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Survival and causes of death in patients with inflammatory bowel disease: A population-based study
GASTROENTEROLOGY
1992;103:954-960
Survival and Causes of Death in Patients With Inflammatory Bowel Disease: A PopulationBased Study ANDERS EKBOM, LARS HOLMBERG,
CHARLES G. HELMICK, MATTHEW and HANS-OLOV ADAM1
ZACK,
Cancer Epidemiology
Unit, University Hospital, Uppsala, Sweden; and Division of Chronic Disease Control and Community Intervention, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control, Atlanta, Georgia
Relative survival up to December 31,1986was analyzed for all patients diagnosed with ulcerative colitis (UC) (n = 2,509) and Crohn’s disease (CD) (n = 1,469) within the Uppsala Region, Sweden 19651983. After 10 years survival was 96% of that expected for UC and CD. Patients with ulcerative proctitis, left-sided colitis, and pancolitis at diagnosis had relative survival rates of 98%, 96%, and 93% respectively. Survival did not differ by extent at diagnosis for patients with CD. After including prevalent cases, 684 deaths occurred compared with 481.1 expected deaths [standardized mortality ratio (SMR) = 1.4; 95% confidence interval (CI) = 1.3-1.51. Inflammatory bowel disease was the main reason for this excess mortality. Colorectal cancer increased mortality (50 deaths observed vs. 15.2 expected). Death from other cancers were not greater than expected. Obstructive respiratory diseases, especially bronchitis, emphysema, and asthma increased mortality SMR = 1.5, (95% CI = 1.1-2.2) in UC. Cerebrovascular disease mortality occurred less often than expected (SMR = 0.7; 95% CI = 0.51.0). Mortality for other diseases and groups of diseases was close to that expected.
The excess mortality rate in patients with IBD relative to the general population has been mostly attributed to the IBD itself.‘7~20-22However, a very broad spectrum of extraintestinal diseases has been associated with either UC or CD.23 Therefore, the possible impact of associated diseases on excess mortality in patients with IBD deserves study. The aims of the present study are to estimate relative survival of a population-based cohort of patients with IBD, to study if the relative survival has changed over time, and to look for differences in cause of death compared with the general population. Material and Methods The Cohort
The Uppsala Health Care Region in central Sweden had a population of 1.2 million in 1965 and 1.3 million in 1983. All patients diagnosed as having IBD from 1965 through 1983 in the Region, 3978 incident cases, were identified as previously describede6 Using the same casefinding methods, we were also able to identify 800 patients diagnosed before 1965 and resident in the Region on January 1, 1965. All 800 of these prevalent cases had had at least one consultation or one period of inpatient care due ost epidemiological studies of inflammatory to the IBD from 1965 through 1983. Only two patients bowel disease (IBD) in Northern America and (0.04%) were lost to follow-up leaving 4776 individuals western Europe indicate an increase in the annual available for follow-up. incidence of both ulcerative colitis (UC) and Crohn’s Three thousand, one hundred twenty-one patients had disease (CD) until the beginning of the 1970s.'-'2 UC and 1655 had CD. Patients with UC were classified at Since then the incidence for both diseases seems to diagnosis as having either proctitis, left-sided colitis (inhave stabilized or decreased. However, mortality volvement up to the hepatic flexure), or pancolitis. Patients with CD were classified at diagnosis as having disrates for UC since the 1950s and for CD since the ease confined to the terminal ileum, confined to the colon, middle of the 1970s have decreased.13 These trends including both terminal ileum and colon, or other have been interpreted as resulting from better medi(Table 1). cal care or to a change in the natural history of the
M
two diseases.14 Only a few studies have compared survival among patients with either CD or UC over different time periods.+”
0 1992 by the American Gastroenterological 0016-5065/92/$3.00
Association
SURVIVAL AND CAUSES OF DEATH IN IBD
September 1992
ofPatients in the Cohort of Patients With IBD by Period of Diagnosis and Type and Extent of Disease at Diagnosis
Table 1. Number
Diagnosed
Diagnosed
All
before 1965 (prevalent cases)
1965-1983 (incident cases)
diagnosed cases
613 304
2508 743
3121 1047
209 100 186
700 1065 1469
909 1165 1655
72
543
615
Other
49 40 25
376 366 184
425 406 209
All IBD
799
3977
4776
UC Pancolitis Left-sided colitis Proctitis CD Terminal ileum Ileum and colon
Colon
Follow-up All Swedish citizens are individually identifiable by a lo-digit national registration number (NRN).24 The NRN was used to follow up the study subjects by record linkage to the Registry of Causes of Death (at Statistics Sweden). This Registry includes all deceased persons, whether they died in Sweden or abroad. The primary underlying cause of death is determined from data on medical death certificates using the International Classification of Diseases 7th version (ICD-7) codes before 1969 and ICD8 codes thereafter.
Statistical
Measures and Methods
Relative survival rates were calculated only for the 3978 incident cases as the ratios of observed to expected survival rates in the general population. Expected rates were calculated with respect to 5-year age group, gender, and calendar year of observation.” To determine if the relative survival had improved, the cohort was divided into those diagnosed from 1965 through 1974 and those diagnosed from 1975 through 1983. The computation of person-years at risk started at the time of diagnosis of IBD or in January 1965 (prevalent cases). Each cohort member was followed up either to the date of death or to the closing date of follow-up (December 31, 1986). Official statistics from the Swedish Death Registry included annual sex- and age-specific incident rates for different ICD-codes for entire Sweden. Multiplication of the number of person-years at risk by 5-year age group, gender, and calendar year by the corresponding age, gender, and year-specific mortality rates yielded the number of expected cases. The standardized mortality ratio (SMR), the ratio of observed to expected number of deaths, was used as a measure of risk. The 95% confidence interval (CI) of the SMR was then calculated on the assumption
955
that the observed number of deaths in each group followed a Poisson distribution. Prevalent and incident cases were initially analyzed separately. Because the SMR’s of different diseases or groups of diseases for prevalent cases did not differ from those for incident cases, incident and prevalent cases were pooled.
Results Survival Overall, the rate of death was slightly higher in patients with UC than in the general population as indicated by a lo-year relative survival rate of 95.9% (95% CI 94.3-97.5) (Figure 1). Patients with ulcerative proctitis, however, did not have a significantly decreased survival 10 years after diagnosis, 97.9% (95% CI 95.2-100.0). On the other hand those with pancolitis at diagnosis had a worse prognosis than left-sided colitis, 92.8% (95% CI 89.8-95.5) and 96.0% (95% CI 93.0-99.0) 10 years after diagnosis, respectively (Figure 1). The survival prospects were similar in patients diagnosed with proctitis or left-sided colitis 1965 through 1974 and those diagnosed from 1975 through 1983. However, in patients with pancolitis at diagnosis, the relative survival was slightly but not significantly higher among those diagnosed later than those diagnosed earlier, especially during the first 2 years after diagnosis (Figure 2). In CD the survival was also significantly lower than expected, relative survival being 96.0% (95% CI 94.3-97.9) ten years after diagnosis. The survival did not differ by extent of disease at diagnosis (Figure 3). As in UC there was no evidence that survival improved over time (Figure 4). Causes
the
of Death
Six hundred whole cohort,
eighty-four compared
deaths occurred in to 481.1 expected
O.9OJ 5
10 Yews
15
20
of follow-up
Figure 1. Relative survival in patients with UC by extent at diagnosis. p, UC all cases; - - -, proctitis; -a -, left-sided colitis: -, pancolitis.
956
GASTROENTEROLOGY Vol. 103, No. 3
EKBOM ET AL.
0.90
0.9oJ. 5
5
10
10
Years of follow-up
Years of follow-up
Figure 2. Relative survival in patients with pancolitis at diagnosis from 1965 through 1974 (- -) and from 1975 through 1983 (-).
(SMR = 1.4, 95% CI 1.3-1.5; Table 2). The standardized mortality ratio was significantly increased for those with UC (SMR = 1.4, 95% CI 1.2-1.5) or CD (SMR = 1.6, 95% CI 1.4-1.9) but not for those with ulcerative proctitis (SMR = 1.0, 95% CI 0.9-1.2). In the whole cohort 159 deaths resulted from IBD according to the death certificate occurring mainly during the first 2 years after diagnosis. After these deaths were excluded, the observed number of deaths was about the same as that expected (SMR = 1.1; 95% CI 1.0-1.2). However, mortality from colorectal cancer, respiratory diseases, and gastrointestinal diseases (other than IBD) was significantly greater than expected (Table 3). Major causes of death in the cohort such as cancer, cardiovascular diseases, and accidents and violence did not occur more often than expected. In patients with UC, deaths from bronchitis and emphysema (SMR = 2.6, 95% CI = 1.3-4.6) and for asthma (SMR = 3.3,95% CI = 1.2-7.3) occurred more often than expected. For gastrointestinal diseases,
Figure 4. Relative survival in patients with CD at diagnosis from 1965 through 1974 (- -_) and from 1975 through 1983 (-).
other than IBD, only diseases of the liver not related to alcohol use (IBD: SMR = 3.7,95% CI = 2.0-6.2; UC: SMR = 3.9, 95% CI = 2.0-7.0; CD: SMR = 3.0, 95% CI = O.6-8.8), and diseases of gallbladder and biliary ducts (SMR = 3.0, 95% CI = 1.1-6.5) had a significantly increased SMR. Mortality from cerebrovascular diseases, standardized mortality ratio, is significantly decreased, especially in those with UC (SMR = 0.7; 95% CI = 0.41.0). Suicides occurred slightly less often than expected (SMR = 0.9; 95% CI limit 0.4-1.5) for CD and UC. Discussion We found with the exception for ulcerative proctitis a modestly excess mortality for both UC and CD most evident the first few years after diagnosis, with no significant difference between those diagnosed from 1965 through 1974 and those diagnosed from 1975 through 1983. The main reason for this early excess mortality was death from IBD, but mortality due to colorectal cancer, respiratory diseases, and other gastrointestinal diseases was also increased in the cohort.
Table 2. Deaths From AI1 Causes by Kind of IBD
10
5
15
20
Years of follow-up
Figure 3. Relative survival in patients with CD by extent at diagnosis. -, CD all cases; - --, terminal ileum and part of colon; -
-,
terminal
ileum; -.
-, confined to colon.
SMR
95% confidence interval
684
1.4
UC
505
1.4
1.2-1.5"
Proctitis Left-sided colitis Pancolitis CD
133
1.0
0.9-1.2
165 207 179
1.2 1.9
1.7-2.2"
1.6
1.4-1.9"
IBD 0.90;1
Number of deaths
‘95% confidence
interval excludes
1.0.
1.3-1.5"
1.0-1.4"
September
Table
SURVIVAL AND CAUSES OF DEATH IN IBD
1992
3. SMR by Different
Groups
957
of Diseases IBD
Cancer (excluding colorectal) ICD-7 140-209 ICD-8 140-239 n/SMR Colorectal cancer ICD-7 153-154 ICD-8 153-154 n/SMR Cardiovascular diseases ICD-7 400-468 ICD-8 390-458 n/SMR Ischemic heart disease ICD-7 420 ICD-8410-414 n/SMR Cerebrovascular diseases ICD-7 330-334 ICD-8 430-438 n/SMR Respiratory diseases ICD-7 470-527 ICD-8 480-519 n/SMR Bronchitis and emphysema ICD-7 500-502 ICD-8 490-492 n/SMR Asthma ICD-7 241 ICD-8 493 n/SMR Gastrointestinal diseases (excluding IBD-diagnosis) ICD-7 530-587 ICD-8 520-577 n/SMR Non-alcohol related diseases of the liver ICD-7 580-583 (excluding 5811) ICD-8 570-573 (excluding 5170) n/SMR Diseases of gallbladder and biliary ducts IDC-7 584-586 ICD-8 574-576 n/SMR Genitourinary tract ICD-7 590-637 ICD-8 580-629 n/SMR Accidents and violence ICD-7 800-999 ICD-8 800-999 n/SMR Suicide ICD-7 E970-E979 ICD-8 E950-E959 n/SMR
CD
UC
24/0.9(0.8-1.3)
64/1.0(0.7-1.5)
5/1.7(0.5-3.9)
45/4.4(3.2-5.9y
241/1.0(0.9-1.1)
59/1.1(0.9-1.4)
182/0.9(0.8-1.1)
156/1.0(0.8-1.1)
37/1.1(0.8-1.5)
119/0.9(0.8-1.1)
32/0.7(0.5-1.0)
8/0.8(0.3-1.5)
24,'0.7 (0.4-1.0)
36/1.4(1.0-1.9)"
4/0.7(0.2-1.8)
32/1.5(1.1-2.2)
12/2.0(1.1-3.6)"
O/O.0(0.0-2.8)
12/2.6(1.3-4.6)"
6/2.4(0.9-5.2)
o/o.0[O.O-5.3)
6/3.3(1.2-7.3)
42/2.4(1.7-3.31a
11/2.6(1.3-4.7)
31/2.4(1.6-3.4)
14/3.7(2.0-6.2)
3/3.0(0.6-8.8)
11/3.9(2.0-7.0)
6/3.0(1.1-6.5)
2/5.0(0.6-18.0)
4/2.5(0.7-6.4)
11/1.5(0.7-2.7)
5/3.1(1.0-7.3)
6/1.0(0.4-2.3)
33/0.8(0.6-1.1)
14/1.1(0.6-1.8)
19/0.7(0.4-1.1)
12/0.9(0.4-1.5)
3/0.7(0.1-1.9)
9/1.0(0.4-1.8)
88/0.9(0.7-1.2)
50/3.8(2.8-5.0)"
NOTE. SMR did not differ significantly from 1.0for the major ICD categories: allergic, nutritional, hormonal, and metabolic disorders; hematopoietic diseases; psychiatric diseases; nervous system diseases: cutaneous diseases; muscle and bone disorders; and symptom unknown. n, number of deaths. “95% confidence interval excluding 1.0 (P i 0.05).
958
EKBOM ET AL.
Surveillance bias resulting in more reliable classification of causes of death because of more regular contanct with the health care system would not affect estimates of relative survival or overall mortality, but could affect mortality ratio for specific diseases, especially those known to be associated with IBD. On the other hand, patients might have UC or CD recorded even when another diagnosis might have been more appropriate. However, in that case deaths due to vague causes such as unspecified cancer and unspecified heart diseases should be less frequent than the background population; this was not observed. The modestly decreased relative survival for UC and CD occurring in the first few years after diagnosis agrees with the findings of other, mostly population-based, studies.8~g~2”-30 In contrast, a substantially decreased relative survival has been reported mainly from referral centers, which may treat sicker patients. 15.16,16,22,31-33 We found no substantial improvement in survival from 1965 to 1974 and from 1975 to 1983. However, overall mortality in IBD in western Europe and the United States has decreased since the beginning of the 1970s.13 Although improvement in treatment may explain this decrease, our results seem to imply another explanation: unchanged survival with a decreased annual incidence of IBD agrees with most incidence studies from this period. This means that it might be possible to monitor trends in incidence over time through mortality figures for extensive UC and CD but not for ulcerative proctitis. Next to death from IBD, colorectal cancer was the cause whose relative excess mortality differed most from the background population, and persisted throughout the period especially in patients with UC.34,35 Mortality from other cancers did not differ from that in the background population.36 The most common cause of death was cardiovascular disease, though the observed number of deaths was very close to that expected. Although several cardiovascular complications have been reported in IBD,37-47 our results indicate that cardiovascular complications do not increase mortality among patients with IBD. The lower than expected mortality from cerebrovascular diseases in UC in this study has never been reported before. On the contrary, a selected sample has implicated cerebrovascular disease as a complication in UC.48 Chance, improved surveillance, early treatment of risk factors for cerebrovascular diseases (for example, hypertension), medication such as salicylates, or a protective effect of IBD could explain our results. The significant excess mortality from respiratory
GASTROENTEROLOGY Vol. 103, No. 3
diseases in patients with UC primarily due to bronchitis, emphysema, and asthma confirms reports of pulmonary involvement in UC.4g-53The excess number of deaths from emphysema and brochitis, both related to smoking, seems paradoxical because fewer current smokers than expected have been found among patients with UC.54 These latter findings have been interpreted as a protective effect of smoking, but no reasonable biological mechanism has been identified. However, another feasible explanation could be that lung disorders are more frequently associated with UC than previously thought making patients with UC unable to smoke. Patients with IBD have a high frequency of hepatobiliary complications.55 Therefore, the fourfold increased mortality in such diseases is not surprising and validates to a certain extent our mortality data. No other disease or group of diseases within the gastrointestinal tract has any significant excess mortality. Previously reported associations between IBD and other gastrointestinal diseases such as pancreatitis 56,57or cholethiasis5’ therefore apparently have only minimal impact on mortality in this cohort. Our results do not confirm reports of an excess number of suicides among patients with IBDg*22*27 but agree with another population-based study from Copenhagen where no difference from the general population in the incidence of mental disorders and intake of alcohol and psychopharmaceutical drugs was found.5g We conclude that relative survival is decreased slightly, in extensive UC and CD, and that the only excess mortality is directly related to the IBD itself, colorectal cancer, respiratory disease, and liver diseases unrelated to alcohol use. References 1.
2.
3.
4.
5.
6.
Berner J, Kiaer T. Ulcerative colitis and Crohn’s disease on the Faroe Islands 1964-83. Stand J Gastroenterol 1986;21:188192. Binder V, Both H, Hansen PK, Hendriksen C, Kreiner S, TorpPedersen K. Incidence and prevalence of ulcerative colitis and Crohn’s disease in the County of Copenhagen 1962-1978. Gastroenterology 1982;83:563-568. Brahme F, Lindstrom C, Wenckert A. Crohn’s disease in a defined population, An epidemiological study of incidence, prevalence, mortality, and secular trends in the city of Malmii. Gastroenterology 1975;69:342-351. von Brandes JW, Lorenz-Myer H. Epidemiologische Aspecte zur Enterocolitis regionalis Crohn und Colitis ulceroca in Marburg Lahn zwischen 1962 und 1975. Z Gastroenterol 1983;21:69-78. Calkins BM, Lilienfeld AM, Garland CF. Mendeloff AI. Trend in incidence rates of ulcerative colitis and Crohn’s disease. Dig Dis Sci 1984:29:913-920. Ekbom A, Helmick C, Zack M, Adami HO. The epidemiology of inflammatory bowel disease: A large, population-based study in Sweden. Gastroenterology 1991;100:350-358.
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1992
7. Evans JG, Acheson D. An epidemiological study of ulcerative colitis and regional enteritis in the Oxford area. Gut 1965;6:311-324. 8. Gollop JH, Phillips SF, Melton III LJ, Zinsmeister AR. Epidemiologic aspects of Crohn’s disease: a population-based study in Olmsted County, Minnesota, 1943-1982. Gut 1988;29:49-56. 9. Hellers G. Crohn’s disease in Stockholm County, 1955-1974. Acta Chir Stand 1979;49O(Suppl):l-84. 10. Kyle J, Stark G. Fall in the incidence of Crohn’s disease. Gut 1980;21:340-343. 11. Lee FI. Costello FT. Crohn’s disease in Blackpool-incidence and prevalence 1968-80. Gut 1985;26:274-278. 12. Stonnington CM, Phillips SF, Melton III LJ, Zinsmeister AR. Chronic ulcerative colitis: incidence and prevalence in a community. Gut 1987;28:402-409. 13. Sonnenberg A. Mortality from Crohn’s disease and ulcerative colitis in England-Wales and the U.S. from 1950 to 1983. Dis Colon Rectum 1986;29:624-629. 14. Softley A, Clamp SE, Watkinson G, Boucher IAD, Myren J, De Dombal FT. The natural history of inflammatory bowel disease: Has there been a change in the last 20 years? Stand J Gastroenterol 1988;23(Suppl 144):20-23. 15. Edwards FC, Truelove SC. The course and prognosis of ulcerative colitis. Gut 1963;4:299-315. 16. Weedon DD, Shorter RG, Ilstrup DM, Huizenga KA, Taylor WF. Crohn’s disease and cancer. N Engl J Med 1973;289:10991102. 17. Weterman IT, Biemond I, Pena AS. Mortality and causes of death in Crohn’s disease. Review of 50 years’ experience in Leiden University Hospital. Gut 1990;31:1387-1390. 18. Devroede GJ, Taylor WF, Sauer WG, Jackman RJ, Stickler GB. Cancer risk and life expectancy of children with ulcerative colitis. New Engl J Med 1971;285:17-21. 19 Mayberry JF, Newcombe RG, Rhodes J. Mortality in Crohn’s disease. Q J Med 1980;193:63-68. 20 Allan R, Steinberg DM, Alexander Williams J, Cooke WT. Crohn’s disease involving the colon: an audit of clinical management. Gastroenterology 1977;73:723-732. 21 Nefzger MD, Acheson ED. Ulcerative colitis in the United States Army in 1944. Gut 1963;4:183-192. 22. Prior P, Gyde S, Cooke WT, Waterhouse JAH, Allan RN. Mortality in Crohn’s disease. Gastroenterology 1981;80:307-312. manifestations of idiopathic inflam23. Danzi JT. Extraintestinal matory bowel disease. Arch Intern Med 1988;148:297-302. 24 Lunde AS. The person number system of Sweden, Norway, Denmark, and Israel. Washington, DC: US Government Printing Office, 1980. (Vital and health statistics. Series 2: Data evaluation and methods research, no. 84) [DHHS publication no. (PHS) 80-13581. 25. Hakulinen T, Abeywickrama KH. A computer program package for relative survival analysis. Comput Programs Biomed 1985;19:197-207, 26. Binder V, Hendriksen C, Kreiner S. Prognosis in Crohn’s disease-based on results from a regional patient group from the county of Copenhagen. Gut 1985;26:146-150. 27. Brostrom 0, Monsen U, Nordenwall B, Sorstad J, Hellers G. Prognosis and mortality of ulcerative colitis in Stockholm County, 1955-1979. Stand J Gastroenterol 1987;22:907-913. 28. Hendriksen C, Kreiner S, Binder V. Long term prognosis in ulcerative colitis-based on results from a regional patient group from the county of Copenhagen. Gut 1985;26:158-163. 29. Sinclair TS, Brunt PW, Mowat NAG. Nonspecific proctocolitis in northeastern Scotland: A community study. Gastroenterology 1983;85:1-11. 30. Stonnington CM, Phillips SF, Zinsmeister AR, Melton III LJ. Prognosis of chronic ulcerative colitis in a community. Gut 1987;28:1261-1266,
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31 Lind E, Fausa
Treatment
0, Gjone E, Mogensen SB. Crohn’s disease. and outcome. Stand J Gastroenterol1985;20:1014-
1018. 32 Storgaard
33 34
35
36
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L, Bischoff N, Henriksen FW, Fischerman K, Jarnum S. Survival rate in Crohn’s disease and ulcerative colitis. Stand J Gastroenterol 1979;14:225-230. Truelove SC, Pena AS. Course and prognosis of Crohn’s disease. Gut 1976;17:192-201. Ekbom A, Helmick C, Zack M, Adami HO. Increased risk of large bowel cancer in Crohn’s disease with colonic involvement. Lancet 1990;336:357-359. Ekbom A. Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 1990:323:1228-1233. Ekbom A, Helmick C, Zack M, Adami HO. Extracolonic malignancies in inflammatory bowel disease. Cancer 1991; 67:2015-2019. Maccini DM, Berg JC, Bell GA. Budd-Chiari syndrome and Crohn’s disease. An unreported association. Dig Dis Sci
1989;34:1933-1936. RA, Goodfield 38 Sheehan-Dare
MJD, Wilson PD, Rowe11 NR. Axillary artery occlusion as a presenting feature of Crohn’s disease. Postgrad Med J 1989;65:758-760. 39 Sakhuja V, Gupta KL, Bhasin DK, Malik N, Chungh KS. Takayasu’s arteritis associated with idiopathic ulcerative colitis. Gut 1990;31:831-833. 40. Wyshock E, Caldwell M, Crowley JP. Deep venous thrombosis, inflammatory bowel disease and protein s deficiency. Am J Clin Path01 1988;90:633-635. 41. Prior A, Strang FA, Whorwell PJ. Internal carotid artery occlusion in association with Crohn’s disease. Dig Dis Sci 1987;32:1047-1050. 42. Talbot RW, Heppell J, Dozois RR, Beart RW. Vascular compli-
cations
of inflammatory
bowel
disease.
Mayo Clin Proc
1986;61:140-145. 43. Gould L, Pate1 C, Betzu R, Din I. Pericarditis
and ulcerative colitis. Am Heart J 1986;802-803. 44. McKeon J, Haagsma B, Bett JHN. Boyle CM. Fatal giant cell myocarditis after colectomy for ulcerative colitis. Am Heart J 1986;1208-1209. 45. Goodman MJ, Moir DJ. Holt JM, Truelove SC. Pericarditis associated with ulcerative colitis and Crohn’s disease. Dig Dis
1976;21:98-102. 46. Frid C, Bjarke B, Eriksson
inflammatory
M. Myocarditis in children bowel disease. J Pediatr Gastroenterol
1986;5:964-965. 47. Mihas AA, Dasher CA. Pericarditis
with Nutr
associated with granulomatous colitis. Am J Gastroenterol 1977;68:494-497. 48. Johns DR. Cerebrovascular complications of inflammatory bowel disease. Am J Gastroenterol 1991;86:367-370. 49. Gionchetti P, Schiavina M, Campieri M, Fabiani A, Cornia BM, Belluzzi A, et al. Bronchopulmonary involvement in ulcerative colitis. J Clin Gastroenterol 1990;12:647-650, 50. Collins WJ, Bendig DW, Taylor WF. Pulmonary vasculitis complicating childhood ulcerative colitis. Gastroenterology 1979;77:1091-1093. 51. Monsen U, Sorstad J, Hellers G, Johansson C. Extracolonic diagnoses in ulcerative colitis: An epidemiological study. Am J Gastroenterol 1990;85:711-716, 52. Moles KW, Varghese G, Hayes JR. Pulmonary involvement in ulcerative colitis. Br J Dis Ches 1988;82:79-83. 53. Hammer B, Ashurst P, Naish J. Diseases associated with ulcerative colitis and Crohn’s disease. Gut 1968;9:17-21. 54. Calkins BM. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci 1989;34:1841-1854, 55. Wewer V. Gluud C, Schlichting P, Burcharth F, Binder V.
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Prevalence of hepatobiliary dysfunction in a regional group of patients with chronic inflammatory bowel disease. Stand J Gastroenterol 1991;26:97-102. 56. Matsumoto T, Matsui T, Iida M, Nunoi K, Fujishima M. Acute pancreatitis as a complication of Crohn’s disease. Am J Gastroenterol 1989;84:804-807. 57. Niemela S, Lehtola J, Karttunen T, Lahde S. Pancreatitis in patients with chronic inflammatory bowel disease. Hepatogastroenterology 1989;36:175-177. 58. Kangas E, Lehmusto P, Matikainen M. Gallstones in Crohn’s disease. Hepatogastroenterology 1990;37:83-84.
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59. Hendriksen C, Binder V. Social prognosis in patients with ulcerative colitis. BMJ 1980;281:581-583. Received December 9, 1991. Accepted March 31, 1992. Address requests for reprints to: Anders Ekbom, M.D., Cancer Epidemiology Unit, University Hospital, S-751 85 Uppsala, Sweden. Supported by grants from Crohn’s and Colitis Foundation of America. The authors thank Dr. Richard Rothenberg for valuable support.
1992;103:954-960
Survival and Causes of Death in Patients With Inflammatory Bowel Disease: A PopulationBased Study ANDERS EKBOM, LARS HOLMBERG,
CHARLES G. HELMICK, MATTHEW and HANS-OLOV ADAM1
ZACK,
Cancer Epidemiology
Unit, University Hospital, Uppsala, Sweden; and Division of Chronic Disease Control and Community Intervention, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control, Atlanta, Georgia
Relative survival up to December 31,1986was analyzed for all patients diagnosed with ulcerative colitis (UC) (n = 2,509) and Crohn’s disease (CD) (n = 1,469) within the Uppsala Region, Sweden 19651983. After 10 years survival was 96% of that expected for UC and CD. Patients with ulcerative proctitis, left-sided colitis, and pancolitis at diagnosis had relative survival rates of 98%, 96%, and 93% respectively. Survival did not differ by extent at diagnosis for patients with CD. After including prevalent cases, 684 deaths occurred compared with 481.1 expected deaths [standardized mortality ratio (SMR) = 1.4; 95% confidence interval (CI) = 1.3-1.51. Inflammatory bowel disease was the main reason for this excess mortality. Colorectal cancer increased mortality (50 deaths observed vs. 15.2 expected). Death from other cancers were not greater than expected. Obstructive respiratory diseases, especially bronchitis, emphysema, and asthma increased mortality SMR = 1.5, (95% CI = 1.1-2.2) in UC. Cerebrovascular disease mortality occurred less often than expected (SMR = 0.7; 95% CI = 0.51.0). Mortality for other diseases and groups of diseases was close to that expected.
The excess mortality rate in patients with IBD relative to the general population has been mostly attributed to the IBD itself.‘7~20-22However, a very broad spectrum of extraintestinal diseases has been associated with either UC or CD.23 Therefore, the possible impact of associated diseases on excess mortality in patients with IBD deserves study. The aims of the present study are to estimate relative survival of a population-based cohort of patients with IBD, to study if the relative survival has changed over time, and to look for differences in cause of death compared with the general population. Material and Methods The Cohort
The Uppsala Health Care Region in central Sweden had a population of 1.2 million in 1965 and 1.3 million in 1983. All patients diagnosed as having IBD from 1965 through 1983 in the Region, 3978 incident cases, were identified as previously describede6 Using the same casefinding methods, we were also able to identify 800 patients diagnosed before 1965 and resident in the Region on January 1, 1965. All 800 of these prevalent cases had had at least one consultation or one period of inpatient care due ost epidemiological studies of inflammatory to the IBD from 1965 through 1983. Only two patients bowel disease (IBD) in Northern America and (0.04%) were lost to follow-up leaving 4776 individuals western Europe indicate an increase in the annual available for follow-up. incidence of both ulcerative colitis (UC) and Crohn’s Three thousand, one hundred twenty-one patients had disease (CD) until the beginning of the 1970s.'-'2 UC and 1655 had CD. Patients with UC were classified at Since then the incidence for both diseases seems to diagnosis as having either proctitis, left-sided colitis (inhave stabilized or decreased. However, mortality volvement up to the hepatic flexure), or pancolitis. Patients with CD were classified at diagnosis as having disrates for UC since the 1950s and for CD since the ease confined to the terminal ileum, confined to the colon, middle of the 1970s have decreased.13 These trends including both terminal ileum and colon, or other have been interpreted as resulting from better medi(Table 1). cal care or to a change in the natural history of the
M
two diseases.14 Only a few studies have compared survival among patients with either CD or UC over different time periods.+”
0 1992 by the American Gastroenterological 0016-5065/92/$3.00
Association
SURVIVAL AND CAUSES OF DEATH IN IBD
September 1992
ofPatients in the Cohort of Patients With IBD by Period of Diagnosis and Type and Extent of Disease at Diagnosis
Table 1. Number
Diagnosed
Diagnosed
All
before 1965 (prevalent cases)
1965-1983 (incident cases)
diagnosed cases
613 304
2508 743
3121 1047
209 100 186
700 1065 1469
909 1165 1655
72
543
615
Other
49 40 25
376 366 184
425 406 209
All IBD
799
3977
4776
UC Pancolitis Left-sided colitis Proctitis CD Terminal ileum Ileum and colon
Colon
Follow-up All Swedish citizens are individually identifiable by a lo-digit national registration number (NRN).24 The NRN was used to follow up the study subjects by record linkage to the Registry of Causes of Death (at Statistics Sweden). This Registry includes all deceased persons, whether they died in Sweden or abroad. The primary underlying cause of death is determined from data on medical death certificates using the International Classification of Diseases 7th version (ICD-7) codes before 1969 and ICD8 codes thereafter.
Statistical
Measures and Methods
Relative survival rates were calculated only for the 3978 incident cases as the ratios of observed to expected survival rates in the general population. Expected rates were calculated with respect to 5-year age group, gender, and calendar year of observation.” To determine if the relative survival had improved, the cohort was divided into those diagnosed from 1965 through 1974 and those diagnosed from 1975 through 1983. The computation of person-years at risk started at the time of diagnosis of IBD or in January 1965 (prevalent cases). Each cohort member was followed up either to the date of death or to the closing date of follow-up (December 31, 1986). Official statistics from the Swedish Death Registry included annual sex- and age-specific incident rates for different ICD-codes for entire Sweden. Multiplication of the number of person-years at risk by 5-year age group, gender, and calendar year by the corresponding age, gender, and year-specific mortality rates yielded the number of expected cases. The standardized mortality ratio (SMR), the ratio of observed to expected number of deaths, was used as a measure of risk. The 95% confidence interval (CI) of the SMR was then calculated on the assumption
955
that the observed number of deaths in each group followed a Poisson distribution. Prevalent and incident cases were initially analyzed separately. Because the SMR’s of different diseases or groups of diseases for prevalent cases did not differ from those for incident cases, incident and prevalent cases were pooled.
Results Survival Overall, the rate of death was slightly higher in patients with UC than in the general population as indicated by a lo-year relative survival rate of 95.9% (95% CI 94.3-97.5) (Figure 1). Patients with ulcerative proctitis, however, did not have a significantly decreased survival 10 years after diagnosis, 97.9% (95% CI 95.2-100.0). On the other hand those with pancolitis at diagnosis had a worse prognosis than left-sided colitis, 92.8% (95% CI 89.8-95.5) and 96.0% (95% CI 93.0-99.0) 10 years after diagnosis, respectively (Figure 1). The survival prospects were similar in patients diagnosed with proctitis or left-sided colitis 1965 through 1974 and those diagnosed from 1975 through 1983. However, in patients with pancolitis at diagnosis, the relative survival was slightly but not significantly higher among those diagnosed later than those diagnosed earlier, especially during the first 2 years after diagnosis (Figure 2). In CD the survival was also significantly lower than expected, relative survival being 96.0% (95% CI 94.3-97.9) ten years after diagnosis. The survival did not differ by extent of disease at diagnosis (Figure 3). As in UC there was no evidence that survival improved over time (Figure 4). Causes
the
of Death
Six hundred whole cohort,
eighty-four compared
deaths occurred in to 481.1 expected
O.9OJ 5
10 Yews
15
20
of follow-up
Figure 1. Relative survival in patients with UC by extent at diagnosis. p, UC all cases; - - -, proctitis; -a -, left-sided colitis: -, pancolitis.
956
GASTROENTEROLOGY Vol. 103, No. 3
EKBOM ET AL.
0.90
0.9oJ. 5
5
10
10
Years of follow-up
Years of follow-up
Figure 2. Relative survival in patients with pancolitis at diagnosis from 1965 through 1974 (- -) and from 1975 through 1983 (-).
(SMR = 1.4, 95% CI 1.3-1.5; Table 2). The standardized mortality ratio was significantly increased for those with UC (SMR = 1.4, 95% CI 1.2-1.5) or CD (SMR = 1.6, 95% CI 1.4-1.9) but not for those with ulcerative proctitis (SMR = 1.0, 95% CI 0.9-1.2). In the whole cohort 159 deaths resulted from IBD according to the death certificate occurring mainly during the first 2 years after diagnosis. After these deaths were excluded, the observed number of deaths was about the same as that expected (SMR = 1.1; 95% CI 1.0-1.2). However, mortality from colorectal cancer, respiratory diseases, and gastrointestinal diseases (other than IBD) was significantly greater than expected (Table 3). Major causes of death in the cohort such as cancer, cardiovascular diseases, and accidents and violence did not occur more often than expected. In patients with UC, deaths from bronchitis and emphysema (SMR = 2.6, 95% CI = 1.3-4.6) and for asthma (SMR = 3.3,95% CI = 1.2-7.3) occurred more often than expected. For gastrointestinal diseases,
Figure 4. Relative survival in patients with CD at diagnosis from 1965 through 1974 (- -_) and from 1975 through 1983 (-).
other than IBD, only diseases of the liver not related to alcohol use (IBD: SMR = 3.7,95% CI = 2.0-6.2; UC: SMR = 3.9, 95% CI = 2.0-7.0; CD: SMR = 3.0, 95% CI = O.6-8.8), and diseases of gallbladder and biliary ducts (SMR = 3.0, 95% CI = 1.1-6.5) had a significantly increased SMR. Mortality from cerebrovascular diseases, standardized mortality ratio, is significantly decreased, especially in those with UC (SMR = 0.7; 95% CI = 0.41.0). Suicides occurred slightly less often than expected (SMR = 0.9; 95% CI limit 0.4-1.5) for CD and UC. Discussion We found with the exception for ulcerative proctitis a modestly excess mortality for both UC and CD most evident the first few years after diagnosis, with no significant difference between those diagnosed from 1965 through 1974 and those diagnosed from 1975 through 1983. The main reason for this early excess mortality was death from IBD, but mortality due to colorectal cancer, respiratory diseases, and other gastrointestinal diseases was also increased in the cohort.
Table 2. Deaths From AI1 Causes by Kind of IBD
10
5
15
20
Years of follow-up
Figure 3. Relative survival in patients with CD by extent at diagnosis. -, CD all cases; - --, terminal ileum and part of colon; -
-,
terminal
ileum; -.
-, confined to colon.
SMR
95% confidence interval
684
1.4
UC
505
1.4
1.2-1.5"
Proctitis Left-sided colitis Pancolitis CD
133
1.0
0.9-1.2
165 207 179
1.2 1.9
1.7-2.2"
1.6
1.4-1.9"
IBD 0.90;1
Number of deaths
‘95% confidence
interval excludes
1.0.
1.3-1.5"
1.0-1.4"
September
Table
SURVIVAL AND CAUSES OF DEATH IN IBD
1992
3. SMR by Different
Groups
957
of Diseases IBD
Cancer (excluding colorectal) ICD-7 140-209 ICD-8 140-239 n/SMR Colorectal cancer ICD-7 153-154 ICD-8 153-154 n/SMR Cardiovascular diseases ICD-7 400-468 ICD-8 390-458 n/SMR Ischemic heart disease ICD-7 420 ICD-8410-414 n/SMR Cerebrovascular diseases ICD-7 330-334 ICD-8 430-438 n/SMR Respiratory diseases ICD-7 470-527 ICD-8 480-519 n/SMR Bronchitis and emphysema ICD-7 500-502 ICD-8 490-492 n/SMR Asthma ICD-7 241 ICD-8 493 n/SMR Gastrointestinal diseases (excluding IBD-diagnosis) ICD-7 530-587 ICD-8 520-577 n/SMR Non-alcohol related diseases of the liver ICD-7 580-583 (excluding 5811) ICD-8 570-573 (excluding 5170) n/SMR Diseases of gallbladder and biliary ducts IDC-7 584-586 ICD-8 574-576 n/SMR Genitourinary tract ICD-7 590-637 ICD-8 580-629 n/SMR Accidents and violence ICD-7 800-999 ICD-8 800-999 n/SMR Suicide ICD-7 E970-E979 ICD-8 E950-E959 n/SMR
CD
UC
24/0.9(0.8-1.3)
64/1.0(0.7-1.5)
5/1.7(0.5-3.9)
45/4.4(3.2-5.9y
241/1.0(0.9-1.1)
59/1.1(0.9-1.4)
182/0.9(0.8-1.1)
156/1.0(0.8-1.1)
37/1.1(0.8-1.5)
119/0.9(0.8-1.1)
32/0.7(0.5-1.0)
8/0.8(0.3-1.5)
24,'0.7 (0.4-1.0)
36/1.4(1.0-1.9)"
4/0.7(0.2-1.8)
32/1.5(1.1-2.2)
12/2.0(1.1-3.6)"
O/O.0(0.0-2.8)
12/2.6(1.3-4.6)"
6/2.4(0.9-5.2)
o/o.0[O.O-5.3)
6/3.3(1.2-7.3)
42/2.4(1.7-3.31a
11/2.6(1.3-4.7)
31/2.4(1.6-3.4)
14/3.7(2.0-6.2)
3/3.0(0.6-8.8)
11/3.9(2.0-7.0)
6/3.0(1.1-6.5)
2/5.0(0.6-18.0)
4/2.5(0.7-6.4)
11/1.5(0.7-2.7)
5/3.1(1.0-7.3)
6/1.0(0.4-2.3)
33/0.8(0.6-1.1)
14/1.1(0.6-1.8)
19/0.7(0.4-1.1)
12/0.9(0.4-1.5)
3/0.7(0.1-1.9)
9/1.0(0.4-1.8)
88/0.9(0.7-1.2)
50/3.8(2.8-5.0)"
NOTE. SMR did not differ significantly from 1.0for the major ICD categories: allergic, nutritional, hormonal, and metabolic disorders; hematopoietic diseases; psychiatric diseases; nervous system diseases: cutaneous diseases; muscle and bone disorders; and symptom unknown. n, number of deaths. “95% confidence interval excluding 1.0 (P i 0.05).
958
EKBOM ET AL.
Surveillance bias resulting in more reliable classification of causes of death because of more regular contanct with the health care system would not affect estimates of relative survival or overall mortality, but could affect mortality ratio for specific diseases, especially those known to be associated with IBD. On the other hand, patients might have UC or CD recorded even when another diagnosis might have been more appropriate. However, in that case deaths due to vague causes such as unspecified cancer and unspecified heart diseases should be less frequent than the background population; this was not observed. The modestly decreased relative survival for UC and CD occurring in the first few years after diagnosis agrees with the findings of other, mostly population-based, studies.8~g~2”-30 In contrast, a substantially decreased relative survival has been reported mainly from referral centers, which may treat sicker patients. 15.16,16,22,31-33 We found no substantial improvement in survival from 1965 to 1974 and from 1975 to 1983. However, overall mortality in IBD in western Europe and the United States has decreased since the beginning of the 1970s.13 Although improvement in treatment may explain this decrease, our results seem to imply another explanation: unchanged survival with a decreased annual incidence of IBD agrees with most incidence studies from this period. This means that it might be possible to monitor trends in incidence over time through mortality figures for extensive UC and CD but not for ulcerative proctitis. Next to death from IBD, colorectal cancer was the cause whose relative excess mortality differed most from the background population, and persisted throughout the period especially in patients with UC.34,35 Mortality from other cancers did not differ from that in the background population.36 The most common cause of death was cardiovascular disease, though the observed number of deaths was very close to that expected. Although several cardiovascular complications have been reported in IBD,37-47 our results indicate that cardiovascular complications do not increase mortality among patients with IBD. The lower than expected mortality from cerebrovascular diseases in UC in this study has never been reported before. On the contrary, a selected sample has implicated cerebrovascular disease as a complication in UC.48 Chance, improved surveillance, early treatment of risk factors for cerebrovascular diseases (for example, hypertension), medication such as salicylates, or a protective effect of IBD could explain our results. The significant excess mortality from respiratory
GASTROENTEROLOGY Vol. 103, No. 3
diseases in patients with UC primarily due to bronchitis, emphysema, and asthma confirms reports of pulmonary involvement in UC.4g-53The excess number of deaths from emphysema and brochitis, both related to smoking, seems paradoxical because fewer current smokers than expected have been found among patients with UC.54 These latter findings have been interpreted as a protective effect of smoking, but no reasonable biological mechanism has been identified. However, another feasible explanation could be that lung disorders are more frequently associated with UC than previously thought making patients with UC unable to smoke. Patients with IBD have a high frequency of hepatobiliary complications.55 Therefore, the fourfold increased mortality in such diseases is not surprising and validates to a certain extent our mortality data. No other disease or group of diseases within the gastrointestinal tract has any significant excess mortality. Previously reported associations between IBD and other gastrointestinal diseases such as pancreatitis 56,57or cholethiasis5’ therefore apparently have only minimal impact on mortality in this cohort. Our results do not confirm reports of an excess number of suicides among patients with IBDg*22*27 but agree with another population-based study from Copenhagen where no difference from the general population in the incidence of mental disorders and intake of alcohol and psychopharmaceutical drugs was found.5g We conclude that relative survival is decreased slightly, in extensive UC and CD, and that the only excess mortality is directly related to the IBD itself, colorectal cancer, respiratory disease, and liver diseases unrelated to alcohol use. References 1.
2.
3.
4.
5.
6.
Berner J, Kiaer T. Ulcerative colitis and Crohn’s disease on the Faroe Islands 1964-83. Stand J Gastroenterol 1986;21:188192. Binder V, Both H, Hansen PK, Hendriksen C, Kreiner S, TorpPedersen K. Incidence and prevalence of ulcerative colitis and Crohn’s disease in the County of Copenhagen 1962-1978. Gastroenterology 1982;83:563-568. Brahme F, Lindstrom C, Wenckert A. Crohn’s disease in a defined population, An epidemiological study of incidence, prevalence, mortality, and secular trends in the city of Malmii. Gastroenterology 1975;69:342-351. von Brandes JW, Lorenz-Myer H. Epidemiologische Aspecte zur Enterocolitis regionalis Crohn und Colitis ulceroca in Marburg Lahn zwischen 1962 und 1975. Z Gastroenterol 1983;21:69-78. Calkins BM, Lilienfeld AM, Garland CF. Mendeloff AI. Trend in incidence rates of ulcerative colitis and Crohn’s disease. Dig Dis Sci 1984:29:913-920. Ekbom A, Helmick C, Zack M, Adami HO. The epidemiology of inflammatory bowel disease: A large, population-based study in Sweden. Gastroenterology 1991;100:350-358.
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1992
7. Evans JG, Acheson D. An epidemiological study of ulcerative colitis and regional enteritis in the Oxford area. Gut 1965;6:311-324. 8. Gollop JH, Phillips SF, Melton III LJ, Zinsmeister AR. Epidemiologic aspects of Crohn’s disease: a population-based study in Olmsted County, Minnesota, 1943-1982. Gut 1988;29:49-56. 9. Hellers G. Crohn’s disease in Stockholm County, 1955-1974. Acta Chir Stand 1979;49O(Suppl):l-84. 10. Kyle J, Stark G. Fall in the incidence of Crohn’s disease. Gut 1980;21:340-343. 11. Lee FI. Costello FT. Crohn’s disease in Blackpool-incidence and prevalence 1968-80. Gut 1985;26:274-278. 12. Stonnington CM, Phillips SF, Melton III LJ, Zinsmeister AR. Chronic ulcerative colitis: incidence and prevalence in a community. Gut 1987;28:402-409. 13. Sonnenberg A. Mortality from Crohn’s disease and ulcerative colitis in England-Wales and the U.S. from 1950 to 1983. Dis Colon Rectum 1986;29:624-629. 14. Softley A, Clamp SE, Watkinson G, Boucher IAD, Myren J, De Dombal FT. The natural history of inflammatory bowel disease: Has there been a change in the last 20 years? Stand J Gastroenterol 1988;23(Suppl 144):20-23. 15. Edwards FC, Truelove SC. The course and prognosis of ulcerative colitis. Gut 1963;4:299-315. 16. Weedon DD, Shorter RG, Ilstrup DM, Huizenga KA, Taylor WF. Crohn’s disease and cancer. N Engl J Med 1973;289:10991102. 17. Weterman IT, Biemond I, Pena AS. Mortality and causes of death in Crohn’s disease. Review of 50 years’ experience in Leiden University Hospital. Gut 1990;31:1387-1390. 18. Devroede GJ, Taylor WF, Sauer WG, Jackman RJ, Stickler GB. Cancer risk and life expectancy of children with ulcerative colitis. New Engl J Med 1971;285:17-21. 19 Mayberry JF, Newcombe RG, Rhodes J. Mortality in Crohn’s disease. Q J Med 1980;193:63-68. 20 Allan R, Steinberg DM, Alexander Williams J, Cooke WT. Crohn’s disease involving the colon: an audit of clinical management. Gastroenterology 1977;73:723-732. 21 Nefzger MD, Acheson ED. Ulcerative colitis in the United States Army in 1944. Gut 1963;4:183-192. 22. Prior P, Gyde S, Cooke WT, Waterhouse JAH, Allan RN. Mortality in Crohn’s disease. Gastroenterology 1981;80:307-312. manifestations of idiopathic inflam23. Danzi JT. Extraintestinal matory bowel disease. Arch Intern Med 1988;148:297-302. 24 Lunde AS. The person number system of Sweden, Norway, Denmark, and Israel. Washington, DC: US Government Printing Office, 1980. (Vital and health statistics. Series 2: Data evaluation and methods research, no. 84) [DHHS publication no. (PHS) 80-13581. 25. Hakulinen T, Abeywickrama KH. A computer program package for relative survival analysis. Comput Programs Biomed 1985;19:197-207, 26. Binder V, Hendriksen C, Kreiner S. Prognosis in Crohn’s disease-based on results from a regional patient group from the county of Copenhagen. Gut 1985;26:146-150. 27. Brostrom 0, Monsen U, Nordenwall B, Sorstad J, Hellers G. Prognosis and mortality of ulcerative colitis in Stockholm County, 1955-1979. Stand J Gastroenterol 1987;22:907-913. 28. Hendriksen C, Kreiner S, Binder V. Long term prognosis in ulcerative colitis-based on results from a regional patient group from the county of Copenhagen. Gut 1985;26:158-163. 29. Sinclair TS, Brunt PW, Mowat NAG. Nonspecific proctocolitis in northeastern Scotland: A community study. Gastroenterology 1983;85:1-11. 30. Stonnington CM, Phillips SF, Zinsmeister AR, Melton III LJ. Prognosis of chronic ulcerative colitis in a community. Gut 1987;28:1261-1266,
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31 Lind E, Fausa
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0, Gjone E, Mogensen SB. Crohn’s disease. and outcome. Stand J Gastroenterol1985;20:1014-
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33 34
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L, Bischoff N, Henriksen FW, Fischerman K, Jarnum S. Survival rate in Crohn’s disease and ulcerative colitis. Stand J Gastroenterol 1979;14:225-230. Truelove SC, Pena AS. Course and prognosis of Crohn’s disease. Gut 1976;17:192-201. Ekbom A, Helmick C, Zack M, Adami HO. Increased risk of large bowel cancer in Crohn’s disease with colonic involvement. Lancet 1990;336:357-359. Ekbom A. Helmick C, Zack M, Adami HO. Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 1990:323:1228-1233. Ekbom A, Helmick C, Zack M, Adami HO. Extracolonic malignancies in inflammatory bowel disease. Cancer 1991; 67:2015-2019. Maccini DM, Berg JC, Bell GA. Budd-Chiari syndrome and Crohn’s disease. An unreported association. Dig Dis Sci
1989;34:1933-1936. RA, Goodfield 38 Sheehan-Dare
MJD, Wilson PD, Rowe11 NR. Axillary artery occlusion as a presenting feature of Crohn’s disease. Postgrad Med J 1989;65:758-760. 39 Sakhuja V, Gupta KL, Bhasin DK, Malik N, Chungh KS. Takayasu’s arteritis associated with idiopathic ulcerative colitis. Gut 1990;31:831-833. 40. Wyshock E, Caldwell M, Crowley JP. Deep venous thrombosis, inflammatory bowel disease and protein s deficiency. Am J Clin Path01 1988;90:633-635. 41. Prior A, Strang FA, Whorwell PJ. Internal carotid artery occlusion in association with Crohn’s disease. Dig Dis Sci 1987;32:1047-1050. 42. Talbot RW, Heppell J, Dozois RR, Beart RW. Vascular compli-
cations
of inflammatory
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1986;61:140-145. 43. Gould L, Pate1 C, Betzu R, Din I. Pericarditis
and ulcerative colitis. Am Heart J 1986;802-803. 44. McKeon J, Haagsma B, Bett JHN. Boyle CM. Fatal giant cell myocarditis after colectomy for ulcerative colitis. Am Heart J 1986;1208-1209. 45. Goodman MJ, Moir DJ. Holt JM, Truelove SC. Pericarditis associated with ulcerative colitis and Crohn’s disease. Dig Dis
1976;21:98-102. 46. Frid C, Bjarke B, Eriksson
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M. Myocarditis in children bowel disease. J Pediatr Gastroenterol
1986;5:964-965. 47. Mihas AA, Dasher CA. Pericarditis
with Nutr
associated with granulomatous colitis. Am J Gastroenterol 1977;68:494-497. 48. Johns DR. Cerebrovascular complications of inflammatory bowel disease. Am J Gastroenterol 1991;86:367-370. 49. Gionchetti P, Schiavina M, Campieri M, Fabiani A, Cornia BM, Belluzzi A, et al. Bronchopulmonary involvement in ulcerative colitis. J Clin Gastroenterol 1990;12:647-650, 50. Collins WJ, Bendig DW, Taylor WF. Pulmonary vasculitis complicating childhood ulcerative colitis. Gastroenterology 1979;77:1091-1093. 51. Monsen U, Sorstad J, Hellers G, Johansson C. Extracolonic diagnoses in ulcerative colitis: An epidemiological study. Am J Gastroenterol 1990;85:711-716, 52. Moles KW, Varghese G, Hayes JR. Pulmonary involvement in ulcerative colitis. Br J Dis Ches 1988;82:79-83. 53. Hammer B, Ashurst P, Naish J. Diseases associated with ulcerative colitis and Crohn’s disease. Gut 1968;9:17-21. 54. Calkins BM. A meta-analysis of the role of smoking in inflammatory bowel disease. Dig Dis Sci 1989;34:1841-1854, 55. Wewer V. Gluud C, Schlichting P, Burcharth F, Binder V.
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Prevalence of hepatobiliary dysfunction in a regional group of patients with chronic inflammatory bowel disease. Stand J Gastroenterol 1991;26:97-102. 56. Matsumoto T, Matsui T, Iida M, Nunoi K, Fujishima M. Acute pancreatitis as a complication of Crohn’s disease. Am J Gastroenterol 1989;84:804-807. 57. Niemela S, Lehtola J, Karttunen T, Lahde S. Pancreatitis in patients with chronic inflammatory bowel disease. Hepatogastroenterology 1989;36:175-177. 58. Kangas E, Lehmusto P, Matikainen M. Gallstones in Crohn’s disease. Hepatogastroenterology 1990;37:83-84.
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59. Hendriksen C, Binder V. Social prognosis in patients with ulcerative colitis. BMJ 1980;281:581-583. Received December 9, 1991. Accepted March 31, 1992. Address requests for reprints to: Anders Ekbom, M.D., Cancer Epidemiology Unit, University Hospital, S-751 85 Uppsala, Sweden. Supported by grants from Crohn’s and Colitis Foundation of America. The authors thank Dr. Richard Rothenberg for valuable support.