INFLAMMATORY COLON DISEASE IN ROCHESTER, MINNESOTA,

GASTROENTEROLOGY Copyright 1972 by The Williams & Wilkins Co. Vol. 62, No.5 Printed in U.S.A. INFLAMMATORY COLON DISEASE IN ROCHESTER, MINNESOTA, 1935-1964 RICHARD E. SEDLACK, M.D., FRED T. NOBREGA, M.D., LEONARD T. KURLAND, M.D., AND WILLIAM G. SAUER, M.D. Mayo Clinic and Mayo Foundation, Rochester, Minnesota The medical records of the residents of Rochester, Minnesota, who depend largely on the Mayo Clinic for their medical care, offer a unique opportunity to study the epidemiology of inflammatory disease of the colon over a 30-year period from 1935 through 1964. Local residents with this condition were divided into the following four arbitrary but distinct anatomic groups: type A, transient proctitis; type B, chronic or recurrent proctitis; type C, typical mucosal ulcerative colitis involving the rectum and continuous portions of the colon above the proctoscopic level; and type D, segmental disease (largely Crohn's disease of the colon). During the study period the disease was newly diagnosed in 108 residents and in an additional 32 patients who took up residence after the diagnosis had been established. Of the 108 cases, 23 (21%) were type A, 35 (32%) were type B, 31 (29%) were type C, and 19 (18%) were type D. The average annual incidence rate for all four types combined was 11.8 per 100,000 with rates for the four subtypes of 2.5, 3.8, 3.4, and 2.1 per 100,000, respectively. Incidence rates over the 30-year period showed a slight rise for all types except D. Fifty-three per cent of all cases represented disease which never progressed beyond proctoscopic level. Carcinoma of the colon occurred subsequently in 5 cases, all type C, which was a significantly higher number than would be expected in the general population. Most existing studies of the incidence and prevalence of chronic ulcerative colitis are complicated by frustrating deficiencies. The investigator may be hampered by inconsistent proctologic and roentgenologic diagnostic opinions, by the lack of adequate follow-up, by the fact that many patients have extremely mild disease and may never be hospitalized, and by population mobility. Some studies have been based on selected population groups, notably those involving members of the United States Army in 1944. 1 Other stud- Received October 6, 1971. Accepted December 17, 1971. Address requests for reprints to: Dr. R. E. Sedlack, Mayo Clinic, Rochester, Minnesota 55901 ies in which an attempt has been made to survey a circumscribed population have included only those patients whose disease necessitated hospitalization, or who died of their disease. 2-4 A comprehensive population study was conducted in Copenhagen County, Denmark,5 but covered a relatively short and recent period (1961 through 1967). A study of inflammatory colon disease in Rochester, Minnesota, offers some distinct advantages over previous studies because of the consistent and integrated proctologic and roentgenologic services available to the community which historically has relied on the Mayo Clinic for its care. The unique record linkage system permits the identification and retrieval of cases of progressive 935

936 SEDLACK ET AL. Vol. 62, No.5 disease over an extended period, and the extensive follow-up program, which includes information regarding the subsequent development of malignancies and other diseases in such patients, furnishes additional advantages to the study of inflammatory bowel disease in this community. The purpose of this paper is to provide information regarding the incidence, prevalence, mortality, and trends of inflammatory colon disease among residents of Rochester for a 30-year period, 1935 through 1964. Experimental Procedure Background This study, based on cases identified in the population of Rochester, Olmsted County, Minnesota, was undertaken to provide accurate base line incidence data to further the study of the etiologic aspects of chronic ulcerative colitis. Since the early part of this century the medical practice in Olmsted County has been centered largely at the Mayo Clinic in Rochester. The records of this clinic, together with those of other institutions in the community, lend themselves to a variety of studies, particularly of diseases of a serious nature. The medical indexing and record retrieval system, developed originally at this clinic many years ago and more recently implemented in the other medical institutions in and around Rochester, assures the identification of practically all local persons in whom a serious illness has been diagnosed. Diagnoses made by physicians at the Mayo Clinic, at its affiliated hospitals, during home visits, or at autopsy are entered on the master sheet of the patient's record, cross-indexed, and processed for automated retrieval. A similar system was developed for the existing records of the Olmsted Medical Group, the Olmsted Community Hospital (used primarily by the Olmsted Medical Group), and other medical facilities in Olmsted County and adjacent counties. The Olmsted Community Hospital, which opened in 1955, also has been used by the two or three physicians in solo general practice in Olmsted County and a few practitioners from adjacent counties. In recent decades autopsy has been performed on about 70% of all local patients who have died at home or in one of the hospitals. Method Hospital and outpatient records covering the population of Rochester, Minnesota, and listing a diagnosis of any type of inflammatory bowel disease made during the period of study 1935 through 1964 were retrieved and examined. The sources included the Mayo Clinic and other medical institutions in Olmsted County and adjacent Minnesota counties, the University of Minnesota, and the Veterans Administration Hospital in Minneapolis. Furthermore, all death certificates containing the diagnosis of ulcerative colitis or similar diagnoses for Rochester residents were retrieved for the years 1935 through 1964. It is of interest that all local residents who died and had a diagnosis of ulcerative colitis on their death certificates had previously been identified from our central case registry. For the 30-year period, records of all patients with the diagnosis of ulcerative colitis, nonspecific ulcerative colitis, proctitis, segmental colitis, and Crohn's disease of the colon who were residents of Rochester at any time during the period of study were retrieved and examined. In addition, records of patients with the diagnosis of regional enteritis were retrieved from the community's central record file. Since the study was concerned with inflammatory disease of the colon, detailed analysis of the cases of regional enteritis was not undertaken. Incidence rates per 100,000 population for ulcerative colitis by date of diagnosis were calculated for each of the three decades from 1935 through 1964, using the number of cases per decade in the numerator and the respective modified decennial census for Rochester, Minnesota, in the denominator. The decennial census was modified by excluding non-rochester residents living in the Rochester State Hospital. Classification Of the 330 cases in which colitis or enteritis was recorded as a possible diagnosis, 89 were found unacceptable as cases of true inflammatory bowel disease and 101 were found to have been residents elsewhere either at the time of their disease or after its onset (table 1). This left 140 patients, 108 of them being patients with newly diagnosed chronic inflammatory colon disease among residents of Rochester and an additional 32 being persons who took up residence in Rochester after the diagnosis had been made but who were judged not to have taken up residence because of their

May 1972 INFLAMMATORY COLON DISEASE 937 disease. The 140 cases of inflammatory bowel disease were then classified as follows: Type A-transient proctitis. Patients with initial proctoscopic findings compatible with ulcerative colitis but subsequent proctoscopic examinations were negative or the patient remained asymptomatic. Patients judged to have specific causes for proctitis (for example, medications and amoebiasis) were excluded from the study group. Type B-chronic proctitis. Patients with proctitis compatible with ulcerative colitis with repeated positive or intermittently positive proctoscopic examinations but with no X-ray evidence of later progression to involve the colon above the proctoscopic level. Type C-mucosal ulcerative colitis. Patients with typical proctoscopic findings of ulcerative colitis and continuous involvement of a portion or all of the colon above the proctoscopic level. Type D-atypical or discontinuous disease. Patients with negative or atypical proctoscopic findings and involvement of the colon in segmental fashion or with X-ray findings TABLE 1. Inflammatory colon disease in Rochester, Minnesota (1935 through 1964) Ulcerative colitis or regional enteritis recorded as diagnosis or possible diagnosis............ After review and reclassification Nonresidents Condition not acceptable as ulcerative or regional enteritis.......... Condition acceptable as ulcerative colitis among residents of Olmsted County diagnosed initially during study period.... Ulcerative colitis among those who took up residence in Olmsted County after diagnosis No. of patients 330 101 89 108 32 most compatible with Crohn's disease. This group is probably somewhat heterogeneous, but largely Crohn's disease. Patients were assigned to one of these groups after all available data were considered, including proctoscopic findings, microbiologic reports, roentgenograms, available tissue from biopsy, surgical specimens, and autopsy material. The authors realize that transient proctitis (type A) may not be considered by some to represent true inflammatory bowel disease, but we did not feel justified in excluding patients in this category from the study group. A diagnosis of proctitis alone was not made without a roentgenogram of the colon to support the fact that disease was indeed limited to the rectum. In fact, some patients initially assigned to this group were seen subsequently with generalized disease. The differentiation of Crohn's disease of the colon from mucosal ulcerative colitis is difficult, even in a prospective study. We did not feel justified in doing more than separating atypical, segmental disease (type D) from that which would be readily accepted by all as typical mucosal ulcerative colitis (type C). In our judgment, however, type D is almost entirely Crohn's disease with perhaps a few cases of ischemic colitis. No cases of "possible disease" based on history or other nonobjective diagnostic means were included. Diagnostic criteria were otherwise similar to those of Monk and associates. 2 Results Among the 108 patients in Rochester the crude incidence rates for types A, B, and C have increased slightly from the first to the third decade as compared to no change in type D (table 2). However, the changes in incidence rates for the three types combined is only of borderline statistical significance. The rates by sex for the 30 years of study showed a slight TABLE 2. Number and average annual incidence rates per 100,000 by decade, sex, and diagnostic category Type 1935-1944 1945-1954 1955-1964 Total, 1935-1964 M F Total Rate M F Total Rate M F Total Rate M F Total Rate A 3 1 4 1.6 3 3 6 2.1 6 7 13 3.3 12 11 23 2.5 B 6 6 2.4 4 6 10 3.5 10 9 19 4.9 14 21 35 3.8 C 2 3 5 2.0 7 4 11 3.9 9 6 15 3.8 18 13 31 3.4 D 2 4 6 2.4 3 4 7 2.5 5 1 6 1.5 10 9 19 2.1 Total 7 14 21 8.4 17 17 34 12.0 30 23 53 13.5 54 54 108 11.8

938 SEDLACK ET AL. Vol. 62, No.5 male predominance (male-female ratio, 1.3: 1) (table 3). Such a finding differs from that noted in Oxford 4 and in Copenhagen 5 where females were found to be affected somewhat oftener than males. In Oxford, for example, the ratio for all types of ulcerative colitis was 1.4: 1 (F: M) and in Copenhagen the ratio was 1.1: 1 (F: M). However, none of these ratios, including the Rochester figures, are significantly different from 1: 1. In addition, it is interesting to note that 58 of the 108 patients (53%) had disease confined to the rectum and rectosigmoid (no disease above) whereas in a recent large clinical series 6 only 4.1 % of the patients had their disease confined to the rectum. The rates by age suggest a possible bimodal distribution with peak rates among patients 20 to 39 and 50 to 69 (table 3). Such a finding has been observed by investigators in Oxford 4 who found that the highest rates were among those 25 to 44 and 65 to 74 years of age. The prevalence as of January 1, 1965, among Rochester residents who had active disease or who were in remission for all four types of inflammatory bowel disease combined was 146 per 100,000 population (table 4). This group comprised persons with active disease and those with disease in remission as well as those persons who had taken up residence in Rochester after the diagnosis of chronic ulcerative colitis had been made (but not because of the diagnosis). The rate for males per 100,000 was 166 whereas for females it was 129 for a ratio of 1.3 to 1. Among the 108 patients with inflammatory bowel disease, carcinoma of the colon subsequently developed in 5 (all type C). Based on person-years' experience of these patients from the time of diagnosis to the time of the last follow-up and applying the age and sex specific incidence rates of colon carcinoma from the Connecticut Tumor Registry or the Rochester Cancer Study (unpublished data), the expected number of cases was 0.4, a significantly lower number than that observed. Of these 108 patients, 18 have died. The remaining 90 survived to January 1, 1970. TABLE 3. Number by age and sex and average annual incidence rates per 100,000 for all cases combined Age Number Male Female Total Total rate O yr 0-9 4 1 5 3 10-19 4 3 7 5 20-29 17 18 35 21 30-39 10 13 23 17 40-49 6 4 10 9 50-59 9 6 15 17 60-69 3 6 9 14 70+ 1 3 4 8 Total 54 54 108 11.7 a Male, 13.2; female, 10.5; age-adjusted rate, 11.6 (adjusted to United States 1950 total white population). TABLE 4. Prevalance rates per 100,000 on January 1, 1965, by sex and diagnostic category Type Number Total Male Female No. Rate A 6 8 14 30 B 13 10 23 49 C 9 9 18 38 D 7 6 13 28 Total 35 33 68 Rate 165.6 129.0 145.6 Among the death certificates for the 18 decedents, 7 (39%) mentioned ulcerative colitis; it was recorded as the underlying cause of death in 6 of the 7 cases. Although ulcerative colitis was not mentioned on 11 of the 18 death certificates, the diagnosis of ulcerative colitis or proctitis had been made prior to death in all cases. The underlying cause of death was attributed to coronary heart disease in 3 cases and to malignancies in 4 cases (2 of which were carcinoma of the colon); and there were single cases of suicide, acute alcoholism, senility, and a bleeding duodenal ulcer (confirmed at operation). The one death in which ulcerative colitis was recorded on the death certificate but was not the underlying cause was attributed to carcinoma of the colon. The average annual mortality rate for the 30-year period based on these 4 cases

May 1972 INFLAMMATORY COLON DISEASE 939 was 0.4 per 100,000 population, which approximates the rates reported elsewhere for the same time period 4, 7 9 (table 5). In addition to cases of inflammatory colon disease there were 20 cases of Crohn's disease of the small bowel (pure regional enteritis) identified from the community's central case registry, Since the primary concern of this study was inflammatory disease of the colon, these cases were not included in the total analysis, Interestingly, however, these 20 comprised 11 males and nine females for an incidence rate during the most recent decade (1955 through 1964) of 4 per 100,000 population, The prevalence rate as of January 1, 1965, was 32 per 100,000. Comment Relatively few population surveys of chronic inflammatory diseases of the colon have been made and none has been reported over a period longer than 10 years. Such population surveys have been primarily retrospective in nature and difficult to interpret in view of our recent appreciation of the difference between chronic ulcerative colitis and Crohn's disease of the colon. Even though the study in Rochester is also retrospective, case identification was based on complete existing records, and there is no reason to believe that the number of diagnosed cases would have been otherwise if the study had been current. The major concern is not whether it is a retrospective identification of existing cases but whether the case identification is as complete as practically possible. A study in which every member of the population is queried regarding symptoms and is examined and diagnosed in the event the history is positive would, over a time, provide a more accurate study of prevalence and incidence but would be unjustifiable from a practical standpoint. In a rather high percentage of Rochester patients the disease was confined to the rectum and rectosigmoid. This strikingly high proportion of patients with limited disease is at variance with the general clinical experience with all patients with TABLE 5. Average annual death rate per 100,000 in Rochester and comparison with other studies from literature I Death rate per 100,000 Rochester, Minnesota, 1935-1964 Acheson,7 1960 1952-1956; USA.. 1952-1957; Canada 1953-1955; EnglandlWales... Evans and Acheson, 1965 1951-1960; Oxford, England.. Mosbech,9 1960 1951-1959: Denmark...... Wigley and MacLaurin, 8 1962 1954-1958: Wellington, New Zealand. 0.40 0.47 0.49 0.85 0.70 0.60 0.90 ulcerative colitis at the Mayo Clinic and serves to illustrate that patients with mild disease who are rarely hospitalized may be missed by studies which consider only hospitalized patients or referrals to a large medical center. A community study with its more complete case ascertainment is, thus, more likely to present a truer cross section of the spectrum of a disease. Contrary to the clinical impression of many gastroenterologists, our study of the Rochester population suggests (1) that Crohn's disease of the colon is not rising in incidence, and (2) that although the increase in incidence rates of typical ulcerative colitis and ufcerative proctitis over the 30-year period is of borderline significance, a trend in that direction is suggested. However, there is no indication that the incidence in diagnosed cases has increased 2-fold during the last 20 years in Rochester despite the fact that such a rise has been suggested elsewhere. 4,10 The trend of ulcerative colitis in Norway, for example, revealed that the average annual incidence rates for typical cases of ulcerative colitis rose from 0.9 per 100,000 in 1946 through 1950 to 2.1 per 100,000 from 1956 through 1960. The average annual rate in Rochester for what we believe to be typical ulcerative colitis (type C) for the comparable decades of 1945 through 1954 and 1955 through 1964 was remarkably stable, however, being

940 SEDLACK ET AL. Vol. 62, No. 5 approximately 4 per 100,000 per year for the 20-year period. In the Oxford area, the average annual incidence rates per 100,000 for all forms of ulcerative colitis increased from 5.2 (1951) to 9.7 (1959). In Rochester, the rates for ulcerative colitis and proctitis for types A, B, and C combined for these decades were 9.5 per 100,000 (1945 through 1954) and 12 per 100,000 (1955 through 1964). In addition, the rate for all types of inflammatory bowel disease in Rochester for this first decade was virtually identical to the rate in Oxford in the year 1959 (9.7 per 100,000 population), again suggesting that little change has taken place in the incidence of these disorders during the past 20 years. In most of the studies to date, 2, 4, 5, 9, 11 the sex ratio showed a slight predominance among females. In Rochester, however, the ratio revealed a slight predominance among males (1.3: 1); the differences, however, are small and are not statistically significant. In the Oxford survey a bimodal age distribution was noted with the peak incidence in the fourth and fifth decades and a second peak in the seventh decade. Other surveys have also suggested a bimodal distribution. I. 4, 12 Although the age distribution in Rochester suggested a bimodal distribution, the peaks were somewhat earlier, being in the third and fourth decades and then later in the sixth and seventh decades. Nevertheless, the possibility of a bimodal distribution suggests that the etiology of colitis in younger persons may be different from that in older people. The age distribution in the Copenhagen study is similar to that in Rochester with peaking in the 20- through 39-year age group but with the peaking in the older age group (50 through 59) in Copenhagen being confined to females. There have been a number of studies which have given a prevalence value for ulcerative colitis.4, 5, 8, 13 In Bristol, England, Houghton and Naish 1 3 made the first projections on prevalence which were almost identical with the later data of Acheson and Nefzger' in Oxford. At least two studies are comparable to Rochester in method apart from the length of the collection period. In Oxford, the prevalence per 100,000 population for all types of inflammatory colon disease over a decade (1951 through 1960) was 80 whereas in Copenhagen the comparable figure over a 6-year period was 44. In Rochester, for all types combined (A, B, C, and D), the total prevalence at the end of a 30-year period on January 1, 1965, was 146. The prevalence rate is, of course, influenced greatly by the length of the study period-being affected by the incidence and mortality experience of the disease and the relative mobility of the patients with respect to the total population. It has been suggested repeatedly in clinical studies that there is an increase in the incidence of carcinoma of the colon in patients with ulcerative colitis. One large study of this type involving the follow-up of more than 1500 patients was reported at the Mayo Clinic in 1954. '4 Such an analysis, however, has not been done for a defined population to our knowledge, but the calculations made in Rochester support the clinical impression and previous studies that the increased incidence of subsequent malignancy m these patients is indeed rather likely. Conclusions The incidence, prevalence, mortality, and trends of chronic inflammatory disease of the colon over a 30-year period in the population of Rochester, Minnesota, are described. The disorders were classified into four major groups: type A transient proctitis, type B-chronic proctitis, type C-typical ulcerative colitis, and type D-segmental colitis. The rates were somewhat higher among males than females during the last two decades of the study in Rochester as compared to a slight predominance among females noted in other community studies. The incidence rates for segmental colitis (type D) have not changed, but an increase in the other types (A, B, and C) of inflammatory bowel disease was suggested,

May 1972 INFLAMMATORY COLON DISEASE 941 although the rise was only of borderline significance. The prevalence rate as of January 1, 1965, was the highest yet reported for chronic inflammatory disease of the colon but the collection time involved a period of 30 years, in contrast to the usual 10 years, with essentially complete follow-up. On follow-up, carcinoma of the colon was found to have developed in 5 of 31 patients with type C disease. This number is considerably higher than the number expected in the general population. REFERENCES 1. Acheson ED, Nefzger MD: Ulcerative colitis in the United States Army in 1944: epidemiology; comparisons between patients and controls. Gastroenterology 44:7-19, 1963 2. Monk M, Mendeloff AI, Siegel CI, et al: An epidemiological study of ulcerative colitis and regional enteritis among adults in Baltimore. I. Hospital incidence and prevalence, 1960 to 1963. Gastroenterology 53:198-210, 1967 3. Birnbaum D, Groen JJ, Kallner G: Ulcerative colitis among the ethnic groups in Israel. Arch Intern Med 105:843-848, 1960 4. Evans JG, Acheson ED: An epidemiological study of ulcerative colitis and regional enteritis in the Oxford area. Gut 6:311-324, 1965 5. Bonnevie 0, Riis P, Anthonisen P: An epidemiological study of ulcerative colitis in Copenhagen county. Scand J Gastroenterol 3:432-438, 1968 6. Farmer RG, Brown CH: Ulcerative proctitis: course and prognosis. Gastroenterology 51:219-230, 1966 7. Acheson ED: The distribution of ulcerative colitis and regional enteritis in United States veterans with particular reference to the Jewish religion. Gut 1:291-293, 1960 8. Wigley RD, MacLaurin BP: A study of ulcerative colitis in New Zealand, showing a low incidence in Maoris. Br Med J 2:228-231, 1962 9. Mosbech J: Mortality from ulcerative colitis in Denmark. Gastroenterology 39:690-693, 1960 10. Gjone E, Myren J: Colitis ulcerosa i norge. Nord Med 71 :143-145, 1964 11. Edwards FC, Truelove SC: The course and prognosis of ulcerative colitis. Gut 4:299-315, 1963 12. Matsunaga F: Clinical studies on ulcerative colitis and its related diseases in Japan, Proceedings of the World Congress of Gastroenterology, Washington DC, 1958, vol 2. Baltimore, Williams & Wilkins Co, 1959, p 955-960 13. Houghton EAW, Naish JM: Familial ulcerative colitis and ileitis. Gastroenterologia (Basel) 89:65-74, 1958 14. Bargen JA, Sauer WG, Sloan WP, et al: The development of cancer in chronic ulcerative colitis. Gastroenterology 26:32-37, 1954