: A Phoenix retrospective Cohort Study.

Real-world data regarding ustekinumab (UST) for ulcerative colitis (UC) particularly in biologics-naïve patients is currently limited. This study aimed to elucidate the real-world effectiveness and safety of UST for UC. Overall, 150 patients with UC treated with UST from March 2020 to January 2023 were enrolled across 7 referral hospitals. To assess the clinical efficacy and persistence of UST, retrospective analyses were conducted from weeks 8 to 56. Predictive factors concerning the response and persistence of UST were examined through univariate and multivariate analyses. Of the 150 patients, 125 received UST for remission induction, including 36% biologics-naïve. The response and remission rates were 72.8% and 56.0% at week 8 and 73.2% and 63.4% at week 56, respectively. Biologics-naïve patients represented higher response and remission rates at week 8 (84.4% and 73.3%) than those with biologics exposure (66.2% and 46.2%). Patients with prior antitumor necrosis factor (anti-TNF) and vedolizumab (VDZ) exposure had relatively lower response and remission rates (34.5% and 24.1%, respectively). The 1-year cumulative persistence rate was 84.0%. Multivariate analysis revealed that the chronic continuous type and prior anti-TNF and VDZ exposure were negative predictive factors for week 8 responsiveness. Clinical response at week 8 was a predictor of 1-year persistence. Adverse event incidence remained notably low at 6.4%. This study highlights the safety and effectiveness of UST as an induction and maintenance therapy for UC. Chronic continuous type and previous anti-TNF and VDZ exposure negatively contributed to short-term effectiveness, whereas short-term effectiveness provided good persistency.

OP36 Risankizumab Versus Ustekinumab for the Achievement of Clinical Outcomes and Symptom Improvement in Patients With Moderate To Severe Crohn’s Disease: Results From the Phase 3b SEQUENCE Trial

Abstract Background The efficacy and safety of risankizumab (RZB) and ustekinumab (UST) in patients (pts) with moderate to severe Crohn's disease (CD) refractory to prior anti-tumour necrosis factor (TNF)α therapy were compared in the SEQUENCE head-to-head study. Previously, wk24 CD activity index (CDAI) clinical remission rates (CDAI&amp;lt;150) were reported for 50% of pts (first primary endpoint);1 here, the efficacy of RZB versus (vs) UST for achieving wk24 clinical remission and other symptomatic improvements in the full pt population was assessed. Methods SEQUENCE (NCT04524611) was an open-label, multicenter, randomised, efficacy assessment-blinded study in pts with moderate to severe CD (defined in Figure footnote) refractory to TNFα therapy. Pts in the primary efficacy analysis set were randomised 1:1 to receive RZB (intravenous [IV] 600mg induction at BL, week (wk)4 and wk8, then 360mg subcutaneous [SC] maintenance every 8 wks [Q8w], starting at wk12) or UST (single weight-based IV induction followed by a 90mg Q8w SC maintenance starting at wk8) up to wk48. A mandatory steroid taper began at wk2. Randomisation was stratified by BL steroid use and number of failed anti-TNFs. Prespecified non-ranked endpoints included CDAI clinical response and stool frequency (SF)/abdominal pain score (APS) clinical remission (definitions in Figure footnote). CDAI clinical remission at wk48 was a ranked secondary endpoint. CDAI clinical remission at wks 8 and 24, and changes from BL in avg daily APS, SF, and CDAI, were evaluated post-hoc. Binary endpoints were analysed using non-responder imputation while incorporating multiple imputation to handle missing data due to COVID-19 and/or geopolitical conflict. Continuous endpoints were analysed using a mixed-effect model with repeated measures. All P values are nominal, except for wk48 CDAI clinical remission (ranked secondary endpoint). Results With RZB vs UST, respectively, greater rates of CDAI clinical remission (59.6% [152/255] vs 42.6% [113/265]; P=0.0001), SF/APS clinical remission (55.7% vs 41.1%; P&amp;lt;0.001) and CDAI clinical response (69.8% vs 54.3%; P&amp;lt;0.001) were observed at wk24; similar results were observed at wk48 (Figure). Mean BL APS in the RZB and UST groups was 1.9 (both groups), SF was 5.5 and 5.6, and CDAI was 309.4 and 310.1, respectively. Least square (LS) mean changes from BL in APS, SF, and CDAI were greater with RZB vs UST and observed early as wk8 (APS: -0.9 vs -0.8; SF: -3.0 vs -2.3; P&amp;lt;0.001; CDAI: -136.3 vs -117.1; P&amp;lt;0.05) (Figure). The safety profiles of RZB and UST were consistent with published results.1 Conclusion In this head-to-head study, improvements in symptomatic outcomes in pts with CD were greater with RZB than UST over 48 wks of treatment. 1doi.org/10.1002/ueg2.12474

P922 A multicenter retrospective real-world study to determine the optimal cases of vedolizumab-treated UC patients

Abstract Background Vedolizumab (VDZ) is a gut-selective monoclonal antibody approved for ulcerative colitis (UC). This real-world study aimed to evaluate the effectiveness of VDZ in the treatment of UC, with the goal of further treatment optimization. Methods In this multicenter, retrospective, observational chart review, 370 patients with UC who received at least one dose of VDZ in clinical practice at 16 tertiary hospitals in Japan were enrolled. Comprehensive analyses of predictors of 2- and 54-week remission, drug persistence, and the development of loss of response were performed. Results Lower partial Mayo scores and lower Mayo endoscopic subscores were significantly associated with 2-week remission in the multivariate analysis. More 2-week remitters achieved clinical remission at Week 52 than non-2-week remitters. Clinical remission rates were significantly higher in biologic-naïve than in biologic-non-naïve patients across Weeks 2 to 54. Higher clinical remission rates at Week 54 were significantly associated with lower baseline disease severity and no prior anti-tumor necrosis factor alpha (anti- TNFα) treatment. Among patients with prior anti-TNFα treatment, longer duration of anti-TNFα treatment was associated with higher clinical remission rates at Week 54 (28.1%, 32.7%, and 60.0% for ≤3 months, &amp;gt;3 to &amp;lt;12 months, and ≥12 months, respectively, p=0.001 between groups). In addition, clinical remission rate at Week 54 was higher in patients who had loss of response to anti-TNFα treatment than in those who had primary nonresponse (54.4% vs 24.6%; p=0.001). The 54-week persistence rate was 64.5%. Concomitant use of tacrolimus (OR 2.76, 95% CI 1.00, 7.62, p=0.05) and shorter disease duration (median:7.8 years), (OR 0.33, 95% CI 0.13, 0.82 for ≥7.8 years vs &amp;lt;7.8 years p=0.017) were associated with loss of response to VDZ in the multivariate analysis, but prior use of anti- TNFα treatment was not. Conclusion This retrospective study confirms favorable outcomes with VDZ in patients without prior exposure to anti-TNFα treatment. However, among patients with history of anti-TNFα- exposure, better outcomes were observed among those who experienced loss of response than those with primary nonresponse, as well as those who had a longer duration of anti-TNFα treatment.

1-Year Comparative Effectiveness of Tofacitinib vs Ustekinumab for Patients With Ulcerative Colitis and Prior Antitumor Necrosis Factor Failure.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Real-world data comparing the effectiveness of tofacitinib to ustekinumab are limited. We compared 52-week outcomes of tofacitinib vs ustekinumab for UC after antitumor necrosis factor (anti-TNF) failure. In this retrospective cohort study, adults initiated tofacitinib or ustekinumab for UC after anti-TNF failure May 1, 2018 to April 1, 2021, at a US academic medical center. The primary outcome was steroid-free clinical remission (SFCR) at 12 and 52 weeks. The secondary outcome was drug survival (ie, time to drug discontinuation due to nonresponse). Adverse events (AEs) were also assessed. Sixty-nine patients initiated tofacitinib, and 97 patients initiated ustekinumab with median follow-up of 88.0 and 62.0 weeks, respectively. After inverse probability of treatment-weighted logistic and Cox regression, there was no association of tofacitinib vs ustekinumab with SFCR at 12 weeks (odds ratio, 1.65; 95% CI, 0.79-3.41), SFCR at 52 weeks (odds ratio, 1.14; 95% CI, 0.55-2.34), or drug survival (hazard ratio, 1.37; 95% CI, 0.78-2.37). Kaplan-Meier analysis demonstrated no separation in drug survival curves. Regression results were similar after excluding patients with prior tofacitinib or ustekinumab exposure. During available follow-up, 17 AEs were reported for tofacitinib (most commonly shingles, n = 4), and 10 AEs were reported for ustekinumab (most commonly arthralgia and rash, each n = 2). Two patients discontinued treatment due to AEs (1 tofacitinib for elevated liver enzymes, 1 ustekinumab for arthralgia). In a real-world UC cohort, tofacitinib and ustekinumab demonstrated similar effectiveness at 52 weeks. Adverse events were consistent with the known safety profiles of these agents.

P376 Efficacy of ozanimod in vedolizumab-exposed patients with ulcerative colitis: a phase 3 True North post hoc analysis

Abstract Background Ozanimod (OZA), an oral sphingosine 1-phosphate receptor modulator that prevents lymphocyte migration to inflamed tissues, is approved for the treatment of patients with moderate to severe ulcerative colitis (UC) in the European Union and United States. The phase 3 True North (TN) randomised trial showed that OZA was effective and well tolerated in these patients. OZA efficacy in patients who have been exposed to vedolizumab (VDZ-exp), an integrin receptor antagonist that interferes with lymphocyte trafficking to the gut, has not yet been described. This post hoc analysis of TN examined OZA efficacy in VDZ-exp patients. Methods In TN, patients were randomised to oral once-daily OZA 0.92 mg (equivalent to OZA HCl 1 mg) or placebo (PBO; Cohort 1) or to open-label OZA (Cohort 2) during the induction period (IP). Patients with a clinical response to OZA at Week 10 were rerandomised to OZA or PBO in the maintenance period (MP). Efficacy at Week 10 (IP) and Week 52 (MP) in the VDZ-exp subgroup was calculated. Differences in proportions between OZA and PBO at Week 10 were based on the Cochran-Mantel-Haenszel (CMH) test, stratified by corticosteroid use at screening and prior anti-tumor necrosis factor (anti-TNF) use. Differences between OZA/OZA and OZA/PBO at Week 52 were based on the CMH test stratified by both remission status and corticosteroid use at Week 10. Results TN included a total of 185 VDZ-exp patients (Cohort 1: PBO, n=35; OZA, n=63; and Cohort 2: OZA, n=87). Baseline demographics and clinical characteristics were balanced across treatment groups. In the VDZ-exp subgroup, 52% of patients had extensive disease at baseline, 78% had a Mayo endoscopic score of 3, 85% were previously exposed to anti-TNF, and 61% were receiving corticosteroid at baseline. At Week 10, OZA (Cohort 1) was numerically more effective vs PBO for all endpoints in VDZ-exp pts (Figure 1A). Notably, in the subgroup of patients previously exposed to VDZ as a first-line advanced therapy, clinical response at Week 10 was achieved in 50% (6/12) of OZA pts in Cohort 1 and 42% (5/12) of OZA patients in Cohort 2. At Week 52, a higher proportion of VDZ-exp patients on continuous OZA achieved all efficacy endpoints vs the OZA/PBO group, with significant differences shown for most endpoints. OZA/OZA vs OZA/PBO differences at Week 52 were larger than OZA vs PBO differences at Week 10 (Figure 1B). Conclusion This post hoc analysis of the phase 3 TN study found that OZA was effective in UC patients who previously failed VDZ, including those who failed VDZ alone or following other advanced therapies. Future studies evaluating OZA in VDZ-exp patients are warranted.

Gluteal Region Plasmablastic Lymphoma in a Crohn’s Disease Patient Treated with Anti-Tumor Necrosis Factor and Immunosuppressive Therapies: Report of a Rare Case with Literature Review

Abstract Introduction/Objective Plasmablastic lymphoma (PBL) is rare, initially described in the oral cavity of HIV patients but can affect other extra-nodal sites and immunodeficiency states. We report an unusual case of PBL in an HIV negative Crohn’s disease (CD) patient with prior anti-tumor necrosis factor (TNF) and immunosuppressive therapies including prednisone. Methods/Case Report A 54-year-old man with recent bleeding from chronic gluteal wounds had CD (five years), a left-lower-quadrant diverting colostomy (three years) and treatment with adalimumab (three years), briefly with infliximab (discontinued after an infusion reaction) and chronic prednisone. Multiple perianal fistulous tracts were present and biopsied. Dermal diffuse infiltrate of pleomorphic plasmacytoid cells had prominent nucleoli, and an immunohistochemical profile as: CD20-/CD22-/CD30-/CD38-/CD45-/CD56+(weak, subset)/CD79a-/CD138+/EBV+(EBER-ISH)/HHV8-/kappa+/lambda-/MUM1+/PAX5-/Ki-67(70-80%) confirming PBL. Chemotherapy with bortezomib combined with etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin resulted in a good response. Results (if a Case Study enter NA) NA. Conclusion A meta-analysis found increased risk of non-Hodgkin lymphomas in CD treated with anti-TNFs, however, lymphoma subtypes were not specified. Seven cases of CD-associated PBL were found in the literature (from 2007). Of all cases 6 were men and 2 women with an average age 49 years (range 32-65), HIV negativity documented in five, involvement sites of gastrointestinal tract (5), perianal skin (2) and paravertebral soft tissue (1), and treatments with anti-TNFs (6), 6-mercaptopurine+budesonide (1) and salazosulfapyridine (1). The average intervals from CD and anti-TNFs to PBL were 14.5 years (range 5-30) and 17 months (range 4-36) respectively. Increased PBL risk may be related to the disease itself, anti-TNF/immunomodulator therapies, EBV reactivation, or other host-related factors. Investigations for potential risks of CD therapies can ensure their safe use in susceptible patients.

The Real-World Effectiveness and Safety of Ustekinumab in the Treatment of Crohn's Disease: Results From the SUCCESS Consortium.

We evaluated the real-world effectiveness and safety of ustekinumab (UST) in patients with Crohn's disease (CD). This study used a retrospective, multicenter, multinational consortium of UST-treated CD patients. Data included patient demographics, disease phenotype, disease activity, treatment history, and concomitant medications. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions were assessed using time-to-event analysis, and clinical predictors were assessed by using multivariate Cox proportional hazard analyses. Serious infections and adverse events were defined as those requiring hospitalization or treatment discontinuation. A total of 1,113 patients (51.8% female, 90% prior antitumor necrosis factor exposure) were included, with a median follow-up of 386 days. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions at 12 months were 40%, 32%, 39%, and 30%, respectively. Biologic-naive patients achieved significantly higher rates of clinical and endoscopic remissions at 63% and 55%, respectively. On multivariable analyses, prior antitumor necrosis factor (hazard ratio, 0.72; 95% confidence interval, 0.49-0.99) and vedolizumab exposure (hazard ratio, 0.65; 95% confidence interval, 0.48-0.88) were independently associated with lower likelihoods of achieving endoscopic remission. In patients who experienced loss of remission, 77 of 102 (75%) underwent dose optimization, and 44 of 77 (57%) achieved clinical response. An additional 152 of 681 patients (22.3%) were dose-optimized because of primary nonresponse incomplete response to UST, of whom 40.1% (61 of 152) responded. Serious infections occurred in 3.4% of patients while other noninfectious adverse events (lymphoma [n = 1], arthralgia [n = 6], rash [n = 6], headache [n = 3], hepatitis [n = 3], hair loss [n = 3], neuropathy [n = 1], and vasculitis [n = 1]) occurred in 2.4% of patients. UST represents a safe and effective treatment option for CD, with 40% of patients from a highly refractory cohort achieving clinical remission by 12 months. The greatest treatment effect of UST was seen in biologic-naive patients, and dose escalation may recapture clinical response.

Comparative Effectiveness of Biologics for Endoscopic Healing of the Ileum and Colon in Crohn's Disease.

We compared the efficacy of adalimumab, infliximab, ustekinumab, and vedolizumab on the ability to achieve endoscopic healing (EH) after 1 year of therapy in moderate-severe Crohn's disease (CD). This was a pooled analysis of patient-level data from 299 patients with CD from 4 clinical trials. Proportions of patients treated with each biologic were compared for achieving 1-year complete EH (Simple Endoscopic Score for CD [SES-CD] <3) and ileal and colonic EH separately (SES-CD = 0). Multivariate logistic regression was used to model the relationship between biologics and 1-year outcomes and adjusted for disease duration, concomitant corticosteroid use, and prior antitumor necrosis factor failure. Compared with vedolizumab (4/56 [7.1%]), adalimumab (17/61 [27.9%], adjusted odds ratio [OR]: 5.79, 95% confidence interval [CI]: 1.77-18.95, P = 0.004) and infliximab (39/141 [27.7%], aOR: 4.59, 95% CI: 1.48-14.22, P = 0.008) had superior rates of 1-year EH. No significant difference was observed between vedolizumab and ustekinumab. Similar results were observed among biologic-naive patients. Among patients with baseline ileal SES-CD ≥3, no significant differences were observed between biologics for 1-year ileal EH. However, for large (>0.5 cm) ileal ulcers, infliximab (20/49 [40.8%]) had superior rates of no ileal ulcers compared with vedolizumab (2/23 [8.7%], aOR: 5.39, 95% CI: 1.03-28.05, P = 0.045). No other differences were observed. For colonic disease, compared with ustekinumab (9/31 [29.0%]), adalimumab (30/48 [62.5%], aOR: 3.97, 95% CI: 1.45-10.90, P = 0.007) had superior rates of 1-year EH in the colon, with similar trends observed for infliximab (55/105 [52.4%], aOR: 2.08, 95% CI: 0.82-5.27, P = 0.121). No other differences were observed. In this post hoc analysis, TNF-α antagonists were overall superior to vedolizumab and ustekinumab for achieving 1-year EH in moderate-severe CD patients.

Paediatric Ulcerative Colitis Is a Fibrotic Disease and Is Linked with Chronicity of Inflammation.

Intestinal fibrosis has recently been characterised in adult ulcerative colitis and may affect motility, diarrhoea, and the symptom of urgency. We aimed to charactersze the presence of fibrosis in paediatric patients with ulcerative colitis, and its link to severity and chronicity of mucosal inflammation, as well as clinical factors of severity. We performed a single-centre cross-sectional study in children ages 1-18 years with ulcerative colitis, undergoing colectomy or proctocolectomy. Tissue cross-sections were derived from proximal, mid, and distal colon and rectum, and inflammation and fibrosis were graded based on previously developed scores. Clinical data were collected prospectively. From 62 patients, 205 intestinal sections were evaluated. Median age at diagnosis was 13 years, 100% had extensive colitis, and all resections were done for refractory disease. The presence, chronicity, and degree of inflammation were linked with the presence of fibrosis. Thickness of the muscularis mucosa was also linked with presence and chronicity of inflammation. The overall submucosal fibrosis burden was associated with prior anti-tumour necrosis factor use. Paediatric patients with ulcerative colitis exhibit colorectal submucosal fibrosis and muscularis mucosa thickening, which correlate with the presence, chronicity, and degree of mucosal inflammation. Fibrosis should be recognised as a complication of paediatric ulcerative colitis, and ulcerative colitis should be considered a progressive disease.

Efficacy of Biologic Drugs in Short-Duration Versus Long-Duration Inflammatory Bowel Disease: A Systematic Review and an Individual-Patient Data Meta-Analysis of Randomized Controlled Trials

Starting biologic treatment early in the course of inflammatory bowel disease (IBD) may be associated with higher efficacy, especially in Crohn's disease (CD). This was a systematic review and individual-patient data meta-analysis of all placebo-controlled trials of biologics approved for IBD at study inception (October 2015), using Vivli data-sharing platform. The primary outcome was the proportional biologic/placebo treatment effect on induction of remission in patients with short-duration (≤18 months) vs long-duration disease (>18 months) analyzed separately for CD and ulcerative colitis (UC). We used meta-regression to examine the impact of patients' characteristics on the primary outcome. We included 25 trials, testing infliximab, adalimumab, certolizumab, golimumab, natalizumab, or vedolizumab (6168 patients with CD and 3227 patients with UC). In CD, remission induction rates were higher in pooled placebo and patients in active arms with short-duration disease of ≤18 months (41.4% [244 of 589]) compared with disease duration of >18 months (29.8% [852 of 2857], meta-analytically estimated odds ratio, 1.33; 95% confidence interval, 1.09-1.64). The primary outcome, proportional biologic/placebo treatment effect on induction of remission, was not different in short-duration disease of ≤18 months (n= 589, odds ratio, 1.47; 95% confidence interval, 1.01-2.15) compared with longer disease duration (n= 2857, odds ratio, 1.43; 95% confidence interval, 1.19-1.72). In UC trials, both the proportional biologic/placebo remission-induction effect and the pooled biologic-placebo effect were stable, regardless of disease duration. Primary outcome results remained unchanged when tested using alternative temporal cutoffs and when modeled for individual patient's covariates, including prior anti-tumor necrosis factor exposure. There are higher rates of induction of remission with biologics and with placebo in early CD, resulting in a treatment to placebo effect ratio that is similar across disease durations. No such relationships between disease duration and outcomes was found in UC. PROSPERO registration: CRD42018041961.

Patients With Low Drug Levels or Antibodies to a Prior Anti–Tumor Necrosis Factor Are More Likely to Develop Antibodies to a Subsequent Anti–Tumor Necrosis Factor

Therapeutic drug monitoring (TDM) with measurement of serum drug and antidrug antibodies (ADAb) is used widely to confirm therapeutic exposure, rule out immunogenicity, and optimize treatment of biologics in patients with inflammatory bowel diseases.1 A recent genome-wide association study found the variant HLA-DQA1∗05 to increase the risk of development of antibodies against infliximab (IFX) and adalimumab (ADM) 2-fold, regardless of concomitant immunomodulator use.2,3 However, there is currently limited evidence showing whether patients who develop antibodies to 1 anti-tumor necrosis factor (TNF) are prone to develop antibodies to the subsequent anti-TNF. Our aim was to investigate the risk of subsequent antibody development in cases (with ADAb to prior anti-TNF) versus control subjects (without ADAb to prior anti-TNF) using a large cohort of patients with inflammatory bowel diseases who underwent TDM with a drug-tolerant assay.

Real-world clinical and endoscopic outcomes after one year tofacitinib treatment in ulcerative colitis.

Tofacitinib, an oral Janus kinase inhibitor, is approved for the treatment of moderate to severe ulcerative colitis (UC). We evaluated clinical and endoscopic efficacy, safety and drug survival of tofacitinib up to one year in a real-world cohort. In this retrospective cohort study, 36 UC patients were included who received tofacitinib. The primary outcome was combined with steroid-free clinical remission [Simple Clinical Colitis Activity Index (SCCAI) ≤2] and endoscopic improvement (Mayo score ≤1) at 52 weeks. Secondary outcomes included clinical (SCCAI drop ≥3) and endoscopic response (Mayo score drop ≥1), biochemical remission [fecal calprotectin (FC) ≤150 mg/kg and C-reactive protein ≤5 mg/L), safety and drug survival. Median disease duration was 7 (3-14) years and 89 and 42% of patients failed prior anti-tumor necrosis factor (anti-TNF) and vedolizumab treatment, respectively. Combined corticosteroid-free clinical remission and endoscopic improvement were observed in 8/36 patients (22%), 6/35 (17%) and 12/31 (39%), at 16, 36 and 52 weeks, respectively. Corresponding combined clinical and endoscopic response rates were 15/36 (42%), 12/35 (34%), 15/31 (48%) and biochemical remission rates were 11/33 (33%), 10/32 (31%) and 10/29 (34%). Nine infections (two herpes zoster) led to dose reduction or (temporary) drug withdrawal. Permanent withdrawal occurred in 14/36 patients (33%) after a median duration of 9 (5-30) weeks. Drug survival at 1 year was 60%. Patients that failed anti-TNF were less likely to discontinue tofacitinib treatment early compared to patients without prior anti-TNF use (hazard ratio 0.20, 95% confidence interval 0.06-0.65). In a refractory UC population, combined steroid-free clinical remission and endoscopic improvement were found in 39% of patients at 1 year.

Vedolizumab Dose Escalation Improves Therapeutic Response in a Subset of Patients with Ulcerative Colitis.

The Gemini trial failed to detect a significant difference in response rate for patients with ulcerative colitis (UC) randomized to standard (every 8week) vedolizumab dosing vs escalated (every 4week) dosing. Subsequent real-world data imply the Gemini trial design may have obscured a benefit of escalated dosing. We investigated outcomes after vedolizumab dose escalation for patients with UC. We also explored potential clinical predictors of dose escalation requirement. In this retrospective study, we included patients with UC who received vedolizumab between 1/2017-1/2019. We compared rates of clinical response (decrease in partial Mayo score by ≥ 2) and remission (partial Mayo < 2) for standard vs escalated dosing. Among the 90 patients reviewed, 52 achieved and maintained remission on standard dosing. The average time to remission with standard dosing was 33.3 ± 6.6weeks. After an average of 56.3 ± 7.4weeks standard dosing, 24 patients (22 "partial responders" and 2 "non-responders") were dose-escalated. Of the 22 "partial responders" dose-escalated, 10 (45%) achieved remission, 10 (45%) achieved further improvement. Neither "non-responder" demonstrated further clinical benefit. Prior anti-tumor necrosis factor (anti-TNF) biologic exposure predicted dose escalation requirement (p = 0.008). Patients requiring dose escalation had more severe disease at baseline as measured by both full Mayo (p = 0.009) and partial Mayo scores (p = 0.01). We show dose escalation benefited patients with UC who exhibit a "partial response" to standard dosing. Early vedolizumab dose escalation should be considered in both patients with severe disease and those with prior anti-TNF experience.

Irish data on the safety and efficacy of vedolizumab in the treatment of inflammatory bowel disease

Introduction: Vedolizumab (VDZ) is a monoclonal antibody designed to inhibit α4β7 integrin and result in gut-selective anti-inflammatory activity. Real-world data are important in providing information to clinicians on the effectiveness and safety of this agent.Methods: A retrospective, multi-centre study was conducted across 9 Irish academic centres. Adult (≥18 years) patients receiving VDZ for active IBD (ulcerative colitis [UC] or Crohn’s disease [CD]) with at least 6 months follow-up were included in the study cohort. Primary study endpoints were defined as 3-month clinical response and 6-month corticosteroid-free remission. Secondary endpoints included 3-month corticosteroid-free clinical remission, 6-month clinical response, change from baseline in CRP, albumin and faecal calprotectin, and adverse events.Results: One hundred and twenty-nine patients were included in total (64 UC, 65 CD). In the UC cohort, baseline median PMCS was 7 [0 – 9] and 78.1% had prior anti-tumour necrosis factor alpha (anti-TNFα) exposure. Three-month and 6-month endpoints were achieved in 40% and 31%, respectively. Milder disease, CRP, albumin and prior anti-TNFa were associated with endpoints. One minor adverse event was documented. In the CD cohort, baseline HBI was 12 [0 – 29] and 94% previously received anti-TNFa therapy. Three-month and 6-month primary endpoints were achieved in 52% and 48%, respectively. Six-month remission was positively associated with Montreal B1 disease and negatively associated with perianal disease and baseline faecal calprotectin. Adverse events occurred in 11% of cases.Conclusion: These real-world data support the effectiveness and safety of vedolizumab in the treatment of IBD and give valuable insight into predictors of treatment outcomes.SUMMARYThis study reviews the safety and efficacy of treatment with vedolizumab for patients with inflammatory bowel disease across 9 Irish hospitals. It generates valuable and timely real-world data on treatment outcomes to add to the existing evidence base. Our population represents a refractory cohort with most patients previously exposed to at least one anti-TNFa agent and expressing an inflammatory phenotype. Results are reassuringly similar to larger international studies with additional insights into potential predictors of treatment response. This study further supports the safety and efficacy of vedolizumab in the treatment of inflammatory bowel disease. Key SummaryVedolizumab has growing real world data on its safety and efficacy in the treatment of IBD. Data on predictors of response are lacking. Studies such as VARSITY require new real-world data to help identify the place VDZ will occupy in the treatment algorithm for IBDThis study provides national Irish data on the safety and efficacy of VDZ in the treatment of IBD. It gives insight into various predictors of response for both UC and CD. It strengthens the available body of evidence on the use of VDZ and helps us determine its position on the treatment algorithm.

Secukinumab Efficacy in Psoriatic Arthritis: Machine Learning and Meta-analysis of Four Phase 3 Trials.

Using a machine learning approach, the study investigated if specific baseline characteristics could predict which psoriatic arthritis (PsA) patients may gain additional benefit from a starting dose of secukinumab 300 mg over 150 mg. We also report results from individual patient efficacy meta-analysis (IPEM) in 2049 PsA patients from the FUTURE 2 to 5 studies to evaluate the efficacy of secukinumab 300 mg, 150 mg with and without loading regimen versus placebo at week 16 on achievement of several clinically relevant difficult-to-achieve (higher hurdle) endpoints. Machine learning employed Bayesian elastic net to analyze baseline data of 2148 PsA patients investigating 275 predictors. For IPEM, results were presented as difference in response rates versus placebo at week 16. Machine learning showed secukinumab 300 mg has additional benefits in patients who are anti-tumor necrosis factor-naive, treated with 1 prior anti-tumor necrosis factor agent, not receiving methotrexate, with enthesitis at baseline, and with shorter PsA disease duration. For IPEM, at week 16, all secukinumab doses had greater treatment effect (%) versus placebo for higher hurdle endpoints in the overall population and in all subgroups; 300-mg dose had greater treatment effect than 150 mg for all endpoints in overall population and most subgroups. Machine learning identified predictors for additional benefit of secukinumab 300 mg compared with 150 mg dose. Individual patient efficacy meta-analysis showed that secukinumab 300 mg provided greater improvements compared with 150 mg in higher hurdle efficacy endpoints in patients with active PsA in the overall population and most subgroups with various levels of baseline disease activity and psoriasis.

P476 Efficacy and safety of 2 vedolizumab IV regimens in patients with perianal fistulising Crohn’s disease: results of the ENTERPRISE study

Abstract Background Perianal fistulae occurring with Crohn’s disease (CD) are a challenge to treat. Vedolizumab (VDZ) is a gut-selective, monoclonal α 4β7 integrin antibody approved to treat patients (patients) with moderately to severely active CD. Here we report results from ENTERPRISE (NCT02630966; EudraCT 2015-000852-12), a randomised, double-blind, phase 4 trial to evaluate 2 VDZ IV dosing regimens in patients with fistulising CD. Methods Patients with moderately to severely active CD and 1–3 draining perianal fistulae received either VDZ 300 mg IV at Weeks (Week) 0, 2, 6, 14, and 22 (VDZ), or the same regimen plus an additional VDZ dose at Wk10 (VDZ+Wk10). The primary endpoint was the proportion of patients with a ≥50% reduction from baseline (BL) in the number of draining fistulae (absence of draining despite gentle finger compression) at Wk30. Secondary endpoints were the proportion of patients with a ≥50% reduction from BL in the number of draining fistulae at Wk22 and Wk30, and the proportion of patients with 100% fistulae closure at Wk30. Patients with missing data at study visits were counted as non-responders. Perianal disease activity index (PDAI), perianal pain score, Van Assche score, gadolinium contrast enhancement by pelvic MRI, and safety were assessed. Study enrolment closed early due to slow recruitment; thus, all analyses are descriptive. Results Of the 32 patients with post-BL assessment of fistulae healing (full analysis set, FAS), 28 had ≥1 draining fistula at BL (modified FAS). Median CD duration was 8.5 years (VDZ [n = 14]: 11.2 years; VDZ+ Week 10 [n = 14]: 6.1 years). In each arm, 11 patients (78.6%) had prior anti-tumour necrosis factor therapy at BL; concomitant corticosteroid use was 21.4% (VDZ) and 14.3% (VDZ+ Week 10), and concomitant immunosuppressant use was 28.6% (VDZ) and 21.4% (VDZ+ Week 10). At Wk30, 53.6% of all patients achieved ≥50% decrease in the number of draining fistulae (VDZ: 64.3%; VDZ+ Week 10: 42.9%; Figure 1). The proportion of patients with fistulae response increased rapidly and remained high through Week 30 (Figure 2); 46.4% of patients (VDZ: 57.1%; VDZ+Week 10: 35.7%) achieved ≥50% decrease in the number of draining fistulae at both Weeks 22 and 30. Closure of all fistulae draining at BL was observed at Week 30 in 42.9% of patients (VDZ: 50.0%; VDZ+ Week 10: 35.7%). In the FAS, mean (SD) PDAI scores changed from BL to Weeks 30–4.1 (3.3) and perianal pain scores changed –2.2 (2.7) (table). At Wk30, mean (SD) Van Assche scores and contrast enhancement scores changed –1.1 (3.1) and –9.5 (69.4) from screening, respectively. No new safety signals were observed. Conclusion Over half of CD patients treated with VDZ had reductions of ≥50% in the number of draining perianal fistulae. Clinically relevant reductions in draining fistulae were seen as early as Wk2 and maintained through Wk30.

P055 Vedolizumab Treatment Persistence up to 5 Years: Post hoc Analysis in Vedolizumab-Naïve Patients From the GEMINI Long-Term Safety Study

BACKGROUND: Vedolizumab (VDZ) is a gut-selective, humanized monoclonal antibody approved for moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD). Although VDZ efficacy and safety are well established, there are limited publications on longer-term (&gt;3 years) treatment persistence. This study evaluated VDZ treatment persistence for up to 5 years in a GEMINI long-term safety (LTS) VDZ de novo cohort. METHODS: All patients in GEMINI LTS (NCT00790933) were treated with VDZ every 4 weeks. A post hoc analysis of data from patients not previously treated with VDZ before Week 0 of GEMINI LTS (de novo cohort) was conducted, with VDZ treatment persistence assessed using Kaplan-Meier survival analysis. Treatment discontinuations due to adverse events (AEs) or lack of efficacy were considered for the analysis; discontinuations due to protocol deviation, patient withdrawal, or loss to follow-up were censored. Treatment persistence analyses were further stratified by Week 12 treatment response (primary response/nonresponder), prior anti-tumor necrosis factor (anti-TNF) failure (Yes/No), type of anti-TNF failure (primary/secondary nonresponse), and concomitant therapy (corticosteroids, 5-aminosalicylates, immunomodulators, or their combinations) at baseline (Yes/No); a log-rank test assessed statistical differences between subgroups. RESULTS: The GEMINI LTS de novo cohort included 421 patients (UC 190; CD 231) with a mean disease duration of 8.7 (UC) and 10.6 (CD) years, 6.0 mean partial Mayo score (UC) and 11.1 mean Harvey-Bradshaw Index; 61% of patients with UC and 74% with CD had prior anti-TNF failure. Up to 5 years follow-up, 276 patients (66%) total discontinued VDZ: 16% with UC and 17% with CD due to AEs, and 24% with UC and 33% with CD due to lack of efficacy. Survival probabilities for VDZ treatment persistence at 54 months were 53% for UC and 41% for CD. These VDZ 54-month survival probabilities were higher in patients with VDZ treatment response at Week 12 vs without (UC, 60% vs 26%, respectively, P &lt; 0.0001; CD, 42% vs 35%, respectively, P = 0.001) and in patients without prior anti-TNF failure vs with (UC, 63% vs 47%, respectively, P = 0.046; CD, 47% vs 42%, respectively, P = 0.016). Among patients with baseline anti-TNF failure, survival probabilities for VDZ treatment persistence at 54 months were higher in UC patients who were secondary nonresponders vs those who were primary nonresponders (65% vs 15%, respectively, P &lt; 0.0001); this difference was not observed in CD patients (44% vs 40%, respectively, P = 0.573). There were no differences in survival probabilities of continuing VDZ at 54 months among patients with UC or CD who initiated VDZ therapy with vs without any concomitant medications. CONCLUSION(S): More than half of patients with UC and 4 of every 10 patients with CD persisted on VDZ for 54 months. Treatment persistence rates in UC and CD cohorts were significantly higher in Week 12 responders and patients without prior anti-TNF failure, whereas there were no differences in persistence rates with baseline use of concomitant medications. Vedolizumab discontinuation rates due to AEs were low. These findings from GEMINI LTS support the longer-term effectiveness and safety of VDZ in patients with moderately to severely active UC and CD.

256 Secukinumab provides sustained improvements in the signs and symptoms of active psoriatic arthritis: 4-year results from the Phase 3 FUTURE 2 study

Background: Secukinumab (SEC), a fully human monoclonal antibody that selectively neutralises interleukin-17A, provided significant and sustained improvement in the signs and symptoms of active psoriatic arthritis (PsA) over 2 years in the FUTURE 2 study (NCT01752634). Objectives: To report 4-year efficacy and safety results from the FUTURE 2 study. 3-year data is presented here, with 4-year data to follow. Methods: Overall, 397 patients with active PsA were randomised to receive subcutaneous SEC (300, 150 or 75 mg) or placebo (PBO) at baseline (BL), Weeks 1, 2, 3 and 4, and every 4 weeks thereafter. Assessments at week 156 are from patients originally randomised to SEC and included ACR20/50, PASI 75, HAQ-DI, and resolution of dactylitis and enthesitis. Analyses by prior anti-tumour necrosis factor (TNF) use (naive/inadequate response [IR]) and with/without concomitant methotrexate (MTX) were assessed. Data are reported as observed for SEC 300 and 150 mg (approved doses). Safety analyses included all patients who received ≥1 dose of SEC. Results: In total, 73/100 (73.0%) and 72/100 (72.0%) patients in the SEC 300 and 150 mg groups, respectively, completed 156 weeks of treatment. Sustained clinical improvements were observed in those continuing with SEC across all endpoints through week 156 (Table 1). ACR20 response rates at week 156 in anti-TNF-naive patients were 85.2% and 76.5% with SEC 300 and 150 mg respectively; corresponding rates in anti-TNF-IR patients were 55.6% and 54.5%, respectively. ACR20 response rates in patients receiving concomitant MTX were 73.0% and 77.1% with SEC 300 and 150 mg, respectively; rates in patients without concomitant MTX use were 77.3% and 63.2%, respectively. Over the study (mean SEC exposure of 991.3 days) the type, incidence and severity of adverse events (AEs) were consistent with that reported previously. Exposure adjusted incidence rates with SEC for selected AEs of interest were: serious infections (1.8), Candida infections (1.8), inflammatory bowel disease (0.1), major adverse cardiovascular event (0.2) and malignant/unspecified tumours (1.2). Conclusion: SEC 300 and 150 mg provided sustained improvements in the signs and symptoms of active PsA through 3 years. Secukinumab was well tolerated, with a safety profile consistent with that reported previously.