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Disease behaviour in Crohn’s disease is dynamic and not stable over time
In their landmark paper of 1932, Crohn, Ginzburg, and Oppenheimer1 described “a disease of the terminal ileum, affecting mainly young adults and characterised by a subacute or chronic necrotising and cicratrising inflammation. The ulceration of the mucosa is accompanied by a disproportionate connective tissue reaction . . . which frequently leads to stenosis of the lumen of the intestine, associated with the formation of multiple fistulas”. In the intervening years however, the term Crohn’s disease has been introduced, and now covers a heterogeneous range of clinical presentations, including the classical phenotype of regional ileitis. A number of attempts have been made to subclassify patients with Crohn’s disease into subgroups with similar stable phenotypic characteristics. These attempts have been catalysed first by attempts to individualise therapy, and most recently by progress in understanding the molecular genetics of Crohn’s disease, and the need to relate genotype to disease phenotype. Indeed, it is increasingly clear that assigning disease phenotype may be difficult, but critical in determining the successful outcome of genetic association and linkage studies. The experience of the Toronto group is particularly instructive in this respect, demonstrating that the erroneous assignation of phenotype may lead to a 40% loss of power in linkage studies.2
The Vienna classification of the working party of the World Congress of Gastroenterology proposed a subclassification of Crohn’s disease according to three overriding phenotypic characteristics, implicated in detailed studies of populations in Europe and North America—age, location of disease, and disease behaviour.3 It is the subclassification of disease behaviour into inflammatory (non-stricturing non-penetrating), stricturing (stenosing), and fistulating (penetrating) disease that has been analysed carefully in recent months. Three publications have examined the stability of disease behaviour over time. In the largest study, Cosnes et al analysed data concerning the long term evolution of disease behaviour in 2002 patients with Crohn’s disease retrospectively, and performed a five year prospective analysis of a subgroup of 646 patients.4 These investigators reported that after 20 years, as many as 88% of the initial cohort had developed either stricturing (18%) or penetrating (70%) disease behaviour. In this study, disease location was the most important factor identified in determining an alteration in disease behaviour, with small bowel and anoperineal involvement predicting early stricturing and/or penetrating complications.
Louis et al examined the stability of phenotype in a Belgian population of patients with Crohn’s disease followed for up to 25 years.5 Again, striking changes in disease behaviour over time were noted. Within 10 years, 46% of patients had changed disease behaviour from purely inflammatory disease to either stricturing (27.1%; p<0.0001) or penetrating (29.4%; p<0.0001) disease. Relative to this finding, disease location was stable, although this also changed in approximately 15% of patients by 10 years.
In the present issue of Gut, Louis and colleagues6 have now examined in detail the factors which may influence the progression of disease behaviour [see page 552]. The authors examined 163 patients with an initial inflammatory (B1) phenotype and assessed changes in behaviour over a five year period. These changes were related to clinical characteristics, NOD2/CARD15 genotype, and serological markers by univariate and multivariate analyses. The authors suggest, consistent with previous studies, that disease location is a critical determinant of progression of disease behaviour. Smoking was a determinant in patients progressing to penetrating complications. Although familial disease distinguished stricturing and penetrating disease, the NOD2/CARD15 genotype was not thought to be a determinant of disease behaviour by the authors.
The major message that emerges from these studies is that disease behaviour is dynamic and not stable over time. Although inflammatory disease is the commonest phenotype at diagnosis, there appears to be an inexorable progression to either stricturing or penetrating disease over time. Approximately 25% of patients with inflammatory disease type at diagnosis will progress to penetrating disease over a five year period, again consistent with previous data from Belgium and France.
Although the progression may be inevitable, analysis of factors that influence the progression to either stricturing or penetrating disease is clearly of great interest. Cigarette smoking is arguably the most important environmental factor identified in inflammatory bowel disease pathogenesis thus far, with consistent literature emphasising the discordant effect on ulcerative colitis and Crohn’s disease. In Crohn’s disease, cigarette smoking not only increases disease susceptibility, but also has a well documented detrimental effect on disease course, success of medical therapy, need for repeat surgery, and overall mortality.7 Recent data even implicate smoking in Infliximab resistance.8 We should therefore not be surprised when it is also implicated in the progression from inflammatory to penetrating disease, a phenotype generally considered more severe.9 In the present study it is remarkable that the effect is seen even in relatively light smokers (one cigarette per day was the definition used). There are clearly many unanswered questions, of which perhaps the most pertinent are the mechanisms involved and the constituent of cigarette smoke that is pathogenic. It is at present unclear why the effect is on the progression to penetrating rather than stricturing disease.
Anatomical location of disease is also strongly implicated in the present study, mirroring previous data. Patients with ileal disease tended to have stricturing disease whereas those with colonic and perianal disease had penetrating complications.
What then of genetic influences on disease behaviour? Germline variants of the NOD2/CARD15 gene are reported in up to 50% of European patients,10 and since the initial identification of this gene, many investigators have performed genotype-phenotype analyses. Different populations and ethnic groups have been studied, and various phenotypic classifications have been used in analysis. The current study failed to identify an association between NOD2/CARD15 status and disease behaviour. In fact, these findings contrast with the three largest published studies which have demonstrated that carriage of one or more NOD2 allelic variants may protect against penetrating disease, and predispose towards stricturing disease.10–12 These cited studies and others have also demonstrated an association with ileal involvement; indeed Ahmad and colleagues11 suggest strongly that the primary association is with location of disease rather than behaviour per se. The Vienna classification was not used to classify disease behaviour in these previous studies. Nevertheless, many aspects of the definitions are broadly similar, and many conclusions consistent. Why do the present data appear inconsistent with these other studies? There are clearly a number of possible explanations, including ethnic variation and phenotypic definitions. Further inspection of the authors’ own data is also revealing and may be most pertinent. Only 62% of the study population were genotyped, and the numbers in each group (B1, B2, B3) were relatively small. The authors chose to compare carriage rates in inflammatory (B1) versus stricturing (B2) versus fistulising (B3) disease at five years. Further analysis of the same data, comparing patients with fistulising disease (B3) against those who did not develop fistulising complications (B1+B2) showed a modest protective effect of NOD2/CARD15 carriage (χ2=4.3, p<0.04). NOD2 therefore may be an influential factor in the progression of disease type over time, but may or may not reflect disease phenotype at one time point in diagnosis. To our mind it remains unclear whether the primary association of NOD2 genotype is with disease location or behaviour, or whether these are indeed independent.
The influence of current therapies—immunosuppressants, and especially the novel biological treatments now commonly used in Crohn’s disease—remains largely unknown. A relatively small percentage of patients in the present study received azathioprine, and there is no evidence that any received Infliximab.
There is a great need for accurate subclassification of Crohn’s disease, notwithstanding the great difficulties involved. It is clear from the present study and others cited that disease behaviour is dynamic, and needs to be viewed as a continuing progress rather than as a snapshot. There are clearly a number of influences on disease progression, and the present study provides a positive step towards identification of disease factors. The consistency of phenotypic data available may be the greatest challenge to progress in unravelling disease complexities in these studies.
Disease behaviour in Crohn’s disease is dynamic and not stable over time
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