The definition of relapse and of disease activity remain central to the issue of the prediction of relapse in Crohn's disease.33 Three major studies have specifically examined clinical markers of relapse in Crohn's disease. The Groupe d'Etudes Therapeutiques des Affections Inflammatoires Digestives (GETAID) group assessed patients in three clinical trials and identified an age less than 25 years, interval since first symptoms of > 5 years, interval since last relapse of less than 6 months and colonic involvement as poor prognostic markers.34 One thousand and eighty-four patients who were entered into the National Co-operative Crohn's Disease Study were analysed by Mekhjian et al.35 In 77 patients who were randomized to the placebo arm, previous surgical removal of all observable disease, absence of perianal disease and a CDAI of less than 200 were favourable prognostic factors, while steroids prior to randomization was a poor prognostic factor. The proportion of patients with colonic disease alone in the National Co-operative Crohn's Disease Study was only 11%, whereas it was greater than 30% in two large European studies.36, 37 Steinhardt et al. investigated 110 patients who were randomized to the placebo group in the European Co-operative Crohn's Disease Study.36 Of these, 53 had quiescent disease and 57 had active disease as defined by CDAI. Favourable predictive factors were a long duration of disease between diagnosis and randomization, normal serum albumin and ileocolonic disease. In contrast, factors that were predictive of a poorer outcome were extensive small bowel and isolated colonic disease, treatment with steroids and bowel resection prior to entry into the study.
Most of the clinical markers of relapse are immutable and, furthermore, a number of studies suffer from a relatively small sample size, heterogeneous populations, differing definitions of relapse and remission and the use of these markers as primary or secondary end-points. In addition, these markers are often not independent variables when assessed with multivariate analysis. Young age has been identified as a marker of relapse,18, 34, 38 but a number of smaller studies have failed to confirm this association.17, 20, 28, 31, 39 The time since last relapse has similarly been identified,18, 34, 39 but the data are conflicting.28, 31 A long interval since diagnosis was identified in a large study,34 but not in smaller cohorts.18, 31, 39 The disease distribution that is most consistently associated with frequent relapse is colonic disease,34, 36, 40 but ileal disease22 and ileocolonic disease40, 41 have also been identified. Perianal disease appears to be an independent marker of a poor prognosis.28, 35, 40, 42 The need for corticosteroids,31, 35, 36, 38 previous surgery36 and the type of presentation41 (inflammatory or obstructive) have also been identified as prognostic markers, but the data are inconsistent. Most of the clinical predictors of relapse are therefore either immutable or inconsistent.
The exception is smoking, the single most important environmental influence conferring a poor prognosis in Crohn's disease. Smoking is not only associated with an increased susceptibility for the disease, but current smoking leads to an increased frequency of relapse, more surgery, more rapid recurrence post-surgery,43, 44 more severe recurrent anastomotic lesions,45 a poorer quality of life46 and an overall greater mortality.47 In addition, there are now prospective data to suggest that the cessation of smoking has a positive impact on the disease course.48 The use of oral contraceptives has been proposed as a poor prognostic marker, although the data are far less convincing.49
Clinical markers of relapse for patients on long-term azathioprine or 6-mercaptopurine have been assessed.50 Whilst on therapy, female gender, an age less than 26 years and a delay in achieving remission of greater than 6 months were poor prognostic markers. When therapy was withdrawn, male gender, an age less than 31 years and a duration of remission of less than 4 years were indicative of a greater chance of relapse.50