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Total and cancer mortality in a cohort of ulcerative colitis and Crohn's disease patients: The Florence inflammatory bowel disease study, 1978–2010

Digestive and Liver Disease, Volume 48, Issue 10, October 2016, Pages 1162 - 1167

Abstract

Background

There is no consensus on the leading causes of death among inflammatory bowel diseases (IBD) patients.

Aim

We present the results of an extended follow-up of the population-based Florence IBD cohort, including 689 ulcerative colitis and 231 Crohn's disease patients.

Methods

The causes of death of cohort members were determined through linkage with the local mortality registry. We calculated standardized mortality ratios (SMR) and 95% confidence intervals (95%CI) by applying gender-, age- and calendar time–death rates to person-years at risk.

Results

Ulcerative colitis patients had overall mortality comparable to the general population (SMR 0.99, 95%CI 0.85–1.14), though being at increased risk of dying from Hodgkin's disease (SMR 11.74, 95%CI 2.94–46.94), rectal cancer (SMR 3.69, 95%CI 1.66–8.22) and Alzheimer's disease (2.40, 95%CI 1.00–5.76). Crohn's disease patients had an increased overall mortality (SMR 1.79, 95%CI 1.39–2.27) and were at higher risk of dying from cancer (SMR 2.57, 95%CI 1.28–5.13) and non-cancer diseases of the respiratory system (SMR 2.51, 95%CI 1.05–6.04), brain cancer (SMR 6.26, 95%CI 1.57–25.02) and non-cancer diseases of the genitourinary system (SMR 4.38, 95%CI 1.10–17.52).

Conclusions

IBD patients should be offered counselling on risk reduction strategies, as much of their mortality excess is potentially avoidable.

Keywords: Cancer mortality, Crohn's disease, Inflammatory bowel diseases, Ulcerative colitis.

1. Introduction

The inflammatory bowel diseases (IBD) are chronic conditions, with an early onset and a clinical course characterized by a succession of remissions and relapses requiring a strict medical follow-up and long-term treatment. The major types of IBD are ulcerative colitis (UC) and Crohn's disease (CD), which differ in several features including the preferred localization and the nature of inflammatory changes of the bowel wall [1]. The characteristic symptoms and complications of IBD are gastrointestinal in nature; however, IBD patients may also present with extra-intestinal manifestations such as arthritis, pyoderma gangrenosum, primary sclerosing cholangitis, and others [2].

Both UC and CD patients may incur a higher risk of dying compared to the general population following a complicated disease course or because of supervening intestinal and extra-intestinal pathologies, including cancer [3], [4], and [5]. The long-term prognosis and cause-specific mortality of IBD patients have been extensively investigated in studies based on either clinical series followed in referral centres or population-based cohorts. Several studies found a higher than expected mortality among IBD patients [6], [7], [8], [9], and [10]: leading causes of death include those related to the gastrointestinal localization of the disease [9] and [11], cancerous and non-cancerous pathologies of the respiratory system [9], and others. Exceptions exist, however, and other studies found no mortality excess among either UC or CD patients [12], [13], and [14]. In particular, the all-cause mortality appears to be stable over time among CD patients, while a decreasing time trend has been shown among UC patients [15].

We previously reported on mortality patterns in a population-based cohort of 920 patients affected by IBD, the Florence IBD cohort [16]. During a median follow-up of 15 years, the overall mortality and the mortality from cardiovascular diseases and lung cancer were reduced among ulcerative colitis patients. Instead, there was a 50% excess total mortality among Crohn's disease patients, caused by an increased mortality from cancer of lung and gastrointestinal tract and from non-cancerous diseases of the gastrointestinal tract.

Here, we present the results of an extended follow-up aiming at re-evaluating the pattern of cause-specific mortality in the Florence IBD cohort.

2. Materials and methods

The Florence IBD cohort was assembled by including all UC and CD patients aged 15 years or older who were residing in the metropolitan area of Florence (referred to as “catchment area” hereinafter) at any time between January 1st, 1978 and December 31st, 1992 (“recruitment period”) [17]. The cohort includes 780 patients who were firstly diagnosed with IBD during the recruitment period while residing in the catchment area (“incident” cases); 103 patients who had already been diagnosed before January 1st, 1978, and were residing in the catchment area at the beginning of the recruitment period (“prevalent” cases); and 37 patients who had been diagnosed elsewhere and migrated into the catchment area during the recruitment period (“migrating” cases).

The life status and cause of deaths of cohort members were determined through linkage with the Regional Mortality Registry of Tuscany and the civil registry of the municipality of residence. To confirm the cause of death, we retrieved the death certificate of deceased patients whenever possible. Also, we retrieved the clinical records of each colorectal cancer, to establish with certainty their anatomical localization (colon or rectum) and whether any of them was localized on the retained rectum of patients who had undergone subtotal colectomy. To allow a comparison with previously published reports on the same IBD cohort [16], we coded all causes of deaths according to the 9th edition of the International Classification of Diseases (ICD-IX).

We applied the gender-, age group- and calendar time- (5 years intervals) cause-specific death rates to person-years at risk to compute the expected number of overall and cause-specific deaths among UC and CD patients. Person-years at risk were computed from the date of IBD diagnosis (incident patients), January 1st, 1978 (prevalent patients), or date of migration into the catchment area (migrating patients), until the date of death, loss to follow-up or end of follow up (December 31st, 2010), whichever came first. For patients who had undergone a complete resection of colon and/or rectum not subsequent to a cancer at that site, the follow-up period at risk for the calculation of expected deaths from colon and/or rectum cancer was right-censored at the date of surgery.

We calculated standardized mortality ratios (SMRs) as the ratio between observed and expected deaths, and their 95% confidence intervals (95%CI) by assuming a Poisson distribution for deaths occurred during the follow-up period. SMRs were only calculated when there were at least two patients who died from the same cause. All analyses were carried out separately among UC and CD patients and, within each sub-cohort defined by the IBD type, by gender as well.

All analyses were performed with STATA software version 11 (Stata Inc., College Station, TX, USA).

3. Results

Overall, the original cohort included 920 IBD patients, 689 affected by UC (410 men and 279 women) and 231 by CD (114 men and 117 women). Incident, prevalent and migrating patients were, respectively, 780 (84.8% of the study cohort), 103 (11.2%) and 37 (4.0%). The median age at diagnosis of IBD was 40.5 years for UC patients and 33.9 for CD patients.

An overall 20,509 person-years were accrued, with a median follow-up of 22.8 years (range 0.1–33 years). UC patients provided 15,381 person-years (9094 for men and 6287 for women), while CD patients provided 5128 person-years (2550 for men and 2578 for women).

We identified 52 patients (37 UC and 15 CD) for which hospital discharge records documented a resection of the colon (n = 29), the rectum (n = 4), or both (n = 19) not related to a malignancy of the bowel.

Overall, 236 (25.7%) cohort members died during the study period, 13 (1.4%) were lost to follow-up, and 671 (72.9%) were still alive on December 31st, 2010. The most frequent causes of death were malignant neoplasms (ICD-IX code 140-208, 81 deaths) and diseases of the circulatory system (ICD-IX code 390-459, 80 deaths). The cause of death was recorded as “symptoms, signs, and ill-defined conditions” (ICD-IX code 780-799) in five cases. The median age at death was 76 years (range 33–96 years) for UC patients and 69 years (range 28–91 years) for CD patients.

The overall mortality in the cohort of ulcerative colitis patients was as expected (SMR 0.99, 95%CI 0.85–1.14) (Table 1). Among malignancies, we observed a significantly increased risk of dying from rectal cancer (SMR 3.69, 95%CI 1.66–8.22) and, based on two deaths, Hodgkin's disease (SMR 11.74, 95%CI 2.94–46.94). The SMR was also increased for Alzheimer's disease (2.40, 95%CI 1.00–5.76). The SMR for the diseases of the digestive systems was significantly increased (1.98, 95%CI 1.19–3.28) due to IBD-associated mortality: once this excess mortality was removed from the calculation, the SMR dropped to a no longer significant 1.06 (95%CI 0.46–2.09).

Table 1

Overall and cause-specific mortality of a population based cohort of 689 ulcerative colitis patients by major groups of diagnostic categories. The Florence inflammatory bowel disease study, 1978–2010.

 

ICD-IX Cause of deatha Ulcerative colitis (n = 689)
Obs. Exp. SMR Lower 95%CI Upper 95%CI
140–208 Malignant neoplasm 56 61.14 0.92 0.70 1.18
150–159 Digestive organs and peritoneum 21 21.54 0.97 0.62 1.46
151 Stomach 4 5.68 0.70 0.26 1.88
153–154 Colon, rectum and rectosigmoid junction 8 6.02 1.33 0.62 2.52
153 Colon 2 4.40 0.46 0.11 1.82
154 Rectum and rectosigmoid junction 6 1.62 3.69 1.66 8.22
155 Liver and intrahepatic bile ducts 4 4.17 0.96 0.36 2.56
160–165 Respiratory and intrathoracic organs 10 15.90 0.63 0.34 1.17
162 Trachea, bronchus, and lung 10 14.28 0.70 0.38 1.30
174 Female breast 3 2.90 1.04 0.33 3.21
185 Prostate 2 2.81 0.71 0.18 2.84
188 Bladder 2 2.27 0.88 0.22 3.52
191 Brain 2 1.22 1.64 0.41 6.57
200–208 Lymphatic and hematopoietic tissue 8 4.49 1.78 0.89 3.57
200 Lymphosarcoma and reticulosarcoma 3 1.57 1.91 0.62 5.91
201 Hodgkin's disease 2 0.17 11.74 2.94 46.94
 
250 Diabetes mellitus 3 4.36 0.69 0.22 2.13
 
320–389 Diseases of the nervous system and the sense organs 7 4.65 1.51 0.72 3.16
331 Other cerebral degenerations b 5 2.09 2.40 1.00 5.76
332 Parkinson's disease 2 1.03 1.94 0.49 7.76
 
390–459 Diseases of the circulatory system 67 65.41 1.02 0.81 1.30
410–414 Ischaemic heart disease 28 21.69 1.29 0.89 1.87
410 Acute myocardial infarction 14 10.28 1.36 0.81 2.30
414 Other forms of chronic ischaemic heart disease 13 10.98 1.18 0.69 2.04
430–438 Cerebrovascular disease 15 19.88 0.75 0.45 1.25
440–448 Diseases of arteries, arterioles, and capillaries 3 4.60 0.65 0.21 2.02
 
460–519 Diseases of the respiratory system 5 10.91 0.46 0.19 1.10
490–496 Chronic obstructive pulmonary disease and allied conditions 3 5.67 0.53 0.17 1.64
 
520–579 Diseases of the digestive system 15 7.59 1.98 1.19 3.28
555–558 Non-infectious enteritis and colitis 7 0.05 140.72 67.09 295.17
 
780–799 Symptoms, signs, and ill-defined conditionsc 4 1.81 2.20 0.83 5.87
 
800–999 Injury and poisoning 8 8.04 1.00 0.50 1.99
 
001–999 All causes 171 173.19 0.99 0.85 1.14

a The ICD-IX codes of other causes of death not shown in the table are as follows (each one): 038.9 (septicaemia, unspecified), 279.1 (deficiency of cell-mediated immunity), 286.6 (defibrination syndrome), 290.9 (senile psychotic condition, unspecified), 586.0 (renal failure, unspecified), 715.3 (osteoarthritis, localized, not specified whether primary or secondary).

b All deaths in this group were coded as 331.0 according to the ICD-IX, corresponding to Alzheimer's disease.

c The ICD-IX codes for deaths in this group were 786.0 (dyspnoea and respiratory abnormalities), 797.0 (senility without mention of psychosis), and 799.9 (other unknown and unspecified causes; two deaths).Obs., observed cases; Exp., expected cases; SMR, standardized mortality ratio; CI, confidence intervals.

The overall mortality was significantly increased by around 80% among Crohn's disease patients (SMR 1.79, 95%CI 1.39–2.27) (Table 2). A similar increase was seen for the risk of dying from cancer at any site (SMR 1.85, 95%CI 1.22–2.69). In particular, there was an increased risk of dying from cancer of respiratory organs (SMR 2.57, 95%CI 1.28–5.13) and, based on two observed deaths, of brain (SMR 6.26, 95%CI 1.57–25.02). An increase in risk was also observed for the diseases of the respiratory system (SMR 2.51, 95%CI 1.05–6.04) and of the digestive system (SMR 7.75, 95%CI 4.50–13.34). Concerning the latter, the SMR dropped to a no longer significant 1.81 (95%CI 0.37–5.28) after removing the excess diagnosis due to IBD-associated mortality. Finally, there was an increased risk of dying from diseases of the genitourinary system (SMR 4.38, 95%CI 1.10–17.52), based on two observed deaths against 0.46 expected.

Table 2

Overall and cause-specific mortality of a population based cohort of 231 Crohn's disease patients by major groups of diagnostic categories. The Florence inflammatory bowel disease study, 1978–2010.

 

ICD-IX Cause of deatha Crohn's disease (n = 231)
Obs. Exp. SMR Lower 95%CI Upper 95%CI
140–208 Malignant neoplasm 25 13.50 1.85 1.22 2.69
150–159 Malignant neoplasm of digestive organs and peritoneum b 7 4.83 1.45 0.63 2.87
151 Malignant neoplasm of stomach 2 1.18 1.69 0.42 6.76
153–154 Colon, rectum and rectosigmoid junction 2 1.37 1.46 0.24 4.82
160–165 Malignant neoplasm of respiratory and intrathoracic organs 8 3.12 2.57 1.28 5.13
162 Malignant neoplasm of trachea, bronchus, and lung 8 2.80 2.86 1.43 5.72
174 Malignant neoplasm of female breast 2 1.02 1.96 0.49 7.82
191 Malignant neoplasm of brain 2 0.32 6.26 1.57 25.02
 
240–279 Endocrine, nutritional and metabolic diseases, and immunity disorders
250 Diabetes mellitus 2 0.95 2.10 0.52 8.39
 
390–459 Diseases of the circulatory system 13 12.72 1.02 0.59 1.76
410–414 Ischaemic heart disease 4 4.36 0.92 0.34 2.45
410 Acute myocardial infarction 3 2.19 1.37 0.44 4.25
430–438 Cerebrovascular disease 4 3.92 1.02 0.38 2.72
 
460–519 Diseases of the respiratory system 5 1.99 2.51 1.05 6.04
490–496 Chronic obstructive pulmonary disease and allied conditions 2 1.01 1.98 0.50 7.93
 
520–579 Diseases of the digestive systemc 12 1.68 7.15 4.06 12.59
555–558 Non-infectious enteritis and colitis 9 0.02 448.56 205.78 854.25
 
580–629 Diseases of the genitourinary systemd 2 0.46 4.38 1.10 17.52
 
800–999 Injury and poisoning 2 2.00 1.00 0.25 3.99
 
001–999 All causes 65 36.33 1.79 1.39 2.27

a The ICD-IX codes of other causes of death not shown in the table are as follows (each one): 117.3 (aspergillosis), 728.8 (other disorders of muscle, ligament and fascia), 799.1 (respiratory arrest).

b The other malignancies in this group were of the colon, rectum, gallbladder, pancreas and retroperitoneum (one each).

c The ICD-IX codes for the five deaths not coded as regional enteritis were 571.5 (cirrhosis of liver without mention of alcohol; two deaths), and 577.0 (acute pancreatitis).

d The ICD-IX codes for deaths in this group were 586.0 (renal failure, unspecified) and 593.9 (unspecified disorder of kidney and ureter).Obs., observed cases; Exp., expected cases; SMR, standardized mortality ratio; CI, confidence intervals.

Among ulcerative colitis patients, all deaths from malignant neoplasm of lymphatic and hematopoietic tissue were among males (SMR 2.65, 95%CI 1.33–5.30). Instead, the mortality from Alzheimer's disease was higher than expected among females (4 cases vs. 1.08 expected, SMR 3.70, 95%CI 1.39–9.85) but not among males (1 case vs. 1.00 expected). Among Crohn's disease patients, the increase in mortality from lung cancer and non-cancerous diseases of the respiratory system was significant only among females. This, in turn, caused the SMR for overall mortality being higher among females (2.17, 95%CI 1.57–3.00) than males (1.45, 95%CI 1.00–2.10).

4. Discussion

We reported the results of an extended vital status follow-up (median duration 23 years) among a population-based series of 689 patients affected with ulcerative colitis and 231 patients affected with Crohn's disease in Florence, Italy. Ulcerative colitis patients had mortality comparable to that of the general population, though being at increased risk of dying from Hogdkin's disease, cancer of the rectum and Alzheimer's disease, in addition to UC-related mortality. Instead, Crohn's disease patients had an increased overall mortality compared to the general population and were at higher risk of dying from cancerous and non-cancerous diseases of the respiratory system, cancer of the brain and non-cancerous diseases of the genitourinary system, in addition to CD-related mortality.

Most papers that investigated the causes of death among ulcerative colitis patients agree that the overall mortality does not significantly differ from that of the general population, but are rather heterogeneous for what concerns cause-specific mortality [11], [18], [19], and [20]. This may due to multiple causes, including differences in the way the study sample is assembled (referral centre- vs. population-based cohorts), varying duration of follow-up (some risks may emerge only after a longer latency), a different distribution of known risk factors for individual causes of death, more or less spread use of immunomodulatory drugs in the treatment of ulcerative colitis, and others.

The increased mortality from Hodgkin's disease among UC patients is consistent with our previous paper on cancer incidence in the same cohort [21]. We found no excess in colorectal cancer mortality in our latest report [16]; however, the increase in mortality from rectal cancer became statistically significant here, with the median follow-up time extended to over 20 years. Earlier investigations on the incidence of colorectal cancer among IBD patients, which were mainly based on patients followed up in tertiary referral centres, reported very high risks compared to the general population [22]. More recent population-based cohort studies consistently showed that these risks were not as high as believed before [3]. In order to strengthen the reliability of our finding, we retrieved and carefully checked the clinical records of each colorectal cancer in our cohort, especially with regard with its localization, UC patients have been reported to be at increased risk of cancer of the retained rectum [23]; however, only one rectal cancer case in our cohort occurred among patients who had previously undergone colectomy with ileorectal anastomosis. Ulcerative colitis usually begins in the rectum and then extends proximally, in a subset of patients, to progressively involve the entire colon. Our findings corroborate the opinion that cancers of the intestinal tract tend to occur after several years upon IBD diagnosis in areas of active disease [24] and [25], and that a sufficiently long follow-up time is therefore required before the increase in mortality becomes apparent, also considering the effect of therapies that have been hypothesized to have the potential to reduce the risk of colorectal cancer, like those based on butyrate [26] or 5-aminosalicylate [27]. In particular, the oral administration of 5-aminosalicylate creates a concentration gradient that decreases distally, with low concentration in the rectum unless patients receive a topical treatment as well [28]. However, 5-aminosalicylate enemas are generally not well accepted by UC patients, so it is possible that the mortality excess from rectal but not colon cancer in our case series is caused by a relative lack of protection in the rectum compared to the colon. If this was true, our results would reinforce the recommendation to treat these patients with oral plus topical 5-aminosalicylate instead of oral treatment only.

To our knowledge, this is the first report of an increased risk of Alzheimer's disease among female UC patients. There exists some evidence of a genetic susceptibility common to the two diseases: carriers of the A allele in the -1082 G/A polymorphism of the interleukin-10 gene are at increased risk of UC (only among women: [29]) and Alzheimer's disease [30]. Dietary habits may explain this finding as well: patients with ulcerative colitis tend to replace the intake of carbohydrates and fibre with fat and proteins in order to relieve symptoms [31], and there is growing evidence that this dietary pattern may increase the risk of cognitive impairment and Alzheimer's disease [32] and [33]. In addition, alcohol consumption has been reported to be associated with the risk of both ulcerative colitis [34] and [35] and Alzheimer's disease [36] and [37]. Blood levels of fetuin-A, a glycoprotein involved in insulin resistance, inflammation and atherogenesis, are decreased among IBD patients [38] and inversely correlated with cognitive decline in patients with Alzheimer's disease [39] and [40]. Overall, more research is needed to confirm the association between ulcerative colitis and Alzheimer's disease and identify the underlying mechanisms.

Despite a substantial heterogeneity in terms of specific causes of deaths, most studies consistently found that Crohn's disease patients present an overall mortality excess compared to the general population [6], [7], [9], and [41]. As in our previous report [16], we found that Crohn's disease patients have an increased overall and cancer mortality and an increased risk of dying from diseases of the respiratory system compared to the general population. A likely explanation of this finding is the high prevalence of smoking among these patients [42]. In the Florence IBD cohort, information on smoking habits is not available for all cohort members. However, we previously found that the proportion of smoking at IBD diagnosis was much higher among CD vs. UC patients who had died at the time of the last follow-up [15]. Several other authors confirmed this finding by reporting a much higher prevalence of smoking among CD vs. UC patients [43] and [44]. It is however unclear why we did not observe a comparable increase in risk of other smoking-correlated malignancies, including rectal cancer: in fact, smoking has been reported as a risk factor for colorectal cancer among CD patients [45], while it may be paradoxically protective among UC patients [46], possibly by reducing the proximal extension of the disease [47]. We also found an increased mortality from brain tumour and non-cancerous diseases of the genitourinary system: while the interpretation of these findings is uncertain, both SMR were based on two observed deaths only, so we can not rule out chance as a possible explanation.

The strengths of our study reside in its being based on a population-based cohort of IBD patients prospectively followed-up for a median of nearly twenty-three years and with a negligible proportion of cohort members lost to follow-up. This cohort is highly representative of the population of IBD patients in the catchment area [48], which adds to the reliability of our findings. Our study has some limitations as well. Some of the significant cause-specific SMRs are based on a limited number of deaths (only two for Hodgkin's disease among UC patients and brain cancer among CD patients), so we cannot exclude chance as an explanation of these findings. We have no information on the severity of disease (extension of colonic involvement and extra-intestinal manifestations of disease). We have no information either on the therapy administered to each of these patients; however, we know that most of them were routinely treated with oral mesalazine, while the use of enema mesalazine and immunomodulatory therapy was uncommon. Several studies have reported an inverse association between mesalazine use and the development of dysplasia and colorectal cancer among IBD patients [49] and [50], which may mitigate or even neutralize the increase in risk related to the underlying disease, but we were unable to assess whether this happened in our cohort as well. Finally, we have no information of any malignancies that might have been diagnosed among “prevalent” patients before January 1st, 1978, or among “migrating” patients before they migrated into the catchment area. However, the SMRs obtained among “incident” patients did not significantly differ from those for the whole cohort (Supplementary table), so this is unlikely to have substantially biased our results.

In conclusion, much of the mortality excess among these patients is potentially avoidable; therefore IBD patients should be offered counselling on how to prevent those diseases for which they are at increased risk. Patients with ulcerative colitis should be carefully monitored for the occurrence of cancer of the bowel, particularly in the areas of most intense disease activity and increasingly with time. A tailored dietary counselling seems appropriate for these patients as well, to help prevent the long-term risks of a poorly balanced diet. Concerning Crohn's disease patient, we renew the recommendation to advise them about the need to stop smoking, as smoking may have detrimental effect on the course of the disease [51] and [52] and is responsible for much of the mortality excess among these patients.

Conflict of interest

None declared.

Acknowledgments

We acknowledge Donatella Zagni (registered nurse) for her support in retrieving death certificates, and Lucia Giovannetti (MD) for helping in the interpretation of results.

Appendix A. Supplementary data

The following are the supplementary data to this article:

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Footnotes

a Cancer Risk Factors and Lifestyle Epidemiology, Cancer Research and Prevention Institute (ISPO), Florence, Italy

b Emergency Department, Gastroenterology, SOD2, AOU Careggi, Florence, Italy

Corresponding author at: Cancer Risk Factors and Lifestyle Epidemiology, Cancer Research and Prevention Institute (ISPO), Via delle Oblate 2, 50141 Florence, Italy. Fax: +39 0557972588.