Journey through Crohn’s Disease Complication: From Fistula Formation to Future Therapies

Crohn’s Disease (CD) is a chronic inflammatory disorder in which up to 50% of patients develop fistula within 20 years after the initial diagnosis, and half of these patients suffer perianal fistulizing disease. The etiopathogenesis of CD-related perianal fistula is still unclear, and its phenotypical and molecular characteristics are even more indefinite. A better understanding would be crucial to develop targeted and more effective therapeutic strategies. At present, the most accredited theory for the formation of CD-related fistula identifies the epithelial-to-mesenchymal transition (EMT) as the driving force. It has been well recognized that CD carries an increased risk of malignancy, particularly mucinous adenocarcinoma is often associated with long-standing fistula in CD patients. Despite the availability of multiple treatment options, perianal fistulizing CD represents a therapeutic challenge and is associated with an important impact on patients’ quality of life. To date, the most effective management is multidisciplinary with the cooperation of gastroenterologists, surgeons, radiologists, and nutritionists and the best recommended treatment is a combination of medical and surgical approaches.

Download Full-text

OP12 The incidence and disease course of perianal Crohn’s disease: A Danish nationwide cohort study

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.011 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S012-S012

Author(s):

M D Wewer ◽

M Zhao ◽

A Nordholm-Carstensen ◽

J B Seidelin ◽

J Burisch

Keyword(s):

Rectal Cancer ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Incidence Rate ◽

Anal Cancer ◽

Perianal Fistula ◽

Disease Course ◽

Perianal Crohn’S Disease ◽

Increased Risk ◽

Perianal Crohn's Disease

Abstract Background Perianal Crohn’s disease (pCD) has a major negative impact on patients’ quality of life and is complex to treat. Despite its putative high frequency and burden for patients, only a few studies have investigated the incidence, disease course and associated cancer-risk in a population-based setting. The aim was to assess the incidence and course of pCD in adult patients with CD within a 19-year period. Specifically, describing changes in medical and surgical management as well as rates of cancer. Methods The cohort comprised all individuals >18 years diagnosed with CD in Denmark between 1 January 1997 and 31 December 2015. Patients were identified in the National Patient Registry. Chi-square test, Mann–Whitney–Wilcoxon test and multivariate Cox regression analysis were used. Results A total of 1,697/9,739 (17%) patients with CD were found to have pCD. Perianal fistulas were the most common manifestation accounting for 943 (56%) cases. The onset of pCD before CD diagnosis occurred in 32%. The overall incidence of pCD was 20/1,000 patient-years. The incidence of pCD remained stable over time. More patients with pCD were treated with immunomodulators (70%) and biologics (35%) than those without pCD (51%, p < 0.001 and 15%, p < 0.001, respectively). Defunctioning stoma was performed in 157/943 (17%) of perianal fistula patients. Stoma formation in relation to resection was performed in 112/943 (12%) of perianal fistula patients. Patients with pCD were found to have a significantly increased risk of undergoing major abdominal surgery compared with patients without pCD (hazard ratio: 1.52, 95% CI: 1.40 to 1.65, p < 0.001). The incidence rate ratios of anal and rectal cancer in pCD patients were 12.46 (95% CI: 5.07 to 30.59, p < 0.001) and 2.41 (95% CI: 1.31 to 4.42, p = 0.003) respectively, when compared with non-IBD matched controls. The incidence rate ratio of anal and rectal cancer in pCD patients was 2.36 (95% CI: 0.86 to 6.50, p = 0.09) and 1.35 (95% CI: 0.68 to 2.68, p = 0.38) respectively, when compared with CD patients without pCD. Conclusion In this nationwide study, 17% of the CD patients developed pCD. The continuing high incidence of pCD suggests a limited disease-modifying effect of biologics. Patients with pCD were at increased risk of undergoing major surgery compared with non-pCD patients. The risk of rectal or anal cancer was increased in patients with pCD compared with non-IBD matched controls. These findings encourage surveillance of rectal and anal cancer.

Download Full-text

Profiling Non-Coding RNA Levels With Clinical Classifiers in Pediatric Crohn’s Disease

10.21203/rs.3.rs-88594/v1 ◽

2020 ◽

Author(s):

Ranjit S. Pelia ◽

Suresh Venkateswaran ◽

Jason D. Matthews ◽

Yael Haberman ◽

David J. Cutler ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Disease Progression ◽

Protein Function ◽

Inflammatory Disorder ◽

Substantial Impact ◽

Chronic Inflammatory Disorder ◽

Inflammatory Status ◽

Disease Behavior ◽

Non Coding Rnas

Abstract Background: Crohn’s disease (CD) is a heritable chronic inflammatory disorder. Non-coding RNAs (ncRNAs) play an important role in epigenetic regulation by affecting gene expression, but can also directly affect protein function, thus having a substantial impact on biological processes. We investigated whether non-coding RNAs (ncRNA) at diagnosis are dysregulated during CD at different CD locations and future disease behaviors to determine if ncRNA signatures can serve as an index to outcomes. Methods: Using subjects belonging to the RISK cohort, we analyzed ncRNA from the ileal biopsies of 345 CD and 71 non-IBD controls, and ncRNA from rectal biopsies of 329 CD and 61 non-IBD controls. Sequence alignment was done (STAR package) using Human Genome version 38 (hg38) as reference panel. The differential expression (DE) analysis was performed with EdgeR package and DE ncRNAs were identified with a threshold of fold change (FC) >2 and FDR < 0.05 after multiple test corrections. Results: In total, we identified 130 CD specific DE ncRNAs (89 in ileum and 41 in rectum) when compared to non-IBD controls. Similarly, 35 DE ncRNAs were identified between B1 and B2 in ileum, whereas no differences among CD disease behaviors were noticed in rectum. We also found inflammation specific ncRNAs between inflamed and non-inflamed groups in ileal biopsies. Overall, we observed that expression of mir1244-2, mir1244-3, mir1244-4, and RN7SL2 were increased during CD, regardless of disease behavior, location, or inflammatory status. Lastly, we tested ncRNA expression at baseline as potential tool to predict the disease status, disease behaviors and disease inflammation at 3-year follow up.Conclusions: We have identified ncRNAs that are specific to disease location, disease behavior, and disease inflammation in CD. Both ileal and rectal specific ncRNA are changing over the course of CD, specifically during the disease progression in the intestinal mucosa. Collectively, our findings show changes in ncRNA during CD and may have a clinical utility in early identification and characterization of disease progression.

Download Full-text

Mucosal Healing in Crohn’s Disease: Bull’s Eye or Bust? “The Pro Position”

Inflammatory Intestinal Diseases ◽

10.1159/000519521 ◽

2021 ◽

pp. 1-6

Author(s):

Neil O’Moráin ◽

Jayne Doherty ◽

Roisin Stack ◽

Glen A. Doherty

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Mucosal Injury ◽

Mucosal Healing ◽

Inflammatory Disorder ◽

Stricture Formation ◽

Chronic Inflammatory Disorder ◽

Non Invasive ◽

Appropriate Treatment ◽

Bull's Eye

Background: Crohn’s disease (CD) is a chronic inflammatory disorder affecting the gastrointestinal tract with disease behaviour based on the depth and severity of mucosal injury. Cumulative injury can result in complications including stricture formation and penetrating complications which often require surgical resection of diseased segments of the intestine resulting in significant morbidity. Accurate assessment of disease activity and appropriate treatment is essential in preventing complications. Summary: Treatment targets in the management of CD have evolved with the advent of more potent immunosuppressive therapy. Targeting the resolution of sub-clinical inflammation and achieving mucosal healing is associated with the prevention of stricturing and penetrating complications. Identifying non-invasive modalities to assess mucosal healing remains a challenge. Key Messages: Mucosal healing minimizes the risk of developing disease complications, prolongs steroid-free survival, and reduces hospitalization and the need for surgical intervention.

Download Full-text

T300A GENETIC POLYMORPHISM: a susceptibility factor for Crohn’s disease?

Arquivos de Gastroenterologia ◽

10.1590/s0004-28032014000200005 ◽

2014 ◽

Vol 51 (2) ◽

pp. 97-101 ◽

Cited By ~ 5

Author(s):

Bruno Lorenzo SCOLARO ◽

Emily dos SANTOS ◽

Leslie Ecker FERREIRA ◽

Paulo Henrique Condeixa de FRANÇA ◽

Harry KLEINUBING ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Fragment Length Polymorphism ◽

Control Group ◽

Polymorphism Analysis ◽

Inflammatory Disorder ◽

Increased Risk ◽

Polymerase Chain ◽

Increased Susceptibility

ContextCrohn’s disease is characterized by a chronic and debilitating inflammatory disorder of the gastrointestinal tract. Several factors may contribute to its development. From extensive studies of the human genome, the polymorphism T300A of the gene ATG16L1 (autophagy-related 16-like 1) has been related to increased risk of developing this disease.ObjectivesAnalyze the role of polymorphism T300A (rs2241880) in patients with Crohn’s disease.Methods238 samples from (control group) and 106 samples from patients with Crohn’s disease recruited at five Southern Brazilian reference centers were evaluated. The genotyping consisted of the amplification via Polymerase Chain Reaction of the genomic segment encompassing T300A, followed by Restriction Fragment Length Polymorphism analysis. The amplicons and fragments were separated by agarose gel electrophoresis and confirmed under ultraviolet light.ResultsThe genotype AG was more prevalent among patients and controls (50% vs 44.8%), followed by genotypes AA (26.4% vs 35.1%) and GG (23.6% vs 20.1%). The frequency of the allele G of the polymorphism T300A was higher in the group of patients with Crohn’s disease (48.6%) than in controls (42.4%), although not reaching statistical significance.ConclusionsIt was not possible to confirm the increased susceptibility on development of Crohn’s disease conferred by polymorphism T300A.

Download Full-text

Mesenchymal Stromal Cell Therapy in the Management of Perianal Fistulas in Crohn’s Disease: An Up-To-Date Review

Medicina ◽

10.3390/medicina56110563 ◽

2020 ◽

Vol 56 (11) ◽

pp. 563

Author(s):

Gaetano Gallo ◽

Vincenzo Tiesi ◽

Serena Fulginiti ◽

Gilda De Paola ◽

Giuseppina Vescio ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Stromal Cells ◽

Tissue Repair ◽

Negative Impact ◽

Inflammatory Disorder ◽

Chronic Inflammatory Disorder ◽

Entire Gastrointestinal Tract

Crohn’s Disease (CD) is a chronic inflammatory disorder that potentially involves the entire gastrointestinal tract. Perianal fistulizing CD (pCD) is a serious and frequent complication associated with significant morbidities and a heavy negative impact on quality of life. The aim of CD treatment is to induce and maintain disease remission and to promote mucosal repair. Unfortunately, even the best therapeutic regimens in pCD do not have long-term efficacy and cause a significant number of side effects. Therefore, it is mandatory to study new therapeutical options such as the use of mesenchymal stromal cells (MSCs). These cells promote tissue repair via the induction of immunomodulation. The present review aims to analyze the existing updated scientific literature on MSCs adoption in the treatment of pCD to evaluate its efficacy and safety and to compare the use of bone marrow and adipose tissue derived MSCs, type of administration, and dose required for recovery.

Download Full-text

Transcriptional and Molecular Pathways Activated in Mesenteric Adipose Tissue and Intestinal Mucosa of Crohn’s Disease Patients

International Journal of Inflammation ◽

10.1155/2017/7646859 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

Andressa Coope ◽

Lívia Bitencourt Pascoal ◽

Francesca Aparecida Ramos da Silva ◽

José Diego Botezelli ◽

Maria de Lourdes Setsuko Ayrizono ◽

...

Keyword(s):

Adipose Tissue ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Signaling Pathways ◽

Intestinal Mucosa ◽

Inflammatory Disorder ◽

Chronic Inflammatory Disorder ◽

Mesenteric Adipose Tissue ◽

Immune Mediated ◽

First Time

Crohn’s disease (CD) is a chronic inflammatory disorder, characterized by cytokine imbalance and transcription signaling pathways activation. In addition, the increase of mesenteric adipose tissue (MAT) near the affected intestinal area is a hallmark of CD. Therefore, we evaluated the transcription signaling pathways and cytokines expression in intestinal mucosa and MAT of active CD patients. Ten patients with ileocecal CD and eight with noninflammatory diseases were studied. The biopsies of intestinal mucosa and MAT were snap-frozen and protein expression was determined by immunoblotting. RNA levels were measured by qPCR. The pIkB/IkB ratio and TNFαlevel were significantly higher in intestinal mucosa of CD when compared to controls. However, STAT1 expression was similar between intestinal mucosa of CD and controls. Considering the MAT, the pIkB/IkB ratio was significantly lower and the anti-inflammatory cytokine IL10 was significantly higher in CD when compared to controls. Finally, the protein content of pSTAT1 was higher in MAT of CD compared to controls. These findings reinforce the predominance of the proinflammatory NF-kB pathway in CD intestinal mucosa. For the first time, we showed the activation of STAT1 pathway in MAT of CD patients, which may help to understand the physiopathology of this immune mediated disease.

Download Full-text

Bacterial Translocation as Inflammatory Driver in Crohn’s Disease

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.703310 ◽

2021 ◽

Vol 9 ◽

Author(s):

Raquel Linares ◽

Rubén Francés ◽

Ana Gutiérrez ◽

Oriol Juanola

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Inflammatory Response ◽

Genetic Predisposition ◽

Intestinal Barrier ◽

Inflammatory Disorder ◽

Bacterial Antigen ◽

Increased Risk ◽

Frequent Event ◽

Bacterial Products

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract responsible for intestinal lesions. The multifactorial etiology attributed to CD includes a combination of environmental and host susceptibility factors, which result in an impaired host–microbe gut interaction. Bacterial overgrowth and dysbiosis, increased intestinal barrier permeability, and altered inflammatory responses in patients with CD have been described in the past. Those events explain the pathogenesis of luminal translocation of bacteria or its products into the blood, a frequent event in CD, which, in turn, favors a sustained inflammatory response in these patients. In this review, we navigate through the interaction between bacterial antigen translocation, permeability of the intestinal barrier, immunologic response of the host, and genetic predisposition as a combined effect on the inflammatory response observed in CD. Several lines of evidence support that translocation of bacterial products leads to uncontrolled inflammation in CD patients, and as a matter of fact, the presence of gut bacterial genomic fragments at a systemic level constitutes a marker for increased risk of relapse among CD patients. Also, the significant percentage of CD patients who lose response to biologic therapies may be influenced by the translocation of bacterial products, which are well-known drivers of proinflammatory cytokine production by host immune cells. Further mechanistic studies evaluating cellular and humoral immune responses, gut microbiota alterations, and genetic predisposition will help clinicians to better control and personalize the management of CD patients in the future.

Download Full-text

XI. Novel mouse models to study pathogenic mechanisms of Crohn's disease

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2000.278.5.g665 ◽

2000 ◽

Vol 278 (5) ◽

pp. G665-G669 ◽

Cited By ~ 29

Author(s):

Theresa T. Pizarro ◽

Kristen O. Arseneau ◽

Fabio Cominelli

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Mouse Models ◽

Intestinal Inflammation ◽

The United States ◽

Inflammatory Disorder ◽

Chronic Inflammatory Disorder ◽

Therapeutic Modalities ◽

Genetically Manipulated ◽

Chronic Intestinal Inflammation

Crohn's Disease (CD) affects more than 500,000 individuals in the United States and represents the second most common chronic inflammatory disorder after rheumatoid arthritis. Although major advances have been made in defining the basic mechanisms underlying chronic intestinal inflammation, the precise etiopathogenesis of CD remains unknown. We have recently characterized two novel mouse models of enteritis that express a CD-like phenotype, namely the TNF ΔARE model of tumor necrosis factor (TNF) overexpression and the SAMP1/Yit model of spontaneous ileitis. The unique feature of these models is that they closely resemble CD for location and histopathology. These genetically manipulated new models of intestinal inflammation offer a powerful tool to investigate potential causes of human disease and may allow the development of novel disease-modifying therapeutic modalities for the treatment of CD.

Download Full-text

Behcet’s Syndrome resembling complex perianal Crohn’s Disease

SAGE Open Medical Case Reports ◽

10.1177/2050313x211009717 ◽

2021 ◽

Vol 9 ◽

pp. 2050313X2110097

Author(s):

Ali P Mourad ◽

Marie Shella De Robles ◽

Robert DR Winn

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Perianal Fistula ◽

Inflammatory Disorder ◽

Behçet’S Syndrome ◽

Left Groin ◽

Behçet's Syndrome ◽

Organ Systems ◽

Behcet’S Syndrome ◽

Behcet's Syndrome

Behcet’s syndrome is a systemic inflammatory disorder that involves several organ systems and is exceptionally rare in the Western world. The diagnosis is frequently difficult as it resembles several other disease processes. A 23-year-old male with a previous presumptive diagnosis of Crohn’s disease presented to our unit with genital ulceration. This is on a background of recurrent perianal abscesses requiring surgical drainage and seton placement. He subsequently developed a complex perianal fistula extending from the rectum to the perineum and left groin. After drainage and an unsuccessful trial of biologic immunosuppressive therapy, he developed several papulopustular cutaneous lesions and oral ulcerations. The diagnostic criteria for Behcet’s syndrome was met and he was referred to a rheumatologist for ongoing management.

Download Full-text

Roles of IL-17A and IL-23 in the Pathogenesis of Ulcerative Colitis and Crohn’s Disease

Iraqi Journal of Science ◽

10.24996/ijs.2021.62.8.5 ◽

2021 ◽

pp. 2526-2535

Author(s):

Sarah S. Abdul-Hussein ◽

Ekhlass N. Ali ◽

Nawal M. F. Alkhalidi ◽

Neihaya H. Zaki ◽

Ali H. Ad'hiah

Keyword(s):

Ulcerative Colitis ◽

Crohn’S Disease ◽

Family History ◽

Crohn's Disease ◽

Smoking Status ◽

Serum Levels ◽

Inflammatory Disorder ◽

Chronic Inflammatory Disorder ◽

History Of ◽

Disease Extension

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder, the etiology and pathogenesis of which have been suggested to be influenced by cytokines. Two main clinical types of IBD are recognized, namely ulcerative colitis (UC) and Crohn's disease (CD). The present study examined serum levels of two cytokines (IL-17A and IL-23) in 60 IBD patients (30 UC and 30 CD) and 30 healthy controls. The levels were correlated with age, gender, cigarette-smoking status, disease duration, family history, disease extension, symptoms, extra-intestinal manifestations, and medication. The results depicted that IL-17A level was significantly higher in UC and CD patients compared to control (45.2 ± 23.3 and 47.5 ± 34.4 vs. 15.6 ± 7.5 pg/ml, respectively; p < 0.001). Serum level of IL-23 was similarly increased in UC and CD patients compared to control (64.1± 23.7 and 62.5 ± 27.3 vs. 25.2 ± 11.1 pg/ml, respectively). However, the level of both cytokines showed no significant variation between UC and CD patients (p = 0.713 and 0.777, respectively). Distributing UC and CD patients into subgroups according to some characteristics revealed that IL-17A level was significantly increased in UC male compared to female patients (57.3 ± 18.2 vs. 34.5 ± 22.5 pg/ml; p = 0.005). It was also significantly increased in smoker UC patients compared with non-smoker patients (51.9 ± 19.4 vs. 31.6 ± 25.5 pg/ml; p = 0.022). Smoker CD patients also showed a significantly increased level of IL-23 compared to non-smoker patients (72.7 ± 28.5 vs. 52.2 ± 22.6 pg/ml; p = 0.038). In the case of family history, IL-23 level was significantly decreased in UC patients with a family history of IBD compared to CD patients with a family history (84.5 ± 24.3 vs. 50.4 ± 17.0 pg/ml.; p = 0.042). In conclusion, the present data suggest a role for IL-17A and IL-23 in the etiology and pathogenesis of UC and CD.

Download Full-text