Anti-fibrotics in Treatment of Crohn's Disease – Lessons Learnt from other Diseases
Review Article: Anti-fibrotic Agents for the Treatment of Crohn's Disease – Lessons Learnt from other Diseases
Alimentary Pharmacology & Therapeutics. 2009;31(2):189-201. © 2009 Blackwell Publishing
Abstract and Introduction
Abstract
Background The current therapies for Crohn's disease (CD) are mainly focused on blockade of inflammation. Fibrosis remains one of the major complications of CD often leading to surgery, affecting patients' quality-of-life.
Aim To summarize the published data regarding the potential anti-fibrotic role of drugs commonly used in CD and the most effective anti-fibrotic drugs used in other diseases evaluating their potential use to treat intestinal fibrosis in CD.
Methods A literature search was performed in the PubMed, Medline, Cochrane and EMBASE databases, considering in vitro, animal and human studies on fibrosis in inflammatory bowel disease and other similar chronic pathologies.
Results Treatment of fibrosis in CD is limited to surgery or endoscopic dilatation, although some of the drugs currently used may have anti-fibrotic activity. In other diseases, anti-fibrotic agents are already used or are in preclinical or clinical trials. ACE inhibitors, Angiotensin Receptor Blockers, and HMG-CoA inhibitors merit further investigation in CD because of their role in preventing fibrosis in cardiovascular and renal diseases.
Conclusions Anti-fibrotic drugs are under evaluation or already used in clinical practice in other chronic inflammatory diseases. In CD, there is a great need for investigation into agents that may prevent, reduce or reverse intestinal fibrosis.
Introduction
Although numerous findings in the field of immunopathology have identified dozens of possible target molecules for the treatment of the inflammatory bowel diseases (IBD),[1] in this article, we concentrate on a less understood, but clinically highly relevant aspect: intestinal fibrosis in Crohn's disease (CD), one of the two major forms of IBD. Chronic inflammation plays a crucial role in fibrotic changes, by disrupting the natural balance of pro- and anti-fibrotic mechanisms. Transmural inflammation because of dysregulated wound healing mechanisms leads to fibrotic stenosis in one-third of patients with CD.[2, 3] In the absence of a reliable marker, ongoing fibrosis and consequent stricture development is often not diagnosed until the process is already irreversible. Being the most common indication for surgical intervention, this very frequent complication of CD can significantly influence the patients' quality-of-life.
The pathogenesis of fibrosis in CD remains poorly understood. Some studies have shown that transforming growth factor (TGF) β1, acting together with SMAD proteins and insulin growth factor (IGF) 1, plays a crucial role in promoting gene transcription for collagenous proteins, especially type III collagen and fibronectin. In addition, fibroblast contraction is facilitated by the hyperexpression of TGFβ1.[4] Investigation into a possible linkage between fibrostenotic CD and gene mutations has demonstrated that any mutation of the NOD2/CARD15 gene concerning R702W, G908R and 3020InsC sequences is frequently associated with this particular phenotype. Fibrosis is also more frequent in patients presenting the V249 CX3CR1 allele polymorphism.[5]
Chronic inflammation can affect almost every human tissue, causing fibrotic changes that significantly impair organ function, with associated therapeutic challenges. Fibrogenesis in every tissue, including the gut, is a complex process characterized by increased production of components of the extracellular matrix (ECM) by activated myofibroblasts. These may be the differentiation of stem cells, perycites, fibrocytes or stellate cells that are activated by cytokines, chemokines and growth factors (Figure 1).[6] The possible inhibitory mechanisms have been examined in several pathologies affecting different organs, such as systemic sclerosis, liver cirrhosis, nephrosclerosis in diabetic and IgA nephropathy, rheumatoid arthritis, and chronic pancreatitis.[7–10] In spite of all the progress that has been made in advancing our understanding of the pathophysiology of these conditions, clinical treatment remains a major challenge. The traditional medical interventions have focused on symptom control and the slowing down of disease progression. Although some of the currently available therapeutics display antifibrotic effects, they are unable to taper pro-fibrotic changes.
Methods
A literature review was performed by searching for the terms 'fibrosis', 'anti-fibrotic' and 'fibrogenesis', combined with the terms 'corticosteroid', 'anti-TNFα', 'azathioprine', 'cyclophosphamide', 'methotrexate', 'systemic sclerosis', 'liver cirrhosis', 'pulmonary fibrosis', 'nephrosclerosis', 'rheumatoid arthritis', 'retroperitoneal fibrosis' and 'cardiac remodelling', in the PubMed, Medline, Cochrane and EMBASE databases. All relevant articles in English published by May 2009 were reviewed. Data were analysed from several in vitro, animal and human studies of fibrosis, pro- and anti-fibrotic therapeutic approaches in IBD and several other pathologies affecting different organs. Reviewed anti-fibrotic agents and their effects on fibrosis are summarized in Table 1.
Results
The Anti-fibrotic Effect of Therapeutics Currently Used for the Treatment of CD
The agents that are currently used for the treatment of CD are not intended to act on intestinal fibrosis, but to reduce inflammation and relieve the patients' symptoms. Nonetheless, some of these agents display additional anti-fibrotic effects.
Corticosteroids are important for controlling inflammation and are used for the treatment of many different pathologies. The anti-fibrotic effect of corticosteroids is a very well-known phenomenon, causing deficiency in general wound healing. This effect results from a decrease in collagen synthesis[3] and for this reason, positive effects have been observed with corticosteroids in other fibrotic diseases, such as retroperitoneal fibrosis,[6, 7] systemic sclerosis[8] and idiopathic pulmonary fibrosis.[9, 10] However, there are several drawbacks associated with steroid use: first of all, long-term systemic use of steroids is not recommended because of several significant side effects and secondly, there is some doubt as to whether this anti-fibrotic action occurs in intestinal smooth muscle cells. Indeed, these cells appear refractory to corticosteroids in vitro, as the administration of dexamethasone increased expression of the procollagen gene.[11] In spite of these data, promising results have been obtained with local endoscopic injections of cortisone in patients undergoing endoscopic dilation for fibrotic strictures due to CD,[12] although a recent study has been giving negative results.[13] Further evidence with controlled studies is necessary to confirm these observations.
Azathioprine, the most common immunosuppressive agent used for the treatment of patients with CD, along with other immunosuppressant agents, such as cyclophosphamide and methotrexate, has been used for the treatment of several chronic inflammatory diseases. This drug was effective for the treatment of mild cases of retroperitoneal fibrosis or in severe disease for maintenance therapy after intravenous cyclophosphamide treatment[14] and may have some additional effects when administered with corticosteroids in fibrotic pulmonary disease.[10, 15–17] The successful use of azathioprine in preventing post-operative recurrence of CD, even in the absence of studies designed to evaluate its effect on intestinal fibrosis, supports the hypothesis that thiopurines can prevent or at least slow the fibrotic process in patients with CD.[18]
The role of TNF-α in intestinal fibrogenesis and the effect of anti-TNF-α agents on fibrotic strictures were not clear for a long time. TNF-α is potentially an anti-fibrogenetic factor, with inhibition therefore theoretically favouring fibrosis. In addition, the mucosal healing effects of anti-TNFα agents suggest that, besides healing, they may induce fibrotic changes in the layers of the intestinal wall.[19, 20] Indeed, early reports seemed to confirm this theory, as obstructive complications were observed in some patients administered infliximab.[21–23] For a long period, its use in cases of known intestinal stenosis was discouraged, even by the manufacturer, although later, multivariable analysis of the data from the observational TREAT registry and the ACCENT I multi-centre trial demonstrated that disease duration, disease severity, ileal disease and new corticosteroid use are the only factors associated with stricture formation.[24] The first positive results with anti-TNF-α therapy were reported in cases of inflammatory or mixed stenosis, but as the diagnostic strategies for characterizing the nature of intestinal strictures were still being evaluated, these reports did not change clinical practice.[25, 26]
Review Article: Anti-fibrotic Agents for the Treatment of Crohn's Disease – Lessons Learnt from other Diseases
Alimentary Pharmacology & Therapeutics. 2009;31(2):189-201. © 2009 Blackwell Publishing
Abstract and Introduction
Abstract
Background The current therapies for Crohn's disease (CD) are mainly focused on blockade of inflammation. Fibrosis remains one of the major complications of CD often leading to surgery, affecting patients' quality-of-life.
Aim To summarize the published data regarding the potential anti-fibrotic role of drugs commonly used in CD and the most effective anti-fibrotic drugs used in other diseases evaluating their potential use to treat intestinal fibrosis in CD.
Methods A literature search was performed in the PubMed, Medline, Cochrane and EMBASE databases, considering in vitro, animal and human studies on fibrosis in inflammatory bowel disease and other similar chronic pathologies.
Results Treatment of fibrosis in CD is limited to surgery or endoscopic dilatation, although some of the drugs currently used may have anti-fibrotic activity. In other diseases, anti-fibrotic agents are already used or are in preclinical or clinical trials. ACE inhibitors, Angiotensin Receptor Blockers, and HMG-CoA inhibitors merit further investigation in CD because of their role in preventing fibrosis in cardiovascular and renal diseases.
Conclusions Anti-fibrotic drugs are under evaluation or already used in clinical practice in other chronic inflammatory diseases. In CD, there is a great need for investigation into agents that may prevent, reduce or reverse intestinal fibrosis.
Introduction
Although numerous findings in the field of immunopathology have identified dozens of possible target molecules for the treatment of the inflammatory bowel diseases (IBD),[1] in this article, we concentrate on a less understood, but clinically highly relevant aspect: intestinal fibrosis in Crohn's disease (CD), one of the two major forms of IBD. Chronic inflammation plays a crucial role in fibrotic changes, by disrupting the natural balance of pro- and anti-fibrotic mechanisms. Transmural inflammation because of dysregulated wound healing mechanisms leads to fibrotic stenosis in one-third of patients with CD.[2, 3] In the absence of a reliable marker, ongoing fibrosis and consequent stricture development is often not diagnosed until the process is already irreversible. Being the most common indication for surgical intervention, this very frequent complication of CD can significantly influence the patients' quality-of-life.
The pathogenesis of fibrosis in CD remains poorly understood. Some studies have shown that transforming growth factor (TGF) β1, acting together with SMAD proteins and insulin growth factor (IGF) 1, plays a crucial role in promoting gene transcription for collagenous proteins, especially type III collagen and fibronectin. In addition, fibroblast contraction is facilitated by the hyperexpression of TGFβ1.[4] Investigation into a possible linkage between fibrostenotic CD and gene mutations has demonstrated that any mutation of the NOD2/CARD15 gene concerning R702W, G908R and 3020InsC sequences is frequently associated with this particular phenotype. Fibrosis is also more frequent in patients presenting the V249 CX3CR1 allele polymorphism.[5]
Chronic inflammation can affect almost every human tissue, causing fibrotic changes that significantly impair organ function, with associated therapeutic challenges. Fibrogenesis in every tissue, including the gut, is a complex process characterized by increased production of components of the extracellular matrix (ECM) by activated myofibroblasts. These may be the differentiation of stem cells, perycites, fibrocytes or stellate cells that are activated by cytokines, chemokines and growth factors (Figure 1).[6] The possible inhibitory mechanisms have been examined in several pathologies affecting different organs, such as systemic sclerosis, liver cirrhosis, nephrosclerosis in diabetic and IgA nephropathy, rheumatoid arthritis, and chronic pancreatitis.[7–10] In spite of all the progress that has been made in advancing our understanding of the pathophysiology of these conditions, clinical treatment remains a major challenge. The traditional medical interventions have focused on symptom control and the slowing down of disease progression. Although some of the currently available therapeutics display antifibrotic effects, they are unable to taper pro-fibrotic changes.
Methods
A literature review was performed by searching for the terms 'fibrosis', 'anti-fibrotic' and 'fibrogenesis', combined with the terms 'corticosteroid', 'anti-TNFα', 'azathioprine', 'cyclophosphamide', 'methotrexate', 'systemic sclerosis', 'liver cirrhosis', 'pulmonary fibrosis', 'nephrosclerosis', 'rheumatoid arthritis', 'retroperitoneal fibrosis' and 'cardiac remodelling', in the PubMed, Medline, Cochrane and EMBASE databases. All relevant articles in English published by May 2009 were reviewed. Data were analysed from several in vitro, animal and human studies of fibrosis, pro- and anti-fibrotic therapeutic approaches in IBD and several other pathologies affecting different organs. Reviewed anti-fibrotic agents and their effects on fibrosis are summarized in Table 1.
Results
The Anti-fibrotic Effect of Therapeutics Currently Used for the Treatment of CD
The agents that are currently used for the treatment of CD are not intended to act on intestinal fibrosis, but to reduce inflammation and relieve the patients' symptoms. Nonetheless, some of these agents display additional anti-fibrotic effects.
Corticosteroids are important for controlling inflammation and are used for the treatment of many different pathologies. The anti-fibrotic effect of corticosteroids is a very well-known phenomenon, causing deficiency in general wound healing. This effect results from a decrease in collagen synthesis[3] and for this reason, positive effects have been observed with corticosteroids in other fibrotic diseases, such as retroperitoneal fibrosis,[6, 7] systemic sclerosis[8] and idiopathic pulmonary fibrosis.[9, 10] However, there are several drawbacks associated with steroid use: first of all, long-term systemic use of steroids is not recommended because of several significant side effects and secondly, there is some doubt as to whether this anti-fibrotic action occurs in intestinal smooth muscle cells. Indeed, these cells appear refractory to corticosteroids in vitro, as the administration of dexamethasone increased expression of the procollagen gene.[11] In spite of these data, promising results have been obtained with local endoscopic injections of cortisone in patients undergoing endoscopic dilation for fibrotic strictures due to CD,[12] although a recent study has been giving negative results.[13] Further evidence with controlled studies is necessary to confirm these observations.
Azathioprine, the most common immunosuppressive agent used for the treatment of patients with CD, along with other immunosuppressant agents, such as cyclophosphamide and methotrexate, has been used for the treatment of several chronic inflammatory diseases. This drug was effective for the treatment of mild cases of retroperitoneal fibrosis or in severe disease for maintenance therapy after intravenous cyclophosphamide treatment[14] and may have some additional effects when administered with corticosteroids in fibrotic pulmonary disease.[10, 15–17] The successful use of azathioprine in preventing post-operative recurrence of CD, even in the absence of studies designed to evaluate its effect on intestinal fibrosis, supports the hypothesis that thiopurines can prevent or at least slow the fibrotic process in patients with CD.[18]
The role of TNF-α in intestinal fibrogenesis and the effect of anti-TNF-α agents on fibrotic strictures were not clear for a long time. TNF-α is potentially an anti-fibrogenetic factor, with inhibition therefore theoretically favouring fibrosis. In addition, the mucosal healing effects of anti-TNFα agents suggest that, besides healing, they may induce fibrotic changes in the layers of the intestinal wall.[19, 20] Indeed, early reports seemed to confirm this theory, as obstructive complications were observed in some patients administered infliximab.[21–23] For a long period, its use in cases of known intestinal stenosis was discouraged, even by the manufacturer, although later, multivariable analysis of the data from the observational TREAT registry and the ACCENT I multi-centre trial demonstrated that disease duration, disease severity, ileal disease and new corticosteroid use are the only factors associated with stricture formation.[24] The first positive results with anti-TNF-α therapy were reported in cases of inflammatory or mixed stenosis, but as the diagnostic strategies for characterizing the nature of intestinal strictures were still being evaluated, these reports did not change clinical practice.[25, 26]