Moderate-severe Crohn's Disease Research Articles

Tissue markers may predict treatment response to antitumor necrosis factor-α agents in children with Crohn's disease.

Patients with moderate-severe Crohn's disease (CD) who are treated with antitumor necrosis factor alpha (TNF-α) agents may be subjected to primary nonresponse or partial response. We aimed to identify tissue markers that may predict response to these agents. Pediatric patients (6-18 years) with either ileal or ileo-colonic CD who were treated with anti-TNF-α were stratified into three different groups based on their overall response to therapy at the end of induction including clinical and laboratory parameters (group 1-full responders [FR], group 2-partial responders [PR], group 3-nonresponders [NR]). Seven tissue markers (fibronectin, interleukin [IL]-23R, IL-23, TNF-α, collagen-III, IL-13R, and hypoxia-inducible factors [HIF]-1α) were evaluated. Immunofluorescence (IF) analyses were performed on biopsies from the terminal ileum, which were retrieved up to 6 months before treatment initiation. Twenty-six CD patients (16 [61.5%] males; age 13.9 ± 2.9 years), including 8 (30.8%) with ileal disease and 18 (69.2%) with ileo-colonic disease, were enrolled. Terminal ileum biopsies from nine patients from group 1, nine from group 2, and eight from group 3 were evaluated. Three antibodies were found to be significantly different between NR and FR groups; Collagen III and fibronectin stains were significantly more prominent in NR patients, while TNF-α stain was significantly more pronounced in FR, p < 0.05 for each. PR could not have been predicted with neither of markers. Decreased tissue IF intensity of fibronectin and collagen III and increased intensity of TNF-α may predict response to anti-TNF-α treatment.

P845 Vedolizumab induces endoscopic healing uniformly irrespective of disease location: post-hoc analysis of the LOVE-CD trial

Abstract Background Vedolizumab (VDZ) is a gut-selective anti–α4β7-integrin monoclonal antibody approved for the treatment of Crohn's disease (CD). We performed a post-hoc analysis of the LOVE-CD trial to evaluate the effect of disease location on endoscopic healing. Methods LOVE-CD is a prospective multicentre study of VDZ therapy in adult patients with moderate-severe CD (Crohn's Disease Activity Index (CDAI) &amp;gt;220 and presence of ulcers at endoscopy). Patients received VDZ 300 mg infusions at weeks 0-2-6 followed by 8 weekly infusions up to week 52. An additional infusion at week 10 was given to patients without clinical response (CDAI decrease &amp;lt;70 points). Corticosteroids had to be withdrawn by week 26. Ileocolonoscopies were performed at weeks 0, 26, and 52, recorded, and centrally scored by 2 independent readers using the Simple Endoscopic Score for Crohn's Disease (SES-CD). The primary endpoint for this analysis was the proportion of patients, stratified by disease location (according to Montreal classification), with ulcer-free endoscopy (absence of any ulceration; SES-CD ulcer score 0) at week 52. Key secondary endpoints at week 52 were the proportion of patients, stratified by disease location, with endoscopic remission (SES-CD &amp;lt;4 for L2/L3 CD or &amp;lt;2 for L1 CD, and no subscores &amp;gt;1), with combined steroid-free clinical and endoscopic remission (CDAI&amp;lt;150 and endoscopic remission), the segmental healing rates, and ulcer healing rates stratified by disease duration. Results 186 patients were included in this intention to treat (ITT) analysis: 42 (22.6%) with L1, 52 (28.0%) with L2, and 92 (49.5%) with L3 disease. Baseline characteristics are shown in table 1. At week 52, the primary endpoint (absence of all ulcerations) was attained in 15/42 patients with L1 (35.7%), 20/52 with L2 (38.5%) and 25/92 with L3 CD (27.2%) (ITT, NRI (p=0.327)). Endoscopic remission was observed in 12/42 patients with L1 (28.6%), 20/52 with L2 (38.5%), and 29/92 with L3 disease (31.5%) (ITT, NRI (p=0.558)). The combined endpoint of clinical-endoscopic remission was reached in 9/42 L1 (21.4%), 16/52 L2 (30.8%), and 23/92 L3 patients (25.0%) (ITT, NRI (p=0.571)). Resolution of ileal ulcers was achieved in 15/40 L1 patients (37.5%) and 37/90 L3 patients (41.1%) (ITT, NRI (p=0.698)), resolution of colonic ulcers in 21/52 L2 (40.4%) and 45/90 L3 patients (50.0%) (ITT, NRI (p=0.268). Patients with early CD (disease duration &amp;lt;2 years) had higher ulcer healing rates than patients with late CD (47.5% versus 24.8%) (ITT, NRI (p=0.002)). Conclusion This post-hoc analysis of LOVE-CD shows that disease location does not affect endoscopic healing rates with VDZ in CD. However, early CD is associated with significantly higher endoscopic remission rates compared to late CD.

Delayed Ustekinumab and Adalimumab Responders Have Similar Outcomes as Early Responders in Biologic-Naïve Crohn's Disease.

Differences in one-year outcomes among early and delayed responders have been demonstrated with some therapies in ulcerative colitis. However, it is unclear whether similar differences exist in patients with Crohn's disease (CD) treated with biologic therapies. This was a post-hoc analysis of patient-level data from the SEAVUE clinical trial program. Ustekinumab and adalimumab-treated patients with clinical response at week 8, defined as a reduction in CDAI score of at least 100 points from baseline or Crohn's Disease Activity Index (CDAI) score < 150, were deemed early responders and their outcomes were compared with delayed responders (week 8 non-responders who subsequently responded at week 16) and non-responders (no response at week 8 or 16). The primary outcome assessed was clinical remission (CR) at week 56, defined as CDAI < 150. There were 373 participants (187 treated with ustekinumab and 186 treated with adalimumab) included in this analysis. The overall rate of delayed clinical response was low in SEAVUE (13.1%). No differences were observed for week 56 CR among early vs. delayed responders to ustekinumab or adalimumab, nor were there significant differences for secondary outcomes assessed. Delayed responders to ustekinumab and adalimumab had a significant decline in CRP by week 8 as compared to non-responders. Among moderate-severe CD patients, early and delayed responders to adalimumab and ustekinumab have similar one-year clinical outcomes. Biomarker decline can be observed through the initial 8 weeks of therapy in patients who will eventually be delayed responders which may help differentiate from non-responders.

Two-year real-world outcome data from a single tertiary centre shows reduced ustekinumab persistence in a non-bio-naïve Crohn's disease cohort with penetrating disease, -ostomies and sarcopenia.

Ustekinumab was approved in 2016 for the treatment of moderate-severe Crohn's disease (CD). Clinical trials and real-world studies have suggested ustekinumab to be a safe and effective treatment; however, studies to date infrequently use imaging techniques to predict response to biologics in CD. We assessed the 2-year real-world effectiveness and safety of ustekinumab in a tertiary CD cohort with the use of novel imaging techniques. Retrospective cohort study. Retrospective data were collected between 2016 and 2021. Study end points included ustekinumab persistence, biological and/or clinical response and remission at 12, 18 and 24 months. Statistical analysis included demographic and inferential analyses. In all, 131 CD patients [57.3% female, median age of 26.0 (21.0-37.0)] were included. Patients were non-bio naïve, and the majority received ustekinumab as third- or fourth-line treatment. At 24 months, 61.0% (80/131) persisted with ustekinumab [52.7% (69/131) steroid free]. Clinical response was reported in 55.2% (37/67), clinical remission in 85.7% (57/67), biological response in 46.8% (22/47) and biological remission in 31.9% (15/47) of patients at 24 months. The low outcome numbers were attributable to missing data. Improvements in routine disease markers, including C-reactive protein and Harvey-Bradshaw Index, were also reflected in magnetic resonance imaging-derived disease scores. The presence of penetrating CD, an -ostomy and sarcopenia were all predictors of poorer ustekinumab outcomes (p < 0.05). Ustekinumab is effective in non-bio-naïve CD patients with non-stricturing, non-penetrating disease with an unremarkable safety profile but may be less effective in those with penetrating disease, -ostomies and sarcopenia.

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.

Does Size Really Matter?

Ileocolonoscopy remains the mainstay of objective disease assessment in Crohn's Disease, and various validated indices are used to grade severity of the disease. The most commonly used indices are the Simple Endoscopic Score for Crohn's Disease (including the size of ulcers) and the Crohn's Disease Endoscopic Index of Severity (including the depth of ulcers). These measurements are highly subjective, especially the depth of an ulcer, and are based solely on the discretion of the endoscopist coupled with the imaging capabilities of the colonoscope and adequacy of the bowel prep. Narula et al. undertook a post hoc analysis of baseline predictors of endoscopic remission (ER) at week 26 in a subset (172 of 508) of moderate-severe Crohn's disease patients participating in the SONIC trial. The authors found no significant differences in the odds of achieving ER when comparing overall or segmental severe inflammation (high Simple Endoscopic Score for Crohn's Disease [>16 overall or >3 per segment] or Crohn's Disease Endoscopic Index of Severity [>12 overall or >3 per segment] scores) with moderate inflammation. The number of affected segments involved also did not impact the likelihood of achieving week 26 ER. The authors then found a potentially synergistic effect with large and deep ulcers in the ileum and rectum. The optimal time to assess whether ulcers ultimately heal or not is unknown, but waiting longer than 26 weeks may negate any lead time bias regarding ulcer size. Therefore, similar to many areas of life, it is likely that size ultimately does not matter, but instead location, location, and location.

Incidence and Outcomes of Home Parenteral Nutrition in Patients With Crohn Disease in Olmsted County, Minnesota.

BackgroundWe sought to estimate the incidence of home parenteral nutrition (HPN) use in a population-based cohort of patients with Crohn disease (CD), and to assess clinical outcomes and complications associated with HPN.MethodsWe used the Rochester Epidemiology Project (REP) to identify residents of Olmsted County, who were diagnosed with CD between 1970 and 2011, and required HPN.ResultsFourteen out of 429 patients (3.3%) with CD received HPN (86% female). Eleven patients (79%) had moderate–severe CD and 12 patients (86%) had fistulizing disease. Thirteen patients (93%) underwent surgery, primarily due to obstruction. Among CD incidence cases, the cumulative incidence of HPN from the date of CD diagnosis was 0% at 1 year, 0.5% at 5 years, 0.8% at 10 years, and 2.4% at 20 years. Indications for HPN included short bowel syndrome in 64%, malnutrition in 29%, and bowel rest in 21%. The median duration of HPN was 2.5 years. There was an average weight gain of 1.2 kg at 6 months, an average weight loss of 1.4 kg at 1 year, and a further weight loss of 2.2 kg at 2 years from the start of HPN. Patients were hospitalized a mean of 5 times after the start of HPN, mainly due to catheter-related bloodstream infections and thrombosis.ConclusionsLess than 4% of patients with CD need HPN. Most have moderate to severe disease with short bowel syndrome or malnutrition. Possible reasons for the patients’ weight loss could be noncompliance, and increased metabolic needs because of active disease.

Enfermedad de Crohn

Crohn's disease (CD) is a chronic inflammatory bowel disease (CIBD). Just like ulcerative colitis (UC), etiology of CD likely involves immunological factors acting on any section of the digestive tract, from the mouth to the anus (most often the distal ileum). The incidence and prevalence of CD are rising. Anus and adjacent structures are involved in perianal Crohn's disease. Diagnosis is based on clinical and imaging data, mainly endoscopy (colonoscopy with ileoscopy) and magnetic resonance enterography (or bowel ultrasound carried out by experts), and on anatomopathological findings. Topical corticosteroids (budesonide) are useful for mild-moderate ileal or ileocecal CD (they are delivered in the distal small intestine). In moderate-severe CD systemic corticosteroids are recommended. Immunomodulatory drugs (azathioprine and 6-mercaptopurine and cyclosporine) and biological drugs, such as anti-TNF (infliximab and adalimumab) are used for refractory CD. Recently, new drugs have been included: vedolizumab (anti-integrin molecule) and ustekinumab (interleukin-12 and interleukin-23 inhibitor).

770 Relationship Between Protocol Specified Corticosteroid Tapering Regimens and Achieving Outcome Measures in Patients With Moderate-Severe Ulcerative Colitis and Crohn's Disease

INTRODUCTION: Corticosteroid-free clinical remission is an important clinical outcome, yet is inconsistently defined and reported in clinical trials. We summarized the protocol specified corticosteroid tapering regimens in clinical trials of moderate-severe ulcerative colitis (UC) and Crohn's disease (CD), and calculated differences in rates of clinical remission versus corticosteroid-free clinical remission (CSF-CR). METHODS: Through a systematic literature review through February 28, 2019, we identified 16 randomized controlled trials (RCTs) of biologics or small molecules in patients with moderate-severe UC or CD that reported CSF-CR as an outcome. We estimated relative risk (RR) [and 95% confidence interval (CI)] of achieving CSF-CR vs. overall clinical remission in patients treated with active intervention or placebo, through random effects meta-analysis. RESULTS: Across trials of UC (11 trials) and CD (5 trials), median 53% (range, 28-81%) and 49% (range, 42-56%) participants were on corticosteroids at time of trial entry, respectively. Participants were allowed to enter trials at median corticosteroid dose 35 mg/d (range, 20-40 mg/d). Doses were kept stable for median 8 weeks (range, 5-10 weeks) during induction therapy, after which a mandatory and structured tapered was implemented, albeit with investigators discretion depending on clinical status. For maintenance trials, pooled rates of CSF-CR in patients with UC (n = 11) treated with placebo was 9.7% (95% CI, 6.8-13.6% vs. overall clinical remission: 14.2%; 95% CI, 10.6-18.7) and with CD (n = 5), 19.1% (95% CI, 11.3-30.2 vs. overall clinical remission: 25.7%; 95% CI, 16.4-37.7). In UC trials, the rate of CSF-CR was 24% lower than the rate of overall clinical remission (RR, 0.76; 95% CI, 0.67-0.86; placebo: RR, 0.74; 95% CI, 0.56-0.97). In patients with CD, rate of CSF-CR was 18% lower than rate of overall clinical remission (RR, 0.82; 95% CI, 0.72-0.94; placebo: RR, 0.75; 95% CI, 0.57-0.98). CONCLUSION: This is the first systematic review and meta-analysis to study corticosteroids handling across clinical trials. Protocol specified corticosteroid tapering regimens varies across trials with considerable investigator discretion. Rates of CSF-CR is 20-25% lower than overall clinical remission. These findings will help to inform design and interpretation of future clinical trials and highlight the need for standardization.

Cost-Effectiveness Comparison of Ustekinumab, Infliximab, or Adalimumab for the Treatment of Moderate-Severe Crohn's Disease in Biologic-Naïve Patients.

Ustekinumab was recently approved by the United States U.S. Food and Drug Administration for the treatment of Crohn's disease. In this analysis, we aimed to compare the cost-effectiveness of ustekinumab, infliximab, or adalimumab for the treatment of moderate-severe Crohn's disease in patients who failed conventional therapy (i.e., corticosteroids and immunomodulators) but were naïve to tumor necrosis factor antagonists (i.e., biologic drugs). Cost-effectiveness analysis using a hybrid model structure (decision tree and Markov model). A decision tree simulated biologic induction, and a Markov model simulated biologic and conventional therapy maintenance. Cycle length was 2 weeks with a discounted 5-year time horizon and a limited U.S. societal perspective in the base case; results from a payer perspective are also reported. Transition probabilities, direct costs, indirect costs, and utilities were obtained from the literature. To measure relative treatment value (i.e., order of treatment cost-effectiveness), net monetary benefits were reported for a $150,000 willingness-to-pay threshold per quality-adjusted life-year in the base case. Infliximab dominated both adalimumab and ustekinumab, with a net monetary benefit (NMB) of $9943 and $29,798, respectively, in the base case. Adalimumab dominated ustekinumab, with an NMB of $19,855. All biologics yielded similar quality-adjusted life-years (~3.5), whereas costs varied substantially ($50,510, $54,985, and $72,921 for infliximab, adalimumab, and ustekinumab, respectively). The payer perspective, alternate time horizons, and scenario analyses consistently showed infliximab dominance. One-way, threshold, and probabilistic sensitivity analyses confirmed the robustness of these results with respect to all parameters. Although biosimilars were not explicitly modeled as comparators, one-way sensitivity analysis showed that drug acquisition costs could alter relative treatment value but would have to be varied by at least 50%. For moderate-severe Crohn's disease, infliximab yields significantly more NMBs compared with both adalimumab and ustekinumab. Additional clinical (e.g., empiric dosing, biologic cycling) and quality-of-life (e.g., lost productivity, disutility of home injections) research is needed to allow for model frameworks and parameters that more accurately reflect the nuances of Crohn's disease treatment.

Systematic review and network meta-analysis: first- and second-line biologic therapies for moderate-severe Crohn's disease.

There are limited data to inform positioning of agents for treating moderate-severe Crohn's disease (CD). We assessed comparative efficacy and safety of first-line (biologic-naïve) and second-line (prior exposure to anti-tumour necrosis factor [TNF]-α) agents) biologic therapy for moderate-severe CD, through a systematic review and network meta-analysis, and appraised quality of evidence (QoE) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We identified randomised controlled trials (RCTs) in adults with moderate-severe CD treated with approved anti-TNF agents, anti-integrin agents and anti-IL12/23 agents, first-line or second-line, and compared with placebo or another active agent. Efficacy outcomes were induction and maintenance of clinical remission; safety outcomes were serious adverse events and infections. Network meta-analyses were performed, and ranking was assessed using surface under the cumulative ranking (SUCRA) probabilities. No head-to-head trials were identified. In biologic-naïve patients, infliximab (SUCRA,0.93) and adalimumab (SUCRA,0.75) were ranked highest for induction of clinical remission (moderate QoE). In patients with prior anti-TNF exposure, adalimumab (SUCRA, 0.91; low QoE, in patients with prior response or intolerance to anti-TNF agents) and ustekinumab (SUCRA, 0.71) were ranked highest for induction of clinical remission. In patients with response to induction therapy, adalimumab (SUCRA, 0.97) and infliximab (SUCRA, 0.68) were ranked highest for maintenance of remission. Ustekinumab had lowest risk of serious adverse events (SUCRA, 0.72) and infection (SUCRA, 0.71; along with infliximab, SUCRA, 0.83) in maintenance trials. Indirect comparisons suggest that infliximab or adalimumab may be preferred first-line agents, and ustekinumab a preferred second-line agent, for induction of remission in patients with moderate-severe CD. Head-to-head trials are warranted.

Sa1771 - Double-Blind, Randomized, Placebo-Controlled, Crossover Trial to Evaluate Induction of Clinical Response in Patients with Moderate-Severe Crohn's Disease Treated with Rifaximin

Sa1771 - Double-Blind, Randomized, Placebo-Controlled, Crossover Trial to Evaluate Induction of Clinical Response in Patients with Moderate-Severe Crohn's Disease Treated with Rifaximin

PGI17 - The Cost-Effectiveness of Ustekinumab Compared to Infliximab And Adalimumab in Adult Patients with Moderate-Severe Crohn's Disease (Tnf Naïve Population)

Ustekinumab was recently approved by the FDA for the treatment of Crohn’s disease (CD). This model evaluates the cost-effectiveness of ustekinumab compared with infliximab and adalimumab for the treatment of moderate-severe CD in patients that have failed conventional therapy but are naïve to tumor necrosis factor antagonists. A decision tree simulated biologic induction and a Markov model simulated biologic and conventional therapy (CT) maintenance. Cycle length was 2 weeks with a discounted 5-year time horizon and a US societal perspective in the base case; the payer perspective is also reported. Transition probabilities, direct costs, indirect costs, and utilities were obtained or derived from literature. Incremental net monetary benefits (NMBs) are reported for a $150,000 willingness to pay (WTP) threshold per quality-adjusted life-year (QALY) in the base case. Infliximab dominates both adalimumab and ustekinumab with incremental NMBs of $9,943 and $29,798 respectively in the base case. All biologics yield similar QALYs while costs vary significantly. The payer perspective, alternate time horizons, and scenario analyses consistently show infliximab dominance. One-way, threshold, and probabilistic sensitivity analyses confirm the robustness of results with respect to all parameters. Threshold sensitivity analysis indicates that lower biologic induction efficacy yields higher treatment value. This result is explained by CT maintenance treatment value: patients who fail to respond during biologic induction avoid high biologic maintenance costs and still experience significant QALY gains from CT maintenance. Threshold sensitivity analysis also indicates that adalimumab has highest relative treatment value when average hourly compensation is more than $621 per hour. For moderate-severe CD, infliximab yields slightly more QALYs at a significantly lower cost compared to both adalimumab and ustekinumab. Drug acquisition costs are the only parameters that could alter relative treatment value but would have to be varied by at least 50% to do so.

Intravenous, Weight-Based Tumor Necrosis Factor (TNF) Antagonists Are Effective in the Treatment of Patients With Moderate to Severe Crohnʼs Disease With Prior Primary Non-response to Subcutaneous, Fixed-Dose TNF

Introduction: Tumor necrosis factor (TNF) antagonists are effective treatments for moderate-severe Crohn's disease (CD). Up to one third of patients have primary-nonresponse to TNF therapy, which has been reported to predict low rates of response to subsequent TNF agents. No study to date has specifically assessed the effectiveness of intravenously (IV) administered TNF therapy following primary-nonresponse to subcutaneously (SC) administered TNF. We hypothesize that IV administration and weight-based dosing of TNF therapy offers advantages over SC fixed dose TNFs and may be effective despite primary-nonresponse to previous SC TNF. This retrospective case series assesses clinical and endoscopic improvement to IV TNF therapy following primary nonresponse to prior SC TNF therapy. Methods: From administrative data at a single site, we identified 19 patients with primary nonresponse to one or more SC TNF therapies (adalimumab (ADA), certolizumab pegol (CZP) and/or golimumab (GLB)) who subsequently received IV infliximab (IFX) for ≥12 weeks. We described baseline characteristics, disease activity by Harvey Bradshaw Index (HBI) and Simple Endoscopic Activity Score in Crohn's Disease (SESCD), and biochemical assessments. Results: Key characteristics of 19 patients described in Table 1. After ≥12 weeks of IFX, 12 (63.2%) patients reported clinical response, defined as ≥3 point decrease in HBI compared to baseline. 15 (78.9%) patients reported clinical remission, defined as HBI ≤4. Mean CRP decreased from 13.7 mg/L pre-IFX to 9.8 mg/L post-IFX (RR 0.0-10.0). Of 11 patients with available endoscopic data, restaging colonoscopy 6-18 months after starting IFX revealed endoscopic improvement in 7 patients, defined as ≥50% decrease in SESCD. Four patients were in endoscopic remission, defined as SESCD ≤2.Table: Table. Patient demographics and disease characteristicsConclusion: Patients with moderate-severe CD with prior primary-nonresponse to one or more SC TNF agent who are subsequently treated with IV TNF therapy have high rates of clinical and endoscopic response and remission. Therefore, despite primary-nonresponse to SC TNF, patients may benefit from IV TNF therapy and may not require a change to a different class of biologic therapy. As these medications all have the same mechanism of action (MOA), this suggests that the different response rates may be due to using an IV, weight-based therapy rather than fixed dose SC therapy and is not due to lack of response to the MOA.

Response and Remission After 16 Weeks of Ustekinumab: An All Patients Analysis From the UNITI Crohnʼs Studies

Introduction: UST has been shown to induce&maintain clinical response & remission in moderate-severe Crohn's disease(CD) in 2 induction[(UNITI-1(anti-TNF failures)&UNITI-2(anti-TNF non-failures) &1 maintenance(IM-UNITI)] randomized, PBO-controlled Ph3 trials. We evaluated efficacy (response & remission) for all pts who received an IV induction dose of approximately 6mg/kg, including responders(CDAI decrease ≥100)&non-responders, 8wks after first UST maintenance dose of 90mg SC, ie, 6wks from the IV induction dose. Methods: Pts achieving clinical response 8wks after a single IV induction dose were randomized to SC PBO, UST 90mg q12wks or q8wks. UST pts not in clinical response 8wks after IV induction dose were given UST90mg SC & if in clinical response 8wks later were continued on 90mg SC q8w. A total of 458pts were exposed to an IV induction dose of 6mg/kg(UNITI-1,N=249 & in UNITI-2 N=209) with a response rate at wk8 of 37.8%&57.9% vs PBO response rate of 20.2%&32.1% respectively. The remission rate at wk8 in UNITI-1 & UNITI-2 was 20.9%&40.7 vs PBO of 7.3%&19.6% respectively. For this evaluation, response & remission status of the entire population exposed to an IV induction dose of 6mg/kg of UST was evaluated 8wks after the first SC maintenance dose of UST. All pts who received 6mg/kg IV UST induction were included, including responders randomized to SC PBO(who did not receive SC UST at wk8). Results: Of the 219 pts not in clinical response in UNITI 1&2, 37.6%&60.5% respectively were in clinical response 8wks after first maintenance UST dose (90 mg SC). Evaluating all pts exposed to 6mg/kg IV UST induction, response rates 8wks after first SC injection(16wks after IV induction dose) for UNITI1&2 are 47.4%&73.7% respectively (Table). Similar assessments were calculated in the sub-population who were anti-TNF naïve upon enrolment into UNITI-2.Table: Table. Response rates and remission rates for all pts 16wks after induction of 6mg/kg IV USTConclusion: These numbers at wk16 are expected to reflect real world experience in pts who receive the induction dose & one additional maintenance dose 8wks later. The resulting rates of response & remission are higher than previously reported in induction studies across all populations(anti-TNF non-failures & anti-TNF failures). About 73% of anti-TNF non-failures attain clinical response & over half are in remission.The data support clinical rationale for providing at least one SC maintenance dose of UST irrespective of clinical response 8wks after IV induction.

Cost-Effectiveness of Vedolizumab Compared to Adalimumab for Patients with Crohnʼs Disease After Loss of Response to Infliximab: A Markov Model

Introduction: Vedolizumab (VDZ), an alpha4-beta7 integrin monoclonal antibody, is approved for the treatment of Crohn's disease (CD). The optimal second-line biologic for patients with CD and loss of response (LOR) to infliximab is unknown. This study sought to evaluate the cost-effectiveness of VDZ compared to the anti-tumor necrosis factor (TNF) agent adalimumab (ADA), in a CD patient with LOR to infliximab. Methods: We developed a decision analytic Markov Model to evaluate the base case of a 30-year old man with moderate-severe CD with LOR to infliximab. Two treatment pathways were compared: VDZ or ADA. Patients in each pathway could go into clinical remission, fail therapy (either primarily or after initial remission), progress to surgery, cross over to the other biologic arm, develop lymphoma (if on an anti-TNF) or die. We evaluated the effect of post-operative prophylaxis with a biologic agent, with a rate of use from 0-100% to see how this would affect our results. We used 3-month cycles, a five-year time horizon and a payer perspective. Transitions and costs were taken from the published literature and available public sources (such as Medicare). Outcome measures were reported in incremental cost-effectiveness ratios (ICERs; 2015 US dollars per quality-adjusted life years [QALY] gained), with a willingness to pay (WTP) threshold set at $100,000/QALY. Results: Initial therapy with ADA was the preferred, cost-effective strategy with higher cost but also greater effectiveness, with an ICER of $62,844/QALY, which is well below our set WTP threshold (Table 1). This remained the preferred strategy even when varying the percentage of patients on post-operative prophylaxis from 0-100%. A Tornado diagram was created (Figure 1) and 1-way and 2-way sensitivity analysis (SA) was performed. The QALY value for disease recurrence was notable for its effect on the preferred strategy (Figure 2). When the disease recurrence QALY was varied to be less than 0.598, VDZ was the preferred strategy; however, for disease recurrence QALY greater than 0.598, ADA was the preferred strategy.Figure 1Figure 2Table 1: Cost-effectiveness results comparing Adalimumab to Vedolizumab for patients with Crohn's Disease, after loss of response to InfliximabConclusion: Our results show that ADA is more cost-effective than VDZ for patients with moderatesevere CD who previously lost response to infliximab. As the QALY of recurrent disease after initial therapy worsened, the strategy of initial VDZ became more cost-effective. This would suggest that if a patient is likely to have a severe disease course, initial VDZ is preferred.

The Real-World Effectiveness and Safety of Vedolizumab for Moderate-Severe Crohn's Disease: Results From the US VICTORY Consortium.

We assessed the real-world effectiveness and safety of vedolizumab (VDZ) in moderate-severe Crohn's disease (CD). Retrospective cohort study of seven medical centers, from May 2014 to December 2015. Adults with moderate-severe CD treated with VDZ, with follow-up after initiation of therapy, were included. Using the multivariable Cox proportional hazard analyses, we identified independent predictors of clinical remission or mucosal healing with VDZ. Rates of serious infection (requiring antibiotics, resulting in discontinuation of VDZ, hospitalization or death) and serious adverse events (discontinuation of VDZ, hospitalization or death) were described quantitatively. We included 212 patients with moderate-severe CD (median age 34 years; 40% male; 90% tumor necrosis factor (TNF)-antagonist exposed) with a median follow-up (IQR) of 39 weeks (25-53). Twelve-month cumulative rates of clinical remission, mucosal healing, and deep remission (clinical remission+mucosal healing) were 35%, 63%, and 26%, respectively. Individuals with prior TNF-antagonist exposure (hazard ratio (HR) 0.40; 95% confidence interval (CI): 0.20-0.81), smoking history (HR 0.47; 95% CI: 0.25-0.89), active perianal disease (HR 0.49; 95% CI: 0.27-0.88), and severe disease activity (HR 0.54; 95% CI: 0.31-0.95) were less likely to achieve clinical remission. Those with prior TNF-antagonist exposure (HR 0.29; 95% CI: 0.12-0.73), and severe disease activity (HR 0.54; 95% CI: 0.31-0.95) were less likely to achieve mucosal healing. During 160 patient years of follow-up (PYF) and 1,433 VDZ infusions, 5 patients developed infusion reactions (3.5 per 1,000 infusions), 21 developed serious infections (13 per 100 PYF), and 17 developed serious adverse events (10 per 100 PYF). A minority of adverse events required discontinuation of therapy (6 per 100 PYF). VDZ is a safe and effective treatment option for moderate-severe CD in routine practice. Clinical remission and deep remission (clinical remission and mucosal healing) can be achieved in 1/3 of individuals, and a minority of individuals require discontinuation of therapy due to adverse events.

O-001 A Multicenter, Double-Blind, Placebo-Controlled Phase3 Study of Ustekinumab, a Human IL-12/23P40 mAB, in Moderate-Service Crohnʼs Disease Refractory to Anti-TFNα

Interleukins 12&23 are implicated in the pathophysiology of Crohn's disease (CD). These pro-inflammatory cytokines are blocked by ustekinumab (UST). In a previous Phase 2b study (CERTIFI), UST IV induction followed by SC maintenance was shown effective in moderate-severe CD refractory to anti-TNF therapy. This Phase 3 study examined the efficacy and safety of IV UST induction in these patients.Patients with moderate-severely active CD (CDAI 220-450) who previously failed or were intolerant to at least 1 TNF-antagonist were randomized (1:1:1) at Week (Wk) 0 to a single dose of IV placebo (PBO), UST 130 mg, or weight-based tiered UST dosing approximating 6 mg/kg (260mg [weight ≤55 kg], 390mg [weight >55 kg and ≤85 kg], 520mg [weight >85 kg]). The primary endpoint was clinical response at Wk6, defined as reduction from baseline in the CDAI score of >100 points; patients with baseline CDAI score >220 to <248 points were considered in clinical response if a CDAI score of <150 was present. At Wk8, patients either transitioned to the IM-UNITI maintenance study or were followed to Wk20.The 741 randomized patients had a history of TNF-antagonist failure, with baseline median CDAI of 317, CRP of 9.9 mg/L, and prior disease duration of 10.1 years. Of these, 51% had previously failed ≥2 anti-TNFs with 29.1%, 69.4%, and 36.4% of patients, respectively, satisfying protocol criteria for primary non-response, secondary non-response, or intolerance to at least one TNF antagonist. Statistical significance was demonstrated for the primary and all 4 major secondary endpoints at both IV doses. Clinical response at Wk6 (primary endpoint) was observed in 33.7% of the ∼6 mg/kg and 34.3% of the 130 mg UST groups versus 21.5% in PBO (P = 0.003 and 0.002, respectively). Clinical remission (CDAI <150) at Wk8 was observed in 20.9% of the ∼6 mg/kg group and 15.9% of the 130 mg UST group versus 7.3% on PBO (P < 0.001, P = 0.003, respectively). Clinical response at Wk8 was seen in 37.8% of the ∼6 mg/kg and 33.5% of the 130 mg UST groups, versus 20.2% on PBO (each P ≤ 0.001). Proportion of patients with 70pt CDAI response at Wk6 was 43.8% of the ∼6 mg/kg and 46.1% of the 130 mg UST groups versus 30.4% in PBO (P = 0.002 and <0.001, respectively) and at the first post-baseline Wk3 visit, 40.6% in ∼6 mg/kg and 38.4% in the 130 mg UST groups versus 27.1% in PBO (P = 0.001 and P = 0.009, respectively), the final major secondary endpoint. Both IV UST induction doses additionally resulted in significant improvements in CDAI, IBDQ, CRP, fecal lactoferrin and calprotectin versus IV PBO. Proportions of patients with AEs, SAEs, and infections were similar in the UST and PBO groups. One opportunistic infection (listeria meningitis) was reported in the ∼6 mg/kg UST group. No malignancies, deaths, major adverse cardiovascular events, or TB occurred in UST-treated patients through Wk20.In a population of moderate-severe CD patients refractory to one or more prior TNF-antagonists, IV UST induced clinical response and remission and was well-tolerated throughout induction, confirming the previous positive induction data from the Phase 2b CERTIFI study.

Role of Vitamin D in Infliximab-induced Remission in Adult Patients with Crohn's Disease.

Vitamin D is a key immunomodulator and its deficiency is prevalent among Crohn's patients. The interaction between vitamin D and the response to infliximab induction therapy has not been previously described. Patients with moderate-severe Crohn's disease, defined as having a modified Harvey Bradshaw index ≥8, who were being induced with infliximab were recruited. Patients were divided into low and normal vitamin D groups. Patients were followed prospectively for 14 weeks for achievement of clinical remission (Harvey Bradshaw index <5). At week 14, vitamin D deficient patients were supplemented with intramuscular cholecalciferol; all patients were re-assessed at week 22. Serum cytokine levels were measured at weeks 0, 14, and 22. Twenty-eight patients initiating infliximab were included, with 54% of patients in the low vitamin D group. The proportion of patients in clinical remission was greater in the low vitamin D group compared with the normal vitamin D group at both week 14 (80% versus 23%, P = 0.007) and week 22 (79% versus 17%, P = 0.005). The low vitamin D group had higher baseline IL-6 levels (median, 4.4 [interquartile range, 2.0-5.7] versus 1.1 [0.8-1.7] pg/mL, P = 0.004) and lower interleukin-12 levels (0.3 [0.1-0.4] versus 0.5 [0.5-0.6] pg/mL, P = 0.006) compared with the normal vitamin D group. At week 14, IL-8 levels were significantly lower in the low vitamin D group compared with the normal vitamin D group (11.2 [9.1-13.8] versus 20.5 [17.9-37.2] pg/mL, P = 0.005). Crohn's patients initiating infliximab with a low vitamin D level are more likely to achieve infliximab-induced clinical remission at week 14.

Sa1264 Drug Trough Levels and Primary Nonresponse to antiTNF Therapy in Moderate-Severe Crohn Disease. Results of the Optimiza Study

Background and aim: Biological therapy is now the mainstay treatment for the patients with moderate/severe IBD. The efficacy of treatment is no longer measured only in the induction of clinical remission, endoscopic healing being considered more important since it's achievement can influence the long term outcome of the disease. The majority of clinical trials report endoscopic results after one year of maintenance treatment. The aim of our study was to observe the frequency of mucosal healing and its persistence in a group of IBD patients with clinical response to biological therapy during long term follow up (over 2 years). Methods: All patients with IBD that received biological treatment admitted in our department were prospectively followed. In all ileocolonoscopies were performed at 6 months intervals with description of all lesions encountered (periodic endoscopic or radiologic evaluations are part of the protocol issued by National Health Insurance House and are required for the approval of reimbursed biological treatment). Mucosal healing (MH) was defined as lack of ulcers, ulcerations or aftous erosions. The presence of erythema, edema, and inflammatory pseudopolyps did not preclude the diagnosis of MH. Demographic and clinical data were noted as well as the type, dose, and frequency of biological and associated (e.g. immunosuppressive) treatments. Only patients treated over 2 years were included in the analysis. Results: 52 patients (27 males, 25 females, mean age 36.9+/-12.2 years) received biological therapy (38 infliximab and 14 adalimumab) for a period longer than 24 months (24-72, mean 38.67 months), 43 with Crohn's disease (CD) and 9 with ulcerative colitis (UC). Mucosal healing was obtained in 80.77% patients. The mean time to MH was of 10.85 (6-36) months. 26.19% of patients needed more than one year to achieve MH. From patients with MH, 40.48% experienced recurrent endoscopic lesions and clinical flare during follow up. The only factor associated with long term MH (maintained during the observation period) was the presence of MH 6 months after initiation of maintenance treatment with biologics (p=0.022). The combined treatment with immunosupressors or the use of biological therapy at first flare of disease did not influence the occurrence or persistence of MH in our group of patients. Conclusions: In patients with clinical remission obtained with biological treatment long term endoscopic follow up shows that mucosal healing can be achieved in the majority of cases. A rapid endoscopic response (mucosal healing after the first 6 months of maintenance therapy) predicts sustained, long term, endoscopic remission.