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1 This article was downloaded by: [UIO University Of Oslo] On: 29 August 2009 Access details: Access Details: [subscription number ] Publisher Informa Healthcare Informa Ltd Registered in England and Wales Registered Number: Registered office: Mortimer House, Mortimer Street, London W1T 3JH, UK Scandinavian Journal of Gastroenterology Publication details, including instructions for authors and subscription information: Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study) Inger Camilla Solberg a ; Idar Lygren a ; Jørgen Jahnsen b ; Erling Aadland b ; Ole Høie c ; Milada Cvancarova d ; Tomm Bernklev b ; Magne Henriksen e ; Jostein Sauar f ; Morten H. Vatn g ; Bjørn Moum h ; And the IBSEN Study Group a Department of Gastroenterology, Ullevål University Hospital, Oslo b Department of Gastroenterology, Aker University Hospital, Oslo c Department of Internal Medicine, Sørlandet Hospital, Arendal d Section for Biostatistics, Rikshospitalet University Hospital, Oslo e Department of Internal Medicine, Østfold Hospital, Fredrikstad f Department of Internal Medicine, Telemark Hospital, Skien g Medical Department, Rikshospitalet and, EpiGen Arhus, Faculty of Medicine, University of Oslo, h Department of Gastroenterology, Aker University Hospital Oslo and Faculty of Medicine, University of Oslo, Norway First Published:April2009 To cite this Article Solberg, Inger Camilla, Lygren, Idar, Jahnsen, Jørgen, Aadland, Erling, Høie, Ole, Cvancarova, Milada, Bernklev, Tomm, Henriksen, Magne, Sauar, Jostein, Vatn, Morten H., Moum, Bjørn and And the IBSEN Study Group(2009)'Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study)',Scandinavian Journal of Gastroenterology,44:4, To link to this Article: DOI: / URL: PLEASE SCROLL DOWN FOR ARTICLE Full terms and conditions of use: This article may be used for research, teaching and private study purposes. Any substantial or systematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material.

2 Scandinavian Journal of Gastroenterology, 2009; 44: ORIGINAL ARTICLE Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort (IBSEN Study) INGER CAMILLA SOLBERG 1, IDAR LYGREN 1, JØRGEN JAHNSEN 2, ERLING AADLAND 2, OLE HØIE 3, MILADA CVANCAROVA 4, TOMM BERNKLEV 2, MAGNE HENRIKSEN 5, JOSTEIN SAUAR 6, MORTEN H. VATN 7 & BJØRN MOUM 8 AND THE IBSEN STUDY GROUP Downloaded By: [UIO University Of Oslo] At: 02:32 29 August Department of Gastroenterology, Ullevål University Hospital, Oslo, 2 Department of Gastroenterology, Aker University Hospital, Oslo, 3 Department of Internal Medicine, Sørlandet Hospital, Arendal, 4 Section for Biostatistics, Rikshospitalet University Hospital, Oslo, 5 Department of Internal Medicine, Østfold Hospital, Fredrikstad, 6 Department of Internal Medicine, Telemark Hospital, Skien, 7 Medical Department, Rikshospitalet and, EpiGen Arhus, Faculty of Medicine, University of Oslo, and 8 Department of Gastroenterology, Aker University Hospital Oslo and Faculty of Medicine, University of Oslo, Norway Abstract Objective. Cohort studies of unselected and newly diagnosed patients are essential for a better understanding of the prognosis in ulcerative colitis (UC). The aim of this study was to evaluate the course of UC in a population-based inception cohort during the first 10 years, and to identify prognostic risk factors based on information gathered at diagnosis. Material and methods. From 1990 to 1994, a population-based cohort of 843 patients with inflammatory bowel disease was enrolled in South-Eastern Norway. The cohort was systematically followed-up at 1, 5 and 10 years after diagnosis. Results. Of 519 patients with UC, 423 completed the 10-year follow-up, 53 died and 43 were lost to follow-up. The mortality risk was not increased compared with that in the general population. The cumulative colectomy rate after 10 years was 9.8% (95% CI: %). Initial presentation with extensive colitis and erythrocyte sedimentation rate (ESR)]30 mm/h was associated with an increased hazard ratio (HR) (3.57, 95% CI: ) and age]50 years at diagnosis, with reduced HR (0.28, 95% CI: 0.65) for subsequent colectomy. Relapsing disease was noted in 83%, but half (48%) of the patients were relapse free during the last 5 years. One-fifth (69/288) of patients with proctitis or left-sided colitis had progressed to extensive colitis. Conclusions. The prognosis for UC during the first 10 years was generally good. The colectomy rate was low, and a large proportion of patients were in remission as time progressed. Patients with initially extensive colitis and elevated ESR could benefit from an early potent medical treatment strategy. Key Words: Clinical course, colectomy, population-based, inception cohort, prognostic risk factors, ulcerative colitis Introduction Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) of unknown aetiology mostly affecting the young and middle aged. The clinical presentation at onset of disease varies, and the subsequent course may be difficult to predict, ranging from a quiescent disease to a chronic refractory disease, leading to surgery or complications such as cancer or death [1]. Hence, more knowledge about early factors influencing the natural history of the disease is important for therapeutic and prognostic purposes. The prognosis for UC seems to have improved in Western Europe and North America since the middle of the 1970s [2]. This is probably due to earlier diagnosis, improved treatment or even a change in the behaviour pattern of the disease. Nevertheless, previous population-based cohort studies from Scandinavia of patients recruited from 1955 to 1987 have shown an increased risk of mortality [3,4] and high Correspondence: Inger Camilla Solberg, MD, Department of Gastroenterology, Ullevål University Hospital, NO-0407 Oslo, Norway. Tel: i.c.solberg@medisin.uio.no (Received 20 August 2008; accepted 3 November 2008) ISSN print/issn online # 2009 Informa UK Ltd. DOI: /

3 Downloaded By: [UIO University Of Oslo] At: 02:32 29 August I. C. Solberg et al. rates of colectomy [5,6] in those with extensive UC at diagnosis, which still suggests significant morbidity in a subgroup of patients. In a recent publication concerning the present population-based inception cohort, the outcome of UC during the first 5 years appeared better than previously reported in the literature [7]. The aim of the present study was to extend the follow-up time in this cohort, and to evaluate the disease course in terms of the risk of colectomy, frequency of proximal disease extension as well as relapse and mortality rates during the first 10 years after diagnosis. Furthermore, we evaluated the prognostic risk factors for subsequent outcome based on information obtained at diagnosis. Material and methods From 1 January 1990 to 31 December 1993, all newly diagnosed patients with IBD or possible IBD were prospectively recorded in four geographically well-defined areas in South-Eastern Norway (the IBSEN cohort). On 1 January 1992 the total population in these areas was 966,427. The population-based recruitment was ensured by the primary invitation of all the 1236 general practitioners in the study area, who were asked to remit all suspected new IBD patients to the local hospital. At each of the participating hospitals (n 15) a senior gastroenterologist was made responsible for the diagnostic procedures and the registration and inclusion of appropriate cases. The clinical information was subsequently reviewed by a gastroenterologist at a university hospital. The organization of the inception cohort has previously been described in detail [8]. Prescheduled follow-up visits were carried out at 1, 5 and 10 years (91 year) after inclusion, at which the diagnosis and disease course were reviewed by the same group of gastroenterologists as in the incidence study. Each visit included a structured interview, a clinical examination, blood tests and, with the consent of the patient, a colonoscopy with biopsies and, if indicated, a small-bowel enema. The interview with patients who were unable to visit the hospital was conducted by telephone and supplemented by information from the hospital records. In a few cases, when the patients could not be reached by telephone, the information was based on hospital records alone, provided that these had been recently brought up to date. Medical and surgical treatments during the study were given according to established clinical practice. In addition to the regular follow-up by private doctors, all patients had access to a gastroenterologist whenever a relapse occurred, or if for any other reason a change of treatment was relevant. The results of the 1- and 5-year studies can be found elsewhere [7,9,10]. Classification and definitions The diagnosis was based on symptoms consistent with IBD lasting for more than 4 weeks, excluding infections and other acute or chronic non-ibd conditions. Microbiologic cultures of stool samples were meticulously examined for pathogens known to cause infectious colitis. Patients were initially classified as having UC, Crohn s disease (CD), indeterminate colitis (IC) or possible IBD. The diagnosis of UC was made on the basis of at least 3 out of 4 criteria: 1) a typical history of diarrhoea and/or blood/pus in stools; 2) macroscopic appearance at endoscopy of continuous mucosal inflammation affecting the rectum in continuity with some or all of the colon; 3) microscopic features on biopsy compatible with UC; 4) no suspicion of CD on small-bowel X-ray, ileocolonoscopy or biopsy. The patients diagnoses were systematically reassessed at each visit. At the 1-year visit the initial classification was used, while at 5 years an attempt was made to determine a definite diagnosis and the patients were reclassified as UC, CD or non-ibd. The diagnostic criteria for this reclassification have already been reported [11]. The extent of colitis during follow-up was endoscopically determined. Proctitis was defined as mucosal changes in the rectum up to 15 cm from the anus, left-sided colitis as mucosal changes up to the splenic flexure and extensive colitis as inflammation beyond the splenic flexure. Status of colectomy was recorded consecutively, and in cases lost to follow-up, the hospital records were reviewed. Relapse after remission was defined as any aggravation of UC symptoms resulting in the need for more intensive medical therapy or colectomy. Cumulative relapse rates between 0 and 1 year, 1 and 5 years and 5 and 10 years after diagnosis were recorded, as were annual relapse rates for the first, fifth and tenth year of follow-up. Erythrocyte sedimentation rate (ESR) and haemoglobin (Hb) levels at diagnosis were measured before treatment was started. Consistent with the Truelove & Witts criteria, [12] the following categorical variables were used in the analyses: ESRB30 versus]30 mm/h and Hb B10.5 versus]10.5 g/dl. The clinical course from diagnosis onwards was visualized using four curves, each reflecting a different disease pattern in terms of the severity of bowel symptoms. At the interview the patients were asked to categorize their clinical course for the previous 10 years according to 1 out of 4 predefined patterns: 1) Remission or mild severity of intestinal symptoms

4 Downloaded By: [UIO University Of Oslo] At: 02:32 29 August 2009 after initial high activity; 2) increase in the severity of intestinal symptoms after initial low activity; 3) chronic continuous or 4) chronic intermittent symptoms. The curves for each disease pattern are depicted in Figure 1. Current smokers were defined as those who smoked more than one cigarette per day at diagnosis. Patients vital status was verified from hospital records and the National Population Register, and at the end of the study, dates and causes of death were crosschecked against mortality figures from Statistics Norway. Study population A total of 843 cases of IBD or possible IBD were enrolled in the inception cohort. During the followup, 87 patients had been excluded because they no longer fulfilled the criteria for the diagnosis of IBD. At the latest follow-up, 756 patients were classified with definite IBD, including 519 patients with UC. Statistical analyses The standardized mortality ratio (SMR) was calculated by dividing observed with expected mortality using age and gender-specific mortality figures from Statistics Norway for the years Crude differences with regard to relapse rates, disease pattern and proximal extension of the disease Results of the IBSEN Study 433 in relation to age, gender, disease extent, smoking status, ESR level and need for systemic steroids at diagnosis were assessed using the Pearson x 2 test or the Mann-Whitney test. Cumulative rates of colectomy were calculated for the whole cohort and selected subgroups using the Kaplan-Meier method. A Cox proportional hazards model was fitted to identify risk factors at diagnosis associated with subsequent colectom. The following covariates measured at baseline were included: gender, age (B30 years, 3050 years and]50 years), extent of colitis, familial IBD (first degree), smoking status, fever, Hb and ESR level. All analyses were performed using SPSS, version 14. Ethics The study was approved by the Regional Committees for Medical Research Ethics, and permission was obtained from the Norwegian Data Inspectorate. Results Follow-up cohort In all, 423 (81.5%) of 519 patients completed the 10-year follow-up (median follow-up time 125 months, range: ); 403 patients (95.3%) were examined at the hospital, while clinical data were based on telephone interviews and hospital records in 13 patients and on hospital records alone Figure 1. Four predefined curves, depicting different courses of ulcerative colitis from diagnosis to 10 years follow-up. Nthe number of non-operated patients (n379) reporting on each of them. Data were missing for six patients (1%).

5 434 I. C. Solberg et al. Downloaded By: [UIO University Of Oslo] At: 02:32 29 August 2009 in 7 patients. Fifty-three patients (10.2%) died (median follow-up time 30 months, range: 0108) and 43 (8.3%) were lost to follow-up (median follow-up time 54 months, range: 0132). There were no statistically significant differences between patients included in the follow-up cohort and those who died or were lost to follow-up in terms of gender, disease extent, smoking status, need for systemic steroids, Hb or ESR levels at diagnosis. However, patients lost to follow-up were younger (median age 27 versus 36 years; p0.016) and those who died were older than those included (median age 70 versus 36 years; p B0.001). All patients were assessed with colonoscopy at diagnosis, and in the follow-up cohort a prescheduled colonoscopy was performed in 352 (83%), 188 (44%) and 269 (63%) of the patients at 1, 5 and 10 years, respectively. In the subgroup of non-colectomized patients with extensive colitis at the latest follow-up, 71% (110/154) had a scheduled colonoscopy in connection with the 10-year visit. The median number of colonoscopies during follow-up was 3 (range 111), and only 17 patients (4%) did not have a colonoscopy after diagnosis. Mortality There was no significant increase in the mortality risk, overall (SMR 1.24; 95% CI: ), or after adjustment for gender, age or extent of disease at diagnosis (Table I). Only three deaths were possibly UC related: a female aged 84 years died of colonic cancer, a male aged 65 with primary sclerosing cholangitis (PSC) died of cholangiocarcinoma, and a female aged 48 died of intestinal perforation 9 months after restorative surgery with ileal pouch anal anastomosis. Colectomy The cumulative colectomy rate for the total cohort is depicted in Figure 2. The crude rate was 3.5% (95% CI: %), 7.6% (95% CI: %) and 9.8% (95% CI: %) after 1, 5 and 10 years. For patients with extensive colitis at diagnosis, the 10- year cumulative colectomy rate was 19% (95% CI: 1227%) compared with 8% (95% CI: 412%) in left-sided colitis and 5% (95% CI: 29%) in proctitis. The time from onset of symptoms to established diagnosis did not differ between operated and non-operated patients (p0.62) Out of 49 colectomies, 25 (51%) were carried out during the first 2 years after diagnosis, and all with the exception of 3 patients had extensive colitis at the time of the procedure. A female with quiescent disease and aged 24 years at onset, and a male, aged 18 with PSC and active disease were operated on due to high-grade dysplasia. Another 3 patients, all above 70 years of age, were operated on due to colorectal cancer; otherwise, the reason for colectomy was medically refractory disease. Risk factors for colectomy Data on the risk of colectomy analysed with the Cox regression model adjusting for selected covariates measured at diagnosis are shown in Table II. Initial presentation including extensive colitis, elevated ESR, anaemia and fever was significantly associated with an increased risk and age]50 years Table I. Estimated standardized mortality ratios (SMRs) in ulcerative colitis during the follow-up adjusted for age, gender and extent of colitis. Female Male Total Dead Exp. SMR 95% CI Dead Exp. SMR 95% CI Dead Exp. SMR 95% CI Age at diagnosis Extent at diagnosis * Proctitis Left-sided colitis Extensive colitis Total Exp.expected number of deaths; 95% confidence intervals (CIs) were calculated by means of Byar s approximation. * Adjusted for age.

6 Results of the IBSEN Study 435 Downloaded By: [UIO University Of Oslo] At: 02:32 29 August 2009 Figure 2. Cumulative rate of colectomy in ulcerative colitis during the first 10 years after diagnosis. Dotted lines: upper and lower limits of 95% confidence intervals. with a reduced risk of subsequent colectomy in univariate analyses. In the adjusted model, ESR]30 mm (HR 2.94; 95 CI: ) and extensive colitis at diagnosis (HR 2.98; 95% CI: ) were the only risk factors for subsequent colectomy. As anticipated, there was a significant interaction between ESR and the extent of UC. When the model was stratified for extent of disease, initially ESR]30 mm was a risk factor for colectomy only in the subgroup with extensive colitis (HR 3.57; 95% CI: ) and, as shown in Figure 3, this association was particularly strong during the first year of the disease. Older age at diagnosis was confirmed to be associated with a lower risk of colectomy in the multivariate analysis: the patients]50 years of age had an about 70% reduced risk compared with those B30 years (HR 0.28; 95% CI: ). Relapse The cumulative relapse rate after 10 years was 83% (95% CI: 8087%). Table III shows the cumulative Table II. Risk of colectomy in ulcerative colitis analysed by Cox regression. Nnumber of patients analysed in each subgroup. Unadjusted Adjusted Variables at diagnosis N HR CI p-value HR CI p-value Age groups B30 years [ref] years Excl. ]50 years Gender Female [ref] Male Ni Extent of colitis Proctitis [ref] Left-sided colitis Excl. Extensive colitis Hb g/dl ]10.5 [ref] B Excl. ESR/h B30 mm [ref] ]30 mm B Temperature 8C B37.8 [ref] Excl. Familial IBD (1st degree) No [ref] Yes Ni Smoking status Never smokers [ref] Current smokers Ex smokers Ni Abbreviations: HRhazard ratio; CI95% confidence interval; Nithe variable was not entered in the multiple analyses; Excl.the variable was entered in the multiple models, but was excluded because of later non-significance; [ref]reference category; IBD inflammatory bowel disease; ESRerythrocyte sedimentation rate.

7 436 I. C. Solberg et al. Patterns of disease Patients reports on the four predefined patterns of disease, (Figure 1) showed that more than one-half of non-colectomized patients reported remission or mild severity of intestinal symptoms after the initial activity (Curve 1), while 37% and 6%, respectively, reported chronic intermittent (Curve 4) and chronic continuous symptoms (Curve 3). Chronic intermittent course during the 10-year period was associated with younger age at diagnosis (p 0.009). No significant differences in the clinical courses were found for gender, extent of colitis, smoking status, ESR level or the need for systemic steroids at diagnosis (data not shown). Downloaded By: [UIO University Of Oslo] At: 02:32 29 August 2009 Figure 3. Kaplan-Meier curves for colectomy in extensive ulcerative colitis during the first 10 years. The solid line represents the proportion not having subsequent colectomy in patients with ESRB30 mm at diagnosis and the dotted line represents the comparable proportion among those with ESR]30 mm at diagnosis. The cumulative colectomy rate after 2 years was 3% in the group with ESRB30 compared with 21% in those with ESR ]30 mm (log-rank test, p0.001). rates of patients with relapsing disease, comparing the periods 01 year, 15 years and 510 years with regard to clinical and demographic variables at baseline. Compared to those younger than 30 years at diagnosis, patients older than 50 years had a reduced risk of relapse during these periods. Furthermore, a smaller proportion of patients with ESR]30 compared to those withb30 mm at diagnosis had relapsing disease during the last 5 years of follow-up (30% versus 50%; pb0.001). This difference remained significant when the patients who had undergone colectomy during the first 5 years were excluded from the analysis (p0.005). None of the other covariates reached statistical significance (Table III). We also performed paired tests of the likelihood of relapse/remission, comparing the periods 15 years and 510 years after diagnosis. Considering the patients who were in remission during the first period, 2/3 remained in remission also during the second period compared with 1/3 of those who had active disease during the first period (70% versus 37%, pb0.001). Proximal extension of disease Out of a total of 288 patients with inflammation distal to the splenic flexure at diagnosis, 61 (21.2%) progressed to extensive colitis; 39 during the first 5 years and 22 during the subsequent 5 years. Of the patients initially diagnosed with proctitis, 28% (39/ 140) and 14% (20/140), respectively, had extended to left-sided colitis and extensive colitis, and of those with left-sided colitis, 28% (41/148) had developed extensive colitis. Patients progressing from left-sided to extensive colitis were of slightly younger age (p 0.04), whereas none of the other covariates at diagnosis influenced the risk of proximal extension significantly (data not shown). There was a trend towards a higher 10-year cumulative colectomy rate in patients who had progressed from proctitis or left-sided colitis to extensive colitis than in those who had extensive colitis initially (crude rate: 28% versus 19%; p0.07). Medical treatment After the initial treatment, the cumulative rate of patients treated with a second course of systemic steroids was 13% (95% CI: 1016%), 41% (95% CI: 3646%) and 48% (95% CI: 4353%) at 1, 5 and 10 years, respectively. Azathioprine, which during the present study generally was accepted as a third-line therapy, was prescribed in 29 (7%) and cyclosporine in two patients. None of the patients had received tumour necrosis factor-a inhibitors. Figure 4 shows the cumulative drug consumption during the first and second 5-year periods. There was a significant decrease in the number of patients treated with systemic steroids and 5-aminosalicylic acid (5-ASA) during the second versus the first 5-year period. However, 73% (112/154) of non-operated patients with extensive colitis at the latest follow-up had been treated with 5-ASA during the last 5-year period. Discussion The findings of this population-based cohort study of newly diagnosed patients suggest an overall good prognosis for UC during the first 10 years of disease. The colectomy rate is lower than was expected, and

8 Results of the IBSEN Study 437 Table III. Cumulative rate (cum %) of ulcerative colitis patients with relapsing disease in the follow-up cohort during the first year, and during the periods 15 years and 510 years after diagnosis. Relapse during the 1st year Relapse between 1 and 5 years Relapse between 5 and 10 years Variables at diagnosis N cum% (CI) p-value cum% (CI) p-value cum% (CI) p-value Age groups B30 years [ref] (5066) 84 (7890) 59 (5068) 3050 years (4458) NS 65 (6169) (4963) NS 50 years (3151) (5272) B (2747) Gender Female [ref] (4761) NS 71 (6577) NS 53 (4660) NS Male (4151) 69 (6672) 52 (4559) Disease extent Proctitis [ref] (4662) NS 71 (6379) NS 57 (4965) NS Left-sided colitis (4349) 70 (6278) 53 (4561) Extensive colitis (3955) 69 (6177) 46 (3755) Downloaded By: [UIO University Of Oslo] At: 02:32 29 August 2009 Use of systemic corticosteroids No [ref] (4758) NS 69 (6474) NS 54 (4959) NS Yes (3959) 75 (6684) 48 (3759) ESR/h B30 mm [ref] (4657) NS 71 (6676) NS 50 (4455) B0.001 ]30 mm (3757) 60 (5070) 30 (2040) Missing 34 Smoking status Never smokers [ref] (4860) NS 52 (4758) NS 57 (5064) NS Current smokers (3258) 49 (3959) 57 (4668) Ex smokers (3957) 65 (5278) 46 (3854) Missing 2 Total 417 $ 52 (5757) 67 (6272) 52 (4559) Abbreviations: CI95% confidence interval; NSnot significant; [ref]reference category; NNumber of patients in each subgroup. The x 2 test performed within each subgroup; $ 6 patients who were colectomized at diagnosis are excluded from the analysis. almost half (48%) of the non-operated patients were in clinical remission during the last five years of follow-up. The majority (78%) of patients did not use any systemic steroids during the second 5-year period and, from the patients points of view, remission or mild symptoms after the initial activity was the most common course, while chronic continuous symptoms were rare. Finally, the mortality risk, overall and in subgroups of patients, did not differ from that in the general population. Nevertheless, 83% of our patients had suffered at least one relapse during the first 10 years, which is in accordance with previous results [1316]. As for the patients with single-attack colitis during the present study, the criteria for their diagnoses had been systematically reviewed and were still supported by endoscopic, histologic and/or laboratory findings. The cumulative colectomy rate after 10 years, which was 9.8% overall and 19% in patients with initially extensive colitis, is markedly lower than that in previous reports [5,6,17], including populationbased Scandinavian studies. In reports from Stockholm [6] and Copenhagen [5], the overall cumulative colectomy rates after 10 years were 28% and 24%, respectively, and for patients with initially extensive colitis, the rate was as high as 42%. However, the cohort from Stockholm was retrospectively recruited and in both studies the inclusion periods were long (decades), which could have influenced the results Figure 4. Cumulative drug consumption after initial treatment in ulcerative colitis (UC) during the first (patterned bars) versus the second 5-year period (grey bars);% of total number of patients (N) in parentheses.

9 Downloaded By: [UIO University Of Oslo] At: 02:32 29 August I. C. Solberg et al. owing to changes in diagnostic methods, treatment policies and/or behaviour of the disease over time. Our study was initiated before biologic active therapies were introduced, and also before immunomodulators were widely used as maintenance therapy in UC. Thus, it is unlikely that the low colectomy rate is due to the use of more potent medical therapy. On the other hand, the discrepancies in outcome may have been influenced by time trends in the attitudes of physicians and/or patients towards colectomy as a treatment option. In a new population-based cohort from Copenhagen County from 2003 to 2005 [18], the 1-year colectomy rate was 6% compared with 9% in the previous cohort [5]. Although still higher than that in the present cohort, this perhaps suggests a trend towards a lower colectomy rate also in Copenhagen. Our finding that most patients required a colectomy within the first years of disease is in line with previous observations [5,6] and emphasizes the need for early predictors for surgery if one should medically influence the colectomy rate further. As previously shown [5,6,17], extensive colitis at diagnosis was an important risk factor for colectomy in the present study. Of the initially severe systemic symptoms manifest as fever, elevated ESR and anaemia according to the Truelove & Witts criteria, only an elevated ESR]30 mm in patients with extensive colitis at diagnosis was confirmed to be a risk factor for colectomy in the multivariate analysis. In this subgroup the colectomy risk was more than 3-fold higher than in those with initially extensive colitis and ESRB30 mm. Conversely, the presence of extensive colitis or elevated ESR at diagnosis was not associated with an increased risk of overall relapse during the follow-up. In fact, a significantly higher proportion of noncolectomized patients with ESR levels]30 compared withb30 mm at diagnosis were relapse free during the last 5-year period. This result might seem surprising, but this discrepancy could be explained by the fact that relapses are quite common in patients with both limited disease distribution and mild to moderate disease activity. Moreover, comparable findings have been reported by Langholz et al. in the Danish cohort [15]. In that study the combination of weight loss and fever at diagnosis was found to be predictive of a more favourable course of disease provided that the patient avoided colectomy. Thus, the authors suggested that a strong immune reaction at disease onset secures a more quiescent course in those who respond to medical treatment. This can partly be supported by previous results from our cohort, showing that endoscopic healing of the mucosa after one year of treatment was related to severe symptoms and extensive disease at diagnosis [19]. Younger age at onset of disease has been associated with a shorter time to relapse [20] and a higher relapse rate in some UC cohorts [21,22]. In contrast, no relationship between initial age and subsequent course, including colectomy, was reported by Langholz et al. [15]. In the present study, age above 50 years at diagnosis was associated with a reduced risk of surgical and clinical relapse, suggesting that the course of UC becomes milder with increasing age, and that the initial age should be a part of the clinical classification of patients. Of other factors possibly influencing the prognosis in UC, cigarette smoking has been associated with a milder course [23] and a lower risk of colectomy [24]. We could not confirm these findings, but this result might have been influenced by the low number of current smokers in the cohort, resulting in a low statistical power. One-fifth of patients with inflammation below the splenic flexure at diagnosis had progressed to extensive colitis during the follow-up. The rate of proximal extension in patients with proctitis was in line with those reported by Ayres et al. and Langholz et al. [25,26], while the progression rate in those with initially left-sided colitis was lower than that in most previous reports [17,25,26]. The extent of colitis in our study was based on endoscopic findings, which should be an advantage compared to the combination of sigmoidoscopy and barium enema used by others [27]. The majority of our patients had been evaluated with at least one scheduled colonoscopy after diagnosis and had uniform access to endoscopy during flare-ups. Nevertheless, the frequency of disease progression in asymptomatic patients may have been underestimated. Our finding that patients who had progressed from distal to extensive colitis during the follow-up were colectomized to a higher extent (28%) than those with extensive colitis at diagnosis (19%) is interesting. However, we were not able to identify any strong predictors for subsequent disease progression, and since few patients were operated on in our cohort, this finding should be reproduced in larger studies. Moreover, a longer observation period than 10 years is needed to clarify the relationship between proximal extension of the disease and outcome, especially with regard to the risk of colorectal cnacer. The strength of the present study was based on the prospective recruitment of unselected and newly diagnosed patients from well-defined areas, a short inclusion period and a systematic follow-up by the same group of gastroenterologists, ensuring uniform diagnostic criteria and treatment policies during the study period. The fact that our study describes the course of UC during the time of introduction of immunomodulators as maintenance therapy, and

10 Downloaded By: [UIO University Of Oslo] At: 02:32 29 August 2009 just before biologic agents were introduced, might also be an advantage, since our results could be used as a historical basis for future comparisons. A weakness of the present study relates to the retrospective recording of clinical information between scheduled visits. For this reason, an estimation of the area under the curve for drug consumption was not justified. Moreover, although the predefined curves depicting the different clinical courses were intuitively understood by the patients, they might have some limitations. A recent flare-up might have led the patient to choose a more severe course, while adaptation to the symptoms over time might have had the opposite effect. The patient s choice might also have been influenced by the examining doctor. In conclusion, in this population-based inception cohort the prognosis during the first 10 years of UC appears to be better than expected. The colectomy rate was low, and our results support previous findings [15] suggesting a decline in the activity of UC over time. Extensive colitis combined with an elevated ESR at diagnosis was strongly associated with early colectomy, which might have an impact on the initial treatment strategy. The inverse relationship between these factors and the risk of relapse can be explained by a frequent relapse rate among patients with light to moderate disease activity and limited disease distribution. An extended follow-up of the present cohort is needed to clarify whether the low colectomy rate or reduced consumption of drugs will affect the risk of mortality or colorectal cancer in long-standing disease. Acknowledgements We express our thanks to the following members of the Inflammatory Bowel South-Eastern Norway (IBSEN) Study Group of gastroenterologists for participating in this study: Njaal Stray, Diakonhjemmet Hospital, Oslo, Stein Dahler, Notodden Hospital, Øystein Kjellevold, Blefjell Hospital and Finn Strøm, Lovisenberg Diakonale Hospital, Oslo. The authors have no conflicts of interest to declare. References [1] Brostrom O. Prognosis in ulcerative colitis. Med Clin North Am 1990;/74:/ [2] Sonnenberg A. Mortality from Crohn s disease and ulcerative colitis in England-Wales and the US from 1950 to Dis Colon Rectum 1986;/29:/6249. [3] Ekbom A, Helmick CG, Zack M, Holmberg L, Adami HO. Survival and causes of death in patients with inflammatory bowel disease: a population-based study. Gastroenterology 1992;/103:/ [4] Persson PG, Bernell O, Leijonmarck CE, Farahmand BY, Hellers G, Ahlbom A. 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