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Surgical management in Ulcerative Colitis (UC) is typically utilised in medically refractory cases and, therefore, it is a useful marker for efficacy of medical management.
Aims
To understand the changing prevalence of colectomy in UC over time.
Methods
A systematic review was conducted using MEDLINE (1946–2021), EMBASE and EMBASE classic (1947–2021) to identify studies with a population of n>500 that reported colectomy rates in UC patients >18 years old. The primary outcome was the prevalence of colectomy at 1-, 5- and 10-years post-diagnosis. Secondary outcomes included colectomy rates in the pre-biologics (defined as pre-2004) and post-biologics eras (defined as post-2004).
Results
Thirty-one studies with 294,359 patients with UC were included for review and meta-analysis. The prevalence of colectomy at 1-, 5- and 10-years post-diagnosis were 3% (95% CI 2%-6%), 5% (95% CI 2%-9%), 10% (95% CI 6%-16%) respectively. The pooled relative risk for colectomy in the post-biologics era was 0.68 (95% CI 0.42 to 1.09, p=0.10) at 1-year and 0.71 (95% CI 0.56 to 0.91, p<0.01) at 5-years post-diagnosis.
Conclusion
The overall colectomy rate has decreased over the past three decades. Biologics may have played a role in reducing the risk of colectomy, however the relative risk reduction is likely to be modest.
Ulcerative Colitis (UC) is a form of Inflammatory Bowel Disease (IBD) characterised by abdominal pain and bloody diarrhoea due to immune-mediated inflammation of the colon and rectum, with a significant impact on quality of life. Treatment for UC usually follows a stepwise approach in concordance with the severity of presentation. Anti-inflammatory drugs, steroids and immunomodulators are utilised with the intention of inducing and subsequently maintaining disease remission. However, there is no cure for UC and despite advancements in these medical therapies a significant number of patients will require a surgical intervention during their lifetime. Colectomy (surgical removal of the colon and rectum) is the closest to a “curative” option for UC but carries peri-operative risks [
Post-operative morbidity and mortality of a cohort of steroid refractory acute severe ulcerative colitis: Nationwide multicenter study of the GETECCU ENEIDA Registry.
Trends in morbidity and mortality following colectomy among patients with ulcerative colitis in the biologic era (2002-2013): a study using the national inpatient sample.
Despite improvements in our understanding of the disease, the development of IBD standards and key performance indicators and advancements in our medical armamentarium, the impact on colectomy rates is debateable. As surgery is predominantly utilised in cases of medically refractory UC, it is a useful marker of efficacy of medical management in UC. Therefore, an understanding of the overall prevalence of colectomy and relative risk of colectomy in the post-biologics era is crucial to patient counselling upon a new diagnosis of UC. By knowing the long-term prevalence of colectomy in different cohorts of UC patients through the different developments in medical management of the condition, clinicians will be better placed to facilitate the discussion around what a diagnosis of UC means for the patient. Furthermore, this type of study will also help with powering future studies looking specifically at non-surgical interventions for UC and their effect on the colectomy rate. We therefore conducted a systematic review with meta-analysis to understand the incidence of colectomy and how this has changed over time.
2. Methods
2.1 Study design
The systematic review followed a prior defined protocol with a comprehensive search of multiple electronic databases including conference proceedings and followed steps as recommended in the PRISMA 2020 guidelines for reporting systematic reviews [
]. The systematic review was registered with PROSPERO with registration number CRD42022307600 prior to any data extraction or analysis. There have been no changes to the study since it was registered.
2.2 Search strategy
A systematic search of the medical literature was conducted using MEDLINE (1946 to May 2021), EMBASE and EMBASE classic (1947 to May 2021) to identify all studies with a population of n>500 that reported colectomy rates in patients >18 years of age with ulcerative colitis. We manually searched conference proceedings (Digestive Diseases Week, American College of Gastroenterology, United European Gastroenterology Week, and the Asian Pacific Digestive Week, Tripartate colorectal meetings and ACPGBI) between 2006 and 2021 to identify studies published only in abstract form. There were no language restrictions and we translated manuscripts where appropriate. The abstracts from the search were screened against eligibility criteria and those that were deemed to potentially fit underwent review of the complete manuscript. Bibliographies of included articles were also interrogated for further studies that may reach the inclusion criteria. If a study was potentially relevant but was missing data required, we contacted the authors for clarification. Eligibility assessment was performed by two authors (ND, OH) independently, using pre-defined eligibility forms. We resolved any disagreements by consensus and measured the degree of agreement with a kappa statistic.
2.3 Inclusion criteria
Population based and cohort studies of patients with ulcerative colitis from an unselected full population were eligible for inclusion if they reported prevalence of colectomy in patients with ulcerative colitis. Studies were excluded if colectomy was reported on those who are not patients with ulcerative colitis, those that were not population-based studies, data could not be extracted, or the study included paediatric populations.
2.4 Data extraction
All data were extracted by two independent researchers (ND, OH) into a Microsoft excel spreadsheet and any disagreements were resolved by consensus with a third reviewer (JPS). The following data were extracted. Study, type of study, country of study, total number of subjects recruited, number of subjects requiring a colectomy for time periods, 1, 2, 3, 5, 10, 15, 20 years and annual colectomy numbers from 2001 up to the present day. 2001 was chosen as it represented the past two decades and therefore a contemporary cohort to try and understand colectomy rates. Studies that included populations with no reported use of biologic therapy and a clearly defined pre-2004 cohort were classified as pre-biologics and those that included a proportion of patients undergoing biologics-therapy were classified as post-biologics.
The primary outcome was the prevalence of colectomy at 1, 5 and 10 years after diagnosis. A secondary outcome was that of colectomy rates at 2, 15 and 20 years and in the pre-biologics (defined as pre-2004) compared to post-biologics eras (defined as post-2004). The included studies were examined for their quality using the validated Newcastle-Ottawa Scale.
3. Results
Search results using the criteria outlined, yielded 995 abstracts published between 1946 and 2021 (Fig. 1). Of these, 949 studies were excluded as they did not fit the inclusion criteria or were duplicates; leaving a total of 46 studies for full text review. One of the manuscripts could not be retrieved despite undertaking numerous avenues, resulting in a total of 45 studies for consideration. However, 14 of these studies were excluded as they either did not include a population which met the inclusion criteria (n=5 studies) or did not offer any data on the rate of colectomy (n=9). A total of 31 studies (n= 294,359) were included (Table 1).
Natural disease course of ulcerative colitis during the first five years of follow-up in a European population-based inception cohort-an Epi-IBD study.
Changes in the rate of and trends in colectomy for ulcerative colitis during the era of biologics and calcineurin inhibitors based on a Japanese nationwide cohort study.
Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during the last 5 decades: a population-based study from Copenhagen, Denmark.
Changes in medical management and colectomy rates: a population-based cohort study on the epidemiology and natural history of ulcerative colitis in Örebro, Sweden, 1963-2010.
Long-term prognosis of ulcerative colitis and its temporal changes between 1986 and 2015 in a population-based cohort in the Songpa-Kangdong district of Seoul, Korea.
Low colectomy rate five years after diagnosis of ulcerative colitis. Results from a prospective population-based cohort in Sweden (ICURE) diagnosed during 2005-2009.
Trends in morbidity and mortality following colectomy among patients with ulcerative colitis in the biologic era (2002-2013): a study using the national inpatient sample.
Increasing incidences of inflammatory bowel disease and decreasing surgery rates in Copenhagen City and County, 2003-2005: a population-based study from the Danish Crohn colitis database.
The quality of the included studies were examined using the validated Newcastle-Ottawa score for observational studies. However, it should be noted that most studies included were single cohort population-based observational studies and therefore score poor on the Newcastle-Ottawa score due to having no comparable cohort.
3.2 Colectomy rate by year post-diagnosis
Separate analyses were undertaken to determine the chances of colectomy at different time intervals (1, 2, 5, 10, 15 and 20- year) after a diagnosis of UC.
3.2.1 Short term colectomy rates post UC diagnosis
Long-term prognosis of ulcerative colitis and its temporal changes between 1986 and 2015 in a population-based cohort in the Songpa-Kangdong district of Seoul, Korea.
Changes in the rate of and trends in colectomy for ulcerative colitis during the era of biologics and calcineurin inhibitors based on a Japanese nationwide cohort study.
Increasing incidences of inflammatory bowel disease and decreasing surgery rates in Copenhagen City and County, 2003-2005: a population-based study from the Danish Crohn colitis database.
] comprising of 67,102 patients that were included in the 1-year analysis and the overall risk of colectomy was 0.03 (95% CI 0.02-0.06, i2 = 99%) (Fig. 2a). Egger's test indicates the presence of funnel plot asymmetry (p = 0.0002). Analysis of the five studies [
Changes in the rate of and trends in colectomy for ulcerative colitis during the era of biologics and calcineurin inhibitors based on a Japanese nationwide cohort study.
] comprising of 7,492 patients provided information on 2-year colectomy results, yielded similar results, with the overall risk of colectomy remaining low (0.03, 95% CI 0.01-0.12, i2 = 98%, Fig. 2b). Given the small number of studies, specific analysis for publication bias was not undertaken. At 5-years post UC diagnosis, the risk of colectomy was again similar to the 1- and 2- year rates (0.05, 95% CI 0.02-0.09, i2 = 100%, Fig. 2c) across 13 studies comprising of 68,618 patients [
Long-term prognosis of ulcerative colitis and its temporal changes between 1986 and 2015 in a population-based cohort in the Songpa-Kangdong district of Seoul, Korea.
Changes in the rate of and trends in colectomy for ulcerative colitis during the era of biologics and calcineurin inhibitors based on a Japanese nationwide cohort study.
Natural disease course of ulcerative colitis during the first five years of follow-up in a European population-based inception cohort-an Epi-IBD study.
Low colectomy rate five years after diagnosis of ulcerative colitis. Results from a prospective population-based cohort in Sweden (ICURE) diagnosed during 2005-2009.
Long-term prognosis of ulcerative colitis and its temporal changes between 1986 and 2015 in a population-based cohort in the Songpa-Kangdong district of Seoul, Korea.
Changes in medical management and colectomy rates: a population-based cohort study on the epidemiology and natural history of ulcerative colitis in Örebro, Sweden, 1963-2010.
] comprising 149,126 patients that were included in the 10-year analysis and the colectomy rates increased significantly to 10% (0.1, 95% CI 0.06-0.16, i2 = 100%, Egger's test: p=0.4 Fig. 2d). This rate remained the same for 15-year analysis (0.1, 95% CI 0.02-0.33, i2 = 99%, Fig. 2e). At 20-years post a diagnosis of UC, across seven studies, that included 12,497 patients [
Long-term prognosis of ulcerative colitis and its temporal changes between 1986 and 2015 in a population-based cohort in the Songpa-Kangdong district of Seoul, Korea.
], the colectomy rate increased to 0.14 (95% CI 0.08-0.22, i2 = 98%). For both the 15- and 20- year analyses, insufficient number of studies prohibited further testing for publication bias.
3.3 Colectomy in the pre-biologics vs. post-biologics era
Sub-group analyses were undertaken to determine whether colectomy rates differed between the pre- and post-biologics era. The analysis which comprised of four studies [
Long-term prognosis of ulcerative colitis and its temporal changes between 1986 and 2015 in a population-based cohort in the Songpa-Kangdong district of Seoul, Korea.
] and 5,126 patients (Fig. 3) revealed that at 1-year post a diagnosis of UC, the risk of colectomy was lower in studies published after the introduction of biologics to clinical practice (RR 0.6, 95% CI 0.42-1.09, p=0.10). Comparing colectomy rates amongst the four studies that reported 5-year post-UC diagnosis colectomy rates comprising 10,063 patients, revealed the RR of colectomy to be lower in the studies published post biologics (0.71, 95% CI 0.56 to 0.9, p<0.01) compared to those published in years before the introduction of biologics [
Long-term prognosis of ulcerative colitis and its temporal changes between 1986 and 2015 in a population-based cohort in the Songpa-Kangdong district of Seoul, Korea.
Mixed effects regression suggested a negative association between the year of publication of the study and the size of effect at 1-year (0.0339, 95% CI 0.0183 to 0.0619), 5-year (0.0462 95% CI 0.0228 to 0.0911) and 10-year (0.1016, 95% CI 0.0650, 0.1553, Fig. 4).
Fig. 4Meta-regression analysis. Bubble and Funnel plots for colectomy rates at 1, 5 and 10-year post-diagnosis.
The present study has demonstrated that colectomy rates for UC at 1, 5, 10-year are 3%, 5% and 10% respectively. More importantly, the results suggest that there has been only a modest reduction in colectomy rates following the introduction of the biologics in 2004. Our results are in keeping with data previously reported in the literature; the proportion of patients undergoing colectomy has decreased over the last three decades. We can infer that the main driver of this change is the improvement and optimisation of medical management. Hendriksen et al., Leijonmarck et al. and Langholz et al. looked at cohorts of UC patients from 1960-1978, 1962-1987 and 1955-1984 respectively where treatment was limited in the form of steroids for acute flares and sulfasalazine treatment to prevent relapse in patients who could tolerate the treatment. Therefore, the colectomy rates reported in these studies are significantly higher than those in more recent studies [
]. In the 1990s there was significant advances in the management of UC with the approval of mesalazine, increasing understanding and application of immunomodulators and the approval of the biologic interferon (although this would not be approved for UC until the early 2000s) [
]. More recent studies have evidenced this temporal change in medical management showing a 3-fold and 4-fold increase in immunomodulator and anti-TNFa use from pre-1990 to post-2000 cohorts [
]. Worley et al. appears an outlier in our analysis, but this can be accounted for as they investigated colectomy rates specifically amongst emergency admissions between 2003 and 2017 [
Interestingly, although there has been a reduction in the risk of colectomy in the post-biologics vs. pre-biologics era, the risk reduction is modest and at 5-years there was a small but significant reduction in colectomy rates. However, this result should be interpreted with caution as the studies included in this systematic review are observational in nature and biologics still comprise a small but increasing share (typically around 10%) of the medical management of UC. The reason for the modest reduction in colectomy rate is likely to be multifactorial. Potentially, it may suggest that in some cases colectomy may be inevitable despite optimum medical therapy. This finding further supports the view that there is a significant evidence gap between biologics in RCTs where there are strict inclusion/exclusion criteria versus biologics in a non-selective population cohort [
]. It is also important to note that it has been well documented that the first biologic used is usually the most successful biologic and that there are diminishing gains with any further additional biologic therapy [
From a health economics perspective, from a single centre in 2004 prior to the introduction of biologic agents the cost of UC whether quiescent, ambulatory with an acute flare or hospitalised with an acute flare carried a cost of £359, £765 and £8,861 respectively [
]. Separate data published in 2014 with biologics showed these costs for UC whether in remission, mild-moderate flare compared to severe flare carried an average cost of £1,693, £2,903 and £10,760 respectively [
] his rise in costs (even when adjusted for inflation) is echoed by data from Denmark showing the average cost at 1-year post-diagnosis with UC for patients on biologics was €6,918 more than for UC patients not on biologics [
]. In the absence of robust evidence supporting a significant decrease in colectomy rates following the introduction of biologics, it raises the question as to their cost-effectiveness.
Importantly, quality of life is one of the most important metrics in assessing a patient with UC and in some cases, colectomy can offer a significantly better early option compared with the patient spending a greater duration on medications whilst remaining very symptomatic. Our results may therefore suggest a continued multi-disciplinary approach to UC where it remains recognised that surgery is a useful early intervention and not a last resort in those with UC. In the present study, there was low heterogeneity in the 1-year and 5-year colectomy rates suggesting that there is a true risk reduction, however further high-quality evidence in the form of randomised-controlled trials specifically investigating the efficacy of biologics compared to other treatment modalities is required to ascertain if this risk reduction is truly from the introduction of biologics. Given the multi-modality approach to UC treatment and the current operating standard of biologics used as a last resort it may still be very difficult to ascertain the true effect of biologics.
To our knowledge this is the largest systematic review with 31 studies (containing data on 294,359 UC patients) specifically investigating colectomy rates over a period of 50 years. Data from this analysis can aid clinicians in better informing newly diagnosed UC patients newly diagnosed as to their risk of requiring colectomy for their disease in the next 1,5,10 and 20 years. At present this is 14% at 20-years which shows a significant improvement compared to the 30% risk for patients diagnosed pre-1990. This figure is also already outdated as the increasing role of biologics the last 15 years is likely to have had a further impact on colectomy rates.
There are several limitations of this study that should be highlighted. All studies were observational retrospective studies and therefore it is difficult to delineate any causation between specific interventions and the decreasing colectomy rate. Secondly, there was significant heterogeneity amongst the studies included and as a result; selection and publication bias cannot be excluded. This heterogeneity is expected as we assume that there will be real differences in treatment effects rather than a common treatment effect because of differences in study population, interventions and follow-up. Thirdly, patients that present emergently with acute colitis, are at far higher risk of undergoing a colectomy as highlighted by Worley et al. [
]. As most studies included in this paper do not specifically investigate/mention colectomy rates during an emergency admission; it is difficult to apply the results to the entire cohort of patients with UC. As such, varying rates of colectomy may be seen in different healthcare systems (or even within the same healthcare system) and the actual rates of colectomy may be substantially lower than what the results of the present study would suggest; particularly in patients who have stable disease and are managed well on medication. We attempted to perform a sensitivity analysis on the indication for colectomy but very few of the studies reviewed offered a detailed breakdown of the indications for colectomy. We have included this data in our appendix (Table 2). Fourth, our selection of 2004 as the marker for pre- and post-biologics eras was based on the first authorisation date of biologics therapy for UC in the UK. However, we appreciate that the authorisation dates vary significantly by worldwide region and time from authorisation to implementation can equally be variable. Importantly, most of the studies included in this study were from westernised populations with limited representation from other areas of the world. Therefore, the generalisability of these results to global populations may be difficult.
Perhaps more importantly, it must be borne in mind that the colectomy rate is heavily influenced by many confounders to include improvements in multi-disciplinary care such as improved dietetics, psychological, and auxiliary support. It is therefore likely that colectomy rates are influenced by much more than just the biological drugs which are important considerations when interpreting this data. In this systematic review and meta-analysis of 294,359 patients with a confirmed diagnosis of UC, the results have demonstrated that the prevalence of colectomy increases as time after diagnosis increases, but the overall colectomy rate has decreased over the past three decades. Biologics may have contributed to reducing the risk of colectomy, but the relative risk reduction is modest and other treatment factors and improved care are likely to have contributed to this reduction.
Declaration of Competing Interest
Jonathan Segal has received speaker fees for Takeda Janssen and Abbvie.
All other authors declare no conflicts of interest
Funding
The authors declare no external funding for this project.
Post-operative morbidity and mortality of a cohort of steroid refractory acute severe ulcerative colitis: Nationwide multicenter study of the GETECCU ENEIDA Registry.
Trends in morbidity and mortality following colectomy among patients with ulcerative colitis in the biologic era (2002-2013): a study using the national inpatient sample.
Long-term prognosis of ulcerative colitis and its temporal changes between 1986 and 2015 in a population-based cohort in the Songpa-Kangdong district of Seoul, Korea.
Changes in the rate of and trends in colectomy for ulcerative colitis during the era of biologics and calcineurin inhibitors based on a Japanese nationwide cohort study.
Increasing incidences of inflammatory bowel disease and decreasing surgery rates in Copenhagen City and County, 2003-2005: a population-based study from the Danish Crohn colitis database.
Natural disease course of ulcerative colitis during the first five years of follow-up in a European population-based inception cohort-an Epi-IBD study.
Low colectomy rate five years after diagnosis of ulcerative colitis. Results from a prospective population-based cohort in Sweden (ICURE) diagnosed during 2005-2009.
Changes in medical management and colectomy rates: a population-based cohort study on the epidemiology and natural history of ulcerative colitis in Örebro, Sweden, 1963-2010.
Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during the last 5 decades: a population-based study from Copenhagen, Denmark.
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