Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Helena Tavares de Sousa
 -- 2188 2023-07-11 09:47:30 |
2 format correct
Catherine Yang
 Meta information modification 2188 2023-07-11 10:33:40 | |
3 format correct
Catherine Yang
 Meta information modification 2188 2023-07-13 08:22:02 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Tavares De Sousa, H.; Magro, F. The Fibrosis in Inflammatory Bowel Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/46630 (accessed on 08 September 2024).
Tavares De Sousa H, Magro F. The Fibrosis in Inflammatory Bowel Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/46630. Accessed September 08, 2024.
Tavares De Sousa, Helena, Fernando Magro. "The Fibrosis in Inflammatory Bowel Disease" Encyclopedia, https://encyclopedia.pub/entry/46630 (accessed September 08, 2024).
Tavares De Sousa, H., & Magro, F. (2023, July 11). The Fibrosis in Inflammatory Bowel Disease. In Encyclopedia. https://encyclopedia.pub/entry/46630
Tavares De Sousa, Helena and Fernando Magro. "The Fibrosis in Inflammatory Bowel Disease." Encyclopedia. Web. 11 July, 2023.
The Fibrosis in Inflammatory Bowel Disease
Edit
This entry is adapted from the peer-reviewed paper 10.3390/diagnostics13132188

Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic intestinal inflammation mediated by dysregulated immune responses to such factors as diet and microbiota. Fibrosis, which is a healing mechanism, becomes progressive and damaging in the scope of long-lasting IBD, in which persistent tissue damage and healing result in scar tissue formation.

inflammatory bowel disease fibrosis inflammation imaging histopathology

1. The Importance of Fibrosis in IBD

Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic intestinal inflammation mediated by dysregulated immune responses to such factors as diet and microbiota [1][2][3][4].
In both CD and UC, chronic inflammation causes disruption of the epithelial barrier and tissue destruction. Fibrosis, which is a healing mechanism, becomes progressive and damaging in the scope of long-lasting IBD, in which persistent tissue damage and healing result in scar tissue formation [5][6]. At tissue and cellular levels, fibrosis is an amplified response characterized by the accumulation of collagen-rich extracellular matrix (ECM) produced by an increased number of mesenchymal cells, including fibroblasts, myofibroblasts, and smooth muscle cells (SMCs) [7]. The proliferation of fibroblastic cells, along with the accumulation of ECM, are the hallmarks of intestinal strictures in IBD [8]. Fibrosis is a frequent outcome in the natural history of IBD and is the background for most of the IBD complications, such as strictures, bowel penetration, and obstruction, often demanding surgery [5][6][9]. It has been estimated that about 30% to 50% of CD patients and 1% to 12% of UC patients would suffer from fibrosis complications during the disease course [6][10][11]. Until recently, intestinal fibrosis was considered an unavoidable complication of IBD in patients that did not respond to anti-inflammatory therapy, often requiring surgical intervention [6]. The emergence of the possibility of an anti-fibrotic approach changed this paradigm, creating challenges in terms of diagnosis and treatment of bowel fibrosis [6][12]. As such, understanding the molecular and cellular mechanisms underpinning fibrosis and improving techniques for the assessment of fibrosis in IBD patients are still relevant research topics.

1.1. Fibrosis in CD

In CD, both inflammation and fibromuscular changes are transmural, leading to progressive thickening of the bowel wall and stricture development, even in the absence of inflammation. Pathologically, intestinal fibrosis in CD is characterized by ECM accumulation and mesenchymal cell expansion affecting all layers of the bowel wall along the intestinal tract [13]. In addition, recent pathologic consensus defined small bowel strictures in CD as a combination of decreased luminal diameter and increased thickness of all layers of the intestinal wall, including expansion of the muscularis mucosae (MM) and inner muscularis propria (MP), muscularization of the submucosa, and fibrosis of the submucosa and intestinal wall [14]. Notwithstanding, the universality of this concept was recently challenged by the description of a non-hypertrophic, constrictive type of stricture in CD [15]. Regardless of the type of stricture, these remain common complications of CD with serious clinical relevance and impact on the patients’ quality of life [12][15][16].
Aside from fibrosis in strictures, it has been proposed that a certain degree of fibrosis would exist in nearly all CD phenotypes, even from early onset. In addition, it has been demonstrated that the degree of fibrosis may be similar in both stricturing and penetrating CD, with differences regarding the degree of transmural inflammation [17].
Though still used in clinical practice, the classification of CD in three-category phenotypes, as inflammatory or non-stricturing, non-penetrating (B1), stricturing (B2), and penetrating (B3) disease, is now considered too rigid [18][19]. As an alternative, CD shall be viewed through the lens of a progressive accumulation of intestinal fibrosis and damage over the course of the disease, leading to stricturing and/or penetrating complications, as supported by epidemiological natural history studies [16][20][21][22][23][24][25][26]. This progressive and cumulative structural bowel damage would occur irrespective of symptoms and, considering current fibrogenesis knowledge, of the degree of intestinal inflammation [6][27][28]. Hence, clinical symptoms, disease activity [29][30], and progression of bowel damage [4][31] are not totally correlated.
Considering that population-based studies have shown a 10-year cumulative risk of surgery between 40% and 71% [32][33][34] and that fibrosis is a marker of advanced disease, its importance is central in the setting of CD, as it underlies the need for surgical resection in stricturing disease and, maybe, also in penetrating complications, as strictures coexist in over 85% of penetrating CD [4][30][31][32][33][34][35].
In this context, to further understand pathology changes in CD, deep research on the basic cellular and molecular mechanisms of fibrogenesis is warranted.

1.2. Fibrosis in UC

In UC patients, fibrosis is characterized by a thickening of MM and excessive ECM deposition in the submucosa, affecting deeper layers only after profound ulceration of the submucosa [36][37][38]. Strictures are uncommon in UC, and the majority are benign and reversible [39]. However, in UC, fibrosis originates the increased wall stiffness, which may result in motility abnormalities, anorectal dysfunction, rectal urgency, and incontinence [10][38].
The evidence regarding fibrosis in UC is limited and controversial, but a comprehensive assessment performed by Gordon et al. in 2018 demonstrated that UC is characterized by progressive fibrosis and MM thickening in correlation with the severity and chronicity of inflammation. Hence, deep remission, including histological remission, should be a priority and a therapeutic target [40]. Recent research in mice with dextran sulfate sodium (DSS)-induced colitis has shown that, in UC, changes in motility may also be related to neuronal modification. The study highlighted that UC does not promote neuron death but induces changes in the chemical code of myenteric neurons [41]. A better comprehension of these data and the translation of these results depend on studies on human tissue.

2. The Future Holding for Fibrosis

2.1. Radiomics

In a 2020 commentary, Lin and colleagues discussed the concept of computer-assisted image analysis in the context of IBD and suggested radiomics as a tool to transform qualitative fibrosis evaluations on quantitative data [42]. The path to this discussion was opened by a study on the applicability of semi-automated analysis to the measurement of bowel structural damage, with evidence of high consistency with measurements performed by experienced radiologists [43]. In line with data from other diseases, at this point, a few studies support that radiomics of MRE and CTE, consisting of the extraction of high-dimensional data from CSI images, are viewed as a potential source of valuable data for the assessment of IBD fibrosis [43][44][45]. In 2021, Li and colleagues developed a novel CTE-radiomic model for the characterization of intestinal fibrosis in CD, which distinguished the histological non-mild from moderate–severe fibrosis with an AUC of 0.888 on the training cohort and AUCs between 0.724 and 0.816 (95% CI) in the three test cohorts. Moreover, the model performed better than visual interpretations by two experienced radiologists (p < 0.001) [45]. The potential of radiomics in this setting was also evidenced in a recent study that reported the integration of CTE on a deep-learning model based on a 3D deep convolutional neural network with 10-fold cross-validation. This model also presented higher accuracy for the assessment of fibrosis severity than CTE evaluation by two radiologists, with the advantage of having a shorter processing time [44]. Despite the robustness of these data, in a letter to the Editor of Gastroenterology, Zhang considered that the validation of these results depends on the development of reliable radiomic biomarkers and criteria to evaluate the design and report of radiomic studies in prospective cohorts [46]. Very recently, the STAR consortium presented the results of a machine-reader evaluation of severe inflammation and fibrosis in CD strictures through quantitative radiomic features and expert radiologist scoring on CTE [47]. Based on the evidenced association of two distinct sets of radiomic features for severe inflammation and fibrosis (p < 0.01), the authors considered that the combination of quantitative radiomics with radiological visual assessment might favor more personalized treatments by providing more accurate phenotyping of CD strictures. In the validation study, however, while confirming the value of radiomics in the identification of fibrosis but not inflammation in stricturing CD, the same group did not find advantages in combining radiomic features with the radiologist’s visual assessment [48]. Hence, it seems very likely that radiomics and AI will set the path for the future in the scope of fibrosis assessment by the CSI techniques in CD. However, it is still not clear whether AI alone (without concomitant human intervention) will be able to accomplish this purpose.

2.2. Others

Even though imaging techniques have been the focus of most of the developed research regarding fibrosis assessment, studies have diverted to other approaches, such as biochemical and genetic markers, including proteomics, genomics, metabolomics, and transcriptomics. The efforts are supported by the assumption that fibrosis biomarkers would provide useful data for risk stratification and treatment optimization of IBD patients. However, the available evidence includes conflicting data and is focused on markers with low diagnostic and prognostic value. Still, considering that past and ongoing research has provided promising data, an update of the most relevant candidate biomarkers seems appropriate in the context of this revision.
In 2014, the fourth scientific workshop of the European Crohn’s and Colitis Organization (ECCO) focused on understanding basic mechanisms and markers of intestinal fibrosis and considered that, as none of the available biomarkers were able to accurately assess fibrosis, research for novel targets should proceed, as it is pivotal for the development of novel therapeutic options for intestinal fibrosis [49].
In 2012, based on previous findings in the scope of renal disease, Chen and coworkers explored the role of miR-200a and miR-200b in intestinal fibrosis in a colorectal adenocarcinoma epithelial cell line [50]. The results showed that miR-200b was overexpressed in the serum of the fibrosis group and could have diagnostic and therapeutic applications for CD patients with fibrosis. This study leveraged further research on this topic, including a revision on the emerging role of micro-RNAs (miRNAs) in IBD [51], exploring their involvement in the pathways of inflammation and fibrosis in IBD. At that point, the authors considered that miR-200 [50][52] and miR-29b [53] seemed to deserve further research due to evidence of their potential as IBD biomarkers. The importance of these two miRNA families was addressed in two 2015 and 2023 reviews [54][55]. In both, it is stated that the research performed so far still warrants confirmation in more robust studies due to small sample sizes, lack of control of patients’ heterogeneity, and absence of a standard protocol to assess miRNAs.
Other studied candidate biomarkers include serum and plasma proteins, such as collagen [56], ECM [57], pentraxin-2 [58], serum glycoproteins [59], enzymes, such as metalloproteinases [60], antimicrobial antibodies [61][62], and serum growth factors, such as YKL-40 [63][64] and gene variants [65]. Similar to miRNAs, data on these topics are conflicting and do not support their utility in the scope of fibrosis measurement.
In conclusion, considering the vast evidence on this topic, it seems that the efforts on the discovery of novel biomarkers to assess fibrosis would be more consequent through the development of more robust clinical trials based on solid and validated endpoints.

2.3. Anti-Fibrotic Therapy

The discussion of fibrosis in the context of IBD can only be completed by addressing the current therapeutic challenges and perspectives toward fibrosis. In the scope of CD, ECCO recommends endoscopic balloon dilatation (EBD) or surgery for patients with short strictures (<5 cm), and strictureplasty for the resection of long segments of the bowel; strictureplasty of the colon is not recommended [66]. Regarding EBD, the PRODILAT study—an RCT with CD patients with the obstructive disease and predominantly fibrotic strictures of less than 10 cm—showed that 80% of the patients approached with this technique were free of a new therapeutic intervention at 1 year; compared with fully covered self-expandable metal stents, EBD proved to be more effective for CD strictures [67].
So far, past and ongoing research did not generate evidence to support the approval of any anti-fibrotic agent. Considering that the fibrosis process is similar in IBD and in systemic and pulmonary fibrosis, several drugs are under investigation as anti-fibrotic agents, in a pre-clinical setting resorting mainly to UC animal models, with promising results in the TGF-β [68][69][70][71][72][73][74][75][76], TNF [77], IL-36 [78], rho-kinase [79], peroxisome-proliferator activated receptor (PPAR) [80], HMG-CoA reductase [81] pathways, among others (Table 1) [5][82]. Table 1 includes the most promising targets and molecules and is not an exhaustive description of all the ongoing research in this field. Regarding phase 2 studies, spesolimab proved to be well tolerated with an adverse event rate similar to placebo (without meeting efficacy criteria) [78], and PF-06480605 demonstrated an acceptable safety profile with concomitant endoscopic improvement (week 14) in patients with moderate to severe UC [77].
Table 1. Potential anti-fibrotic agents under research.
Agent Pathway Model Research Status Reference
Pirfenidone TGFβ Human cells Pre-clinical [68][69][70][71][72][73]
Murine models
Mice
Tranilast TGFβ Rats Pre-clinical [74][75]
Rat models
Patients with CD
EW-7197 TGFβ Murine model Pre-clinical [76]
PF-06480605 TNF Patients with UC Phase 2 [77]
Spesolimab IL-36 Patients with UC Phase 2 [78]
AMA0825 Rho-kinase inhibitor Mice models Pre-clinical [79]
Cells
CD biopsies
GED-0507-34 PPARγa agonist Mice Pre-clinical [80]
Statins HMG-CoA reductase inhibitors Human intestinal fibroblasts Pre-clinical [81]
CD: Crohn’s disease; IL-36: interleukin 36; HMG-CoA: 3-hydroxy-3-methylglutaryl-CoA; PPARγa: peroxisome proliferator-activated receptor-γ; TGFβ: transforming growth factor β; TNF: tumor necrosis factor; UC: ulcerative colitis.
Several molecules are now awaiting clinical trials in humans, and in the near future, new therapeutic agents may be approved. Further improvements in this field have been hindered by the reduced research in CD models and by the lack of research standards. The intensive work of the STAR consortium regarding the standardization of the conditions to measure response to anti-fibrotic agents will be determinant for the success of these processes.

References

  1. Sairenji, T.; Collins, K.L.; Evans, D.V. An Update on Inflammatory Bowel Disease. Prim. Care 2017, 44, 673–692.
  2. Quaresma, A.B.; Kaplan, G.G.; Kotze, P.G. The Globalization of Inflammatory Bowel Disease. Curr. Opin. Gastroenterol. 2019, 35, 259–264.
  3. Baumgart, D.C.; Sandborn, W.J. Inflammatory Bowel Disease: Clinical Aspects and Established and Evolving Therapies. Lancet 2007, 369, 1641–1657.
  4. Cosnes, J.; Gowerrousseau, C.; Seksik, P.; Cortot, A. Epidemiology and Natural History of Inflammatory Bowel Diseases. Gastroenterology 2011, 140, 1785–1794.
  5. D’Haens, G.; Rieder, F.; Feagan, B.G.; Higgins, P.D.R.; Panés, J.; Maaser, C.; Rogler, G.; Löwenberg, M.; van der Voort, R.; Pinzani, M.; et al. Challenges in the Pathophysiology, Diagnosis, and Management of Intestinal Fibrosis in Inflammatory Bowel Disease. Gastroenterology 2022, 162, 26–31.
  6. Rieder, F.; Fiocchi, C.; Rogler, G. Mechanisms, Management, and Treatment of Fibrosis in Patients With Inflammatory Bowel Diseases. Gastroenterology 2017, 152, 340–350.e6.
  7. Latella, G.; di Gregorio, J.; Flati, V.; Rieder, F.; Lawrance, I.C. Mechanisms of Initiation and Progression of Intestinal Fibrosis in IBD. Scand. J. Gastroenterol. 2014, 50, 53–65.
  8. Wang, J.; Lin, S.; Brown, J.M.; van Wagoner, D.; Fiocchi, C.; Rieder, F. Novel Mechanisms and Clinical Trial Endpoints in Intestinal Fibrosis. Immunol. Rev. 2021, 302, 211–227.
  9. Bamias, G.; Pizarro, T.T.; Cominelli, F. Immunological Regulation of Intestinal Fibrosis in Inflammatory Bowel Disease. Inflamm. Bowel Dis. 2022, 28, 337–349.
  10. Gordon, I.O.; Agrawal, N.; Willis, E.; Goldblum, J.R.; Lopez, R.; Allende, D.; Liu, X.; Patil, D.Y.; Yerian, L.; El-Khider, F.; et al. Fibrosis in Ulcerative Colitis Is Directly Linked to Severity and Chronicity of Mucosal Inflammation. Aliment. Pharmacol. Ther. 2018, 47, 922–939.
  11. Yoo, J.H.; Holubar, S.; Rieder, F. Fibrostenotic Strictures in Crohn’s Disease. Intest. Res. 2020, 18, 379–401.
  12. Sleiman, J.; el Ouali, S.; Qazi, T.; Cohen, B.; Steele, S.R.; Baker, M.E.; Rieder, F. Prevention and Treatment of Stricturing Crohn’s Disease–Perspectives and Challenges. Expert. Rev. Gastroenterol. Hepatol. 2021, 15, 401–411.
  13. Lin, X.; Wang, Y.; Liu, Z.; Lin, S.; Tan, J.; He, J.; Hu, F.; Wu, X.; Ghosh, S.; Chen, M.; et al. Intestinal Strictures in Crohn’s Disease: A 2021 Update. Ther. Adv. Gastroenterol. 2022, 15, 17562848221104951.
  14. Gordon, I.O.; Bettenworth, D.; Bokemeyer, A.; Srivastava, A.; Rosty, C.; de Hertogh, G.; Robert, M.E.; Valasek, M.A.; Mao, R.; Li, J.; et al. International Consensus to Standardise Histopathological Scoring for Small Bowel Strictures in Crohn’s Disease. Gut 2022, 71, 479–486.
  15. Liu, Q.; Zhang, X.; Ko, H.M.; Stocker, D.; Ellman, J.; Chen, J.; Hao, Y.; Bhardwaj, S.; Liang, Y.; Cho, J.; et al. Constrictive and Hypertrophic Strictures in Ileal Crohn’s Disease. Clin. Gastroenterol. Hepatol. 2022, 20, e1292–e1304.
  16. Rieder, F.; Zimmermann, E.M.; Remzi, F.H.; Sandborn, W.J. Crohn’s Disease Complicated by Strictures: A Systematic Review. Gut 2013, 62, 1072–1084.
  17. de Sousa, H.T.; Gullo, I.; Castelli, C.; Dias, C.C.; Rieder, F.; Carneiro, F.; Magro, F. Ileal Crohn’s Disease Exhibits Similar Transmural Fibrosis Irrespective of Phenotype. Clin. Transl. Gastroenterol. 2021, 12, E00330.
  18. Gasche, C.; Scholmerich, J.; Brynskov, J.; D’Haens, G.; Hanauer, S.B.; Irvine, J.E.; Jewell, D.P.; Rachmilewitz, D.; Sachar, D.B.; Sandborn, W.J.; et al. A Simple Classification of CrohN’s Disease: Report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm. Bowel Dis. 2000, 6, 8–15.
  19. Satsangi, J. The Montreal Classification of Inflammatory Bowel Disease: Controversies, Consensus, and Implications. Gut 2006, 55, 749–753.
  20. Cosnes, J.; Cattan, S.; Blain, A.; Beaugerie, L.; Carbonnel, F.; Parc, R.; Gendre, J.-P. Long-Term Evolution of Disease Behavior of Crohn’s Disease. Inflamm. Bowel Dis. 2002, 8, 244–250.
  21. Louis, E.; Collard, A.; Oger, A.F.; Degroote, E.; Aboul Nasr El Yafi, F.A.; Belaiche, J. Behaviour of Crohn’s Disease According to the Vienna Classification: Changing Pattern over the Course of the Disease. Gut 2001, 49, 777–782.
  22. Freeman, H.J. Natural History and Clinical Behavior of Crohn’s Disease Extending beyond Two Decades. J. Clin. Gastroenterol. 2003, 37, 216–219.
  23. Vernier–Massouille, G.; Balde, M.; Salleron, J.; Turck, D.; Dupas, J.L.; Mouterde, O.; Merle, V.; Salomez, J.L.; Branche, J.; Marti, R.; et al. Natural History of Pediatric Crohn’s Disease: A Population-Based Cohort Study. Gastroenterology 2008, 135, 1106–1113.
  24. Freeman, H.J. Temporal and Geographic Evolution of Longstanding Crohn’s Disease over More than 50 Years. Can. J. Gastroenterol. 2003, 17, 696–700.
  25. Burisch, J.; Kiudelis, G.; Kupcinskas, L.; Kievit, H.A.L.; Andersen, K.W.; Andersen, V.; Salupere, R.; Pedersen, N.; Kjeldsen, J.; D’Incà, R.; et al. Natural Disease Course of Crohn’s Disease during the First 5 Years after Diagnosis in a European Population-Based Inception Cohort: An Epi-IBD Study. Gut 2019, 68, 423–433.
  26. Thia, K.T.; Sandborn, W.J.; Harmsen, W.S.; Zinsmeister, A.R.; Loftus, E.V. Risk Factors Associated With Progression to Intestinal Complications of Crohn’s Disease in a Population-Based Cohort. Gastroenterology 2010, 139, 1147–1155.
  27. Pariente, B.; Cosnes, J.; Danese, S.; Sandborn, W.J.; Lewin, M.; Fletcher, J.G.; Chowers, Y.; D’Haens, G.; Feagan, B.G.; Hibi, T.; et al. Development of the Crohn’s Disease Digestive Damage Score, the Lémann Score. Inflamm. Bowel Dis. 2011, 17, 1415–1422.
  28. Magro, F.; Magalhães, D.; Patita, M.; Arroja, B.; Lago, P.; Rosa, I.; Tavares de Sousa, H.; Ministro, P.; Mocanu, I.; Vieira, A.; et al. Subclinical Persistent Inflammation as Risk Factor for Crohn’s Disease Progression: Findings from a Prospective Real-World Study of 2 Years. Clin. Gastroenterol. Hepatol. 2022, 20, 2059–2073.e7.
  29. Peyrin-Biroulet, L.; Reinisch, W.; Colombel, J.-F.; Mantzaris, G.J.; Kornbluth, A.; Diamond, R.; Rutgeerts, P.; Tang, L.K.; Cornillie, F.J.; Sandborn, W.J. Clinical Disease Activity, C-Reactive Protein Normalisation and Mucosal Healing in Crohn’s Disease in the SONIC Trial. Gut 2014, 63, 88–95.
  30. Fernandes, S.R.; Rodrigues, R.V.; Bernardo, S.; Cortez-Pinto, J.; Rosa, I.; da Silva, J.P.; Gonçalves, A.R.; Valente, A.; Baldaia, C.; Santos, P.M.; et al. Transmural Healing Is Associated with Improved Long-Term Outcomes of Patients with Crohn’s Disease. Inflamm. Bowel Dis. 2017, 23, 1403–1409.
  31. Torres, J.; Mehandru, S.; Colombel, J.-F.; Peyrin-Biroulet, L. Crohn’s Disease. Lancet 2017, 389, 1741–1755.
  32. Solberg, I.C.; Vatn, M.H.; Høie, O.; Stray, N.; Sauar, J.; Jahnsen, J.; Moum, B.; Lygren, I. Clinical Course in Crohn’s Disease: Results of a Norwegian Population-Based Ten-Year Follow-Up Study. Clin. Gastroenterol. Hepatol. 2007, 5, 1430–1438.
  33. Ramadas, A.V.; Gunesh, S.; Thomas, G.A.O.; Williams, G.T.; Hawthorne, A.B. Natural History of Crohn’s Disease in a Population-Based Cohort from Cardiff (1986–2003): A Study of Changes in Medical Treatment and Surgical Resection Rates. Gut 2010, 59, 1200–1206.
  34. Peyrin-Biroulet, L.; Loftus, E.V.; Colombel, J.-F.; Sandborn, W.J. The Natural History of Adult Crohn’s Disease in Population-Based Cohorts. Am. J. Gastroenterol. 2010, 105, 289–297.
  35. Tavares de Sousa, H.; Carneiro, F. Understanding Progression of Strictures in Ileal Crohn’s Disease—The Importance of Setting Methodological Standards. United Eur. Gastroenterol. J. 2022, 10, 915–916.
  36. de Bruyn, J.R.; Meijer, S.L.; Wildenberg, M.E.; Bemelman, W.A.; van den Brink, G.R.; D’Haens, G.R. Development of Fibrosis in Acute and Longstanding Ulcerative Colitis. J. Crohns Colitis 2015, 9, 966–972.
  37. Ippolito, C.; Colucci, R.; Segnani, C.; Errede, M.; Girolamo, F.; Virgintino, D.; Dolfi, A.; Tirotta, E.; Buccianti, P.; di Candio, G.; et al. Fibrotic and Vascular Remodelling of Colonic Wall in Patients with Active Ulcerative Colitis. J. Crohns Colitis 2016, 10, 1194–1204.
  38. Magro, F.; Sousa, H.T. Editorial: Ulcerative Colitis Submucosal Fibrosis and Inflammation: More than Just Strictures. Aliment. Pharmacol. Ther. 2018, 47, 1033–1034.
  39. Goulston, S.J.M.; McGovern, V.J. The Nature of Benign Strictures in Ulcerative Colitis. N. Engl. J. Med. 1969, 281, 290–295.
  40. Pandey, A.; Achrafie, L.; Kodjamanova, P.; Tencer, T.; Kumar, J. Endoscopic Mucosal Healing and Histologic Remission in Ulcerative Colitis: A Systematic Literature Review of Clinical, Quality-of-Life and Economic Outcomes. Curr. Med. Res. Opin. 2022, 38, 1531–1541.
  41. da Silva Watanabe, P.; Cavichioli, A.M.; D’Arc de Lima Mendes, J.; Aktar, R.; Peiris, M.; Blackshaw, L.A.; de Almeida Araújo, E.J. Colonic Motility Adjustments in Acute and Chronic DSS-Induced Colitis. Life Sci. 2023, 321, 121642.
  42. Lin, S.; Lin, X.; Li, X.; Chen, M.; Mao, R. Making Qualitative Intestinal Stricture Quantitative: Embracing Radiomics in IBD. Inflamm. Bowel Dis. 2020, 26, 743–745.
  43. Stidham, R.W.; Enchakalody, B.; Waljee, A.K.; Higgins, P.D.R.; Wang, S.C.; Su, G.L.; Wasnik, A.P.; Al-Hawary, M. Assessing Small Bowel Stricturing and Morphology in Crohn’s Disease Using Semi-Automated Image Analysis. Inflamm. Bowel Dis. 2020, 26, 734–742.
  44. Meng, J.; Luo, Z.; Chen, Z.; Zhou, J.; Chen, Z.; Lu, B.; Zhang, M.; Wang, Y.; Yuan, C.; Shen, X.; et al. Intestinal Fibrosis Classification in Patients with Crohn’s Disease Using CT Enterography–Based Deep Learning: Comparisons with Radiomics and Radiologists. Eur. Radiol. 2022, 32, 8692–8705.
  45. Li, X.; Liang, D.; Meng, J.; Zhou, J.; Chen, Z.; Huang, S.; Lu, B.; Qiu, Y.; Baker, M.E.; Ye, Z.; et al. Development and Validation of a Novel Computed-Tomography Enterography Radiomic Approach for Characterization of Intestinal Fibrosis in Crohn’s Disease. Gastroenterology 2021, 160, 2303–2316.e11.
  46. Zhang, B.; Zhang, S. The Potential of Radiomics in the Assessment of Intestinal Fibrosis in Crohn’s Disease. Gastroenterology 2021, 161, 2065–2066.
  47. Sleiman, J.; Chirra, P.; Gandhi, N.; Gordon, I.; Viswanath, S.; Rieder, F. Evaluation of clinical variables, radiological visual analog scoring, and radiomics features on ct enterography for characterizing severe inflammation and fibrosis in stricturing crohn’s disease. Gastroenterology 2023, 164, S16–S17.
  48. Sleiman, J.; Chirra, P.; Gandhi, N.; Gordon, I.O.; Viswanath, S.; Rieder, F. DOP12 Validation of Radiomics Features on MR Enterography Characterizing Inflammation and Fibrosis in Stricturing Crohn’s Disease. J. Crohns Colitis 2023, 17, i73.
  49. Rieder, F.; de Bruyn, J.R.; Pham, B.T.; Katsanos, K.; Annese, V.; Higgins, P.D.R.; Magro, F.; Dotan, I. Results of the 4th Scientific Workshop of the ECCO (Group II): Markers of Intestinal Fibrosis in Inflammatory Bowel Disease. J. Crohns Colitis 2014, 8, 1166–1178.
  50. Chen, Y.; Ge, W.; Xu, L.; Qu, C.; Zhu, M.; Zhang, W.; Xiao, Y. MiR-200b Is Involved in Intestinal Fibrosis of Crohn’s Disease. Int. J. Mol. Med. 2012, 29, 601–606.
  51. Chapman, C.G.; Pekow, J. The Emerging Role of MiRNAs in Inflammatory Bowel Disease: A Review. Therap Adv. Gastroenterol. 2015, 8, 4–22.
  52. Chen, Y.; Xiao, Y.; Ge, W.; Zhou, K.; Wen, J.; Yan, W.; Wang, Y.; Wang, B.; Qu, C.; Wu, J.; et al. MiR-200b Inhibits TGF-Β1-Induced Epithelial-Mesenchymal Transition and Promotes Growth of Intestinal Epithelial Cells. Cell Death Dis. 2013, 4, e541.
  53. Nijhuis, A.; Biancheri, P.; Lewis, A.; Bishop, C.L.; Giuffrida, P.; Chan, C.; Feakins, R.; Poulsom, R.; Di Sabatino, A.; Corazza, G.R.; et al. In Crohn’s Disease Fibrosis-Reduced Expression of the MiR-29 Family Enhances Collagen Expression in Intestinal Fibroblasts. Clin. Sci. 2014, 127, 341–350.
  54. Lewis, A.; Nijhuis, A.; Mehta, S.; Kumagai, T.; Feakins, R.; Lindsay, J.O.; Silver, A. Intestinal Fibrosis in Crohn’s Disease: Role of MicroRNAs as Fibrogenic Modulators, Serum Biomarkers, and Therapeutic Targets. Inflamm. Bowel Dis. 2015, 21, 1141–1150.
  55. Innocenti, T.; Bigagli, E.; Lynch, E.N.; Galli, A.; Dragoni, G. MiRNA-Based Therapies for the Treatment of Inflammatory Bowel Disease: What Are We Still Missing? Inflamm. Bowel Dis. 2022, 29, 308–323.
  56. Ballengee, C.R.; Stidham, R.W.; Liu, C.; Kim, M.O.; Prince, J.; Mondal, K.; Baldassano, R.; Dubinsky, M.; Markowitz, J.; Leleiko, N.; et al. Association Between Plasma Level of Collagen Type III Alpha 1 Chain and Development of Strictures in Pediatric Patients With Crohn’s Disease. Clin. Gastroenterol. Hepatol. 2019, 17, 1799–1806.
  57. Wu, J.; Lubman, D.M.; Kugathasan, S.; Denson, L.A.; Hyams, J.S.; Dubinsky, M.C.; Griffiths, A.M.; Baldassano, R.N.; Noe, J.D.; Rabizadeh, S.; et al. Serum Protein Biomarkers of Fibrosis Aid in Risk Stratification of Future Stricturing Complications in Pediatric Crohn’s Disease. Am. J. Gastroenterol. 2019, 114, 777–785.
  58. Levitte, S.; Peale, F.V.; Jhun, I.; McBride, J.; Neighbors, M. Local Pentraxin-2 Deficit Is a Feature of Intestinal Fibrosis in Crohn’s Disease. Dig. Dis. Sci. 2023, in press.
  59. Stidham, R.W.; Wu, J.; Shi, J.; Lubman, D.M.; Higgins, P.D.R. Serum Glycoproteome Profiles for Distinguishing Intestinal Fibrosis from Inflammation in Crohn’s Disease. PLoS ONE 2017, 12, e0170506.
  60. O’Sullivan, S.; Gilmer, J.F.; Medina, C. Matrix Metalloproteinases in Inflammatory Bowel Disease: An Update. Mediat. Inflamm. 2015, 2015, 964131.
  61. Schoepfer, A.M.; Schaffer, T.; Mueller, S.; Flogerzi, B.; Vassella, E.; Seibold-Schmid, B.; Seibold, F. Phenotypic Associations of Crohn’s Disease with Antibodies to Flagellins A4-Fla2 and Fla-X, ASCA, p-ANCA, PAB, and NOD2 Mutations in a Swiss Cohort. Inflamm. Bowel Dis. 2009, 15, 1358–1367.
  62. Mow, W.S.; Vasiliauskas, E.A.; Lin, Y.-C.; Fleshner, P.R.; Papadakis, K.A.; Taylor, K.D.; Landers, C.J.; Abreu-Martin, M.T.; Rotter, J.I.; Yang, H.; et al. Association of Antibody Responses to Microbial Antigens and Complications of Small Bowel Crohn’s Disease. Gastroenterology 2004, 126, 414–424.
  63. Vind, I.; Johansen, J.S.; Price, P.A.; Munkholm, P. Serum YKL-40, a Potential New Marker of Disease Activity in Patients with Inflammatory Bowel Disease. Scand. J. Gastroenterol. 2003, 38, 599–605.
  64. Pieczarkowski, S.; Kowalska-Duplaga, K.; Kwinta, P.; Wędrychowicz, A.; Tomasik, P.; Stochel-Gaudyn, A.; Fyderek, K. Serum Concentrations of Fibrosis Markers in Children with Inflammatory Bowel Disease. Folia Med. Cracov 2020, LX, 61–74.
  65. Adler, J.; Rangwalla, S.C.; Dwamena, B.A.; Higgins, P.D.R. The Prognostic Power of the Nod2 Genotype for Complicated Crohn’s Disease: A Meta-Analysis. Am. J. Gastroenterol. 2011, 106, 699–712.
  66. Torres, J.; Bonovas, S.; Doherty, G.; Kucharzik, T.; Gisbert, J.P.; Raine, T.; Adamina, M.; Armuzzi, A.; Bachmann, O.; Bager, P.; et al. ECCO Guidelines on Therapeutics in Crohn’s Disease: Medical Treatment. J. Crohns Colitis 2020, 14, 4–22.
  67. Loras, C.; Andújar, X.; Gornals, J.B.; Sanchiz, V.; Brullet, E.; Sicilia, B.; Martín-Arranz, M.D.; Naranjo, A.; Barrio, J.; Dueñas, C.; et al. Self-Expandable Metal Stents versus Endoscopic Balloon Dilation for the Treatment of Strictures in Crohn’s Disease (ProtDilat Study): An Open-Label, Multicentre, Randomised Trial. Lancet Gastroenterol. Hepatol. 2022, 7, 332–341.
  68. Antar, S.A.; ElMahdy, M.; Khodir, A.E. A Novel Role of Pirfenidone in Attenuation Acetic Acid Induced Ulcerative Colitis by Modulation of TGF-Β1 / JNK1 Pathway. Int. Immunopharmacol. 2021, 101, 108289.
  69. Cui, Y.; Zhang, M.; Leng, C.; Blokzijl, T.; Jansen, B.H.; Dijkstra, G.; Faber, K.N. Pirfenidone Inhibits Cell Proliferation and Collagen I Production of Primary Human Intestinal Fibroblasts. Cells 2020, 9, 775.
  70. Iswandana, R.; Pham, B.T.; Suriguga, S.; Luangmonkong, T.; Van Wijk, L.A.; Jansen, Y.J.M.; Oosterhuis, D.; Maria Mutsaers, H.A.; Olinga, P. Murine Precision-Cut Intestinal Slices as a Potential Screening Tool for Antifibrotic Drugs. Inflamm. Bowel Dis. 2020, 26, 678–686.
  71. Li, G.; Ren, J.; Hu, Q.; Deng, Y.; Chen, G.; Guo, K.; Li, R.; Li, Y.; Wu, L.; Wang, G.; et al. Oral Pirfenidone Protects against Fibrosis by Inhibiting Fibroblast Proliferation and TGF-β Signaling in a Murine Colitis Model. Biochem. Pharmacol. 2016, 117, 57–67.
  72. Kadir, S.-I.; Wenzel Kragstrup, T.; Dige, A.; Kok Jensen, S.; Dahlerup, J.F.; Kelsen, J. Pirfenidone Inhibits the Proliferation of Fibroblasts from Patients with Active Crohn’s Disease. Scand. J. Gastroenterol. 2016, 51, 1321–1325.
  73. Meier, R.; Lutz, C.; Cosín-Roger, J.; Fagagnini, S.; Bollmann, G.; Hünerwadel, A.; Mamie, C.; Lang, S.; Tchouboukov, A.; Weber, F.E.; et al. Decreased Fibrogenesis After Treatment with Pirfenidone in a Newly Developed Mouse Model of Intestinal Fibrosis. Inflamm. Bowel Dis. 2016, 22, 569–582.
  74. Kojo, Y.; Suzuki, H.; Kato, K.; Kaneko, Y.; Yuminoki, K.; Hashimoto, N.; Sato, H.; Seto, Y.; Onoue, S. Enhanced Biopharmaceutical Effects of Tranilast on Experimental Colitis Model with Use of Self-Micellizing Solid Dispersion Technology. Int. J. Pharm. 2018, 545, 19–26.
  75. Sun, X.; Suzuki, K.; Nagata, M.; Kawauchi, Y.; Yano, M.; Ohkoshi, S.; Matsuda, Y.; Kawachi, H.; Watanabe, K.; Asakura, H.; et al. Rectal Administration of Tranilast Ameliorated Acute Colitis in Mice through Increased Expression of Heme Oxygenase-1. Pathol. Int. 2010, 60, 93–101.
  76. Binabaj, M.M.; Asgharzadeh, F.; Avan, A.; Rahmani, F.; Soleimani, A.; Parizadeh, M.R.; Ferns, G.A.; Ryzhikov, M.; Khazaei, M.; Hassanian, S.M. EW-7197 Prevents Ulcerative Colitis-associated Fibrosis and Inflammation. J. Cell Physiol. 2019, 234, 11654–11661.
  77. Danese, S.; Klopocka, M.; Scherl, E.J.; Romatowski, J.; Allegretti, J.R.; Peeva, E.; Vincent, M.S.; Schoenbeck, U.; Ye, Z.; Hassan-Zahraee, M.; et al. Anti-TL1A Antibody PF-06480605 Safety and Efficacy for Ulcerative Colitis: A Phase 2a Single-Arm Study. Clin. Gastroenterol. Hepatol. 2021, 19, 2324–2332.e6.
  78. Ferrante, M.; Irving, P.M.; Selinger, C.P.; D’Haens, G.; Kuehbacher, T.; Seidler, U.; Gropper, S.; Haeufel, T.; Forgia, S.; Danese, S.; et al. Safety and Tolerability of Spesolimab in Patients with Ulcerative Colitis. Expert. Opin. Drug. Saf. 2023, 22, 141–152.
  79. Holvoet, T.; Devriese, S.; Castermans, K.; Boland, S.; Leysen, D.; Vandewynckel, Y.-P.; Devisscher, L.; Van den Bossche, L.; Van Welden, S.; Dullaers, M.; et al. Treatment of Intestinal Fibrosis in Experimental Inflammatory Bowel Disease by the Pleiotropic Actions of a Local Rho Kinase Inhibitor. Gastroenterology 2017, 153, 1054–1067.
  80. Speca, S.; Rousseaux, C.; Dubuquoy, C.; Rieder, F.; Vetuschi, A.; Sferra, R.; Giusti, I.; Bertin, B.; Dubuquoy, L.; Gaudio, E.; et al. Novel PPARγ Modulator GED-0507-34 Levo Ameliorates Inflammation-Driven Intestinal Fibrosis. Inflamm. Bowel Dis. 2016, 22, 279–292.
  81. Burke, J.P.; Watson, R.W.G.; Murphy, M.; Docherty, N.G.; Coffey, J.C.; O’Connell, P.R. Simvastatin Impairs Smad-3 Phosphorylation and Modulates Transforming Growth Factor Β1-Mediated Activation of Intestinal Fibroblasts. Br. J. Surg. 2009, 96, 541–551.
  82. Santacroce, G.; Lenti, M.V.; Di Sabatino, A. Therapeutic Targeting of Intestinal Fibrosis in Crohn’s Disease. Cells 2022, 11, 429.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Pathology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Helena Tavares de Sousa
,
Fernando Magro
View Times: 298
Revisions: 3 times (View History)
Update Date: 13 Jul 2023
Table of Contents
    1000/1000
    Hot Most Recent
    ScholarVision Creations
    Feedback