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Clinical Predictors of the Risk of Early Colectomy in Ulcerative Colitis: A Population-based Study

Al-Darmaki, Ahmed MD; Hubbard, James MSc; Seow, Cynthia H. MD, MSc; Leung, Yvette MD; Novak, Kerri MD; Shaheen, Abdel Aziz MD, MSc; Panaccione, Remo MD; Kaplan, Gilaad G. MD, MPH

doi: 10.1097/MIB.0000000000001211
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Background: A subset of patients with ulcerative colitis (UC) will require colectomy within a few years of diagnosis. Thus, our aim was to determine the clinical predictors of early colectomy among patients with UC who are hospitalized with an acute flare.

Methods: Using population-based surveillance (1996–2009), all adults (≥18 years) hospitalized for UC within 3 years of diagnosis (n = 489) were identified. The primary outcome was a colectomy within 3 years of diagnosis. All medical charts were reviewed. A logistic regression model evaluated clinical variables that predicted colectomy within 3 years of diagnosis, and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were reported.

Results: Among patients admitted to hospital with UC within 3 years of diagnosis, 57.7% underwent colectomy, with the odds of colectomy decreasing by 12% per year. Early colectomy was more likely among patients aged 35 to 64 years versus 18 to 34 years (OR 2.18 [95% CI, 1.27–3.74]), males (OR 2.03 [95% CI, 1.24–3.34]), those with pancolitis (OR 5.38 [95% CI, 3.20–9.06]), and living in rural areas (OR 2.81 [95% CI, 1.49–5.29]). Prescription of infliximab before hospitalization increased odds of surgery (OR 5.12 [95% CI, 1.36–19.30]).

Conclusions: Patients hospitalized for UC have a high risk of early colectomy. This is particularly true in middle-aged men, those living in rural areas, and those without response to infliximab.

Article first published online 17 July 2017.

*Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada;

Departments of Medicine,

Community Health Sciences, University of Calgary, Calgary, Alberta, Canada; and

§Inflammatory Bowel Disease Clinic, University of Calgary, Calgary, Alberta, Canada.

Address correspondence to: Gilaad G. Kaplan, MD, MPH, FRCPC, Departments of Medicine and Community Health Sciences, University of Calgary, 3280 Hospital Drive NW, 6D56, Calgary, AB T2N 4N1, Canada (e-mail: ggkaplan@ucalgary.ca).

The authors have no conflict of interest to disclose.

Author disclosures are available in the Acknowledgments.

Received February 12, 2017

Accepted May 22, 2017

Ulcerative colitis is a chronic inflammatory condition affecting the large bowel, ranging in severity from mild-to-fulminant colitis.1,2 Patients who experience a complication, lack of response to medical therapy, or develop dysplasia may require a colectomy.3–5 Approximately 5% of patients will require colectomy within 1 year of diagnosis and 16% within 10 years.5 Despite being considered curative therapy, surgery is associated with significant complications.6–10 A recent meta-analysis has shown that risk of mortality following surgery were 0.7% and 5.3% for elective and emergency surgeries, respectively.11 Despite the decline in rates of elective colectomy over time, the risk of emergent colectomy has not changed,12 and most patients requiring emergent colectomy do so within the first 3 years of diagnosis.12

Thus, the early identification of patients with more aggressive disease who may advance to early colectomy is important, yet the window to identify them is narrow. Identification may facilitate appropriate counseling, optimized medical management, or timely elective colectomy. The objective of our study is to identify the factors that can predict the risk of colectomy early in diagnosis.

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MATERIALS AND METHODS

Data Sources

We conducted a population-based surveillance cohort study. The Data Integration, Measurement, and Reporting Hospital Discharge Abstract Database (DAD) was used to identify patients with ulcerative colitis (UC) who were hospitalized in the Calgary Health Zone (CHZ) in Alberta, Canada. The CHZ is a population-based health region of over 1 million residents of Calgary and over 20 nearby cities under a public single-payer system.13 The DAD uses the International Classification of Disease, Ninth and Tenth Revisions, Clinical Modification (ICD-9-CM & ICD-10-CM) and the Canadian Classification of Health Intervention (CCI) to code diagnostic and procedural codes during admission to a hospital.6,14 The DAD has been locally validated to be used in studies of UC.14

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Study Population

We identified all patients with discharge diagnosis code of UC (ICD-9-CM 556.X or ICD-10-CA K51.X) in any diagnostic position between January 1, 1996, and December 31, 2009 at a Calgary Health Zone hospital. Medical charts were reviewed of all patients. The inclusion criteria included a confirmed diagnosis of UC based on standard clinical diagnostic criteria, age ≥18 years at the time of admission to hospital, primary reason for admission to hospital because of a flare of UC, and admission occurring within 3 years of diagnosis. We a priori defined risk of colectomy at 3 years based on previously published literature that showed a higher rate of colectomy in our health region within the first 3 years.12 These criteria allowed us to identify a study population consisting of patients with UC who were emergently admitted to hospital with a flare of UC within 3 years of diagnosis. The date of admission served as the index date. All admitted patients received standard care of acute severe UC including intravenous corticosteroids. Included patients in this study were followed-up for hospitalization and/or surgery from diagnosis to their third year of disease duration.

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Outcomes

The primary outcome of interest was a colectomy within 3 years of diagnosis. Colectomy was confirmed through medical chart review. We a priori selected the window of 3 years based on a previous publication showing that most patients with UC who required an emergent colectomy underwent surgery within 3 years of diagnosis.12

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Study Variables

Patients' charts were reviewed and relevant data were extracted. The diagnosis of UC and the date of diagnosis in relation to the admission date were confirmed. Extracted variables included age defined as 18 to 34, 35 to 64, and >64 years; sex; smoking status defined as current, former, or never smoker at the time of admission; residence in the Calgary Health Zone; year of first index hospital admission (for patients with noncolectomy); year of surgery (for patients with colectomy); length of flare defined as <2 weeks, 2 to 8 weeks, and >8 weeks; comorbidities, based on a previously validated list of preexisting health conditions for UC14; disease extent stratified as left sided or pancolitis; and hemoglobin level. In addition, drug utilization before hospitalization was recorded for 5-ASA, azathioprine, oral prednisone, and infliximab. Patients who received their induction of infliximab in hospital (i.e., naive to anti-TNF therapy before admission) were evaluated separately.

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Statistical Analysis

Bivariate analyses were performed using Fisher's exact test to examine the association between each study variable and colectomy within 3 years of diagnosis. Continuous variables were expressed as medians with interquartile ranges and compared using the Wilcoxon rank sum test. A logistic regression model was created to evaluate variables (age, sex, smoking, residence, year, length of flare, comorbidities, disease extent, hemoglobin, and inflammatory bowel disease medications) that independently predicted the need for colectomy within 3 years of diagnosis. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) are reported. We conducted a sensitivity analysis restricted to the biological era as defined by hospitalization occurring between 2005 and 2009. In this study population, we conducted a multivariate logistic regression model to evaluate the effect of infliximab before admission or during hospital admission on need for colectomy. All statistical analyses were performed using SAS, version 9.4 (SAS Institute Inc., Cary, NC). In all instances, an a priori significance level of 0.05 was used.

The study was approved by the Conjoint Health Research Ethics Board at the University of Calgary. Our study was conducted in accordance with the strengthening of the reporting of observational studies in epidemiology (STROBE) statement.15

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RESULTS

In total, 489 patients with UC were hospitalized within 3 years of diagnosis and 57.7% underwent colectomy within 3 years of diagnosis. Among patients with UC who had a colectomy: 51% (144) had surgery in the first year, 31% (86) in the second year, and 18% (52) in the third year. Table 1 summarizes the clinical characteristics of patients with colectomy and noncolectomy.

TABLE 1-a

TABLE 1-a

TABLE 1-b

TABLE 1-b

Individuals aged 35 to 64 years were more likely to undergo a colectomy as compared to younger patients, aged 18 to 35 years: OR 2.18 (95% CI, 1.27–3.74). Males were more likely to require colectomy earlier in the course of the disease: OR 2.03 (95% CI, 1.24–3.34). Smoking status did not influence a patients' risk of colectomy: never versus current smokers: OR 0.72 (95% CI, 0.29–1.76) and never versus former smokers: OR 1.14 (95% CI, 0.65–1.98). Individuals living in the Calgary Health Zone were less likely to require colectomy than patients living outside the zone but were admitted or transferred to a hospital in Calgary: OR 2.81 (95% CI, 1.49–5.29). Patients with pancolitis had a 5-fold increased odds of colectomy when compared to those with left-sided disease: OR 5.38 (95% CI, 3.20–9.06). Anemia with hemoglobin less than 100 g/L and previous treatment with 5-aminosalysilates (5-ASA) did not correlate with colectomy risk: OR 0.54 (95% CI, 0.29–1.02) and OR 1.29 (95% CI, 0.75–2.22), respectively. The odds of having a colectomy within 3 years of diagnosis decreased 12% per year from 1996 to 2009: OR 0.88 (95% CI, 0.82–0.94) (Table 2).

TABLE 2

TABLE 2

Exposures to oral corticosteroids, azathioprine, or infliximab before admission were independent predictors of colectomy: OR 5.44 (95% CI, 3.03–9.75), OR 2.95 (95% CI, 1.42–6.09), and OR 5.12 (95% CI, 1.36–19.30), respectively. In contrast, receiving an induction dose of infliximab during hospitalization in biologic-naive patients was associated with reduced odds of colectomy: OR 0.28 (95% CI, 0.10–0.77).

In the sensitivity analysis that restricted the study population to the biologics era, previous infliximab use increased the odds of colectomy (OR 6.51; 95% CI, 1.63–26.00), whereas infliximab use in hospital was no longer significant (OR = 0.43; 95% CI, 0.15–1.25).

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DISCUSSION

Optimizing medical therapy in UC is aimed at improving symptoms, preventing complications, and avoiding colectomy.16 Early identification of patients who are at higher risk of colectomy may help guide clinicians in targeting those patients who would require earlier aggressive therapy and more frequent monitoring. In this population-based study, we evaluated factors that may help identify patients at higher risk of colectomy and thus predict worse outcome in patients who require hospitalization for active UC within 3 years of diagnosis.

This is the first population-based study to evaluate clinical predictors of early colectomy among patients with severe UC requiring admission to hospital within 3 years of diagnosis. Overall analysis showed that patients who were males, diagnosed between the ages of 34 to 64 years with pancolitis, were more likely to require early colectomy. Although sex, age, and disease extent cannot be modified, they reflect a patient profile that warrants close monitoring during the early course following diagnosis of UC. Patients exposed to prednisone, azathioprine, and infliximab before hospitalization were more likely to need early colectomy. This suggests that UC patients with fulminant colitis may quickly progress to colectomy. In these cases, earlier introduction of biologics with immunomodulators may be required.

One-third of our population did not receive a course of oral prednisone before their index admission to hospital. This observation reflects the high disease severity of the study population. Patients who were not prescribed prednisone as outpatients were primarily those with UC who were diagnosed at their index hospital admission or who presented directly to the emergency department during their flare. Living in smaller towns or rural areas outside of the Calgary Health Zone increased the odds of colectomy. This finding suggests that those living in underserviced areas or areas requiring transfer to a tertiary care hospital are more likely to require surgery than those who have greater access to specialist care in hospital. The reasons for this could be delayed access to more effective therapy like anti-TNF or longer duration of exposure to steroids before transfer.

In a recent meta-analysis of 20 studies, Dias et al17 showed that gender, hospitalization, extent of UC, requirement for steroids, smoking habits, and CRP were associated with increased risk of colectomy. The studies included were heterogeneous with mixed prospective and retrospective design, and were not restricted to population-based studies. Using the population-based IBSEN data from Norway on patients diagnosed between 1990 and 1994 then followed-up for 10 years, Solberg et al18 showed that age ≤40 years, requirement of systemic steroids, pancolitis, and CRP ≥30 were associated with increased risk of colectomy over a course of 10 years following diagnosis. Our study is different as we report the relatively short-term colectomy outcome; that is, within 3 years of diagnosis.

The risk of colectomy reported in our cohort was relatively high, approaching 58%. This does not reflect the actual rate of colectomy among all patients with UC, which we have previously shown to be lower and decreasing significantly over time.12 A meta-analysis in 2013 revealed that colectomy rates were 4.9%, 11.6%, and 15.6% at 1, 5, and 10 years from diagnosis, respectively.5 Our study population focused on patients with severe disease requiring a hospital admission within 3 years of diagnosis. Among this population, 58% underwent early colectomy; however, this risk decreased throughout the course of study period. This likely reflects improvement in therapy optimization and early intervention based on identifying the risk factors for worse outcome. In addition, improved medical therapy for UC by the introduction of biologics early in the course of steroid, refractory acute severe UC might have contributed to this decrease over time. As our data collection started in 1996, many patients were treated in the pre-biologics era. In a retrospective study which evaluated a cohort of patients admitted with acute severe UC at different periods of time, it was shown that the early colectomy rate was >44% between 1976 and 2000, whereas it was 9.8% between 2000 and 2006.19 In addition, the risk of colectomy is highest in the first few years after diagnosis,12,18 and studies which have reported lower incidence of colectomy included patients with variable disease severity.

Only 7% of patients hospitalized with UC were prescribed infliximab in hospital because our study period spanned 1996 to 2009. Routine prescription of infliximab in our health region started in 2005. In the overall analysis, patients who received induction infliximab during hospitalization had lower risk of proceeding to colectomy; however, this association lost significance when analysis was restricted to the biological era. In part, the loss of significance was due to reduced small sample size. In addition, in the first few years of infliximab use in hospital, induction dosing with rapid dose escalation to 10 mg/kg and dose optimization following measurement of drug levels were not performed. Other studies demonstrated that early introduction of infliximab in the course of refractory severe UC was associated with a reduction in colectomy rates,19–21 even up to 75% reduction in one study.22 Infliximab was found to be effective in significantly reducing the risk of colectomy.12,19,23–27 Rescue therapy with infliximab has preferential outcome in terms of lower colectomy risk for longer follow up.25 Nonresponders to infliximab rescue therapy, however, were shown to have worse outcomes.28,29

In our study, smoking status did not influence the need for early colectomy. This is in agreement with the findings of the IBSEN study as well as others,30,31 which demonstrated no effect of smoking status on risk of colectomy during the first 10 years of UC diagnosis. On the other hand, several other studies demonstrated that smoking status affects the need for a colectomy32–35 with an increased risk of colectomy in nonsmokers and those who quit smoking before their diagnosis with UC. In part, the inconsistencies may be driven by study design, as our population was focused on those with severe UC early in the course of diagnosis.

This study has some limitations. Firstly, a retrospective chart review cannot adequately control for disease severity. Although we evaluated some indirect proxies of disease severity like anemia and pancolitis, other biomarkers (e.g., C-reactive protein) were not reliably measured in our study population. Nonetheless, by restricting our study population to those who were admitted to hospital early after diagnosis, our patients were universally considered to have severe or fulminant colitis. In addition, less than 10% of our cohort was exposed to infliximab because routine prescription of infliximab in UC started in 2006. Further, Berkson's fallacy may be a source of bias in our study population. Study populations arising from hospitalized patients, rather than the general population, may result in a selection bias that leads to a false negative association between a risk factor and a disease. Therefore, the findings of our study should be generalized to hospitalized patients with severe disease, and not to those with milder disease activity and who did not require hospitalization. Further studies with prospective design should be undertaken to validate the predictive clinical factors.

Among patients hospitalized with UC within 3 years of diagnosis, the need for colectomy is high. Importantly, this risk is decreasing across time. The profile of a patient at a higher risk of early colectomy includes middle-aged men with pancolitis, a finding that clinicians can use for risk stratification at diagnosis of UC. As well, patients from rural areas had higher odds of colectomy. Programs to support patients living in underserviced areas should be evaluated to improve access to specialist care.

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ACKNOWLEDGMENTS

Disclosures: G. G. Kaplan has served as a speaker for Jansen, Merck, Schering-Plough, Abbvie, and UCB Pharma. He has participated in advisory board meetings for Jansen, Abbvie, Merck, Schering-Plough, Shire, and UCB Pharma. G. G. Kaplan has received research support from GlaxoSmith Kline, Abbvie, and Shire. R. Panaccione has served as a speaker, a consultant, and an advisory board member for Abbott Laboratories, Merck, Schering-Plough, Shire, Centocor, Elan Pharmaceuticals, and Procter and Gamble. He has served as a consultant and speaker for Astra Zeneca. He has served as a consultant and an advisory board member for Ferring and UCB. He has served as a consultant for Glaxo-Smith Kline and Bristol Meyers Squibb. He has served as a speaker for Byk Solvay, Axcan, Jansen, and Prometheus. He has received research funding from Merck, Schering-Plough, Abbott Laboratories, Elan Pharmaceuticals, Procter and Gamble, Bristol Meyers Squibb, and Millennium Pharmaceuticals. He has received educational support from Merck, Schering-Plough, Ferring, Axcan, and Jansen. C. H. Seow has served as a speaker for Janssen, Merck, Schering-Plough, and Warner Chilcott. She has participated in advisory board meetings for Janssen, Abbvie, Merck, and Schering-Plough. Y. Leung has served as a speaker for Ferring, Abbvie, Takeda, Jannsen, and Shire. K. Novak has received research support (independent investigator award) from AbbVie, in addition to consultancy and/or speaker fees from Abbvie, Janssen, UCB Canada, Pfizer, Pendopharm, Takeda, and Merck. A. Al-Darmaki, A. Aziz Shaheen, and J. Hubbard have no disclosures.

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Keywords:

ulcerative colitis; colectomy; predicators; inflammatory bowel disease

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