Mucosal Biomarker of Innate Immune Activation Predicts Response to Vedolizumab in Crohn’s Disease

2019 ◽  
Author(s):  
Mark T Osterman ◽  
Ilyssa O Gordon ◽  
Elisabeth M Davis ◽  
Matthew Ciorba ◽  
Sarah C Glover ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Response ◽  
Immune Activation ◽  
Clinical Remission ◽  
Response Rate ◽  
Intestinal Inflammation ◽  
Innate Immune ◽  
Clinical Response Rate ◽  
Innate Immune Activation

Abstract Objective Mucosal barrier dysfunction plays a crucial role in intestinal inflammation in Crohn’s disease (CD). Intestinal epithelial cell (IEC) death resulting from innate immune activation, termed pyroptosis, was recently found to be a cause of this barrier defect. The aim of this study was to determine the predictive value of pretreatment ileal biopsy pyroptosis as a biomarker for clinical response to vedolizumab in CD. Design Crohn’s disease patients ranging 18 to 80 years old from 5 IBD centers with pre-vedolizumab ileal biopsies during colonoscopy were enrolled. Biopsies were stained for activated caspases, and levels of ileal IEC pyroptosis levels were quantified. The primary outcome was clinical response 6 months after therapy, defined as a reduction of Harvey-Bradshaw Index (HBI) of ≥5 points from baseline. Secondary outcomes included clinical remission, defined as HBI <5, and endoscopic improvement, as measured by the Simple Endoscopic Score for Crohn’s Disease (SES-CD). Results One hundred CD patients (45 male, 55 female), median age 47 (19, 78) years, were included; clinical response rate was 60%, and clinical remission was 36%. The response rate in patients with ileal pyroptosis <14 positive cells per 1000 IECs was significantly higher than those above the threshold: 89% (25 of 28) vs 49% (35 of 72), odds ratio (OR) 8.8 (95% CI, 2.3–48.6; P < 0.001). Corresponding remission rates were 54% (15 of 28) vs 29% (21 of 72; OR 2.8 [1.03–7.59; P = 0.036]). For endoscopic improvement, ileal pyroptosis of 22 positive cells per 1000 IECs was the optimal threshold that determines the magnitude SES-CD change. Conclusions Ileal biopsy IEC pyroptosis was predictive of clinical response and endoscopic improvement to vedolizmab in CD patients.

P087 ILEAL BIOMARKER OF INNATE IMMUNE ACTIVATION CAN PREDICT CLINICAL RESPONSE TO VEDOLIZUMAB IN CROHN’S DISEASE

2019 ◽  
Vol 25 (Supplement_1) ◽  
pp. S41-S41 ◽  
Author(s):  
Mark T Osterman ◽  
Ilyssa O Gordon ◽  
Elisabeth M Davis ◽  
Matthew A Ciorba ◽  
Sarah C Glover ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Response ◽  
Immune Activation ◽  
Innate Immune ◽  
Innate Immune Activation

P087 ILEAL BIOMARKER OF INNATE IMMUNE ACTIVATION CAN PREDICT CLINICAL RESPONSE TO VEDOLIZUMAB IN CROHN’S DISEASE

2019 ◽  
Vol 156 (3) ◽  
pp. S59-S60
Author(s):  
Mark T. Osterman ◽  
Ilyssa O. Gordon ◽  
Elisabeth M. Davis ◽  
Matthew A. Ciorba ◽  
Sarah C. Glover ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Response ◽  
Immune Activation ◽  
Innate Immune ◽  
Innate Immune Activation

scholarly journals P613 Use of adalimumab biosimilar ABP 501 in Crohn’s disease: A real-life experience

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S510-S511
Author(s):  
D G Ribaldone ◽  
M Vernero ◽  
R Pellicano ◽  
M Morino ◽  
G M Saracco ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Adverse Events ◽  
Clinical Response ◽  
Clinical Remission ◽  
Retention Rate ◽  
Real Life ◽  
University Hospital ◽  
Clinical Response Rate ◽  
Abp 501

Abstract Background The use of biologics in Crohn’s disease (CD) entails an increasing cost on national health systems. The use of biosimilars of adalimumab in CD is based on the concept of extrapolation of the results obtained in rheumatoid arthritis and in psoriasis, while no study about the efficacy and safety on CD of the biosimilars approved in Europe have been published. The aim of our study was to analyse, for the first time in literature, the effectiveness and safety of ABP 501 in CD patients naïve to adalimumab and its retention rate in CD patients who switched from adalimumab originator. Methods We performed an observational study on patients prospectively followed at the gastroenterology clinic of the Turin University Hospital. Inclusion criteria are (a) CD diagnosed according to ECCO criteria; (b) age ≥16 years; (c) initiation of therapy with ABP 501. Exclusion criterian is follow-up duration of less than 3 months for adalimumab-naïve patients, less than 6 months for patients who switched to ABP 501. Primary outcomes were (a) for patients treated with ABP 501 as first adalimumab: clinical response rate at 12 weeks and (b) for patients who switched to ABP 501: drug retention at 24 weeks. Secondary outcomes were (a) clinical remission rate at week 12 (for patients treated with ABP 501 as first adalimumab); (b) HBI and CRP reduction at week 12 (for patients treated with ABP 501 as first adalimumab), no significant change in HBI and CRP values at week 24 (for patients who switched to ABP 501); (c) analysis of predictors; and (d) adverse events incidence. Results Eighty-seven patients were included, of which 25 were naïve to adalimumab originator and 62 were switched to ABP 501. In adalimumab-naïve patients, the clinical response at 3 months was 60% (15/25), clinical remission at 3 months was 56% (14/25). At 6 months, 95.2% (59/62) of the patients switched to ABP 501 were still in therapy, without a significant increment of clinical activity (Harvey–Bradshaw Index from 3.4, 95% CI = 2.4 – 4.4, to 3.8, 95% CI = 2.7 – 4.9, p = 0.23), and inflammatory biomarker (CRP from 4.2 mg/l, 95% CI = 2.5 mg/l – 5.9 mg/l, to 3.6 mg/l, 95% CI = 2.2 mg/l – 5 mg/l, p = 0.32). No unexpected adverse events occurred during the study period. Conclusion Our results support ABP 501 as an efficacious and well-tolerated drug, at least in the short-term, and its interchangeability with its originator in the treatment of CD.

scholarly journals Clinical Experience with Infliximab for Crohn’s Disease: The First 100 Patients in Edmonton, Alberta

2002 ◽  
Vol 16 (3) ◽  
pp. 165-170 ◽  
Author(s):  
Clifford Sample ◽  
Robert J Bailey ◽  
Dennis Todoruk ◽  
Daniel Sadowski ◽  
Gramlich Leah ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Response ◽  
Patient Group ◽  
Response Rate ◽  
Complete Response ◽  
Infusion Reaction ◽  
Clinical Response Rate ◽  
Randomized Controlled Clinical Trials ◽  
Duration Of Response

OBJECTIVE: To determine whether the clinical efficacy and safety of infliximab in diverse clinical referral practices was similar to that seen in the randomized, controlled clinical trials.METHODS: Data were gathered from a review of charts of 109 consecutive patients with inflammatory and/or fistulizing Crohn’s disease who received infliximab infusions. Responses were recorded based on the physician’s global clinical assessment and classified as complete, partial or nonresponse.RESULTS: One hundred nine patients were treated with one to nine infusions of infliximab at a dose of 5 mg/kg and followed up for a median of 24 weeks (range one to 40 weeks). Fifty-four patients were treated for inflammatory disease, 38 for fistulizing disease and 17 for both. Clinical response occurred in 73% (17% complete response, 55% partial response). The clinical response rate did not vary relative to patient demographics, disease distribution, indication for infliximab, or the concomitant use of corticosteroids or immune modifiers. For those taking concomitant immune modifiers, the response rate was 75%. The median time to response was two weeks (range one to six weeks). The median duration of response was 12 weeks (range six to 88 weeks). Reduction or cessation of steroids was possible in 17 of 32 patients. Adverse events related to infliximab occurred in 7% of patients. These events were characterized as mild and did not require stoppage of infliximab therapy, except in one patient who had a treatable anaphylactic-like infusion reaction.CONCLUSIONS: The patient group in the present study realized significant clinical benefit, with minimal adverse effects, following treatment with infliximab. Clinical response rates paralleled those previously described in placebo controlled trials and retrospective clinical practice reviews. Nevertheless, the complete response rate (ie, remission) in this patient group was lower than that previously described.

scholarly journals DOP66 The effect of exclusive enteral nutrition on circulating inflammatory protein levels in paediatric patients with Crohn’s Disease

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S100-S101
Author(s):  
M Pidoux ◽  
M Logan ◽  
S Milling ◽  
U Z Ijaz ◽  
R Hansen ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Enteral Nutrition ◽  
Clinical Response ◽  
Clinical Remission ◽  
Innate Immune ◽  
Plasma Samples ◽  
Exclusive Enteral Nutrition ◽  
Protein Levels ◽  
Inflammatory Proteins

Abstract Background Exclusive enteral nutrition (EEN) is the recommended first line treatment for active paediatric Crohn’s disease (CD). The mechanism of action and immunological effects of EEN remain unclear. This study compared circulating inflammatory proteins of patients with CD and ulcerative colitis (UC) with non-inflammatory bowel disease (non-IBD) controls and explored the effect of EEN in children with active CD. Methods Patients with CD were treated with EEN for 8 weeks, with plasma samples collected prior to EEN start and upon EEN completion. Levels of 92 inflammatory proteins were quantified using Olink Inflammation panel. Paired faecal samples were collected to measure faecal calprotectin (FC) levels by ELISA. Patients in which FC decreased &gt;50% during EEN were classed as FC responders; whereas patients who had a &lt;50% decrease in FC were classed as FC non-responders. Results 84 patients were recruited (CD:54, UC:11, non-IBD:19). Paired plasma samples were collected from 18 patients with CD receiving EEN. Of these 18 patients, 72% achieved clinical remission by the end of EEN (wPCDAI &lt;12.5 points). Prior to EEN start, 29 proteins were significantly different between patients with CD compared to non-IBD; and 25 proteins were significantly different between UC and non-IBD, Fig 1. EEN lead to the significant alteration of 23 proteins. This included 5 proteins, CCL23, CXCL10, IL6, IL24, and MMP-1 which were higher in patients with CD prior to EEN start compared to non-IBD, Fig 2. In patients who achieved clinical remission during EEN, 22 proteins significantly changed from their EEN start levels by the end of EEN, Fig 3. FC responders had a similar pattern of protein changes, in which 22 proteins changed significantly during EEN, Fig 4. 16/22 (72%) of the proteins that changed significantly in the FC responder group during EEN, also changed during EEN in patients who entered clinical remission including significant reductions in several innate immune proteins such as IL-6 and IL-18. Patients who did not achieve clinical remission did not have significant reductions in these proteins. Despite being higher in patients with CD prior to treatment compared to non-IBD, the level of 17 proteins, including IL17a and oncostatin M, did not change in FC responders during EEN. Conclusion EEN leads to alteration of multiple inflammatory proteins, in keeping with a reduction in innate immune pro-inflammatory activity and improvement in clinical response, although some inflammatory proteins remain elevated. Figure 1: Venn diagram of proteins significantly different Figure 2: Effect of EEN on protein levels Figure 3: Effect of EEN on protein levels, stratified based on clinical response during EEN Figure 4: Effect of EEN on protein levels, stratified based on FC response

scholarly journals OP26 Risankizumab induces early clinical remission and response in patients with Moderate-to-Severe Crohn’s Disease: Results from the phase 3 ADVANCE and MOTIVATE studies

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S026-S027
Author(s):  
S W Schreiber ◽  
M Ferrante ◽  
R Panaccione ◽  
J F Colombel ◽  
T Hisamatsu ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Response ◽  
Induction Therapy ◽  
Clinical Remission ◽  
Activity Index ◽  
Unmet Need ◽  
Inadequate Response ◽  
Biologic Treatment ◽  
Double Blind

Abstract Background Present therapies leave an unmet need for early and effective treatment for patients with Crohn’s disease (CD). Risankizumab (RZB), a humanized immunoglobulin G1 monoclonal antibody against the p19 subunit of interleukin-23, was evaluated as an induction therapy to induce early clinical remission and response in patients with moderate-to-severe CD in two double-blind, randomized, placebo (PBO)-controlled studies (ADVANCE [NCT03104413] and MOTIVATE [NCT03105128]). Methods Patients with moderate-to-severe CD (CD Activity Index [CDAI] of 220–450, Simple Endoscopic Score for CD [SES-CD] ≥ 6 [≥ 4 for isolated ileal disease] excluding the narrowing component, and average daily [liquid/very soft] stool frequency [SF] ≥ 4 and/or average daily abdominal pain [AP] score ≥ 2) who had inadequate response or intolerance to conventional and/or biologic treatment (ADVANCE), or biologic treatment only (MOTIVATE) were randomised 2:2:1 (ADVANCE) or 1:1:1 (MOTIVATE) to receive intravenous RZB 600 mg, RZB 1200 mg, or PBO as induction therapy at weeks 0, 4, and 8. Clinical remission (per either CDAI or a composite of SF and AP criteria), clinical response (per CDAI criterion), and enhanced clinical response (per a composite of SF and AP criteria) were evaluated at weeks 4, 8, and 12 (endpoints defined in Figure 1 footnotes). Safety was assessed throughout the studies. Results A total of 1419 patients from ADVANCE (N = 850) and MOTIVATE (N = 569) respectively, were randomised and included in the intention-to-treat population. In both studies, starting at week 4 (the first prespecified measurement), greater proportions of RZB 600 mg or RZB 1200 mg- vs PBO-treated patients achieved clinical remission per either CDAI (P = .01/P &lt; .05) or SF/AP criteria (P &lt; .01/P &lt; .01), clinical response per CDAI criterion (P = .001/P &lt; .01), and enhanced clinical response per SF/AP criteria (P &lt; .01/P = .14) (Figure 1). For both RZB 600 mg and RZB 1200 mg, the efficacy and treatment effect increased through week 12 (P ≤ .001/P ≤ .001) (Figure 1). Treatment with RZB 600 mg or 1200 mg was well tolerated, and no new safety risks were identified.1,2 Conclusion Induction therapy with both RZB 600 mg and 1200 mg intravenous resulted in significantly greater clinical remission and response vs PBO as early as week 4 and sustained through week 12 in patients with moderate-to-severe CD who had inadequate response or intolerance to conventional and/or biologic treatment. References

Vitamin D Status Is Associated with Intestinal Inflammation as Measured by Fecal Calprotectin in Crohn’s Disease in Clinical Remission

2015 ◽  
Vol 60 (8) ◽  
pp. 2427-2435 ◽  
Author(s):  
Tara Raftery ◽  
Megan Merrick ◽  
Martin Healy ◽  
Nasir Mahmud ◽  
Colm O’Morain ◽  
...  
Keyword(s):  
Vitamin D ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Remission ◽  
Intestinal Inflammation ◽  
Fecal Calprotectin ◽  
Vitamin D Status

scholarly journals DOP16 An evaluation of the exposure–efficacy relationship for subcutaneous vedolizumab maintenance treatment of Crohn’s disease: Pharmacokinetic findings from VISIBLE 2

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S056-S057
Author(s):  
C Chen ◽  
M Rosario ◽  
D Polhamus ◽  
N Dirks ◽  
W Zhang ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Response ◽  
Clinical Remission ◽  
Maintenance Treatment ◽  
Activity Index ◽  
Controlled Trial ◽  
Enzyme Linked Immunosorbent Assay ◽  
Serum Concentrations ◽  
Efficacy Outcome

Abstract Background The exposure–efficacy relationship and immunogenicity rates of the new vedolizumab subcutaneous (SC) formulation have been established for maintenance treatment of ulcerative colitis (UC).1 Here, we report vedolizumab SC exposure–efficacy and immunogenicity in Crohn’s disease (CD). Methods VISIBLE 2 (NCT02611817; EudraCT 2015-000481-58) was a pivotal, phase 3, randomised, double-blind, placebo-controlled trial evaluating the efficacy and safety of vedolizumab SC (108 mg every 2 weeks) as maintenance treatment in patients with moderately to severely active CD. Following intravenous (IV) vedolizumab (300 mg Week 0 and 2) induction, patients with a clinical response at Week 6 (≥70-point decrease in CD activity index [CDAI] from Week 0) were randomised to blinded maintenance treatment and included in the analyses. Vedolizumab serum concentrations were measured prior to dosing using an enzyme-linked immunosorbent assay. Immunogenicity was assessed with a drug-tolerant electrochemiluminescence assay. Predicted vedolizumab trough concentrations at Week 52 were grouped by quartiles (Q), and Week 52 efficacy outcome rates calculated for each Q. Missing efficacy outcome data were imputed as failures. Efficacy outcomes were clinical remission (CDAI ≤150) and enhanced clinical response (≥100-point decrease in CDAI from Week 0 at Week 52). Results Following vedolizumab IV induction (N = 644), patients with a clinical response were randomised and received vedolizumab SC (N = 275) or placebo (N = 134) as maintenance treatment. At Week 52, patients on vedolizumab SC maintenance had a positive exposure–efficacy relationship for clinical remission (Q1: 37.7%; Q4: 50.7%) and enhanced clinical response (Q1: 37.7%; Q4: 53.6%; Figures 1 and 2). Overall, 7/275 (2.5%) patients on vedolizumab SC (following vedolizumab IV induction) developed anti-vedolizumab antibodies (AVAs): 3/7 patients were persistently AVA positive and 4/7 had neutralising antibodies. Five of 7 AVA-positive patients on vedolizumab SC did not achieve clinical remission and enhanced clinical response at Week 52; 2 of those patients were persistently AVA-positive. Immunogenicity was not associated with injection-site reactions or hypersensitivity reactions. Conclusion These preliminary results suggest a trend for higher vedolizumab SC serum concentrations with greater efficacy in CD, but the association was less pronounced than was reported in UC. (1) The AVA rate was similar to what was observed in prior vedolizumab IV studies. (2) In this study, vedolizumab immunogenicity appeared to be associated with clinical outcome. References

scholarly journals P577 Ustekinumab in actual clinical practice: our centre experience

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S485-S486
Author(s):  
J M LOPEZ TOBARUELA ◽  
A D Sanchez-Capilla ◽  
E J Ortega-Suazo ◽  
M C Fernandez-Cano ◽  
M Herrador-Paredes ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Clinical Response ◽  
Safety Profile ◽  
Clinical Remission ◽  
Clinical Manifestations ◽  
Previous Treatment ◽  
Biological Therapies ◽  
Response Predictors ◽  
Wide Variability

Abstract Background Crohn’s disease is an entity with wide variability in its clinical manifestations, which mainly affects the gastrointestinal tract, and may also involve another organs. We have a wide variety of treatments available, being the most recent ones biological therapies. One of them is ustekinumab, which due to its innovative mechanism of action has improved the quality of life of many patients with an excellent safety profile. Our objective was to analyze the baseline situation of 37 patients undergoing treatment with ustekinumab in our centre and the evolution of different clinical and analytical parameters at 12, 24 and 52 weeks after starting it. Methods 37 patients currently receiving ustekinumab treatment with indication of Crohn’s disease at Virgen de las Nieves Hospital were selected (Tables 1 and 2). Clinical response was analyzed according to the Harvey–Bradshaw Index (HBI) (clinical remission &lt;4, clinical response decrease ≥3 points above the baseline), blood and stool test (CRP and calprotectin) at weeks 12, 24 and 52, need for surgery and safety profile (Table 3). Results There are no significant differences in HBI or baseline CRP depending on previous or not treatment with anti-TNF or vedolizumab. No differences in HBI, CRP at weeks 12, 24 and 52 depending on if previous treatment with anti-TNF or vedolizumab. The decrease in the median values of HBI was statistically significant at weeks 12, 24 and 52; as well as CRP values at weeks 24 and 52 (Table 3). According to HBI, clinical response was obtained in 41,38%, 50% and 61,11% of patients at weeks 12, 24 and 52 and clinical remission in 20,69%, 33,33% and 27,78% respectively (Table 3). No response predictors were identified at week 12 except for non-perianal fistulas associated with a greater response (58,3% vs. 41,7%; p = 0,0459) (Table 4). Conclusion In this group of patients potentially difficult to treat (62% previous surgery, long-term disease, 95% previous treatment with immunomodulators and/or biological therapies (66% ≥2 anti-TNF), etc.), ustekinumab achieves clinical response in 41,38%, 50%, 61,11% at week 12, 24 and 52. Surgery was required in 2 cases and only 3 patients suffered relevant adverse effects. In a pivotal study of ustekinumab UNITI-1, 50,6% of patients who received the induction dose of 6 mg/kg had previously been treated with ≥2 anti-TNF, in our group, 65,71%. In our cohort, only 29,73% of patients received corticosteroids concomitantly at the start of ustekinumab treatment vs. 43,3% at UNITI-1. Despite these differences against our group, clinical response and remission data are similar to UNITI-1 (41,38% vs. 37,8% and 20,69% vs. 20,9% respectively). Prospective studies with more patients could identify who would benefit most from this treatment.

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