Natural History Dig Dis 2014;32:328–336 DOI: 10.1159/000358132
Can We Predict the High-Risk Patient? Jose-Manuel Benitez Edouard Louis Department of Gastroenterology, CHU Liège, and GIGA Research, Liège University, Liège, Belgium
Abstract Background: While therapeutic strategies able to change the natural history of inflammatory bowel diseases (IBD) are being developed, factors predicting aggressive disease are needed to be able to choose the appropriate therapeutic strategy for the individual patient based on the risk/benefit ratio. The aim of this review is to focus on the tools assisting the clinician in routine practice regarding the prediction of disease evolution. Methods: A literature review was performed, which was mainly based on PubMed search, using the following terms: Crohn’s disease, ulcerative colitis, inflammatory bowel disease, genetics, serology, biomarkers, endoscopy, C-reactive protein, faecal calprotectin, disease evolution and complications. Results: For the prediction of disease evolution, clinical characteristics, particularly disease location and behaviour, are probably currently the most useful. In addition, a series of biomarkers, including genetic, serological and inflammatory markers, as well as characteristics of endoscopic lesions may have an added value. Conclusions: Simple clinical, biological and endoscopic
© 2014 S. Karger AG, Basel 0257–2753/14/0324–0328$39.50/0 E-Mail [email protected] www.karger.com/ddi
tools may help the clinician in predicting disease evolution in IBD. However, these tools are still insufficient, and prospective evaluation of new genetic and biological markers are needed. © 2014 S. Karger AG, Basel
Introduction
Prediction of inflammatory bowel disease (IBD) has always been a topic of great interest. The reason is that IBD are highly heterogeneous diseases characterised by very different disease evolution profiles and by unequal responses to treatment. Furthermore, these treatments may be costly, and significant toxicity renders them inappropriate for a systematic widespread use. Heterogeneity in the evolution of Crohn’s disease (CD) has been clearly shown in several population-based studies, particularly in studies from Scandinavia [1–3]. In the most recent study and according to patients’ assessment of their disease course over the first 10 years of CD, more than 40% described a very benign and inactive disease after the first flare, while about one third reported chronic active disease and a last third frequent relapses [2]. Likewise, although probably not completely correlated, approxiProf. Edouard Louis Department of Gastroenterology CHU Liège BE–4000 Liège (Belgium) E-Mail edouard.louis @ ulg.ac.be
Downloaded by: Univ. of California San Diego 132.239.1.231 - 11/18/2014 7:10:23 PM
Key Words C-reactive protein · Crohn’s disease · Endoscopy · Genetics · Prediction · Serology · Ulcerative colitis
Table 1. Selection of simple clinical, endoscopic and biological tools to predict the disease course of IBD Predicted outcome
Validated in independent studies yes no partly yes yes yes yes
Normal C-reactive protein Endoscopic lesions 1 year after curative surgery Deep colonic ulcers Absence of endoscopic lesions Absence of mucosal healing
Stricturing and internal penetrating complications, risk of surgery Recurrence after first flare, risk of surgery Perianal lesions Risk of surgery Disabling disease Disabling disease More relapses, development of complications, suboptimal response to anti-TNF Suboptimal response to anti-TNF Clinical recurrence Colectomy Suboptimal response to anti-TNF Clinical relapse
Ulcerative colitis Absence of mucosal healing Extensive colitis Elevated C-reactive protein in severe disease Severe endoscopic lesions Smoking
Clinical relapse Colorectal cancer, colectomy, mortality Treatment failure Treatment failure Less relapses, decreased risk of surgery
partly yes yes no partly
Crohn’s disease Ileal location Disease location proximal to the last third of the ileum Colonic and rectal disease Stricturing or internal penetrating behaviour at diagnosis Perianal lesion at diagnosis Age 150 genes or loci closely associated with IBD Blood proteomic profile Mucosal proteomics or micro-array Precise type of endoscopic lesions at diagnosis in CD
Evolution profile, development of complications, need for surgery Response to treatment Response to treatment Evolution profile, development of complications, need for surgery
tients with limited colon involvement. In a European population-based study, proximal small bowel and upper gastro-intestinal tract location (category L4 in the Montreal classification) have been associated with the risk of disease recurrence [15], and it was an independent predictor of more complicated disease, including hospitalisations. In a recent Asian study, it was also associated with the risk of surgery [16]. Colonic disease, particularly rectal disease, is associated with the development of perianal disease, a complication which develops in 12% of the patients with ileal disease, 41% of the patients with colonic disease and 92% of the patients with rectal disease [17]. While the behaviour of CD, characterised as non-stricturing non-penetrating, stricturing or penetrating, may change over time [4, 5], its behaviour at diagnosis may be an indicator of its future disease course, as it may reflect the propensity of the patient to develop disease complications. A stricturing or intra-abdominal penetrating behaviour has repeatedly been linked with the development of more severe disease and has been associated with an increased risk of surgery [13, 18]. Other studies have also shown that abdominal penetrating behaviour at the time 330
Dig Dis 2014;32:328–336 DOI: 10.1159/000358132
of the first surgery was associated with a more rapid recurrence, particularly when disease behaviour was reclassified according to the pathological report [19], and usually with an abdominal penetrating disease as an indication of further surgery, too [20]. The presence of perianal lesions at diagnosis has been associated with a more frequent use of immunosuppressive treatment [18, 21], poor mid-term outcome [22] and an increased risk of surgical resection, post-operative recurrence [23] and permanent stoma placement. More recently, attempts have been made to define factors predicting the development of disabling or severe disease over time. In a first study in a large cohort using both retrospective analysis and prospective validation, an assessment of factors present at diagnosis and associated with the subsequent development of disabling disease defined by chronic symptoms, need for surgery, immunosuppressive treatment, biological agents and hospitalisation disclosed that perianal disease together with young age at diagnosis and the need for steroids to treat the first flare are factors associated with the development of disabling disease within 5 years after diagnosis [24]. In a secBenitez/Louis
Downloaded by: Univ. of California San Diego 132.239.1.231 - 11/18/2014 7:10:23 PM
Table 3. Selection of potentially new promising markers requiring extensive assessment of their ability to predict disease course and response to treatment in IBD
Biological Markers Biomarkers have also been assessed for their potential to predict CD evolution, particularly serological and genetic markers. As CD is a multifactorial polygenic disease, it seems logical to hypothesise that different genetic backgrounds may lead to different disease profiles. A further theoretical advantage of genetic markers is that they exist before the disease is diagnosed and that they could thus be early predictors of disease outcome. A very large number of genes (>150) have recently been proven to be Factors Predicting IBD
associated with the predisposition to develop CD [31]. An extensive search for their implication in the development of specific subtypes of CD has not been performed yet. Several obstacles, which have not yet been fully overcome, exist for such a study: the necessity of a very precise definition of disease subphenotypes, the need of a very large patient cohort to reach enough statistical power and the availability of specific mathematical tools to test potential interactions between a large number of factors. Nevertheless, since the discovery of the association between the CARD15 gene and CD, a series of preliminary studies have suggested potentially meaningful associations (table 2). The CARD15 gene has been the most broadly studied. Several studies have suggested an association with stricturing and/or internal penetrating disease behaviour, need for surgical resection and early risk of postoperative relapse [32–34]. In several studies, however, this association was shown to be secondary to the main association with ileal involvement [11, 35], which has been extensively demonstrated [36, 37]. Variants at the IBD5 locus located on 5q31 as well as in the OCTN (carnitine/organic cation transporter) gene within this locus have been associated with the development of perianal and penetrating disease [38, 39]. More recently, the numbers of CD risk alleles and genotypes in the CARD15 gene, IBD5 locus and DLG5 (Drosophila disc large homologue 5) and ATG16L1 (autophagy-related 16-like 1) genes, and the IL23R (interleukin 23 receptor) gene have been associated with a more severe course of the disease, including the development of stricturing and/or penetrating behaviour as well as the need for surgery [40]. Probably the most advanced study in this field to date assessed the influence of a large number of demographic, clinical, environmental (mainly smoking), serological and genetic factors on the development of stricturing, internal penetrating and perianal CD, as well as the need for surgical resection in a large tertiary referral centre cohort of 875 patients [41]. Together with ileal involvement, homozygosity for the rs1363670 G allele in a gene encoding a hypothetical protein located nearby the IL12B gene was associated with stricturing behaviour and a shorter delay towards the development of a stricture. Together with male gender, the carriage of the rs12704036 T allele was associated with internal penetrating disease. The carriage of the CDKAL1 rs6908425 C allele combined with the absence of the CARD15 variant, colonic location and smoking was associated with the development of perianal disease. Although all these associations remain to be confirmed and their clinical impact validated, they first suggest the potential usefulness of genetic markers in CD classifications Dig Dis 2014;32:328–336 DOI: 10.1159/000358132
331
Downloaded by: Univ. of California San Diego 132.239.1.231 - 11/18/2014 7:10:23 PM
ond study, these factors were partly confirmed, particularly the presence of perianal disease at diagnosis [25]. Furthermore, the presence of stricturing disease at diagnosis together with weight loss (>5 kg) was associated with progression to severe disease defined by the surgical resection of two small bowel segments (or at least 70 cm) or any colonic segment, complex perianal disease or a definitive stoma [25]. However, in a European populationbased study, stricturing or penetrating behaviour at diagnosis was not associated with further recurrence after the first flare, need for surgery [15] or with increased mortality [26]. Disease activity in the year following diagnosis predicts disease activity in subsequent years. Up to 80% of patients in remission maintain remission during the following years, whereas 70–80% of patients with active CD will show similar activity over time. Young age at onset, especially
Can We Predict the High-Risk Patient? Jose-Manuel Benitez Edouard Louis Department of Gastroenterology, CHU Liège, and GIGA Research, Liège University, Liège, Belgium
Abstract Background: While therapeutic strategies able to change the natural history of inflammatory bowel diseases (IBD) are being developed, factors predicting aggressive disease are needed to be able to choose the appropriate therapeutic strategy for the individual patient based on the risk/benefit ratio. The aim of this review is to focus on the tools assisting the clinician in routine practice regarding the prediction of disease evolution. Methods: A literature review was performed, which was mainly based on PubMed search, using the following terms: Crohn’s disease, ulcerative colitis, inflammatory bowel disease, genetics, serology, biomarkers, endoscopy, C-reactive protein, faecal calprotectin, disease evolution and complications. Results: For the prediction of disease evolution, clinical characteristics, particularly disease location and behaviour, are probably currently the most useful. In addition, a series of biomarkers, including genetic, serological and inflammatory markers, as well as characteristics of endoscopic lesions may have an added value. Conclusions: Simple clinical, biological and endoscopic
© 2014 S. Karger AG, Basel 0257–2753/14/0324–0328$39.50/0 E-Mail [email protected] www.karger.com/ddi
tools may help the clinician in predicting disease evolution in IBD. However, these tools are still insufficient, and prospective evaluation of new genetic and biological markers are needed. © 2014 S. Karger AG, Basel
Introduction
Prediction of inflammatory bowel disease (IBD) has always been a topic of great interest. The reason is that IBD are highly heterogeneous diseases characterised by very different disease evolution profiles and by unequal responses to treatment. Furthermore, these treatments may be costly, and significant toxicity renders them inappropriate for a systematic widespread use. Heterogeneity in the evolution of Crohn’s disease (CD) has been clearly shown in several population-based studies, particularly in studies from Scandinavia [1–3]. In the most recent study and according to patients’ assessment of their disease course over the first 10 years of CD, more than 40% described a very benign and inactive disease after the first flare, while about one third reported chronic active disease and a last third frequent relapses [2]. Likewise, although probably not completely correlated, approxiProf. Edouard Louis Department of Gastroenterology CHU Liège BE–4000 Liège (Belgium) E-Mail edouard.louis @ ulg.ac.be
Downloaded by: Univ. of California San Diego 132.239.1.231 - 11/18/2014 7:10:23 PM
Key Words C-reactive protein · Crohn’s disease · Endoscopy · Genetics · Prediction · Serology · Ulcerative colitis
Table 1. Selection of simple clinical, endoscopic and biological tools to predict the disease course of IBD Predicted outcome
Validated in independent studies yes no partly yes yes yes yes
Normal C-reactive protein Endoscopic lesions 1 year after curative surgery Deep colonic ulcers Absence of endoscopic lesions Absence of mucosal healing
Stricturing and internal penetrating complications, risk of surgery Recurrence after first flare, risk of surgery Perianal lesions Risk of surgery Disabling disease Disabling disease More relapses, development of complications, suboptimal response to anti-TNF Suboptimal response to anti-TNF Clinical recurrence Colectomy Suboptimal response to anti-TNF Clinical relapse
Ulcerative colitis Absence of mucosal healing Extensive colitis Elevated C-reactive protein in severe disease Severe endoscopic lesions Smoking
Clinical relapse Colorectal cancer, colectomy, mortality Treatment failure Treatment failure Less relapses, decreased risk of surgery
partly yes yes no partly
Crohn’s disease Ileal location Disease location proximal to the last third of the ileum Colonic and rectal disease Stricturing or internal penetrating behaviour at diagnosis Perianal lesion at diagnosis Age 150 genes or loci closely associated with IBD Blood proteomic profile Mucosal proteomics or micro-array Precise type of endoscopic lesions at diagnosis in CD
Evolution profile, development of complications, need for surgery Response to treatment Response to treatment Evolution profile, development of complications, need for surgery
tients with limited colon involvement. In a European population-based study, proximal small bowel and upper gastro-intestinal tract location (category L4 in the Montreal classification) have been associated with the risk of disease recurrence [15], and it was an independent predictor of more complicated disease, including hospitalisations. In a recent Asian study, it was also associated with the risk of surgery [16]. Colonic disease, particularly rectal disease, is associated with the development of perianal disease, a complication which develops in 12% of the patients with ileal disease, 41% of the patients with colonic disease and 92% of the patients with rectal disease [17]. While the behaviour of CD, characterised as non-stricturing non-penetrating, stricturing or penetrating, may change over time [4, 5], its behaviour at diagnosis may be an indicator of its future disease course, as it may reflect the propensity of the patient to develop disease complications. A stricturing or intra-abdominal penetrating behaviour has repeatedly been linked with the development of more severe disease and has been associated with an increased risk of surgery [13, 18]. Other studies have also shown that abdominal penetrating behaviour at the time 330
Dig Dis 2014;32:328–336 DOI: 10.1159/000358132
of the first surgery was associated with a more rapid recurrence, particularly when disease behaviour was reclassified according to the pathological report [19], and usually with an abdominal penetrating disease as an indication of further surgery, too [20]. The presence of perianal lesions at diagnosis has been associated with a more frequent use of immunosuppressive treatment [18, 21], poor mid-term outcome [22] and an increased risk of surgical resection, post-operative recurrence [23] and permanent stoma placement. More recently, attempts have been made to define factors predicting the development of disabling or severe disease over time. In a first study in a large cohort using both retrospective analysis and prospective validation, an assessment of factors present at diagnosis and associated with the subsequent development of disabling disease defined by chronic symptoms, need for surgery, immunosuppressive treatment, biological agents and hospitalisation disclosed that perianal disease together with young age at diagnosis and the need for steroids to treat the first flare are factors associated with the development of disabling disease within 5 years after diagnosis [24]. In a secBenitez/Louis
Downloaded by: Univ. of California San Diego 132.239.1.231 - 11/18/2014 7:10:23 PM
Table 3. Selection of potentially new promising markers requiring extensive assessment of their ability to predict disease course and response to treatment in IBD
Biological Markers Biomarkers have also been assessed for their potential to predict CD evolution, particularly serological and genetic markers. As CD is a multifactorial polygenic disease, it seems logical to hypothesise that different genetic backgrounds may lead to different disease profiles. A further theoretical advantage of genetic markers is that they exist before the disease is diagnosed and that they could thus be early predictors of disease outcome. A very large number of genes (>150) have recently been proven to be Factors Predicting IBD
associated with the predisposition to develop CD [31]. An extensive search for their implication in the development of specific subtypes of CD has not been performed yet. Several obstacles, which have not yet been fully overcome, exist for such a study: the necessity of a very precise definition of disease subphenotypes, the need of a very large patient cohort to reach enough statistical power and the availability of specific mathematical tools to test potential interactions between a large number of factors. Nevertheless, since the discovery of the association between the CARD15 gene and CD, a series of preliminary studies have suggested potentially meaningful associations (table 2). The CARD15 gene has been the most broadly studied. Several studies have suggested an association with stricturing and/or internal penetrating disease behaviour, need for surgical resection and early risk of postoperative relapse [32–34]. In several studies, however, this association was shown to be secondary to the main association with ileal involvement [11, 35], which has been extensively demonstrated [36, 37]. Variants at the IBD5 locus located on 5q31 as well as in the OCTN (carnitine/organic cation transporter) gene within this locus have been associated with the development of perianal and penetrating disease [38, 39]. More recently, the numbers of CD risk alleles and genotypes in the CARD15 gene, IBD5 locus and DLG5 (Drosophila disc large homologue 5) and ATG16L1 (autophagy-related 16-like 1) genes, and the IL23R (interleukin 23 receptor) gene have been associated with a more severe course of the disease, including the development of stricturing and/or penetrating behaviour as well as the need for surgery [40]. Probably the most advanced study in this field to date assessed the influence of a large number of demographic, clinical, environmental (mainly smoking), serological and genetic factors on the development of stricturing, internal penetrating and perianal CD, as well as the need for surgical resection in a large tertiary referral centre cohort of 875 patients [41]. Together with ileal involvement, homozygosity for the rs1363670 G allele in a gene encoding a hypothetical protein located nearby the IL12B gene was associated with stricturing behaviour and a shorter delay towards the development of a stricture. Together with male gender, the carriage of the rs12704036 T allele was associated with internal penetrating disease. The carriage of the CDKAL1 rs6908425 C allele combined with the absence of the CARD15 variant, colonic location and smoking was associated with the development of perianal disease. Although all these associations remain to be confirmed and their clinical impact validated, they first suggest the potential usefulness of genetic markers in CD classifications Dig Dis 2014;32:328–336 DOI: 10.1159/000358132
331
Downloaded by: Univ. of California San Diego 132.239.1.231 - 11/18/2014 7:10:23 PM
ond study, these factors were partly confirmed, particularly the presence of perianal disease at diagnosis [25]. Furthermore, the presence of stricturing disease at diagnosis together with weight loss (>5 kg) was associated with progression to severe disease defined by the surgical resection of two small bowel segments (or at least 70 cm) or any colonic segment, complex perianal disease or a definitive stoma [25]. However, in a European populationbased study, stricturing or penetrating behaviour at diagnosis was not associated with further recurrence after the first flare, need for surgery [15] or with increased mortality [26]. Disease activity in the year following diagnosis predicts disease activity in subsequent years. Up to 80% of patients in remission maintain remission during the following years, whereas 70–80% of patients with active CD will show similar activity over time. Young age at onset, especially
