Challenges in the Pathophysiology, Diagnosis, and Management of Intestinal Fibrosis in Inflammatory Bowel Disease

Intestinal fibrosis is a common complication of inflammatory bowel disease (IBD) that is usually the consequence of chronic inflammation. Although the anti-inflammatory therapies currently available have had little impact on intestinal fibrosis in Crohn’s disease (CD), increased understanding of the pathophysiology and the development of therapies targeting fibrogenic pathways hold promise for the future. One of the critical challenges is how reduction or reversal of intestinal fibrosis should be defined and measured in the setting of clinical trials and drug approval. The International Organization for Inflammatory Bowel Disease organized a workshop in Amsterdam, The Netherlands, on December 19–20, 2018 in an attempt to review the current knowledge of the biological background, diagnosis, treatment of intestinal fibrosis, and clinical trial end points. Basic and clinical scientists discussed the pathophysiology of intestinal fibrosis, the current status of biomarkers and imaging modalities in stenosing CD, and recent clinical studies in this area. Researchers from outside the IBD field presented advances in the understanding of fibrotic processes in other organs, such as the skin, liver, and lungs. Lastly, the design of clinical trials with antifibrotic therapy for IBD was discussed, with priority on patient populations, patient-reported outcomes (PROs), and imaging. This report summarizes the key findings, discussions, and conclusions of the workshop. Fibrosis represents excessive production of extracellular matrix (ECM) by activated mesenchymal cells. ECM-producing cells are predominantly myofibroblasts that differentiate from epithelial, endothelial, and stellate cells, as well as from fibroblasts and bone marrow–derived stem cells (Figure 1).1Rieder F. Fiocchi C. Rogler G. Mechanisms, management, and treatment of fibrosis in patients with inflammatory bowel diseases.Gastroenterology. 2017; 152: 340-350Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar Luminal microorganisms and bacterial products, in addition to growth factors and cytokines released from immune and nonimmune cells, are the main drivers of mesenchymal cell activation and differentiation that ultimately result in fibrosis. Preclinical models of intestinal fibrosis have been developed to better understand the pathophysiology, including a heterologous transplant model in rats and mice. For example, it was demonstrated that the bacteria-responsive adaptor protein MYD88 (myeloid differentiation primary response 88) and the cytokine interleukin 10 do not play critical roles in intestinal fibrosis, despite the theoretical plausibility of this interaction. Pirfenidone and antibodies against matrix metalloproteinase 9, agents currently approved for the treatment of idiopathic pulmonary fibrosis, prevented the development of experimental intestinal fibrosis. Other translational studies indicated that inhibition of the pH-sensing OGR1 (ovarian cancer G-protein-coupled receptor 1) and the apoptosis regulator BCL2 (B-cell lymphoma 2) are potential approaches to prevent fibrosis in IBD. Prediction of the development and progression of intestinal fibrosis and stricture formation is of great importance in the management of IBD. Multiple studies have tried to identify markers that can stratify patients in fibrotic risk groups, detect early stages of fibrosis before the onset of symptoms, and predict the outcomes of therapy. This search resulted in the identification of several phenotypic characteristics and serologic and genetic markers associated with stenotic complications. Of the more than 200 genes connected to IBD, several have been associated with fibrostenotic CD, such as variants of NOD 2 (nucleotide-binding oligomerization domain-containing protein 2) gene and matrix metalloproteinase 3. Epigenetic regulation of the genes encoding WNT2B (wingless-type mouse mammary tumor virus integration site family 2B) and 2 eicosanoid synthesis pathway enzymes was also associated with CD fibrosis. In addition, several serologic parameters, including ECM molecules; growth factors; and antibodies against microbial products, are associated with the development of IBD and, in some cases, with fibrosis. In the RISK (Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn’s Disease) study, which included more than 900 children and adolescents with newly diagnosed IBD, a competing-risk model based on demographic characteristics, clinical, serologic, and genetic markers could predict a complicated disease course and response to anti-tumor necrosis factor therapy.2Kugathasan S. Denson L.A. Walters T.D. et al.Prediction of complicated disease course for children newly diagnosed with Crohn's disease: a multicentre inception cohort study.Lancet. 2017; 389: 1710-1718Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar Other risk models, such as the Bacardi model, have been developed to facilitate therapeutic decisions. Histopathologic analysis of intestinal fibrosis may provide critical information beyond that available from these clinical phenotype-based instruments. Smooth muscle hyperplasia of the submucosa, hypertrophy of the muscularis propria, and chronic inflammation are the most prominent changes in CD strictures.3Chen W. Lu C. Hirota C. et al.Smooth muscle hyperplasia/hypertrophy is the most prominent histological change in Crohn's fibrostenosing bowel strictures: a semiquantitative analysis by using a novel histological grading scheme.J Crohns Colitis. 2017; 11: 92-104Crossref PubMed Scopus (61) Google Scholar Because the overall muscular hyperplasia and hypertrophy correlated positively with chronic inflammation and negatively with fibrosis, the “inflammation-smooth muscle hyperplasia axis” appears to play a dominant role in the pathogenesis of CD-associated strictures. Sensitive and specific diagnostic methods, including imaging modalities and biomarkers, are required to quantify different components of stenosis. An ideal instrument must be valid, reliable, and responsive. Outcome measures in clinical trials should also be noninvasive, widely available, inexpensive, and, if possible, radiation-free. An instrument with all of these desirable properties could become validated as a surrogate end point in clinical trials in stenosing CD. A number of tools are currently available as potential outcome measures in stenosing CD, each of which has specific advantages and disadvantages. Critical components are the assessment of bowel wall thickness, mechanical and vascular characteristics, infiltration of immune cells, and expression of genes and proteins. However, it should be recognized that none of these candidate modalities has undergone the comprehensive validation process required for a robust outcome measure. Cross-sectional imaging techniques, such as magnetic resonance imaging (MRI) and computer tomography scanning, are the most widely explored methods to differentiate fibrosis and inflammation. For instance, whereas inflammation in CD is associated with increased T2 hyperintensity, mucosal enhancement, ulcerations, and blurred margins, fibrosis is rather characterized by abnormalities in contrast uptake (“enhancement”). Diffusion-weighted MRI and magnetization transfer MRI are potentially useful for quantification of fibrosis. Other promising modalities include T2* mapping, intravoxel incoherent motion diffusion-weighted MRI, MRI-defined motility, and magnetic resonance elastography. Intestinal ultrasound is being used increasingly for the evaluation of CD and assessment of complications and treatment response. Intestinal ultrasound is noninvasive, convenient for the patient and physician, inexpensive, and associated with overall sensitivity and specificity for strictures of 80% and 95%, respectively.4Kucharzik T. Maaser C. Intestinal ultrasound and management of small bowel Crohn's disease.Therap Adv Gastroenterol. 2018; 111756284818771367Crossref Scopus (19) Google Scholar The use of contrast media can further increase the sensitivity and specificity. Limitations of intestinal ultrasound include the lack of a “panoramic” view of the whole bowel, the currently missing standard for image documentation, and the difficulty assessing the proximal ileum and jejunum. Innovative imaging modalities are contrast-enhanced ultrasonography and elastography. Contrast-enhanced ultrasonography is time-consuming, relatively expensive, and not yet validated. Elastography, including quantitative shear wave elastography and qualitative strain elastography, might be especially useful to distinguish fibrotic from inflammatory stenosis, and to discriminate low-grade from high-grade fibrosis. Limitations include variability in manual compression and lack of standardization. Photoacoustic imaging, which uses specific laser wavelengths to produce detectable vibrations in specific molecules, such as hemoglobin and collagen, is also being developed currently as a tool to quantify intestinal inflammation and fibrosis. Fibrosis is a complication of many chronic diseases and aging, and occurs in virtually all organs. Accumulating evidence indicates that the pathogenic pathways involved in systemic sclerosis (SSc) and hepatic fibrosis display similarities with intestinal fibrosis. SSc is an autoimmune disorder characterized by extensive fibrosis, vasculopathy, and immune dysfunction. Although the pathogenesis of SSc is largely unknown, translational studies have revealed altered fibroblast biology, in addition to activation and accumulation of immune cells. CXC-chemokine ligand 4, a chemokine secreted by plasmacytoid dendritic cells, is highly overexpressed in SSc, and correlates with the severity of pulmonary fibrosis and pulmonary arterial hypertension, the 2 most serious complications of the disease. Transforming growth factor β–dependent signaling through STAT3 (signal transducer and activator of transcription 3) is also up-regulated in SSc. STAT3 inhibitors, which are currently being tested for other indications, offer an attractive approach in SSc and other fibrotic conditions. The inhibition of serotonin signaling is another potential approach, given that inhibition of serotonin receptors prevents the onset of experimental fibrosis and reduces established fibrosis in animal models. Clinical trials in SSc assess disease modification in skin or lungs, using both composite clinical end points and other organ-specific readouts. For instance, the modified Rodnan skin score is used for the clinical assessment of skin sclerosis, the forced vital capacity measures lung function in pulmonary fibrosis, and the Composite Response Index in Systemic Sclerosis is used commonly to evaluate disease activity in early diffuse cutaneous SSc. At present, tocilizumab, nintedanib, riociguat, and abatacept have been approved in various jurisdictions for the treatment of SSc. In addition, many other agents, including inhibitors of adhesion molecules, growth factors, and cytokines and their receptors, are being evaluated as monotherapy or combination therapy. Myeloablative autologous hematopoietic stem cell transplantation has also been of benefit to patients with severe SSc. Hepatic fibrosis is characterized by excessive accumulation of ECM components, resulting from chronic liver injury associated with nonalcoholic steatohepatitis, viral hepatitis, or alcoholic liver disease. Several methods are available to quantify the degree of hepatic fibrosis in nonalcoholic fatty liver disease, of which nonalcoholic steatohepatitis is the advanced stage. These include the Fibrosis-4 score, the enhanced liver fibrosis test, FibroScan, serum biomarkers, and magnetic resonance elastography. A central factor in the pathobiology of hepatic fibrosis is the activation of hepatic stellate cells with subsequent transformation into myofibroblasts, cells that have both fibrogenic and immunomodulatory capacity. Antifibrotic therapies that deactivate, silence, or eliminate hepatic stellate cells that have been explored include the peroxisome proliferator-activated receptor-γ agonist pioglitazone and the farnesoid X receptor agonist obeticholic acid. Alternative strategies have interfered with biogenesis, remodeling of connective tissue or specific inflammatory processes. Although no antifibrotic agents have been approved for nonalcoholic steatohepatitis, a number of agents have shown encouraging results in phase 2 and 3 trials. Examples include the farnesoid X receptor agonist cilofexor, the antioxidant vitamin E, the chemokine receptor inhibitor cenicriviroc, and the ASK-1 (apoptosis signal–regulating kinase 1) inhibitor selonsertib. Innovative 3-dimensional models composed of human liver tissue or cells are anticipated to boost the development of effective and clinically relevant therapies for liver fibrosis. In idiopathic pulmonary fibrosis, agents that inhibit activation or differentiation of fibroblasts or immune cells or decrease the production of ECM molecules have shown promising results. Of these, the immunosuppressive agent pirfenidone and the tyrosine kinase inhibitor nintedanib have been approved in selected jurisdictions. Although treatment with these agents resulted in short-term improvement in lung function, existing data do not support a benefit on overall prognosis. Other effective agents in development include the connective tissue growth factor inhibitor FG3019, recombinant pentraxin 2, the lysophosphatidic acid receptor antagonist BMS-986020, and the αvβ6 integrin inhibitor BG00011. No antifibrotic therapies have been approved for IBD, but several agents showed promising results in preclinical studies. A recent study demonstrated that an antibody to the interleukin-36 receptor reduced fibrosis in a murine model of chronic intestinal inflammation (Table 1).5Scheibe K. Kersten C. Schmied A. et al.Inhibiting interleukin 36 receptor signaling reduces fibrosis in mice with chronic intestinal inflammation.Gastroenterology. 2019; 156: 1082-1097Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Other potentially interesting agents include inhibitors of antibodies against tumor necrosis factor–like cytokine 1A and agents that are used for the treatment of fibrosis in other organs (Table 1). Blockade of the fibrosis-inducing cytokine Oncostatin M with the monoclonal GSK2330811 offers an attractive strategy as well. Topical Rho kinase inhibition may also be effective by reducing myocardin-related transcription factor and p38 mitogen-activated protein kinase activation and activation of fibroblast autophagy.Table 1Potential Agents for the Treatment of Intestinal FibrosisAgentClassOriginal indicationStatusSpesolimabIL-36RiUCPhase 2PF-06480605TL1AiUCPhase 2GSK2330811Oncostatin MiCut SScPhase 2PirfenidoneunknownIPFRegisteredaRegistered by the US Food and Drug Administration and the European Medicines Agency.NintedanibTKIIPFRegisteredaRegistered by the US Food and Drug Administration and the European Medicines Agency.FG-3019CTGFiIPFPhase 2bPRM-151rhPTX-2IPF, HFPhase 2LebrikizumabIL-13iIPFPhase 2SAR-156597IL-4/13iIPFPhase 2BG-00011αvβ6iIPFPhase 2BMS-986020LPARiIPFPhase 2PioglitazonePPARγaNASHPhase 3ElafibranorPPARγaNASHPhase 3GS-9674FXRaNASHPhase 2Vitamin Eanti-oxidantNASHPhase 3Emricasancaspase iNASHPhase 2bCenicrivirocCCR2/5iNASHPhase 3SelonsertibASK-1iNASHPhase 3GR-MD-02galectin 3iNASHPhase 2ba, agonist; ASK-1, apoptotic signal regulating kinase 1; CCR, CC chemokine receptor; CTGF, connective tissue growth factor; cut SSc, cutaneous systemic sclerosis; FXR, farnesoid X receptor; HF, hepatic fibrosis; i, inhibitor; IL, interleukin; IPF, idiopathic pulmonary fibrosis; LPAR, lysophosphatidic acid receptor; NASH, nonalcoholic steatohepatitis; PTX-2, pentraxin 2; R, receptor; rh, recombinant human; TKI, tyrosine kinase inhibitor; TL1A, tumor necrosis factor-like cytokine 1A.a Registered by the US Food and Drug Administration and the European Medicines Agency. Open table in a new tab a, agonist; ASK-1, apoptotic signal regulating kinase 1; CCR, CC chemokine receptor; CTGF, connective tissue growth factor; cut SSc, cutaneous systemic sclerosis; FXR, farnesoid X receptor; HF, hepatic fibrosis; i, inhibitor; IL, interleukin; IPF, idiopathic pulmonary fibrosis; LPAR, lysophosphatidic acid receptor; NASH, nonalcoholic steatohepatitis; PTX-2, pentraxin 2; R, receptor; rh, recombinant human; TKI, tyrosine kinase inhibitor; TL1A, tumor necrosis factor-like cytokine 1A. No antifibrotic agents have been approved for CD, which is partially due to a lack of standardized definitions, diagnostic modalities, and validated treatment end points. The interdisciplinary CONSTRICT (Crohn’s Disease Anti-fibrotic Stricture Therapies) group used a modified RAND Corporation and University of California Los Angeles appropriateness methodology trying to reach consensus definitions for small bowel strictures, outcome measures, and treatment end points in stricturing CD.6Rieder F. Bettenworth D. Ma C. et al.An expert consensus to standardise definitions, diagnosis and treatment targets for anti-fibrotic stricture therapies in Crohn's disease.Aliment Pharmacol Ther. 2018; 48: 347-357Crossref PubMed Scopus (88) Google Scholar Consensus was reached on MRI as the preferred imaging technique to define strictures and assess response to therapy, and 24–48 weeks of therapy was considered appropriate for pharmacologic trials. The only large prospective trial that evaluated the efficacy of treatment for stenosing CD was the CREOLE study. This cohort study assessed the efficacy of adalimumab in symptomatic CD small bowel strictures using a composite end point of treatment success at week 24, defined as continuation of adalimumab without prohibited treatment, endoscopic dilation, or bowel resection.7Bouhnik 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: 53-60Crossref PubMed Scopus (120) Google Scholar However, the Crohn’s disease obstructive score used was designed by physicians and not a valid PRO. Sixty-four percent of the patients met the end point. A prognostic score was proposed to define patients with a good, intermediate, and poor prognosis. For trials in symptomatic CD patients with fibrosis, the identification of the most optimal study population with radiologic confirmation will be essential. Measurement of stenotic fibrosis by validated magnetic resonance and computed tomography criteria is likely to be preferred for assessment of treatment efficacy. Nevertheless, evaluation of symptoms by rigorously developed PROs is also necessary to show the value of new treatments to patients’ well-being and for regulatory approval. Expert members of the International Organization for Inflammatory Bowel Disease recently proposed 13 end points for use in clinical trials that assess the efficacy and safety of antifibrotic agents in CD.8Danese S. Bonovas S. Lopez A. et al.Identification of endpoints for development of antifibrosis drugs for treatment of Crohn's disease.Gastroenterology. 2018; 155: 76-87Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Currently, the international STAR (Stenosis Therapy and Anti-Fibrotic Research) consortium is developing a PRO instrument for stricturing CD according to US Food and Drug Administration–recommended methodology and internationally developed best practices. Most likely, antifibrotic treatment in isolation has relatively little chance of success if not combined with anti-inflammatory treatment. It remains unclear and a matter of discussion what this component of a “combined intervention” should look like. Moreover, it remains unclear whether smooth muscle hyperplasia observed in the submucosa and hypertrophy of the muscularis propria would need different targeted treatment. Also, the ideal study population remains uncertain: should it be patients who have had a complete bowel obstruction? Can they have a balloon dilatation or stricturoplasty before entering an antifibrotic trial? How can dietary changes be controlled? Patients tend to alter their intake based on symptoms caused by specific food products, which may interfere with subjective wellbeing and even with prestenotic dilatation as documented on imaging. Although MR enterography was proposed as the most attractive imaging modality, validated and reliable scores for fibrostenotic IBD are lacking. In addition, waiting times for MR can be challenging and, therefore, less invasive ultrasound-based technologies warrant further investigation. During this International Organization for Inflammatory Bowel Disease workshop, the pathophysiology, diagnosis, and potential therapies for intestinal fibrosis and other chronic fibrotic diseases were reviewed. The pathways of fibrosis were analyzed and compared, and potential therapeutic targets were identified. Currently approved and investigational therapies for systemic sclerosis and pulmonary and hepatic fibrosis were discussed. The workshop fueled continuing efforts to formulate definitions, end points, and trial designs that are highly needed for the optimal evaluation of antifibrotic agents in IBD. Progress in the development of a PRO for stricturing CD is anticipated to further facilitate clinical studies in this field. Although intestinal fibrosis is a complex and challenging disorder, numerous preclinical and clinical efforts have resulted in promising advances.