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I hasten to congratulate Louis et al on their meticulous and insightful study on the stability of Crohn's disease phenotypes according to the Vienna classification (Gut 2001;49:777–82). It was particularly gratifying to learn from them (in a separate communication) of the remarkably high degree of interobserver agreement in classifying patients by this system.
The principal message that the authors draw from their study is that the initial “behavioural” classification of B1 (non-stricturing non-penetrating) at the onset of Crohn's disease hardly ever remains stable over the lifetimes of the patient but almost invariably progresses in time to either B2 (stricturing) or B3 (penetrating) disease. Naturally, this finding hardly comes as a surprise either to the authors of the Vienna classification1 or in fact to any clinician caring for patients with Crohn's disease. More important and revealing, in my opinion, is the observation by Louis et al that “the proportion of initially B2 patients changing from B2 to B3 was [only] 15.4% (only 2/13 patients)”.
Therefore, once “inflammatory” (B1) disease has made its almost invariable progression to either B2 or B3, why should we not be able to incorporate this relatively stable “choice” of pathway into a phenotyping system suitable for genotypic correlations?
We thank Professor Sachar for his kind comments on our work. As it has become obvious that Crohn's disease is a multifactorial polygenic heterogeneous entity, apart from molecular genetic studies a major task is now to identify stable phenotypes of Crohn's disease that may correspond to particular genetic backgrounds. The propensity of Crohn's disease to develop as a stricturing or as a penetrating disease (Crohn's disease behaviour) has been considered for some time as a potential suitable phenotype for genetic correlations. However, results to date have been inconclusive. Several explanations are plausible: (a) there is no major genetic influence on Crohn's disease behaviour and the significant concordance within multiply affected families is essentially due to shared environmental factors; (b) the genes involved have not yet been tested and it is true that only a small number of candidate genes have been tested in this setting; and (c) patients with Crohn's disease have not been classified adequately into subphenotypes, and it is true that several classifications have been proposed and that the application of these various classifications does not result in homogeneous categories.
In relation to the first two hypotheses, progress in the understanding of the physiology and biology of strictures and fistulas as well as of the influence of environmental factors, including smoking and medical treatment of the disease, is needed. Regarding the third point, the classification used necessarily must result in stable categories of patients. As we have shown, even the most recent and reproducible classification1 is not suitable as patients change categories over time. As emphasised by Sachar, it seems from our data that patients who are classified as B2 (stricturing) tend to remain B2 over time. This is mainly true for patients who are already B2 at diagnosis as 88% remained B2 over a median follow up of seven years (range 1–30 years). It seems as if patients who develop penetrating lesions (B3) associated with stricturing lesions tend to develop these simultaneously and thus are directly classified as B3 while patients who develop clinically significant stricturing disease without concurrent penetrating lesions do not tend to develop such lesions afterwards. Furthermore, in our population, only a few pure stricturing lesions (B2) developed after 10 years of evolution. Therefore, in our experience, patients who develop a pure stricturing disease over 10 years of evolution seem to represent a homogeneous phenotype that may be suitable for studies of genetic factors potentially involved in stricture development. However, this does not seem to be the case for penetrating disease (B3). In our patients, penetrating phenotypes continued to develop at a constant rate (approximately 25% of patients/five years), even after 20 years of evolution, mainly directly from the non-penetrating non-stricturing phenotype (B1). Therefore, the subgroup of patients with non-penetrating non-stricturing disease can never be considered as homogeneous as even after 25 years some may evolve to the penetrating phenotype (B3). Furthermore, a patient who develops penetrating lesions within two years of evolution may be biologically and genetically very different from a patient who develops such lesions after 25 years. To some extent this point can also be applied to the stricturing phenotype (B2).
An alternative would be to take into account the speed of development of the B2 or B3 phenotype. Indeed, the inclination to develop such a phenotype is most probably multifactorial. We would be surprised if a unique gene were responsible for stricture development for example. Therefore, if a gene is involved it may be rather by facilitating or by speeding up the development of these phenotypes, together with other genes and environmental factors. In this hypothesis we may have more chance to disclose predisposing genes when comparing patients who have rapidly developed stricturing or penetrating phenotypes (within five years for example) with other patients. We believe that when performing genotype-phenotype correlations for Crohn's disease behaviour, several classification options have to be tested according to these various hypotheses of gene implication. Furthermore, we should aim towards disclosing environmental factors and stratify patients according to these factors or to consider these factors in multivariate analyses.
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