scholarly journals Mucosal Inflammatory and Wound Healing Gene Programmes Reveal Targets for Stricturing Behaviour in Paediatric Crohn’s Disease

2020 ◽  
Author(s):  
Yael Haberman ◽  
Phillip Minar ◽  
Rebekah Karns ◽  
Phillip J Dexheimer ◽  
Sudhir Ghandikota ◽  
...  
Keyword(s):  
Gene Expression ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Small Molecules ◽  
Area Under The Curve ◽  
Gene Signature ◽  
Oncostatin M ◽  
Fibroblast Activation ◽  
Pre Treatment

Abstract Background and Aims Ileal strictures are the major indication for resective surgery in Crohn’s disease [CD]. We aimed to define ileal gene programmes present at diagnosis and linked with future stricturing behaviour during 5-year follow-up, and to identify potential small molecules to reverse these gene signatures. Methods Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicentre paediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behaviour and for model testing to predict stricturing behaviour. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. Results A total of 19 of the 249 patients developed isolated B2 stricturing behaviour during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our previous report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix [ECM] gene expression, in those who developed stricturing complications. We further computationally prioritise small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by Year 5 after diagnosis {AUC (area under the curve) (95th CI [confidence interval]) = 0.82 [0.7–0.94)}. Conclusions An ileal gene programme for macrophage and fibroblast activation is linked to stricturing complications in treatment of naïve pediatric CD, and may inform novel small molecule therapeutic approaches.

scholarly journals DOP89 Pre-treatment mucosal inflammatory and wound healing gene programmes reveal mechanisms associated with future stricturing behaviour during 5-year follow-up in paediatric Crohn’s disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S127-S127
Author(s):  
Y Haberman Ziv ◽  
P Minar ◽  
R Karns ◽  
P Dexheimer ◽  
S Ghandikota ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Small Molecules ◽  
Gene Signature ◽  
Type I ◽  
Expression Signature ◽  
Fibroblast Activation ◽  
Sirius Red

Abstract Background Stricturing complications account for substantial morbidity in Crohn’s disease (CD). We aimed to define ileal gene programmes present at diagnosis in paediatric CD associated with future stricturing behaviour (B2), and to identify potential small molecules to reverse these gene signatures. Methods Antimicrobial serologies and ileal gene expression (RNASeq) were assessed at diagnosis in 249 CD patients enrolled in a 5-year inception cohort study. These data were used to define genes associated with stricturing behaviour and for model testing to predict stricturing. Sirius Red immuno-histochemistry was utilised to determine the extent of collagen infiltration into the sub-cryptal space. A bioinformatics approach defined small molecules which may reverse the stricturing gene signature. Results Of 249 (8%) patients, 19 developed B2 behaviour during the 5-year follow-up, while 218 remained B1 inflammatory. We defined 518 genes that were differentially expressed in the ileum at diagnosis (FC≥1.5, FDR<0.05) in B1 patients who later developed B2 stricturing complications vs. those who remained B1 throughout. These were notable for baseline up-regulation of OSM implicated in anti-TNF non-response, NCF2 and CSF3R implicated in myeloid cell activation, TGFBI implicated in tissue fibrosis, and a panel of 17 collagen genes in patients who progressed to stricturing. Sirius red staining confirmed an increase in sub-cryptal type I/III collagen in B1 patients at diagnosis who progressed to B2 behaviour. Of these 518 genes, we highlighted an inflammatory OSM co-expression signature that was tightly associated with an extracellular matrix COL1A2 co-expression signature (Pearson r = 0.88, p < 0.0001). Network annotation analyses of those co-expression signatures showed that response to wounding, myeloid dendritic cells, and gp38+ stromal cells signatures are linked to both. Extracellular matrix (ECM) annotation, collagen binding, fibroblasts, and angiogenesis were more specific to the COL1A2 signature, and granulocytes and response to other organisms were more specific to the OSM co-expression signature. We further define small molecules targeting macrophage and fibroblast activation, and angiogenesis, which may reverse the stricturing gene signature including ephrin inhibitors, eicosatetraynoic acid (cyclooxygenase/lipoxygenase inhibitor), orantinib (PDGFR inhibitor), and PT-630 (fibroblast activation inhibitor). Our previous model containing serologies and a refined ECM gene set was significantly associated with stricturing development by year 5 (AUC:0.82) Conclusion An ileal gene program for macrophage and fibroblast activation is linked to future stricturing complications in treatment naïve paediatric CD, and may inform small-molecule therapeutic approaches.

935 PRE-TREATMENT MUCOSAL INFLAMMATORY AND WOUND HEALING GENE PROGRAMS REVEAL MECHANISMS ASSOCIATED WITH FUTURE STRICTURING BEHAVIOR DURING FIVE YEAR FOLLOW-UP IN PEDIATRIC CROHN'S DISEASE

2020 ◽  
Vol 158 (6) ◽  
pp. S-187-S-188
Author(s):  
Yael Haberman ◽  
Phillip P. Minar ◽  
Rebekah Karns ◽  
Phillip J. Dexheimer ◽  
Sudhir Ghandikota ◽  
...  
Keyword(s):  
Wound Healing ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Pre Treatment

scholarly journals Analyses of Changing Disease Patterns and Factors Related to Disease Outcomes in Patients with Crohn’s Disease after 7 Years of Follow-up: A Single-center Retrospective Study

2021 ◽  
Author(s):  
Dong Yoon Han ◽  
So Hyun Park ◽  
Mirinae Seo ◽  
Seong Jin Park ◽  
Zi-Xin Liu ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Area Under The Curve ◽  
Disease Course ◽  
Disease Patterns ◽  
Disease Characteristics ◽  
Disease Behavior ◽  
Significant Factors

Abstract Background: The clinical spectrum and disease course of Crohn’s disease (CD) are heterogeneous and difficult to predict based on initial presentation. Aim: To analyze the long-term disease course and factors leading to poor prognosis of the disease.Methods: In total, 112 patients with CD who were initially diagnosed or treated at our institution were included. We analyzed their clinical data, disease characteristics according to Montreal classification, endoscopic and computed tomography (CT) examinations at initial visit, and 2-year, 5-year, and last follow-ups. We categorized the long-term disease course into four categories: remission, stable, chronic refractory, and chronic relapsing. Significant factors associated with a poorer prognosis were analyzed.Results: The median follow-up period was 107 (range, 61-139) months. Complicated disease behavior increased slightly (20.5% to 26.2%). Chronic refractory (19.6%) and relapsing (16.1%) courses were defined as unfavorable disease course. Two-year disease characteristics were significant factors for unfavorable disease course, and the combination of 2-year perianal disease and 2-year moderate-to-severe CT activity could predict unfavorable disease course with the highest accuracy (0.722, area under the curve 0.768, p<.0001). Conclusions: One-third of our CD patients showed an unfavorable disease course (35.7%) and 2-year disease characteristics were significant factors for an unfavorable disease course.

Bone loss in patients with Crohn's disease: A longterm-follow up study

2001 ◽  
Vol 120 (5) ◽  
pp. A628-A628
Author(s):  
P CLEMENS ◽  
V HAWIG ◽  
M MUELLER ◽  
J SCAENZLIN ◽  
B KLUMP ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Bone Loss ◽  
Follow Up Study

UNEXPECTED FINDING DURING CROHN’S DISEASE FOLLOW-UP

2020 ◽  
Author(s):  
LM Grazioli ◽  
V Gerardi ◽  
SM Milluzzo ◽  
C Spada
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Unexpected Finding

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

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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