P385 Relationship between adalimumab concentration and efficacy for the induction of clinical remission in pediatric patients with moderate to severe Crohn's disease

Abstract Background Despite the well-established efficacy of Tumor Necrosis Factor (TNF) antagonists as treatment options for Crohn’s Disease, many pediatric patients need a change in therapy due to adverse events, as well as primary and secondary loss of response, highlighting the necessity for medications with a different mechanism of action. Ustekinumab, a monoclonal antibody targeting IL-12 and IL-23, has been approved to treat psoriatic arthritis, plaque psoriasis, and adults with Crohn’s disease. While utekinumab has been shown to be effective in inducing clinical remission in adults with Crohn’s disease refractory to anti-TNF agents, minimal data exists in the pediatric population. Aims We retrospectively describe 11 pediatric patients who received ustekinumab at the Montreal Children’s Hospital with the goal of assessing its efficacy in inducing clinical, biochemical, and endoscopic remission. Methods We abstracted baseline data, prior treatment and response, indications for starting ustekinumab, clinical response, endoscopic data, and laboratory parameters pre- and post- therapy. Clinical response was defined as decrease in abbrPCDAI (Pediatric Crohn’s Disease Activity Index) score. Results Patients ranged in age from 12–17 years old upon initiation of treatment with ustekinumab and had all previously failed either one (N=8) or both (N=3) anti-TNF therapies. Follow-up ranged from 6 to 22 months. We examined three indices of response to ustekinumab: symptomatic improvement, biomarker normalization, and endoscopic changes. Five of eleven patients demonstrated a clinical response – two maintained clinical remission across available follow-up data, while the remaining three experienced a secondary loss of response. The other six patients studied were primary non-responders. Two of these patients had normal abbrPCDAI scores upon initiation of ustekinumab and terminated therapy due to persistent stricturing disease. The other four non-responders either remained unwell or demonstrated clinical worsening, as measured by the abbrPCDAI. Of the clinical responders, 3/5 had elevated CRP values prior to initiating ustekinumab therapy, all of which normalized within one month of clinical improvement. Endoscopic data both pre- and post- ustekinumab was available in two responders and two non-responders, with endoscopic improvement seen in both of the responders and in one of the two non-responders. Conclusions These results demonstrate that ustekinumab has the potential ability to induce not only clinical and biochemical remission, but also endoscopic improvement, in the pediatric population. An area of concern is the fact that only one patient maintained remission for longer than one year. Future research should focus on maximizing and lengthening the effect of ustekinumab, as well as determining factors that influence response to therapy. Funding Agencies None

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Association between Fecal Calprotectin and Mucosal Healing in Pediatric Patients with Crohn’s Disease Who Have Achieved Sustained Clinical Remission with Anti-Tumor Necrosis Factor Agents

Gut and Liver ◽

10.5009/gnl20300 ◽

2021 ◽

Author(s):

Yoo Min Lee ◽

Sujin Choi ◽

Byung-Ho Choe ◽

Hyo-Jeong Jang ◽

Seung Kim ◽

...

Keyword(s):

Crohn’S Disease ◽

Tumor Necrosis Factor ◽

Crohn's Disease ◽

Clinical Remission ◽

Tumor Necrosis ◽

Pediatric Patients ◽

Fecal Calprotectin ◽

Mucosal Healing ◽

Necrosis Factor

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P375 A simulation study to evaluate the performance of a multiple imputation method to address missing data in an analysis of clinical effectiveness using the ImproveCareNow Registry of pediatric patients with Crohn’s disease

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.499 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S391-S391

Author(s):

N Zhang ◽

C Liu ◽

E King ◽

S Chen ◽

K Olano ◽

...

Keyword(s):

Crohn’S Disease ◽

Missing Data ◽

Crohn's Disease ◽

Multiple Imputation ◽

Clinical Remission ◽

Pediatric Patients ◽

Remission Rate ◽

Base Case ◽

Clinical Remission Rate ◽

Complete Dataset

Abstract Background Patient registries are a source of real-world data (RWD) that are increasingly used to generate real-world evidence (RWE) for the safety and effectiveness of medical therapies. However, in registries, outcome data typically collected in clinical trials may be missing in some patients, creating a major challenge in evaluating RWD reliably. Clinical remission in pediatric Crohn’s disease (PCD), defined by the Short Pediatric Crohn’s disease Activity Index (sPCDAI) <10, is routinely collected in the ImproveCareNow (ICN) Registry, the world’s largest registry of pediatric patients with inflammatory bowel disease (IBD). A feasibility analysis of ICN as a RWD source to estimate the efficacy of therapies in PCD found about one-third of patients were missing at least 1 of the 6 components needed to calculate the sPCDAI scores at Week 52. We conducted a simulation study to evaluate the performance of the multiple imputation (MI) method in addressing the missing data issue. Methods A Starting Dataset from the ICN registry included CD patients age 2 to <18 yr when beginning treatment with a biologic agent other than ustekinumab during 2014 to 2019, who had a baseline visit and a “Week 52” visit. A Complete Dataset included only patients in the Starting Dataset who had all components required to calculate a sPCDAI score at the Week 52 visit. The true remission rate was calculated for the Complete Dataset. For the simulation, missing data patterns for individual sPCDAI components that were observed in the Starting Dataset were randomly imposed in the Complete Dataset. Variables that were predictive of sPCDAI scores, its components, and sPCDAI missingness were included. Ten thousand datasets were simulated for each of three scenarios: base case of the observed missingness in the Starting Dataset, 1.5 times the base case and 2 times the base case. The MI method was applied to the simulated datasets to estimate the remission rate. MI performance was measured by bias and coverage of the true remission rate from the Complete Dataset. Results The Starting and Complete Datasets included 1,458 and 1,212 patients, respectively. The true clinical remission rate in the Complete Dataset was 75.1% (95% CI: 72.6%-77.5%). Analysis without MI for the missing sPCDAI data resulted in underestimation of clinical remission rate, with bias about -2% to -5% (Table 1). The MI method eliminated the bias and had 100% coverage in all simulation scenarios by using a large number of independent predictors. Conclusion The MI method improved the validity, reliability, and efficiency of using RWD for estimating clinical remission in pediatric patients with CD and could be valuable in other registry studies.

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P302 The impact of induction and maintenance therapy with infliximab on mucosal healing and clinical remission in Polish pediatric patients with moderate to severe Crohn's disease

Journal of Crohn s and Colitis ◽

10.1016/s1873-9946(12)60322-5 ◽

2012 ◽

Vol 6 ◽

pp. S130

Author(s):

J. Kierkus ◽

E. Szymanska ◽

M. Dadalski ◽

A. Wegner ◽

G. Oracz ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Maintenance Therapy ◽

Clinical Remission ◽

Pediatric Patients ◽

Mucosal Healing ◽

The Impact

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P084 DEEP REMISSION WITH DOUBLE BIOLOGIC THERAPY: A SUCCESSFUL CASE OF COMBINATION USTEKINUMAB AND VEDOLIZUMAB FOR SEVERE REFRACTORY CROHN’S DISEASE

Inflammatory Bowel Diseases ◽

10.1093/ibd/zaa010.182 ◽

2020 ◽

Vol 26 (Supplement_1) ◽

pp. S72-S72

Author(s):

Ahmed Elmoursi ◽

Courtney Perry ◽

Terrence Barrett

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Combination Therapy ◽

Clinical Remission ◽

Biologic Therapy ◽

Case Reports ◽

Sigmoid Resection ◽

Safety And Efficacy ◽

Ileal Stricture

Abstract Background Stricturing Crohn’s disease (CD) constitutes a severe phenotype often associated with a high degree of morbidity (3). Surgical resection is first-line therapy for symptomatic strictures, but most patients relapse without subsequent medical therapy (4–5). Biologics are the mainstay for inducing and maintaining remission, but some cases are refractory despite maximum dosage of therapy. Reports of dual biological therapy (DBT) in refractory, stricturing CD are sparse, and prior case reports document only clinical remission (1). To contribute further knowledge regarding the use of DBT in stricturing CD, we present the case of a refractory CD patient who achieved deep remission with ustekinumab and vedolizumab. Case Presentation A 35 year old non-smoking, Caucasian male was referred to our clinic in 2014 for refractory CD complicated by multiple strictures. Prior to establishing care with us, he received two jejunal resections and a sigmoid resection. Previously failed therapies included azathioprine with infliximab, adalimumab, and certolizumab. He continued to progress under our care despite combination methotrexate/certolizumab, as well as methotrexate/golimumab. He underwent proctocolectomy with end ileostomy in 2015 and initiated vedolizumab q8weeks post-operatively. He reoccurred in 2018, when he presented with an ulcerated ileal stricture. He was switched from vedolizumab to ustekinumab q8weeks and placed on prednisone, but continued to progress, developing significant hematochezia requiring hospitalization and blood transfusions. Ileoscopy performed during hospital admission confirmed severe, ulcerating disease in the ileum with stricture. Ustekinumab dosing was increased to q4weeks, azathioprine was initiated, and he underwent stricturoplasty. Follow-up ileoscopy three months later revealed two ulcers in the neo- TI (Figure 1). Vedolizumab q8weeks was initiated in addition to ustekinumab q4weeks and azathioprine 125mg. After four months on this regimen the patient felt better, but follow-up ileoscopy showed two persistent ulcers in the neo-TI. Vedolizumab dosing interval was increased to q4weeks. After four months, subsequent ileoscopy demonstrated normal neo-TI (Figure 2). Histologic evaluation of biopsies confirmed deep remission of crohn’s disease. No adverse side effects have occurred with maximum doses of both ustekinumab and vedolizumab combination therapy. Discussion This case supports both the safety and efficacy of ustekinumab and vedolizumab dual biologic therapy for treatment of severe, refractory Crohn’s disease. While there are reports of DBT inducing clinical remission, this case supports efficacy for vedolizumab and ustekinumab combination therapy to induce deep histologic remission. Large practical clinical trials are needed to better investigate the safety and efficacy of DBT with vedolizumab and ustekinumab, but our case suggests this combination may be a safe and efficacious therapy for refractory CD patients.

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P089 REAL-WORLD EXPERIENCE: CLINICAL AND ENDOSCOPIC EFFECTIVENESS OF STANDARD VEDOLIZUMAB DOSING AND MODIFIED MAINTENANCE DOSING IN PATIENTS WITH MODERATE-SEVERE CROHN’S DISEASE

Inflammatory Bowel Diseases ◽

10.1093/ibd/zaa010.187 ◽

2020 ◽

Vol 26 (Supplement_1) ◽

pp. S75-S75

Author(s):

Scott D Lee ◽

Anand Singla ◽

Caitlin Kerwin ◽

Kindra Clark-Snustad

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Adverse Events ◽

Real World ◽

Clinical Remission ◽

Mucosal Healing ◽

Clinical Disease ◽

Endoscopic Remission ◽

Starting Dose

Abstract Background Vedolizumab (VDZ) is an effective treatment for Crohn’s disease (CD); however, inadequate and loss of response is common. Pivotal VDZ trials evaluated alternative dosing intervals, demonstrating numeric but not statistical superiority in efficacy as compared to FDA-approved dosing. The safety and effectiveness of FDA-approved and modified-dosing schedules in a real-world population are unknown. We aimed to evaluate clinical and endoscopic effectiveness & safety of standard and modified maintenance VDZ dosing in a real world cohort. Methods We retrospectively reviewed CD patients (pts) treated with >3 months VDZ, assessing Harvey Bradshaw Index (HBI), Simple Endoscopic Score for Crohn’s disease (SESCD), Short Inflammatory Bowel Disease Questionnaire (SIBDQ), C-reactive protein (CRP), albumin and hematocrit prior to and following standard VDZ dosing, and prior to and following modified VDZ maintenance dosing. We measured duration on therapy and adverse events. Results We identified 226 eligible pts, mean age 41.5 years, 55.3% female, median disease duration 10 years, 88.9% with prior biologic exposure. Mean duration on VDZ was 28.3 months. Standard VDZ dosing: 61.5% of pts with active clinical disease and adequate follow up data achieved clinical response after 3–12 months; 41.0% had clinical remission. 51.9% of pts with active endoscopic disease and adequate follow up data achieved mucosal improvement; 42.3% had endoscopic remission; 26.0% had mucosal healing after 3–24 months. 50.0% of pts with elevated CRP and adequate follow up data normalized CRP after 3–12 months. Modified maintenance dosing: 72 non-remitters to standard VDZ dosing received modified VDZ maintenance dosing. 51.5% of pts with active clinical disease prior to starting dose modification and adequate follow up data achieved clinical response after 3–12 months of modified maintenance dosing; 42.4% had clinical remission. 22.2% of pts with SESCD ≥3 prior to starting dose modification achieved mucosal improvement after 3–24 months; 22.2% had mucosal healing. 26.7% of pts with SESCD ≥4 prior to starting modified dosing had endoscopic remission after 3–24 months. 50.0% of pts with elevated CRP and adequate follow up data normalized their CRP after 3–12 months. Safety: 82.7% of pts reported ≥1 adverse events, most commonly infection and worsening CD symptoms. Discussion Standard VDZ dosing resulted in clinical and endoscopic improvement in pts with moderate-severe CD, with prior exposure to multiple advanced therapies. For non-remitters to standard dosing, modified VDZ maintenance dosing improved clinical disease activity in ∼50% of pts and improved endoscopic disease activity in ∼20% of pts, suggesting that for pts who did not achieve remission with standard VDZ dosing, modified VDZ dosing may result in clinical and endoscopic improvement.

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