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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

tools may help the clinician in predicting disease evolution in IBD. However, these tools are still insufficient, and pro-spective 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 inap-propriate 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% de-scribed a very benign and inactive disease after the first flare, while about one third reported chronic active dis-ease and a last third frequent relapses [2] . Likewise, al-though probably not completely correlated, approxi-

Key Words

C-reactive protein · Crohn’s disease · Endoscopy · Genetics · Prediction · Serology · Ulcerative colitis

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 per-formed, which was mainly based on PubMed search, using the following terms: Crohn’s disease, ulcerative colitis, in-flammatory 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 dis-ease location and behaviour, are probably currently the most useful. In addition, a series of biomarkers, including ge-netic, serological and inflammatory markers, as well as char-acteristics of endoscopic lesions may have an added value. Conclusions: Simple clinical, biological and endoscopic

Prof. Edouard Louis Department of Gastroenterology CHU Liège BE–4000 Liège (Belgium) E-Mail edouard.louis   @   ulg.ac.be

© 2014 S. Karger AG, Basel0257–2753/14/0324–0328$39.50/0

www.karger.com/ddi

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mately one third to one half of the patients will remain free of stricturing or penetrating (intra-abdominal or perianal) complications after 10 years of disease evolution [4, 5] . These complications are the main reason for surgi-cal operations in CD. In ulcerative colitis (UC), approxi-mately 10% of the patients will require colectomy over 10 years and around one third of the patients over the whole disease course [6, 7] . Colectomy may be indicated in case of chronic active refractory disease, fulminant colitis or development of preneoplastic or neoplastic lesions, which represent the main complications of UC.

Management of IBD is classically adapted to disease evolution and response to treatment to alleviate symp-toms and decrease the relapse rate. Effective prediction would allow and aim to more tightly control the disease by choosing and adapting the treatment strategy and mit-igating individual risks. The hope is then to be able to re-ally alter the natural history of the disease, avoiding hos-pitalisations, complications and surgeries [8–10] .

The aim of this review paper is to focus on available simple clinical or biological tools assisting the clinician in predicting the disease course ( table 1 ) as well as to give an overview of promising markers with their limitations and required validations ( tables 2 , 3 ).

Prediction of Disease Evolution in CD

Clinical Predictors The variable course of CD has been well described in

several population-based studies [1–3] . In particular in the most recent study from Norway, 4 profiles have been described with their respective frequency: (1) severe flare at diagnosis but rapid decrease and disappearance of dis-ease activity in 43%; (2) mild activity at the beginning with secondary progressive worsening of the disease in 3%; (3) recurrent flares interspersed with periods of full remission in 32%, and (4) chronic active disease with fluc-tuating but constant disease activity in 19% [9] . No clini-cal predictors have been associated with these different profiles of disease evolution so far. However, numerous studies have been devoted to the search for factors pre-dicting disease complications and it can be assumed that some correlations exist between disease evolution profiles and the development of these complications ( table 1 ).

The most striking characteristic of CD that has been associated with the development of complications is dis-ease location. Terminal ileal location has been very strongly associated with the risk of stricturing and inter-nal penetrating behaviour in several independent studies [11, 12] . Hence, it has also been associated with the risk of surgery [13, 14] , which is increased compared with pa-

Table 1. Selection of simple clinical, endoscopic and biological tools to predict the disease course of IBD

Markers Predicted outcome Validated inindependent studies

Crohn’s diseaseIleal location Stricturing and internal penetrating complications, risk of surgery yesDisease location proximal to the last third of the ileum Recurrence after first flare, risk of surgery noColonic and rectal disease Perianal lesions partlyStricturing or internal penetrating behaviour at diagnosis Risk of surgery yesPerianal lesion at diagnosis Disabling disease yesAge <40 years at diagnosis Disabling disease yesSmoking More relapses, development of complications, suboptimal

response to anti-TNFyes

Normal C-reactive protein Suboptimal response to anti-TNF yesEndoscopic lesions 1 year after curative surgery Clinical recurrence yesDeep colonic ulcers Colectomy noAbsence of endoscopic lesions Suboptimal response to anti-TNF yesAbsence of mucosal healing Clinical relapse partly

Ulcerative colitisAbsence of mucosal healing Clinical relapse partlyExtensive colitis Colorectal cancer, colectomy, mortality yesElevated C-reactive protein in severe disease Treatment failure yesSevere endoscopic lesions Treatment failure noSmoking Less relapses, decreased risk of surgery partly

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tients with limited colon involvement. In a European population-based study, proximal small bowel and upper gastro-intestinal tract location (category L4 in the Mon-treal classification) have been associated with the risk of disease recurrence [15] , and it was an independent pre-dictor of more complicated disease, including hospitali-sations. In a recent Asian study, it was also associated with the risk of surgery [16] . Colonic disease, particularly rec-tal disease, is associated with the development of perianal disease, a complication which develops in 12% of the pa-tients 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-stric-turing 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 complica-tions. A stricturing or intra-abdominal penetrating be-haviour 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

of the first surgery was associated with a more rapid re-currence, particularly when disease behaviour was reclas-sified according to the pathological report [19] , and usu-ally with an abdominal penetrating disease as an indica-tion of further surgery, too [20] . The presence of perianal lesions at diagnosis has been associated with a more fre-quent 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 fac-tors 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 de-fined by chronic symptoms, need for surgery, immuno-suppressive treatment, biological agents and hospitalisa-tion 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 dis-abling disease within 5 years after diagnosis [24] . In a sec-

Table 2. Selection of specific biological tools associated with either disease course or response to treatment in IBD, but requiring further studies to demonstrate their added value over simple clinical tools

Markers Predicted outcome Specific validation required

Crohn’s diseaseCARD15 variants Stricturing and internal penetrating

behaviour, risk of surgeryMeaningful added value over the prediction by ileal location, meaningful positive predictive value

IBD5 locus and OCTN gene variants Perianal lesions Meaningful positive and negative predictive value

Anti-glycan and anti-bacterial antibodies Stricturing and internal penetrating behaviour, risk of surgery

Meaningful added value over the prediction by ileal location, meaningful positive predictive value

Apoptosis genes and ADAM-17 gene variants Response to anti-TNF Meaningful positive and negative predictive value

Ulcerative colitisIL-13Rα2 mucosal expression Response to anti-TNF Meaningful positive and negative predictive value

HLADRB1*0103 allele Risk of colectomy Meaningful added value over the prediction by extensive colitis, meaningful positive and negative predictive value

Table 3. Selection of potentially new promising markers requiring extensive assessment of their ability to predict disease course and re-sponse to treatment in IBD

Markers Main outcome that could be predicted

>150 genes or loci closely associated with IBD Evolution profile, development of complications, need for surgery Blood proteomic profile Response to treatmentMucosal proteomics or micro-array Response to treatmentPrecise type of endoscopic lesions at diagnosis in CD Evolution profile, development of complications, need for surgery

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ond study, these factors were partly confirmed, particu-larly the presence of perianal disease at diagnosis [25] . Furthermore, the presence of stricturing disease at diag-nosis 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 de-finitive stoma [25] . However, in a European population-based study, stricturing or penetrating behaviour at diag-nosis was not associated with further recurrence after the first flare, need for surgery [15] or with increased mortal-ity [26] .

Disease activity in the year following diagnosis pre-dicts disease activity in subsequent years. Up to 80% of patients in remission maintain remission during the fol-lowing years, whereas 70–80% of patients with active CD will show similar activity over time.

Young age at onset, especially <40 years, has also been associated with a higher severity of the disease and more extensive and complicated disease, particularly the risk of disabling disease [24, 25] . However, on the contrary, old-er age at onset has been associated with a slight increase in mortality [26] .

The influence of gender is not consistent in the pro-gression of CD when comparing males and females, al-though women may be at higher risk of surgery.

While, as indicated earlier, weight loss at diagnosis has been associated with more severe disease characterised by the development of non-reversible tissue damage [25] , in a recent study, obesity has been associated with a more rapid need for surgery, which may indicate a more ag-gressive course in obese patients [27] .

Smoking has been one of the most studied prognostic factors in IBD. Active smoking has been associated with disease activity [28] as well as with the development of stricturing and fistulising complications as well as a great-er risk of surgery [11, 12, 29] . In a recent study, light smoking already increased disease activity and the num-ber of hospitalisations but not the need for surgery [30] .

Biological Markers Biomarkers have also been assessed for their potential

to predict CD evolution, particularly serological and ge-netic markers. As CD is a multifactorial polygenic dis-ease, it seems logical to hypothesise that different genetic backgrounds may lead to different disease profiles. A fur-ther 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

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 defi-nition 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. Neverthe-less, since the discovery of the association between the CARD15 gene and CD, a series of preliminary studies have suggested potentially meaningful associations ( ta-ble 2 ). The CARD15 gene has been the most broadly stud-ied. 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 associa-tion was shown to be secondary to the main association with ileal involvement [11, 35] , which has been exten-sively demonstrated [36, 37] . Variants at the IBD5 locus located on 5q31 as well as in the OCTN (carnitine/organ-ic cation transporter) gene within this locus have been associated with the development of perianal and pene-trating disease [38, 39] . More recently, the numbers of CD risk alleles and genotypes in the CARD15 gene, IBD5 lo-cus 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, environmen-tal (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 pro-tein located nearby the IL12B gene was associated with stricturing behaviour and a shorter delay towards the de-velopment 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 as-sociated with the development of perianal disease. Al-though all these associations remain to be confirmed and their clinical impact validated, they first suggest the po-tential usefulness of genetic markers in CD classifications

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and stratifications, but they also emphasise the need for studying interactions between a large number of genetic and other factors in enormous cohorts of rigorously phe-notyped patients. A very ambitious ongoing study by the international consortium for the study of IBD genetics aiming to elucidate the influence of all the genetic mark-ers associated with CD so far on disease behaviour in a cohort of several thousands of patients will represent the next major step forward in that direction ( table 3 ).

Serological markers may also be of interest in predict-ing the course of CD. The markers studied so far are es-sentially anti-glycan and anti-bacterial antibodies ( ta-ble 2 ). In a series of cross-sectional studies, the presence and, in some studies, the magnitude of the reaction against Saccharomyces cerevisiae (ASCA), various glycans (ALCA, ACCA and AMCA), CBir (flagellin), OmpC ( Escherichia coli outermembrane porin) and I2 ( Pseudo-monas fluorescens -related protein) were shown to be as-sociated with complicated disease behaviour (stricturing and/or internal penetrating) and the need for surgery [42–44] . In paediatric CD patients, ASCA has been asso-ciated with relapsing disease, earlier complications and need for additional surgery. This is not sufficient, how-ever, to state the predictive value of these markers, since they could simply represent surrogate markers appearing concomitant with such complications. Importantly, such a predictive value has been suggested in several large pro-spective paediatric cohort studies. In these studies, the positivity for these antibodies was present before the de-velopment of complications and sometimes from the time of diagnosis [45, 46] . Nevertheless, several aspects remain to be clarified before one can consider these mark-ers as clinically useful: (1) their independent association with the complications, particularly when studied togeth-er with simple demographic or clinical parameters, such as disease location, must be confirmed; (2) the positive and negative predictive values of these predictors calcu-lated from available data seem rather low, and (3) even if not clinically manifest, these complications may already be present at the pathological level, which would signifi-cantly limit the impact of a specific treatment strategy.

More recently, the transcriptomic profile of circulat-ing CD8 T cells showed a specific pattern in frequently relapsing CD or UC patients requiring further treatment escalation. This profile was consistently similar to the one previously found in systemic lupus erythematous and ANCA vasculitis. It was defined by elevated expression of genes involved in antigen-dependent T cell responses, in-cluding signalling initiated by both IL-7 and TCR ligation [47] .

Endoscopic Predictors While ileocolonoscopy is considered necessary for the

diagnosis of CD, the predictive value of the characteristics of endoscopic lesions has been very little studied, particu-larly at diagnosis. Nevertheless, a few important studies in this field deserve further discussion ( table 1 ). The first one is a monocentric retrospective study on 102 patients assessing the impact of endoscopic lesions at a unique but variable time point during the disease on the further risk of colonic resection [48] . In this study, the presence of deep ulcers covering more than 10% of at least 1 colonic segment was associated with a significant increase in the risk of colectomy at 3 and 8 years, when it exceeded 60%. A small number of patients also had penetrating compli-cations during the follow-up: all had severe endoscopic lesions at index colonoscopy. The second study concerns recurrence of the disease after curative surgery [49] . In this prospective study, the severity of recurrent endo-scopic lesions at the anastomosis or in the neoterminal ileum 6–12 months after surgery was predictive of further clinical relapse of the disease. Particularly patients with less than 5 aphthous ulcers were at low risk of relapse (<10% at 4 years), while those having more than 10 aph-thoïd lesions or broader ulcers, diffuse ileitis or strictures relapsed (100%).

Beyond this, evidence has also recently accumulated to show that mucosal healing obtained during medical treat-ment was associated with a reduced risk of further re-lapse, complications [50] or surgery [2] . While clear guidelines are currently missing on how to treat patients without mucosal response despite being in full clinical remission and while it remains to be determined whether in these patients mucosal healing can be achieved by a change in treatment, a recent study showed that, in those circumstances, treatment reduction, particularly anti-TNF withdrawal, was associated with a higher risk of clin-ical relapse [51] .

Prediction of Disease Evolution in UC

Clinical Predictors The disease course varies markedly among UC pa-

tients. Particularly in a recent population-based study from Norway, nearly one fifth of the patients experienced no significant relapse during the 10 years following diag-nosis, while about half of the patients had a quiescent dis-ease over the last 5 years [52] . As for CD, it is the disease location that has been most strikingly associated with the course of the disease ( table 1 ). Particularly extensive coli-

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tis has been associated with an increased risk of colectomy [53] and colon cancer [54] as well as a slight increase in mortality [55] . Colectomy rates reached 35% in extensive colitis while it was less than 20% in left-sided colitis and less than 10% in proctitis [53] . The same is true for the risk of colon cancer, which reached 45% after 30 years in extensive colitis in early historic series, while it was around 30% in left-sided colitis and 10% in proctitis [54] . These risks have been shown to be much lower in most recent series, with a long-term risk of colon cancer of around 5–10%, probably due to sustained control of in-flammation and maybe surveillance. This risk was, how-ever, still higher in extensive colitis [56, 57] . Likewise, in a recent population-based European study, the global risk of colectomy was 8.7% over 10 years [7] .

Age also seems to have an impact on the prognosis of UC patients. Age below 30 years at diagnosis has been as-sociated with an increased risk of relapse. In a recent study, patients with distal colitis were at increased risk of disease extension if they were younger at diagnosis or if they had sclerosing cholangitis [58] . Furthermore, after disease extension, these patients were at increased risk of more aggressive disease with resistance to treatment and more frequent development of colonic malignancies. In another recent paediatric study, disease extension was strongly associated with the risk of colectomy [59] . It was also the case, albeit to a lesser extent, in case of extra-in-testinal manifestations.

In the recent Norwegian population-based study men-tioned previously, age over 50 years at diagnosis was as-sociated with a decreased risk of colectomy and a more benign course over the long term [52] .

The number of relapses and the time interval to the first relapse have been prognostic factors in some studies. A large number of relapses during follow-up and a short-er time interval between diagnosis and first relapse are predictors of an unfavourable course with further re-lapses.

No differences have been found between men and women in disease evolution and outcome. However, young age at diagnosis and female gender have been as-sociated with a higher number of relapses.

Some studies have reported that appendicectomy cor-relates with a less severe disease course and lower need for colectomy.

Finally, smoking has been associated with a less ag-gressive disease course in UC with lower numbers of re-lapses within 10 years after diagnosis [60, 61] . Smokers had a lower rate of admission for flares and required less corticosteroid and immunosuppressive therapy. In a re-

cent study from Hungary, it even decreased the risk of colectomy [62] .

Biological Predictors Although more than 50 genes or loci have now been

clearly associated with UC, the impact of these genes on disease course, particularly the progression to extensive colitis, the risk of fulminant colitis and the risk of cancer, has not been widely studied. The strongest association, which has been broadly replicated, is the one between the carriage of the HLADRB1 * 0103 allele and the propensity to develop pancolitis and undergo colectomy [63, 64] ( ta-ble 2 ). From a clinical point of view, however, the added value of this genotyping over the simple assessment of the extent of colitis on the prediction of a worse clinical out-come has not been demonstrated. In UC patients under-going ileo-anal pouch surgery, high preoperative levels of pANCA have been prospectively associated with the de-velopment of pouchitis in some studies [65]. This risk may be increased by the simultaneous presence of anti-CBir1 [66] . In the same setting, patients positive for ASCA, particularly if they have relatives with CD, are at higher risk of developing CD of the pouch [67] .

Endoscopic Predictors While an attack of severe colitis has long been consid-

ered as a contraindication to any endoscopic procedure, this exploration can bring highly predictive information, providing that it is carefully performed ( table 1 ). In a co-hort study of 85 patients, it has been shown to be feasible in the majority of cases. Some patients only required rec-tosigmoïdoscopy since, in case of the presence of distal severe lesions, a further exploration was not more infor-mative. The proportion of colectomy rose from 26% in patients without severe lesions to 93% in patients with such severe lesions, including mainly extensive deep ul-cerations [68] .

As in CD, and probably even more consistently, the mucosal healing obtained with medical treatment has been associated with a lower risk of relapse [69, 70] . In a population-based Norwegian study before the use of bio-logical agents [71] as well as in a retrospective study on infliximab treatment in a tertiary referral centre [72] , it was even associated with a decrease in the rate of colec-tomy, while patients with no mucosal response after their 1st year of disease subsequently showed higher disease activity and greater requirement for corticosteroids.

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Conclusion

Although still imperfect, a series of simple clinical, bi-ological and endoscopic markers may help the clinician to predict disease evolution in routine practice in IBD. Particularly disease location and behaviour, smoking habits, blood levels of C-reactive protein, and the pres-ence and severity of endoscopic lesions have proven to be of predictive value. In the near future, an extensive evalu-ation of very large numbers of genes recently associated with the development of IBD, a better characterisation of the individual immuno-inflammatory process by pro-teomics, micro-array or serologic profiling as well as a

careful description and assessment of intestinal lesions by endoscopy or imaging techniques should further im-prove our predicting performances.

Disclosure Statement

E. Louis has received research grants from AstraZeneca, Scher-ing-Plough and Abbott. Speaker fees from Abbott, Abbvie, Astra-Zeneca, Ferring, Schering-Plough, MSD, Chiesi, Menarini, Ny-comed and Falk, UCB. He is in the advisory board of Abbott,Abbvie, Ferring, UCB, MSD, Millenium, Mitsubishi Pharma, Ta-keda and a consultant of Abbvie.

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