Factors associated with disease evolution in Greek patients with inflammatory bowel disease
© Chatzicostas et al; licensee BioMed Central Ltd. 2006
Received: 04 April 2006
Accepted: 25 July 2006
Published: 25 July 2006
The majority of Crohn's disease patients with B1 phenotype at diagnosis (i.e. non-stricturing non-penetrating disease) will develop over time a stricturing or a penetrating pattern. Conflicting data exist on the rate of proximal disease extension in ulcerative colitis patients with proctitis or left-sided colitis at diagnosis. We aimed to study disease evolution in Crohn's disease B1 patients and ulcerative colitis patients with proctitis and left-sided colitis at diagnosis.
116 Crohn's disease and 256 ulcerative colitis patients were followed-up for at least 5 years after diagnosis. Crohn's disease patients were classified according to the Vienna criteria. Data were analysed actuarially.
B1 phenotype accounted for 68.9% of Crohn's disease patients at diagnosis. The cumulative probability of change in disease behaviour in B1 patients was 43.6% at 10 years after diagnosis. Active smoking (Hazard Ratio: 3.01) and non-colonic disease (non-L2) (Hazard Ratio: 3.01) were associated with behavioural change in B1 patients. Proctitis and left-sided colitis accounted for 24.2%, and 48.4% of ulcerative colitis patients at diagnosis. The 10 year cumulative probability of proximal disease extension in patients with proctitis and left-sided colitis was 36.8%, and 17.1%, respectively (p: 0.003). Among proctitis patients, proximal extension was more common in non-smokers (Hazard Ratio: 4.39).
Classification of Crohn's disease patients in B1 phenotype should be considered as temporary. Smoking and non-colonic disease are risk factors for behavioural change in B1 Crohn's disease patients. Proximal extension is more common in ulcerative colitis patients with proctitis than in those with left-sided colitis. Among proctitis patients, proximal extension is more common in non-smokers.
Inflammatory bowel diseases (IBD) are chronic heterogeneous disorders with unpredictable clinical course. Studies on Crohn's disease (CD) behaviour have been hampered by the variability of classifications used and by their unsatisfactory degree of inter-rater agreement [1–4]. The Vienna classification of CD  has been proposed in an effort to stratify patients on the basis of widely accepted and reproducible criteria . Although CD location, as defined by the Vienna classification is a relatively stable phenotype, its behaviour varies over time . The majority of patients with B1 phenotype (i.e. non-stricturing non-penetrating disease) will develop over time a stricturing or a penetrating pattern (i.e. B2 and B3 respectively) [7–11]. The environmental and genetic factors affecting disease behaviour evolution are not fully characterized. Ileal location (i.e. L1) [8, 9, 11], active smoking  and number of flares per year  were reported to be the major determinants of phenotypic changes. Moreover, some authors suggested that intra-abdominal penetrating disease (IAPD) and perianal penetrating disease (PAPD) represent distinct clinic entities which should be studied independently [8, 11].
The extent of colonic involvement in ulcerative colitis (UC) patients is clinically relevant because it has some bearing on the severity of disease and on the needs for medical supervision, drug therapy and surgical excision [12–14]. Although in certain patients with proctitis and left-sided UC, the inflammation spreads proximally, studies on the stability of disease extent over time and risk factors influencing disease extent progression have failed to offer conclusive information [12–21].
We aimed to study the long-term outcome of a homogeneous and well-defined group of Cretan patients with IBD. Particular emphasis was given on the study of rate and risk factors that might influence: change of disease behaviour over time in B1 CD patients; and proximal disease extension in UC patients with proctitis and left-sided colitis at diagnosis;
The Gastroenterology Department of the University Hospital of Heraklion has previously conducted prospective and population-based epidemiologic studies of UC and CD in the prefecture of Heraklion, and participated in the European collaborative study of IBD (EC-IBD) [22–26].
The patient cohort seen at the aforementioned institution has been enriched with cases followed-up at the Gastroenterology Department of Venizelion General Hospital of Heraklion (since its opening at 1996). During the study period these two units were the sole centers providing health care for patients with GI tract problems living in the island of Crete (approximately 600 000 people). Clinical details were collected in a special designed form, by patient interview and case note review. Our study protocol was approved by the Ethics Committee of the Medical School of the University of Crete. Written consent was obtained from the patients.
Of the 736 patients listed in the IBD registry (498 with UC and 238 with CD), 372 (256 with UC and 116 with CD) met the following criteria for inclusion in this analysis:
1. A confirmed diagnosis of UC or CD by standard clinical, radiologic, endoscopic and histologic criteria. Patients with an initial diagnosis of UC later changed to CD or vice versa were included in the analysis with the final diagnosis.
2. A satisfactory assessment of the extent of disease at the initial examination in patients with UC and of disease behaviour at diagnosis in patients with CD. Extent, location, and behaviour of UC and CD were evaluated by ileo-colonoscopy, upper GI tract endoscopy, enteroclysis, CT scan of abdomen and surgical reports.
3. A follow-up period of at least 60 months. Time of diagnosis was defined as the date of first detection of unequivocal inflammatory abnormalities of the intestine, as assessed from radiologic, endoscopic, or operative observations .
The extent of UC was defined as proctitis (rectum involvement), left-sided colitis (involvement up to the splenic flexure) and extensive colitis (involvement proximal to the splenic flexure). Proximal disease extension was defined as the finding at any follow-up colonoscopy of macroscopic inflammation extending beyond 15 cm from the anus in case of proctitis or beyond the splenic flexure in case of left-sided colitis.
The clinical classification of patients with CD was carried out in strict accordance with the Vienna criteria . In patients with B1 phenotype at diagnosis the first morphologic demonstration of narrowing or penetrating complication was used to mark the occurrence of the complication. Some patients had stricturing disease and then developed a fistula. The sequence was taken into account (i.e. B2 then B3 disease) when the time interval between the two events was greater than one year, otherwise the disease was considered as B3 . According to previous analyses, patients who were diagnosed with PAPD before CD diagnosis were assumed to have developed their fistula on the day after diagnosis . Only major operations (i.e. bowel resections) were considered as surgical therapy in patients with CD.
Patients were seen regularly depending on their needs, and had easy access in flare-up episodes. At each visit, symptoms and signs, laboratory and diagnostic examinations, medications and surgery were prospectively registered on a predesigned data sheet. Asymptomatic patients were fully investigated on a yearly basis. Finally, an assessment was made for each year of follow-up, comprising the clinical activity within the year, disease course, intestinal complications, extent of disease, diagnostic procedures, medical treatments, operations, hospitalizations, and outpatient visits.
Chronic continuous course was defined as continuous activity within and during each year of follow-up . Patients were defined as smokers if they consumed at least 7 cigarettes/week and non-smokers if they had never smoked or had stopped smoking before diagnosis . A familial form of the disease was defined as the presence of UC or CD in a relative, whatever the familial degree (i.e. parent, child, sibling, grandparent, grandchild, aunt, uncle, and cousin).
Descriptive statistics are expressed as mean and standard deviation or as frequency counts and percentages. Categorical data were analyzed using Pearson's chi-square test. Equalities of means and proportions were tested using Student's t test and analysis of variance with Bonferroni correction for group comparisons. P values of less than 0.05 were considered statistically significant.
Survival analyses, using the Kaplan-Meier method with log-rank test [29, 30], and Cox's proportional hazards model for multivariate analyses  were used to study the predefined end-points. Patients with UC were included in these calculations only as long as they had not undergone colectomy. Patients not reaching the end point under consideration were censored at the time of the last clinical follow-up. The multivariate analysis was applied to those of the variables having a p = 0.2 in order to identify possible confounding effects . In the multivariate procedure, p = 0.05 was considered as the level of significance. Results of analysis are presented as hazard ratios (HR) with 95% confidence intervals (95% CI). The following variables suspected as possible predictors were included in the analysis: age at diagnosis, months from onset to diagnosis, sex, positive family history of IBD, active smoking, disease location in patients with CD, need for immunosuppressive therapy, chronic continuous course, and previous major operation in patients with CD. To examine an age-related effect, patients with CD were classified as the A1/A2 Vienna classification of under or over 40 years of age. Continuous variables (i.e. age at diagnosis in patients with UC and months from onset to diagnosis in patients with UC and CD) were dichotomized by splitting mean values, which were then compared.
Crohn's disease patients
Demographic and clinical parameters depending on Crohn's disease behaviour at diagnosis
Disease behaviour at diagnosis
B1 (N = 80)
B2 (N = 15)
B3 (N = 21)
Overall (N = 116)
10.8 ± 6.5
9.9 ± 4
10.4 ± 6.9
10.5 ± 6.4
Months to diagnosis
44.6 ± 42.4
38.8 ± 45.9
26.2 ± 36.1
40.6 ± 42.1
Positive family history
Location of disease
Univariate analysis of risk of change of disease behaviour in patients with B1 disease at diagnosis
Patients without change of disease behaviour (N = 42)
Patients with change of disease behaviour (N = 38)
Months to diagnosis
49.2 ± 43.5
39.6 ± 41.2
Positive family history
Location of disease
15 (35.7 %)
Surgery at diagnosis‡
Fifteen patients with initially B1 phenotype (18.7%) developed IAPD and 12 patients (15%) PAPD. Regression model analysis selected active smoking (HR: 5.18; 95% CI: 1.12–23.96; P: 0.035), L1 disease (HR: 5.87; 95% CI: 1.41–24.42; P: 0.015) and chronic continuous course (HR: 4.56; 95% CI: 1.25–16.61; P: 0.021) as significantly associated with the development of IAPD in patients with initially B1 phenotype. In univariate analysis the only factor significantly associated with reclassification from B1 to PAPD was active smoking (P: 0.049), which was however rejected from the regression model (HR: 3.21; 95% CI: 0.96–10.71; P: 0.058) when it was combined with other variables having a p value between 0.51–0.2.
None of our B1 patients reclassified as B2 became B3, whereas 3 out of 15 patients with B2 phenotype at diagnosis became B3. The cumulative probability of B3 reclassification in patients with B2 phenotype at diagnosis was 27.8% (± SE: 15.1%) at 10 years after diagnosis (Figure 1).
At the end of follow-up, 51 patients had B3 phenotype. Overall, B3 phenotype remained unchanged in 23 patients with IAPD and 17 patients with PAPD. However, 5 out of 28 patients (17.8%) with IAPD developed subsequently PAPD, and 6 out of 23 patients (26%) with PAPD developed subsequently IAPD. The cumulative probability of appearance of the other penetrating phenotype in an already B3 patient was 22.7% (± SE: 6.7%) and 32.4% (± SE: 10.8%) at 5 and 10 years, respectively. The probability of appearance of PAPD in patients with IAPD was not related to age at diagnosis, disease location, or active smoking. Similarly, the probability of appearance of IAPD in patients with PAPD was not related to age at diagnosis or active smoking. Although this was also the case for patients with L1, L2 and L4 disease, L3 patients with PAPD had a greater risk of developing IAPD (P: 0.021).
Six patients underwent a second operation. The cumulative probability of 2nd intestinal resection was 7.4% (± SE: 5%) and 17.2% (± SE: 7.9%) at 5 and 10 years after 1st intestinal resection, respectively.
Ulcerative colitis patients
Demographic and clinical parameters depending on ulcerative colitis extent at diagnosis
Proctitis (N = 62)
Left-sided colitis (N = 124)
Extensive colitis (N = 70)
Overall (N = 256)
11.3 ± 7.4
12.5 ± 7.1
12.5 ± 8.2
12.2 ± 7.5
Months to diagnosis
24.6 ± 40
8.9 ± 13.7*
7.7 ± 15.8*
12.4 ± 24.3
Age at diagnosis (yr)
38.3 ± 14.8
43.3 ± 15.6
40.3 ± 16.3
41.3 ± 15.7
Positive family history
Univariate analysis of overall risk for proximal extension in patients with proctitis at diagnosis
Patients with disease progression (N = 25)
Patients without disease progression (N = 37)
Months to diagnosis
21 ± 50.4
27.1 ± 31.7
Age at diagnosis (yr)
43.8 ± 15.4
34.6 ± 13.4
Positive family history
Chronic continuous course
Many patients with severe GI problems from other parts of mainland Greece seek medical care in Athens, thus by strict criteria the patients included in series originating from referral Athenian hospitals cannot be considered to be a representative sample for all cases with IBD in Greece [33–37]. It is a well known fact that patients with benign clinical course are under-represented at a tertiary referral center . The advantage of the present study is that, our population is dispersed over a small geographical area and referred to only two Gastroenterology Units which have registered practically all patients with IBD in Crete.
There is only one study analyzing the natural history of CD in Greece . In this series, only crude rates were reported, and emphasis was given on disease location, not behaviour.
Progression over time of CD pathologic changes has been suggested in a previous report by Kelly et al . Other series, using the Vienna [7, 9, 11] or other classifications [27, 40] have also focused on the changing nature of CD over time. Although our results fit well with those previously reported, they should be interpreted with caution as only 22 patients with B1 behaviour and 5 patients with B2 behaviour were available for follow-up at 10 years after diagnosis. Some authors found that patients who are classified as B2 at diagnosis tend to remain B2 over time [8, 41]. Although these observations are suggestive more of a parallel than of a sequential progression from B1 to either B2 or B3 behaviours, it is quite clear that at least some patients with stricturing behaviour at presentation will finally develop penetrating disease [8, 41, 42].
An important factor for determining disease behaviour is the location of lesions. In our series, active smoking and L1 or non-L2 disease were associated with change of disease behaviour in patients with B1 phenotype at diagnosis. Location and smoking have also been reported by others as factors associated with complicated CD [8, 9, 11, 40, 43, 44]. Tobacco use has been a risk factor for ileal rather than colonic-only disease [45–47].
The cumulative probability of surgery in our CD patients was lower than that reported in other series [48–51]. Once again, our results should be interpreted with caution as only 43 patients were available for follow-up at 10 years after diagnosis. As expected, the probability of surgery was significantly higher in patients with either B2 or B3 phenotypes (Figure 2). The probability of surgery in B1 patients without change of disease behaviour was minimal, a finding quite similar to that previously reported by others [11, 49]. Smoking has been previously shown to be associated with increased risk of surgery in CD patients [40, 45, 47, 52, 53]. The lower probability of surgery in patients with colonic disease has been previously reported by other authors using different classifications [40, 48, 50, 54, 55].
The risk for a second resection in our patients previously operated on for CD was lower than that reported in other series [53, 56]. Previous reports using different classifications identified more frequent reoperation in those with perforating disease [1, 57, 58], but others have failed to confirm this association [59, 60].
Both intra-abdominal and perianal fistulas were classified by the Vienna Working Party Group as penetrating disease . However, some studies suggested that they represent distinct entities [8, 11, 61]. We found that in a significant proportion of B3 patients both penetrating phenotypes appear. Although this was also the case in other reports, in some series no data were clearly reported [27, 62], whereas in other series only crude rates were reported [8, 9, 11, 49, 63].
There are four Athenian studies investigating the clinical course of UC [34–37]. In all these series only crude rates were reported. The age and distribution of macroscopic inflammation at presentation in our patient cohort fits well with that reported in other series [25, 26]. The rate of colectomy seems quite low in our patient cohort, especially when compared to other much larger series . However, the rate of colectomy after 5 years is well known to be quite small, about 1% per year [64, 65], and this low rate of colectomy equally applies to patients with initial distal disease and those with initial pancolitis . The cumulative probability of colorectal cancer in our patients falls within the wide confidence intervals calculated by others [65, 66].
Conflicting data exist on the rate of proximal disease extension of ulcerative proctitis. [13–16, 20, 21]. When considering only those two studies in which diagnosis and disease progression were confirmed using endoscopy and survival analysis was carried out, the cumulative rates of proximal extension was reported to range between 30 and 54% at 10 years, and between 50% and 84% at 20 years after diagnosis [20, 21]. Our results fit well with those previously reported, however only 19 patients with proctitis at diagnosis were available for follow-up at 10 years after diagnosis. We found that the risk of progression was higher in non-smokers, a finding previously confirmed by some [18, 20] but not all authors . There are several possible explanations for these conflicting results. Some are related to differences in disease extent definition (true proctitis [15, 18–21] vs proctosigmoiditis [12–14]) and means of follow-up surveillance (endoscopic [17, 19–21] vs radiologic  vs a combination of sigmodoscopy and barium enema [12–15]). Furthermore, there is poor agreement between extent assessed by histology and endoscopy both at diagnosis and at follow-up [17, 19, 25].
Fifty eight of our ulcerative colitis patients were available for follow-up at 10 years after diagnosis. Thus, we have found the cumulative probability of proximal extension in these patients to be 17.1% at 10 years after diagnosis. Others reported cumulative rates ranging between 14% and 32% at 10 years after diagnosis [13, 14]. However, these figures were evaluated using barium enemas and calculated for mixed groups of patients with proctitis and procto-sigmoiditis , or with left-sided and extensive colitis at diagnosis . We were unable to find a single demographic or clinical factor associated with change of disease extent from left-sided to extensive colitis.
Classification of Crohn's disease patients in B1 phenotype should be considered as temporary. Smoking and non-colonic disease are risk factors for behavioural change in B1 Crohn's disease patients. At least some patients with stricturing behaviour will finally develop penetrating disease. In a significant proportion of B3 patients both penetrating phenotypes appear. Proximal extension is more common in ulcerative colitis patients with proctitis than in those with left-sided colitis. Among proctitis patients, proximal extension is more common in non-smokers. Further studies are required to identify factors associated with proximal disease extension in ulcerative colitis patients with left-sided colitis at diagnosis.
inflammatory bowel diseases
intra-abdominal penetrating disease
perianal penetrating disease
- Greenstein AJ, Lackman P, Sachar DB, Springhorn J, Heimann T, Janowitz HD, Aufses AH: Perforating and non-perforating indications for repeated operations in Crohn's disease: evidence for two clinical forms. Gut. 1988, 29: 588-592.PubMed CentralView ArticlePubMed
- Sachar DB, Andrews HA, Farmer RG, Pallone F, Pena AS, Prantera C: Proposed classification of patient subgroups in Crohn's disease. Gastroenterol Intern. 1992, 5: 141-154.
- Greenway SE, Buckmire MA, Marroquin C, Jadon L, Rolandelli RH: Clinical subtypes of Crohn's disease according to surgical outcome. J Gastrointest Surg. 1999, 3: 145-151. 10.1016/S1091-255X(99)80024-9.View ArticlePubMed
- Steinhart AH, Girgrah N, McLeod RS: Reliability of a Crohn's disease clinical classification scheme based on disease behaviour. Inflamm Bowel Dis. 1998, 4: 228-234.View ArticlePubMed
- Gasche C, Scholmerich J, Brynskov J, D'Haens G, Hanauer SB, Irvine EJ, Jewell DP, Rachmilewitz D, Sachar DB, Sandborn WJ, Sutherland LR: A simple classification of Crohn's disease: report of the working party of the world congress of gastroenterology, Vienna 1998. Inflamm Bowel Dis. 2000, 6: 8-15.View ArticlePubMed
- Achkar JB, Brzezinski A: Interobserver agreement for disease behaviour phenotype in Crohn's disease. Gastroenterology. 2002, 122 (suppl): W1293-
- Louis E, Collard A, Oger AF, Degroote E, Aboul Nasr El, Yafi FA, Belaiche J: Behaviour of Crohn's disease according to the Vienna classification: changing pattern over the course of the disease. Gut. 2001, 49: 777-782. 10.1136/gut.49.6.777.PubMed CentralView ArticlePubMed
- Louis E, Michel V, Hugot JP, Reenaers C, Fontaine F, Delforge M, El Yafi F, Colombel JF, Belaiche J: Early development of stricturing or penetrating pattern in Crohn's disease is influenced by disease location, number of flares, and smoking but not by NOD2/CARD 15 genotype. Gut. 2003, 52: 552-557. 10.1136/gut.52.4.552.PubMed CentralView ArticlePubMed
- Cosnes J, Cattan S, Blain A, Beaugerie L, Carbonnel F, Parc R, Gendre JP: Long-term evolution of disease behaviour of Crohn's disease. Inflamm Bowel Dis. 2002, 8: 244-250. 10.1097/00054725-200207000-00002.View ArticlePubMed
- Freeman HJ: Natural history and clinical behaviour of Crohn's disease extending beyond two decades. J Clin Gastroenterol. 2003, 37: 216-219. 10.1097/00004836-200309000-00005.View ArticlePubMed
- Smith BR, Arnott RID, Drummond HE, Nimmo ER, Satsangi J: Disease localization, Anti-Saccharomyces cerevisiae antibody, and NOD2/CARD15 genotype influence the progression of disease behaviour in Crohn's disease. Inflamm Bowel Dis. 2004, 10: 521-528. 10.1097/00054725-200409000-00005.View ArticlePubMed
- Farmer RG, Easley KA, Rankin GB: Clinical patterns, natural history, and progression of ulcerative colitis. A long-term follow-up of 1116 patients. Dig Dis Sci. 1993, 38: 1137-1146. 10.1007/BF01295733.View ArticlePubMed
- Ayres RC, Gillen CD, Walmsley RS, Allan RN: Progression of ulcerative proctosigmoiditis: incidence and factors influencing progression. Eur J Gastroenterol Hepatol. 1996, 6: 555-558.View Article
- Langholz E, Munkholm P, Davidsen M, Nielsen OH, Binder V: Changes in extent of ulcerative colitis. A study on the course and prognostic factors. Scand J Gastroenterol. 1996, 31: 260-266.View ArticlePubMed
- Powell-Tuck J, Ritchie JK, Lennard-Jones JE: The prognosis of idiopathic proctitis. Scand J Gastroenterol. 1977, 12: 727-732.View ArticlePubMed
- Sinclair TS, Brunt PW, Mowatt NAG: Non-specific proctocolitis in northeastern Scotland: a community study. Gastroenterology. 1983, 85: 1-11.PubMed
- Niv Y, Bat L, Ron E, Theodor E: Change in the extent of colonic involvement in ulcerative colitis: a colonoscopic study. Am J Gastroenterol. 1987, 82: 1046-1051.PubMed
- Samuelsson SM, Ekbom A, Zack M, Helmick CG, Adami HO: Risk factors for extensive ulcerative colitis and ulcerative proctitis: a population based case-control study. Gut. 1991, 32: 1526-1530.PubMed CentralView ArticlePubMed
- Moum B, Ekbom A, Vatn MH, Elgjo K: Change in the extent of colonoscopic and histological involvement in ulcerative colitis over time. Am J Gastroenterol. 1999, 94: 1564-1569. 10.1111/j.1572-0241.1999.01145.x.View ArticlePubMed
- Meucci G, Vecchi M, Astegiano M, Beretta L, Cesari P, Dizioli P, Ferraris L, Panelli MR, Prada A, Sostegni R, de Franchis R: The natural history of ulcerative proctitis: A multicenter, retrospective study. Am J Gastroenterol. 2000, 95: 469-73. 10.1111/j.1572-0241.2000.t01-1-01770.x.View ArticlePubMed
- Pica R, Paoluzi OA, Iacopini F, Marcheggiano A, Crispino P, Rivera M, Bella A, Consolazio A, Paoluzi P: Oral mesalazine (5-ASA) treatment may protect against proximal extension of mucosal inflammation in ulcerative proctitis. Inflamm Bowel Dis. 2004, 10: 731-6. 10.1097/00054725-200411000-00006.View ArticlePubMed
- Manousos ON, Giannadaki E, Mouzas IA, Tzardi M, Koutroubakis I, Skordilis P, Vassilakis S, Kouroumalis E, Vlachonikolis IG: Ulcerative colitis is as common in Crete as in Northern Europe: a 5-year prospective study. Eur J Gastroenterol Hepatol. 1996, 8: 893-8.PubMed
- Manousos ON, Koutroubakis I, Potamianos S, Roussomoustakaki M, Gourtsoyiannis N, Vlachonikolis IG: A prospective epidemiologic study of Crohn's disease in Heraklion, Crete. Scand J Gastroenterol. 1996, 31: 599-603.View ArticlePubMed
- Shivananda S, Lennard-Jones J, Logan R, Fear N, Price A, Carpenter L, van Blakenstein M: Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European collaborative study on inflammatory bowel disease (EC-IBD). Gut. 1996, 39: 690-7.PubMed CentralView ArticlePubMed
- Lennard-Jones JE, Shivananda S, the EC-IBD study group: Clinical uniformity of inflammatory bowel disease at presentation and during the first year of disease in the north and south of Europe. Eur J Gastroenterol Hepatol. 1997, 9: 353-359.View ArticlePubMed
- Witte J, Shivananda E, Lennard-Jones JE, Beltrami M, Politi P, Bonanomi A, Tsianos EV, Mouzas I, Schultz TB, Monteiro E, Clofent J, Odes S, Limonard CB, Stockbrugger RW, Russel MG: Disease outcome in inflammatory bowel disease: Mortality, morbidity, and therapeutic management of a 796-person inception cohort in the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Scand J Gastroenterol. 2000, 35: 1272-1277. 10.1080/003655200453610.View ArticlePubMed
- Swartz DA, Loftus EV, Tremaine WJ, Panaccione R, Harmsen WS, Zinsmeister AR, Sandborn WJ: The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota. Gastroenterology. 2002, 122: 875-880. 10.1053/gast.2002.32362.View Article
- Munkholm P, Langholz E, Davidsen M, Binder V: Disease activity courses in a regional cohort of Crohn's disease patients. Scand J Gastroenterol. 1995, 30: 699-706.View ArticlePubMed
- Kaplan EL, Meier P: Non parametric estimation from incomplete observations. J Am Stat Assoc. 1958, 53: 457-481. 10.2307/2281868.View Article
- Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966, 50: 163-170.PubMed
- Cox DR: Regression models and life tables. J R Stat Soc. 1972, 34: 187-220.
- Mickey RM, Greenland S: The impact of confounder selection criteria on effect estimation. Am J Epidemiol. 1989, 129: 125-137.PubMed
- Triantafillidis JK, Emmanouilidis A, Manousos ON, Nikolakis D, Kogevinas M: Clinical patterns of Crohn's disease in Greece: a follow-up study of 155 cases. Digestion. 2000, 61: 121-128. 10.1159/000007744.View ArticlePubMed
- Emmanouilidis A, Manousos ON, Papadimitriou C, Triantafillidis JK: Ulcerative colitis in Greece: course and prognostic factors. Digestion. 1988, 39: 181-6.View ArticlePubMed
- Manousos ON, Triantafillidis JK, Emmanouilidis A, Papademitriou C: Ulcerative colitis in Greece. Epidemiological and clinical data. Scand J Gastroenterol. 1989, 170: 25-6.View Article
- Triantafillidis JK, Emmanouilidis A, Manousos ON, Pomonis E, Tsitsa C, Cheracakis P, Barbatzas C: Ulcerative colitis in Greece: clinicoepidemiological data, course, and prognostic factors in 413 consecutive patients. J Clin Gastroenterol. 1998, 27: 204-210. 10.1097/00004836-199810000-00005.View ArticlePubMed
- Archimandritis AJ, Kourtesas D, Sougioultzis S, Giontzis A, Grigoriadis P, Davaris P, Tzivras M: Inflammatory bowel disease in Greece – a hospital based clinical study of 172 consecutive patients. Med Sci Monit. 2002, 8: CR158-64.PubMed
- Zankel E, Rogler G, Andus T, Reng CM, Scholmerich J, Timmer A: Crohn's disease patient characteristics in a tertiary referral center: comparison with patients from a population-based cohort. Eur J Gastroenterol Hepatol. 2005, 17: 395-401. 10.1097/00042737-200504000-00002.View ArticlePubMed
- Kelly JK, Sutherland LR: The chronological sequence in the pathology of Crohn's disease. J Clin Gastroenterol. 1988, 10: 28-33.View ArticlePubMed
- Picco MF, Bayless TM: Tobacco consumption and disease duration are associated with fistulizing and stricturing behaviours in the first 8 years of Crohn's disease. Am J Gastroenterol. 2003, 98: 363-368. 10.1111/j.1572-0241.2003.07240.x.View ArticlePubMed
- Sachar DB: Behaviour of Crohn's disease according to the Vienna classification. Gut. 2002, 51: 614-615. 10.1136/gut.51.4.614.PubMed CentralView ArticlePubMed
- Papi C, Festa V, Fagnani C, Stazi A, Antonelli G, Moretti A, Koch M, Capurso L: Evolution of clinical behaviour in Crohn's disease: predictive factors of penetrating complications. Dig Liver Dis. 2005, 37: 247-253. 10.1016/j.dld.2004.10.012.View ArticlePubMed
- Cosnes J, Carbonnel F, Beaugerie L, Le Quintrec Y, Gendre JP: Effect of smoking on the long term course of Crohn's disease. Gastroenterology. 1996, 110: 424-431. 10.1053/gast.1996.v110.pm8566589.View ArticlePubMed
- Cottone M, Rosselli M, Orlando A, Oliva L, Puleo A, Cappello M, Traina M, Tonelli F, Pagliaro L: Smoking habits and recurrence in Crohn's disease. Gastroenterology. 1994, 106: 643-648.PubMed
- Lindberg E, Jarnerot G, Huitfeldt B: Smoking in Crohn's disease: effect on localisation and clinical course. Gut. 1992, 33: 779-782.PubMed CentralView ArticlePubMed
- Russel MG, Volovics A, Schoon EJ, van Wijlick EH, Logan RF, Shivananda S, Stockbrugger RW: Inflammatory bowel disease: is there any relation between smoking status and disease presentation? European Collaborative IBD study Group. Inflamm Bowel Dis. 1998, 4: 182-6.View ArticlePubMed
- Brant SR, Picco MF, Achar JP, Bayless TM, Kane SV, Brzezinski A, Nouvet FJ, Bonen D, Karban A, Dassopoulos T, Karaliukas R, Beaty TH, Hanauer SB, Duerr RH, Cho JH: Defining complex contributions of NOD2/CARD15 gene mutations, age at onset, and tobacco use on Crohn's disease phenotypes. Inflamm Bowel Dis. 2003, 9: 281-289. 10.1097/00054725-200309000-00001.View ArticlePubMed
- Munkholm P, Langholz E, Davidsen M, Binder V: Intestinal cancer risk and mortality in patients with Crohn's disease. Gastroenterology. 1993, 105: 1716-1723.PubMed
- Veloso FT, Ferreira JT, Barros L, Almeida S: Clinical outcome of Crohn's disease: Analysis according to the Vienna classification and clinical activity. Inflamm Bowel Dis. 2001, 7: 306-313. 10.1097/00054725-200111000-00005.View ArticlePubMed
- Agrez MV, Valente RM, Pierce W, Melton J, van Heerden JA, Beart RW: Surgical history of Crohn's disease in a well-defined population. Mayo Clin Proc. 1982, 57: 742-752.
- Silverstein MD, Loftus EV, Sandborn WJ, Tremaine WJ, Feagan BG, Nietert PJ, Harmsen WS, Zinsmeister AR: Clinical course and costs of care for Crohn's disease: Markov model analysis of a population-based cohort. Gastroenterology. 1999, 117: 49-57. 10.1016/S0016-5085(99)70549-4.View ArticlePubMed
- Cosnes J, Carbonnel F, Carrat F, Beaugerie L, Cattan S, Gendre J: Effects of current and former cigarette smoking on the clinical course of Crohn's disease. Aliment Pharmacol Ther. 1999, 13: 1403-1411. 10.1046/j.1365-2036.1999.00630.x.View ArticlePubMed
- Chardavoyne R, Flint GW, Pollack S, Wise L: Factors affecting recurrence following resection for Crohn's disease. Dis Colon Rectum. 1986, 29: 495-502.View ArticlePubMed
- Binder V, Hendriksen C, Kreiner S: Prognosis in Crohn's disease based on results from regional patient group from the county of Copenhagen. Gut. 1985, 26: 146-150.PubMed CentralView ArticlePubMed
- Sands BE, Arsenault JE, Rosen MJ, Alsahli M, Bailen M, Banks P, Bensen S, Bousvaros A, Cave D, Cooley JS, Cooper HL, Edwards ST, Farrell RJ, Griffin MJ, Hay DW, John A, Lidofsky S, Olans LB, Peppercorn MA, Rothstein RI, Roy MA, Saletta MJ, Shah SA, Warner AS, WolfJ L, Vecchio J, Winter HS, Zawacki JK: Risk of early surgery for Crohn's disease: Implications for early treatment strategies. Am J Gastroenterol. 2003, 98: 2712-2718. 10.1111/j.1572-0241.2003.08674.x.View ArticlePubMed
- Nordgren SR, Fasth SB, Oresland TO, Hulten LA: Long-term follow up in Crohn's disease. Scand J Gastroenterol. 1994, 11: 22-28.
- Aeberhard P, Berchtold W, Riedtmann HJ, Stadelmann G: Surgical recurrence of peforating and nonperforating Crohn's disease-a study of 101 surgically treated patients. Dis Colon Rectum. 1996, 39: 80-87. 10.1007/BF02048274.View ArticlePubMed
- Lautenbach E, Berlin JA, Lichtenstein GR: Risk factors for early postoperative recurrence of Crohn's disease. Gastroenterology. 1998, 115: 259-267. 10.1016/S0016-5085(98)70191-X.View ArticlePubMed
- Hamon JF, Carbonnel F, Beaugerie L, Sezeur A, Gallot D, Malafosse M, Parc R, Gendre JP, Cosnes J: Comparison of long-term course of perforating and non-perforating Crohn's disease. Gastroenterol Clin Biol. 1998, 22: 601-606.PubMed
- Yamamoto T, Allan RN, Keighley MR: Perforating ileocecal Crohn's disease does not carry a high risk of recurrence but usually re-presents as perforating disease. Dis Colon Rectum. 1999, 42: 519-524. 10.1007/BF02234180.View ArticlePubMed
- Vasiliauskas EA, Kam LY, Karp LC, Gaiennie J, Yang H, Targan SR: Marker antibody expression stratifies Crohn's disease into immunologically homogenous subgroups with distinct clinical characteristics. Gut. 2000, 47: 487-496. 10.1136/gut.47.4.487.PubMed CentralView ArticlePubMed
- Bell SJ, Williams AB, Wisel P, Wilkinson K, Cohen RC, Kamm MA: The clinical course of fistulating Crohn's disease. Aliment Pharmacol Ther. 2003, 17: 1145-1151. 10.1046/j.1365-2036.2003.01561.x.View ArticlePubMed
- Sachar DB, Bodian CA, Goldstein ES, Present DH, Bayless TM, Picco M, van Hogezand RA, Annese V, Schneider J, Korelitz BI, Cosnes J, Task Force on Clinical Phenotyping of the IOIBD: Is perianal Crohn's disease associated with intestinal fistulization?. Am J Gastroenterol. 2005, 100: 1547-1549. 10.1111/j.1572-0241.2005.40980.x.View ArticlePubMed
- Langholz E, Munkholm P, Davidsen M, Binder W: Colorectal cancer risk and mortality in patients with ulcerative colitis. Gastroenterology. 1992, 103: 1444-51.PubMed
- Leijonmarck CE, Persson PG, Hellers G: Factors affecting colectomy rate in ulcerative colitis: an epidemiologic study. Gut. 1990, 31: 329-333.PubMed CentralView ArticlePubMed
- Eaden JA, Abrams KR, Mayberry JF: The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001, 48: 526-535. 10.1136/gut.48.4.526.PubMed CentralView ArticlePubMed
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-230X/6/21/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.