Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Anti-fibrotic Drugs for Crohn’s Disease: Ready for Prime Time?

Author(s): Marjorie Argollo, Daniela Gilardi, Giulia Roda, Gionata Fiorino, Laurent Peyrin-Biroulet and Silvio Danese*

Volume 25 , Issue 1 , 2019

Page: [47 - 56] Pages: 10

DOI: 10.2174/1381612825666190308100844

Price: $65


Intestinal fibrosis, driven by chronic inflammation in Crohn’s disease, can be defined as an excessive accumulation of extracellular matrix in the affected gut segment ultimately leading to an impaired wound healing and cumulative tissue damage, possibly resulting in organ dysfunction, formation of stenotic lesions and necessity of surgical intervention. Despite continuous advances in developing novel treatment modalities targeting different pathways to control chronic gut inflammation in CD, no effective anti-fibrotic agents have been released, to date. Thus, a better understanding of the molecular and cellular mechanisms underlying intestinal fibrosis is key to move this area of investigation forward.

Keywords: Anti-fibrotic drugs, Crohn's disease, intestinal fibrosis, treatment, stenotic lesions, chronic inflammation.

Freeman HJ. Natural history and clinical behavior of Crohn’s disease extending beyond two decades. J Clin Gastroenterol 2003; 37(3): 216-9.
Pariente B, Cosnes J, Danese S, et al. Development of the Crohn’s disease digestive damage score, the Lémann score. Inflamm Bowel Dis 2011; 17(6): 1415-22.
Peyrin-Biroulet L, Cieza A, Sandborn WJ, et al. Development of the first disability index for inflammatory bowel disease based on the international classification of functioning, disability and health. Gut 2012; 61(2): 241-7.
Rungoe C, Langholz E, Andersson M, et al. Changes in medical treatment and surgery rates in inflammatory bowel disease: a nationwide cohort study 1979-2011. Gut 2014; 63(10): 1607-16.
Bouguen G, Peyrin-Biroulet L. Surgery for adult Crohn’s disease: what is the actual risk? Gut 2011; 60(9): 1178-81.
Bobanga ID, Bai S, Swanson MA, et al. Factors influencing disease recurrence after ileocolic resection in adult and pediatric onset Crohn’s disease. Am J Surg 2014; 208(4): 591-6.
Fornaro R, Caratto E, Caratto M, et al. Post-operative recurrence in Crohn’s disease. Critical analysis of potential risk factors. An update. Surgeon 2015; 13(6): 330-47.
de Barcelos IF, Kotze PG, Spinelli A, et al. Factors affecting the incidence of early endoscopic recurrence after ileocolonic resection for Crohn’s disease: a multicentre observational study. Colorectal Dis 2017; 19(1): 39-45.
Yamamoto T. Factors affecting recurrence after surgery for Crohn’s disease. World J Gastroenterol 2005; 11(26): 3971-9.
Rieder F, Zimmermann EM, Remzi FH, Sandborn WJ. Crohn’s disease complicated by strictures: a systematic review. Gut 2013; 62(7): 1072-84.
Rieder F, Fiocchi C, Rogler G. Mechanisms, Management, and Treatment of Fibrosis in Patients With Inflammatory Bowel Diseases. Gastroenterology 2017; 152(2): 340-350.e6.
Rieder F, Latella G, Magro F, et al. European Crohn’s and Colitis Organisation Topical Review on Prediction, Diagnosis and Management of Fibrostenosing Crohn’s Disease. J Crohn’s Colitis 2016; 10(8): 873-85.
Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med 2012; 18(7): 1028-40.
Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 2011; 140(6): 1785-94.
Rieder F, Fiocchi C. Intestinal fibrosis in IBD--a dynamic, multifactorial process. Nat Rev Gastroenterol Hepatol 2009; 6(4): 228-35.
Speca S, Giusti I, Rieder F, Latella G. Cellular and molecular mechanisms of intestinal fibrosis. World J Gastroenterol 2012; 18(28): 3635-61.
Bailey J, Rogler G. Factors Promoting Development of Fibrosis in Crohn ’ s Disease. 2017; 4: 4-9.
Yugandhar VG. Clark M a. Cellular and molecular mechanisms of fibrosis. J Pathol 2013; 46(2): 26-32. retrieve/pii/S0196978113001721 [Internet].
Latella G, Di Gregorio J, Flati V, Rieder F, Lawrance IC. Mechanisms of initiation and progression of intestinal fibrosis in IBD. Scand J Gastroenterol 2015; 50(1): 53-65.
Burke JP, Mulsow JJ, O’Keane C, Docherty NG, Watson RWG, O’Connell PR. Fibrogenesis in Crohn’s disease. Am J Gastroenterol 2007; 102(2): 439-48.
Danese S, Vuitton L, Peyrin-Biroulet L. Biologic agents for IBD: practical insights. Nat Rev Gastroenterol Hepatol 2015; 12(9): 537-45.
Peyrin-Biroulet L, Loftus EV Jr, Colombel JF, Sandborn WJ. The natural history of adult Crohn’s disease in population-based cohorts. Am J Gastroenterol 2010; 105(2): 289-97.
Bouguen G, Levesque BG, Feagan BG, et al. Treat to target: a proposed new paradigm for the management of Crohn’s disease. Clin Gastroenterol Hepatol 2015; 13(6): 1042-50.e2.
Rutgeerts P, Van Assche G, Sandborn WJ, et al. Adalimumab induces and maintains mucosal healing in patients with Crohn’s disease: data from the EXTEND trial. Gastroenterology 2012; 142(5): 1102-1111.e2.
Papi C, Fascì-Spurio F, Rogai F, Settesoldi A, Margagnoni G, Annese V. Mucosal healing in inflammatory bowel disease: treatment efficacy and predictive factors. Dig Liver Dis 2013; 45(12): 978-85.
Wisniewski A, Danese S, Peyrin-Biroulet L. Evolving Treatment Algorithms in Crohn’s Disease. Curr Drug Targets 2018; 19(7): 782-90.
Cosnes J, Cattan S, Blain A, et al. Long-term evolution of disease behavior of Crohn’s disease. Inflamm Bowel Dis 2002; 8(4): 244-50.
Fiocchi C, Lund PK. Themes in fibrosis and gastrointestinal inflammation. Am J Physiol Gastrointest Liver Physiol 2011; 300(5): G677-83.
Rieder F, Fiocchi C. Mechanisms of tissue remodeling in inflammatory bowel disease. Dig Dis 2013; 31(2): 186-93.
Zhang H-J, Zhang Y-N, Zhou H, Guan L, Li Y, Sun M-J. IL-17A Promotes Initiation and Development of Intestinal Fibrosis Through EMT. Dig Dis Sci 2018; 63(11): 2898-909.
Li J, Qiu S-J, She W-M, et al. Significance of the balance between regulatory T (Treg) and T helper 17 (Th17) cells during hepatitis B virus related liver fibrosis. PLoS One 2012; 7(6): e39307.
Lian L, Huang Q, Zhang L, et al. Anti-fibrogenic Potential of Mesenchymal Stromal Cells in Treating Fibrosis in Crohn’s Disease. Dig Dis Sci 2018; 63(7): 1821-34.
Li H, Song J, Niu G, et al. TL1A blocking ameliorates intestinal fibrosis in the T cell transfer model of chronic colitis in mice. Pathol Res Pract 2018; 214(2): 217-27.
Mechanism of fibrosis: therapeutic transplation for fibrotic disease. Nat Med 2013; 18(7): 1028-40.
Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med 2013; 5(167): 167sr1.
Rieder F, Brenmoehl J, Leeb S, Schölmerich J, Rogler G. Wound healing and fibrosis in intestinal disease. Gut 2007; 56(1): 130-9.
Lakatos G, Hritz I, Varga MZ, et al. The impact of matrix metalloproteinases and their tissue inhibitors in inflammatory bowel diseases. Dig Dis 2012; 30(3): 289-95.
Rosenbloom J, Castro SV, Jimenez SA. Narrative review: fibrotic diseases: cellular and molecular mechanisms and novel therapies. Ann Intern Med 2010; 152(3): 159-66.
Lutz M, Knaus P. Integration of the TGF-beta pathway into the cellular signalling network. Cell Signal 2002; 14(12): 977-88.
Monteleone G, Pallone F, MacDonald TT. Smad7 in TGF-beta-mediated negative regulation of gut inflammation. Trends Immunol 2004; 25(10): 513-7.
Ma Y, Guan Q, Bai A, et al. Targeting TGF-beta1 by employing a vaccine ameliorates fibrosis in a mouse model of chronic colitis. Inflamm Bowel Dis 2010; 16(6): 1040-50.
Di Sabatino A, Jackson CL, Pickard KM, et al. Transforming growth factor beta signalling and matrix metalloproteinases in the mucosa overlying Crohn’s disease strictures. Gut 2009; 58(6): 777-89.
Fichtner-Feigl S, Young CA, Kitani A, Geissler EK, Schlitt H-J, Strober W. IL-13 signaling via IL-13R alpha2 induces major downstream fibrogenic factors mediating fibrosis in chronic TNBS colitis. Gastroenterology 2008; 135(6): 2003-13.
Rieder F, Kessler S, Sans M, Fiocchi C. Animal models of intestinal fibrosis: new tools for the understanding of pathogenesis and therapy of human disease. Am J Physiol Gastrointest Liver Physiol 2012; 303(7): G786-801.
Kulkarni AB, Huh CG, Becker D, et al. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 1993; 90(2): 770-4.
Glick AB, Kulkarni AB, Tennenbaum T, et al. Loss of expression of transforming growth factor beta in skin and skin tumors is associated with hyperproliferation and a high risk for malignant conversion. Proc Natl Acad Sci USA 1993; 90(13): 6076-80.
Latella G, Vetuschi A, Sferra R, et al. Smad3 loss confers resistance to the development of trinitrobenzene sulfonic acid-induced colorectal fibrosis. Eur J Clin Invest 2009; 39(2): 145-56.
Latella G, Sferra R, Speca S, Vetuschi A, Gaudio E. Can we prevent, reduce or reverse intestinal fibrosis in IBD? Eur Rev Med Pharmacol Sci 2013; 17(10): 1283-304.
Sferra R, Pompili S, Ventura L, et al. Interaction between sphingosine kinase/sphingosine 1 phosphate and transforming growth factor-β/Smads pathways in experimental intestinal fibrosis. An in vivo immunohistochemical study. Eur J Histochem 2018; 62(3): 2956.
Bettenworth D, Rieder F. Reversibility of Stricturing Crohn’s Disease-Fact or Fiction? Inflamm Bowel Dis 2016; 22(1): 241-7.
Arthur MJP. Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C 2002; 122: 1525-8.
Yamamoto T, Fazio VW, Tekkis PP. Safety and efficacy of strictureplasty for Crohn’s disease: a systematic review and meta-analysis. Dis Colon Rectum 2007; 50(11): 1968-86.
Vasavada BB, Chan CL. Rapid fibrosis and significant histologic recurrence of hepatitis C after liver transplant is associated with higher tumor recurrence rates in hepatocellular carcinomas associated with hepatitis C virus-related liver disease: a single center retrospective analysis. Exp Clin Transplant 2015; 13(1): 46-50.
Dong J, Ma Q. TIMP1 promotes multi-walled carbon nanotube-induced lung fibrosis by stimulating fibroblast activation and proliferation. Nanotoxicology 2017; 11(1): 41-51.
Sanmiguel C, Gupta A, Mayer EA. Gut Microbiome and Obesity: A Plausible Explanation for Obesity. Curr Obes Rep 2015; 4(2): 250-61.
Kirpich IA, Marsano LS, McClain CJ. Gut-liver axis, nutrition, and non-alcoholic fatty liver disease. Clin Biochem 2015; 48(13-14): 923-30.
Flowers SA, Ellingrod VL. The microbiome in mental health: potential contribution of gut microbiota in disease and pharmacotherapy management. Pharmacotherapy 2015; 35(10): 910-6.
Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140(6): 805-20.
Otte J-M, Rosenberg IM, Podolsky DK. Intestinal myofibroblasts in innate immune responses of the intestine. Gastroenterology 2003; 124(7): 1866-78.
Rieder F, Bhilocha S, Schirbel AOZ, West G, Atreja A, Rho H. DLMC, C F. Activation of toll-like receptor (TLR) 5 induces a pro-fibrogenic phenotype on human intestinal myofibroblasts (HIF) – a novel pathway mediated by caspase 1. Gastroenterology 2011; 142: S116. [abstract].
Hasan UA, Trinchieri G, Vlach J. Toll-like receptor signaling stimulates cell cycle entry and progression in fibroblasts. J Biol Chem 2005; 280(21): 20620-7.
Mourelle M, Salas A, Guarner F, Crespo E, García-Lafuente A, Malagelada JR. Stimulation of transforming growth factor beta1 by enteric bacteria in the pathogenesis of rat intestinal fibrosis. Gastroenterology 1998; 114(3): 519-26.
Rigby RJ, Hunt MR, Scull BP, et al. A new animal model of postsurgical bowel inflammation and fibrosis: the effect of commensal microflora. Gut 2009; 58(8): 1104-12.
van Tol EA, Holt L, Li FL, et al. Bacterial cell wall polymers promote intestinal fibrosis by direct stimulation of myofibroblasts. Am J Physiol 1999; 277(1): G245-55.
Grassl GA, Valdez Y, Bergstrom KSB, Vallance BA, Finlay BB. Chronic enteric salmonella infection in mice leads to severe and persistent intestinal fibrosis. Gastroenterology 2008; 134(3): 768-80.
Ruiz-Perez B, Chung DR, Sharpe AH, et al. Modulation of surgical fibrosis by microbial zwitterionic polysaccharides. Proc Natl Acad Sci USA 2005; 102(46): 16753-8.
Park J-S, Choi J, Jhun J, et al. Lactobacillus acidophilus Improves Intestinal Inflammation in an Acute Colitis Mouse Model by Regulation of Th17 and Treg Cell Balance and Fibrosis Development. J Med Food 2018; 21(3): 215-24.
de Souza HSP, Fiocchi C. Immunopathogenesis of IBD: current state of the art. Nat Rev Gastroenterol Hepatol 2016; 13(1): 13-27.
Jacob N, Jacobs JP, Kumagai K, et al. Inflammation-independent TL1A-mediated intestinal fibrosis is dependent on the gut microbiome. Mucosal Immunol 2018; 11(5): 1466-76.
Swaminathan S, Shah SV. New insights into nephrogenic systemic fibrosis. J Am Soc Nephrol 2007; 18(10): 2636-43.
Wood MJ, Powell LW, Ramm GA. Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis. Blood 2008; 111(9): 4456-62.
Lumeng CN, Maillard I, Saltiel AR. T-ing up inflammation in fat. Nat Med 2009; 15(8): 846-7.
Ley RE, Bäckhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad Sci USA 2005; 102(31): 11070-5.
Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006; 444(7122): 1027-31.
Schiavo L, Busetto L, Cesaretti M, Zelber-Sagi S, Deutsch L, Iannelli A. Nutritional issues in patients with obesity and cirrhosis. World J Gastroenterol 2018; 24(30): 3330-46.
Ding S, Chi MM, Scull BP, et al. High-fat diet: bacteria interactions promote intestinal inflammation which precedes and correlates with obesity and insulin resistance in mouse. PLoS One 2010; 5(8): e12191.
Yan X, Huang Y, Wang H, et al. Maternal obesity induces sustained inflammation in both fetal and offspring large intestine of sheep. Inflamm Bowel Dis 2011; 17(7): 1513-22.
Peyrin-Biroulet L, Harmsen WS, Tremaine WJ, Zinsmeister AR, Sandborn WJ, Loftus EVJ Jr. Surgery in a population-based cohort of Crohn’s disease from Olmsted County, Minnesota (1970-2004). Am J Gastroenterol 2012; 107(11): 1693-701.
Adler J, Rangwalla SC, Dwamena BA, Higgins PDR. The prognostic power of the NOD2 genotype for complicated Crohn’s disease: a meta-analysis. Am J Gastroenterol 2011; 106(4): 699-712.
Naser SA, Arce M, Khaja A, et al. Role of ATG16L, NOD2 and IL23R in Crohn’s disease pathogenesis. World J Gastroenterol 2012; 18(5): 412-24.
Verstockt B, Cleynen I. Genetic Influences on the Development of Fibrosis in Crohn’s Disease. Front Med (Lausanne) 2016; 3: 24.
Ventham NT, Kennedy NA, Nimmo ER, Satsangi J. Beyond gene discovery in inflammatory bowel disease: the emerging role of epigenetics. Gastroenterology 2013; 145(2): 293-308.
Nijhuis A, Biancheri P, Lewis A, et al. In Crohn’s disease fibrosis-reduced expression of the miR-29 family enhances collagen expression in intestinal fibroblasts. Clin Sci (Lond) 2014; 127(5): 341-50.
Lewis A, Mehta S, Hanna LN, et al. Low Serum Levels of MicroRNA-19 Are Associated with a Stricturing Crohn’s Disease Phenotype. Inflamm Bowel Dis 2015; 21(8): 1926-34.
Xiong Y, Wang G-Z, Zhou J-Q, Xia B-Q, Wang X-Y, Jiang B. Serum antibodies to microbial antigens for Crohn’s disease progression: a meta-analysis. Eur J Gastroenterol Hepatol 2014; 26(7): 733-42.
Rovedatti L, Di Sabatino A, Knowles CH, et al. Fibroblast activation protein expression in Crohn’s disease strictures. Inflamm Bowel Dis 2011; 17(5): 1251-3.
Acharya PS, Zukas A, Chandan V, Katzenstein A-LA, Puré E. Fibroblast activation protein: a serine protease expressed at the remodeling interface in idiopathic pulmonary fibrosis. Hum Pathol 2006; 37(3): 352-60.
Gorrell MD, Wang XM, Levy MT, et al. Intrahepatic expression of collagen and fibroblast activation protein (FAP) in hepatitis C virus infection. Adv Exp Med Biol 2003; 524: 235-43.
Meier JK-H, Scharl M, Miller SN, et al. Specific differences in migratory function of myofibroblasts isolated from Crohn’s disease fistulae and strictures. Inflamm Bowel Dis 2011; 17(1): 202-12.
Panés J, Bouzas R, Chaparro M, et al. Systematic review: the use of ultrasonography, computed tomography and magnetic resonance imaging for the diagnosis, assessment of activity and abdominal complications of Crohn’s disease. Aliment Pharmacol Ther 2011; 34(2): 125-45.
Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn’s disease: a prospective multicentre study. Groupe d’Etudes Thérapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Gut 1989; 30(7): 983-9.
Rimola J, Rodriguez S, García-Bosch O, et al. Magnetic resonance for assessment of disease activity and severity in ileocolonic Crohn’s disease. Gut 2009; 58(8): 1113-20.
Allocca M, Fiorino G, Bonifacio C, et al. Comparative accuracy of bowel ultrasound versus magnetic resonance enterography in combination with colonoscopy in assessing Crohn’s disease and guiding clinical decision-making. J Crohn’s Colitis 2018; 12(11): 1280-7.
Rimola J, Planell N, Rodríguez S, et al. Characterization of inflammation and fibrosis in Crohn’s disease lesions by magnetic resonance imaging. Am J Gastroenterol 2015; 110(3): 432-40.
Brahme F, Lindström C. A comparative radiographic and pathological study of intestinal vaso-architecture in Crohn’s disease and in ulcerative colitis. Gut 1970; 11(11): 928-40.
Gramlich T, Petras RE. Pathology of inflammatory bowel disease. Semin Pediatr Surg 2007; 16(3): 154-63.
Fornasa F, Benassuti C, Benazzato L. Role of Magnetic Resonance Enterography in Differentiating between Fibrotic and Active Inflammatory Small Bowel Stenosis in Patients with Crohn’s Disease. J Clin Imaging Sci 2011; 1: 35.
Oto A, Zhu F, Kulkarni K, Karczmar GS, Turner JR, Rubin D. Evaluation of diffusion-weighted MR imaging for detection of bowel inflammation in patients with Crohn’s disease. Acad Radiol 2009; 16(5): 597-603.
Freiman M, Perez-Rossello JM, Callahan MJ, et al. Characterization of fast and slow diffusion from diffusion-weighted MRI of pediatric Crohn’s disease. J Magn Reson Imaging 2013; 37(1): 156-63.
Oussalah A, Laurent V, Bruot O, et al. Diffusion-weighted magnetic resonance without bowel preparation for detecting colonic inflammation in inflammatory bowel disease. Gut 2010; 59(8): 1056-65.
Hordonneau C, Buisson A, Scanzi J, et al. Diffusion-weighted magnetic resonance imaging in ileocolonic Crohn’s disease: validation of quantitative index of activity. Am J Gastroenterol 2014; 109(1): 89-98.
Rimola J, Alvarez-Cofiño A, Pérez-Jeldres T, et al. Comparison of three magnetic resonance enterography indices for grading activity in Crohn’s disease. J Gastroenterol 2017; 52(5): 585-93.
Adler J, Swanson SD, Schmiedlin-Ren P, et al. Magnetization transfer helps detect intestinal fibrosis in an animal model of Crohn disease. Radiology 2011; 259(1): 127-35.
Li X-H, Mao R, Huang S-Y, et al. Characterization of Degree of Intestinal Fibrosis in Patients with Crohn Disease by Using Magnetization Transfer MR Imaging. Radiology 2018; 287(2): 494-503.
Coelho R, Ribeiro H, Maconi G. Bowel Thickening in Crohn’s Disease: Fibrosis or Inflammation? Diagnostic Ultrasound Imaging Tools. Inflamm Bowel Dis 2017; 23(1): 23-34.
Baumgart DC, Müller HP, Grittner U, et al. US-based Real-time Elastography for the Detection of Fibrotic Gut Tissue in Patients with Stricturing Crohn Disease. Radiology 2015; 275(3): 889-99.
Palatka K, Kacska S, Lovas S, Garai I, Varga J, Galuska L. The potential role of FDG PET-CT in the characterization of the activity of Crohn’s disease, staging follow-up and prognosis estimation: a pilot study. Scand J Gastroenterol 2018; 53(1): 24-30.
Pellino G, Nicolai E, Catalano OA, et al. PET/MR Versus PET/CT Imaging: Impact on the Clinical Management of Small-Bowel Crohn’s Disease. J Crohn’s Colitis 2016; 10(3): 277-85.
Catalano OA, Gee MS, Nicolai E, et al. Evaluation of Quantitative PET/MR Enterography Biomarkers for Discrimination of Inflammatory Strictures from Fibrotic Strictures in Crohn Disease. Radiology 2016; 278(3): 792-800.
Knieling F, Neufert C, Hartmann A, et al. Multispectral optoacoustic tomography for assessment of Crohn’s disease activity. N Engl J Med 2017; 376(13): 1292-4.
Zhu Y, Johnson LA, Huang Z, et al. Identifying intestinal fibrosis and inflammation by spectroscopic photoacoustic imaging: an animal study in vivo. Biomed Opt Express 2018; 9(4): 1590-600.
Lei H, Johnson LA, Liu S, et al. Characterizing intestinal inflammation and fibrosis in Crohn’s disease by photoacoustic imaging: feasibility study. Biomed Opt Express 2016; 7(7): 2837-48.
Gomollón F, Dignass A, Annese V, et al. 3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and Medical Management. J Crohn’s Colitis 2017; 11(1): 3-25.
Yaffe BH, Korelitz BI. Prognosis for nonoperative management of small-bowel obstruction in Crohn’s disease. J Clin Gastroenterol 1983; 5(3): 211-5.
Allocca M, Bonifacio C, Fiorino G, et al. Efficacy of tumour necrosis factor antagonists in stricturing Crohn’s disease: A tertiary center real-life experience. Dig Liver Dis 2017; 49(8): 872-7.
Bouhnik Y, Carbonnel F, Laharie D, et al. Efficacy of adalimumab in patients with Crohn’s disease and symptomatic small bowel stricture: a multicentre, prospective, observational cohort (CREOLE) study. Gut 2018; 67(1): 53-60.
Wo WCP, Mourad F, Leong RWL. Crohn’s Disease associated Strictures. J Gastroenterol Hepatol 2018; 1(Il): 998-1008.Available from:
Morar PS, Faiz O, Warusavitarne J, et al. Systematic review with meta-analysis: endoscopic balloon dilatation for Crohn’s disease strictures. Aliment Pharmacol Ther 2015; 42(10): 1137-48.
Lan N, Shen B. Endoscopic Stricturotomy with Needle Knife in the Treatment of Strictures from Inflammatory Bowel Disease. Inflamm Bowel Dis 2017; 23(4): 502-13.
Campos C, Perrey A, Lambert C, et al. Medical Therapies for Stricturing Crohn’s Disease: Efficacy and Cross-Sectional Imaging Predictors of Therapeutic Failure. Dig Dis Sci 2017; 62(6): 1628-36.
Bettenworth D, Gustavsson A, Atreja A, et al. A Pooled Analysis of Efficacy, Safety, and Long-term Outcome of Endoscopic Balloon Dilation Therapy for Patients with Stricturing Crohn’s Disease. Inflamm Bowel Dis 2017; 23(1): 133-42.
Paz Z, Shoenfeld Y. Antifibrosis: to reverse the irreversible. Clin Rev Allergy Immunol 2010; 38(2-3): 276-86.
Rosenbloom J, Mendoza FA, Jimenez SA. Strategies for anti-fibrotic therapies. Biochim Biophys Acta 2013; 1832(7): 1088-103.
Bonafoux D, Lee W-C. Strategies for TGF-beta modulation: a review of recent patents. Expert Opin Ther Pat 2009; 19(12): 1759-69.
Denton CP, Merkel PA, Furst DE, et al. Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum 2007; 56(1): 323-33.
Homey B. [Fresolimumab: A new treatment option for systemic scleroderma on the horizon?]. Hautarzt 2015; 66(10): 797-8.
Trachtman H, Fervenza FC, Gipson DS, et al. A phase 1, single-dose study of fresolimumab, an anti-TGF-β antibody, in treatment-resistant primary focal segmental glomerulosclerosis. Kidney Int 2011; 79(11): 1236-43.
Vincenti F, Fervenza FC, Campbell KN, et al. A Phase 2, Double-Blind, Placebo-Controlled, Randomized Study of Fresolimumab in Patients With Steroid-Resistant Primary Focal Segmental Glomerulosclerosis. Kidney Int Rep 2017; 2(5): 800-10.
Catania JM, Chen G, Parrish AR. Role of matrix metalloproteinases in renal pathophysiologies. Am J Physiol Renal Physiol 2007; 292(3): F905-11.
Kim H, Oda T, López-Guisa J, et al. TIMP-1 deficiency does not attenuate interstitial fibrosis in obstructive nephropathy. J Am Soc Nephrol 2001; 12(4): 736-48.
Kisseleva T, Brenner DA. Hepatic stellate cells and the reversal of fibrosis. J Gastroenterol Hepatol 2006; 21(Suppl. 3): S84-7.
Bansal R, Prakash J, De Ruiter M, Poelstra K. Interferon gamma peptidomimetic targeted to hepatic stellate cells ameliorates acute and chronic liver fibrosis in vivo. J Control Release 2014; 179: 18-24.
Danese S, Bonovas S, Lopez A, et al. Identification of Endpoints for Development of Antifibrosis Drugs for Treatment of Crohn’s Disease. Gastroenterology 2018; 155(1): 76-87.
Oikarinen AI, Vuorio EI, Zaragoza EJ, Palotie A, Chu ML, Uitto J. Modulation of collagen metabolism by glucocorticoids. Receptor-mediated effects of dexamethasone on collagen biosynthesis in chick embryo fibroblasts and chondrocytes. Biochem Pharmacol 1988; 37(8): 1451-62.
Vaglio A, Salvarani C, Buzio C. Retroperitoneal fibrosis. Lancet 2006; 367(9506): 241-51.
Vaglio A, Palmisano A, Corradi D, Salvarani C, Buzio C. Retroperitoneal fibrosis: evolving concepts. Rheum Dis Clin North Am 2007; 33(4): 803-17. [vi-vii.].
Badea I, Taylor M, Rosenberg A, Foldvari M. Pathogenesis and therapeutic approaches for improved topical treatment in localized scleroderma and systemic sclerosis. Rheumatology (Oxford) 2009; 48(3): 213-21.
Peikert T, Daniels CE, Beebe TJ, Meyer KC, Ryu JH. Assessment of current practice in the diagnosis and therapy of idiopathic pulmonary fibrosis. Respir Med 2008; 102(9): 1342-8.
Graham MF, Willey A, Adams J, Diegelmann RF. Corticosteroids increase procollagen gene expression, synthesis, and secretion by human intestinal smooth muscle cells. Gastroenterology 1995; 109(5): 1454-61.
Dheda K, Lalloo UG, Cassim B, Mody GM. Experience with azathioprine in systemic sclerosis associated with interstitial lung disease. Clin Rheumatol 2004; 23(4): 306-9.
Raghu G, Depaso WJ, Cain K, et al. Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial. Am Rev Respir Dis 1991; 144(2): 291-6.
Peyrin-Biroulet L, Deltenre P, Ardizzone S, et al. Azathioprine and 6-mercaptopurine for the prevention of postoperative recurrence in Crohn’s disease: a meta-analysis. Am J Gastroenterol 2009; 104(8): 2089-96.
Liu JJ. Purine analog for the prevention of postoperative recurrence of Crohn’s disease: is it really better? Inflamm Bowel Dis 2011; 17(2): 665-6.
Di Sabatino A, Pender SLF, Jackson CL, et al. Functional modulation of Crohn’s disease myofibroblasts by anti-tumor necrosis factor antibodies. Gastroenterology 2007; 133(1): 137-49.
Di Sabatino A, Ciccocioppo R, Benazzato L, Sturniolo GC, Corazza GR. Infliximab downregulates basic fibroblast growth factor and vascular endothelial growth factor in Crohn’s disease patients. Aliment Pharmacol Ther 2004; 19(9): 1019-24.
Guan Q, Weiss CR, Wang S, et al. Reversing Ongoing Chronic Intestinal Inflammation and Fibrosis by Sustained Block of IL-12 and IL-23 Using a Vaccine in Mice. Inflamm Bowel Dis 2018.
Speca S, Rousseaux C, Dubuquoy C, et al. Novel PPARγ Modulator GED-0507-34 Levo Ameliorates Inflammation-driven Intestinal Fibrosis. Inflamm Bowel Dis 2016; 22(2): 279-92.

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy