Lack of Association Between Smoking and Inflammatory Bowel Disease in Jewish Patients in Israel

Transcription

1 GASTROENTEROLOGY 1995;108: Lack of Association Between Smoking and Inflammatory Bowel Disease in Jewish Patients in Israel SHIMON REIF, IFAT KLEIN, NADIR ARBER, and TUVIA GILAT Departments of Gastroenterology and Pediatric Gastroenterology, Tel Aviv Sourasky Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Background/Aims: An excess of smokers in patients with Crohn's disease (CD) and a paucity of smokers in patients with ulcerative colitis (UC) were reported in many studies. The aim of this study was to examine the association between smoking and inflammatory bowel disease (IBD) in Israel. Methods: Two independent studies were performed. Patients with recent IBD in comparison with matched population and outpatient controls and patients with chronic UC and CD were studied. Altogether, 475 subjects were investigated. Results: In both studies, the presence of current smokers was lower in CD (9% and 18%) than in UC (24% and 26%). The proportions of nonsmokers in both studies were similar (UC, 61% and 65%; CD, 67% and 70%) and comparable to those found in their two control groups (57% and 61%; 63% and 68%, respectively) and to the general population of Israel. All differences in smoking habits between patient groups and their controls were not statistically significant, except for the paucity of current smokers in the small group of patients with newly diagnosed CD (P < 0.05). A matched analysis produced similar results. Conclusions: The expected associations between smoking and IBD could not be confirmed. Two hypotheses are considered: (1) the association between smoking and IBD may not be universal, and (2) our findings may be related to the higher genetic predisposition to IBD in Jewish people. T he etiology and pathogenesis of inflammatory bowel disease (IBD) is still unclear. Although the effects of both genetic and environmental factors have been established by epidemiologic, twin and genetic-linkage analyses, the nature of the putative environmental factors has not been elucidated. 1-4 An interesting series of studies has shown strikingly different patterns of cigarette smoking among patients with IBD. These studies indicate that patients with ulcerative colitis (UC) are less likely to smoke. 5-8 The "protective" effect seems to be limited to current smokers, because the risk of UC was shown in several studies to be actually higher among exsmokers. 9'1 The opposite seems to be true with Crohn's disease (CD), with these patients being more likety to be smokers Many of the studies on smoking and IBD were limited by having used only contemporary data; there are potential recall problems for subjects who have had the disease for many years. There are, however, limited supportive data on smoking habits before the onset of IBD. 13'14 The nature of the potential link between smoking and IBD is unknown. Smoking is also one of the few factors that seem to be different between CD and UC. Because smoking habits had not been investigated in the Jewish population in Israel, we recently conducted two independent studies of this link. We could not confirm the reported association between smoking and IBD. Our findings are hereby reported. Patients and Methods The data were derived from two independent studies performed in the Tel Aviv area. Study I During , we conducted a prospective survey on preillness diets and other habits of newly diagnosed patients with IBD. We included patients between the ages of 10 and 60 years who had been diagnosed up to 1 year before entering the study. Two controls matched for age (by 5-year intervals), sex, community, and socioeconomic group were examined for each study patient. One control group came from the hospital outpatient clinic (orthopedic or ophthalmologic). These were patients with a mild, usually transient illness that did not affect their diet or habits. Patients with any type of malignant disease, cardiovascular or respiratory illness, or chronic disease were excluded. A similarly matched control group was randomly chosen from the general population using the registry of the Interior Ministry. Matched controls could not be found for a few patients because of the rigid matching criteria. However, each patient had at least one control. Patients and controls were interviewed comprehensively concerning their daily routine and nutrient consumption. Patients' 1995 by the American Gastroenterological Association /95/$3.00

2 1684 REIF ET AL. GASTROENTEROLOGY Vol. 108, No. 6 Table 1. Data of Patients With Recent-Onset IBD and Their Controls (Study I) All Patients UC Controls CD Population Clinic Number Age (yr) (mean _+ SE) _ _ _ Sex (M/F) 52/36 30/24 20/13 48/28 39/29 Community group Ashkenazi Sephardi Mixed Disease location Small bowel only Large bowel + small bowel habits and diet were recorded separately for the current period as well as for the period before the onset of symptoms. Similar time periods were recorded in the controls. All data were recorded on a standard questionnaire. Smoking was among the nondietary habits evaluated in the study. Smoking status was categorized as nonsmokers (who have never smoked), ex-smokers (who stopped smoking more than 1 year before the study), and current smokers (subdivided into those smoking fewer than 10, between 10 and 20, or more than 20 cigarettes per day). Study II In 1993, we performed a prospective study of inflammation indices in IBD. The study patients had established UC or CD of variable duration and had not been included in study I. A smoking history identical to that obtained in study I was recorded. Smoking patterns of patients with UC were compared with those of patients with CD but not to a control group. Studies I and II were performed by different and independent investigators, unaware of each other's findings. The two studies involved different patients. Data on study subjects are shown in Tables 1 and 2. All study subjects were Jewish, with their community group having been determined by the country of origin of the father. Table 2. Data of Patients With Chronic CD and UC (Study il) CD UC Total Number Age (yr) (mean _+ SD) _ _+ 15 Sex (M/F) 81/60 58/47 139/107 Community group Ashkenazi Sephardi Mixed Disease location Small bowel only 87 none 87 Large bowel _+ small bowel Statistical Analysis Differences between group percentages (e.g., smokers and nonsmokers) were examined by using Fisher's Exact Test.*5 Odds ratios were calculated from discordant pairs when comparing one disease group (UC or CD) with one control group (population or clinic). Comparisons of one disease group against its two control groups were performed using a conditional logistic analysis) 6 The two control groups were similar in the percentages of nonsmokers, allowing such an analysis. Results A comparison of smoking habits of patients and matched controls (study I, Table 3) showed that patients with CD were less likely to be current smokers (9%) compared with their controls (33% and 31%; P < 0.05). The absolute numbers were small. Patients with UC were current smokers in a proportion similar to that of their controls (24% vs. 24%; and 21%). Thus, the proportion of current smokers was higher in patients with UC than in those with CD (24% vs. 9%). The proportion of exsmokers was higher among patients with CD (24%) than patients with UC (15%). The proportion of nonsmokers was similar in all groups: in CD, it was 67% vs. 57% and 61% in their controls; in UC, it was 61% vs. 63% and 68% in their controls. None of these differences was statistically significant. These numbers are similar to those for the general population of Israel, in which about 32%-37% are smokers, iv Of all the current smokers, the majority (12 of 16) smoked between 10 and 20 cigarettes per day, only 2 smoked fewer than 10 cigarettes per day, and only 2 smoked more than 20 cigarettes per day, The ex-smokers could be divided into two groups according to when they had stopped smoking before the onset of symptoms: 44% stopped up to 3 years and 56% more than 3 years before onset of symptoms. Of the 8 patients with UC, 4 stopped

3 June 1995 SMOKING AND IBD IN JEWS 1685 Table 3. Study I: Smoking Habits in Patients With Recent-onset IBD and Their Controls No. of No. of No, of No. of patients population No. of clinic patients population No. of clinic Group with CD (%) controls (%) controls (%) with UC (%) controls (%) controls (%) Current smokers 3 (9) 10 (33) 9 (32) 13 (24) 11 (24) 8 (21) Ex-smokers 8 (24) 3 (10) 2 (7) 8 (15) 6 (13) 4 (11) Nonsmokers 22 (67) 17 (57) 17 (61) 33 (61) 29 (63) 26 (68) Total 33 (100) 30 (100) 28 a (100) 54 (100) 46 (100) 38" (100) aln 2 clinic controls, the data for smoking were incomplete and are not included in the table. smoking fewer than 3 years and 4 stopped smoking more than 3 years before the appearance of symptoms. In the control group, 80% of previous smokers had stopped smoking more than 3 years before the study period. In study II, the smoking habits of patients with CD were compared with those of patients with UC. The proportion of nonsmokers was 70% in patients with CD and 65% in patients with UC. The proportions for current smokers were 18% in patients with CD and 26% in patients with UC (NS). When patients in study I were compared with those in study II, the results were roughly similar. The proportions of nonsmokers in patients with CD were 67% in study I and 70% in study II. For patients with UC, the numbers were 61% and 65%, respectively. In both studies, the percentages of current smokers were higher in patients with UC compared with patients with CD. In study I, there were 12 patients younger than 16 years of age (8 with UC and 4 with CD). Their controls were matched for age. In addition to the group analyses (Tables 3 and 4), a matched analysis was performed for patients in study I only (Table 5). Odds ratios for smoking in patients with UC were (against clinic controls) and (against population controls). For patients with CD, the odds ratios were 0.5 and 0.5, respectively. None of these values was significantly different from unity. When subjects older than 16 years of age were analyzed separately, the results were similar. When patients were analyzed against both control groups together, the odds ratio for Table 4. Study I1: Smoking Habits in Patients With Chronic CD and Patients With Chronic UC No. of patients No. of patients Group with CD (%) with UC (%) Present smokers 26 (18) 27 (26) Ex-smokers 17 (12) 10 (9) Nonsmokers 98 (70) 68 (65) Total 141 (100) 105 (100) smoking in patients with UC was and in patients with CD (NS). Power Calculations The actual number in patients with UC ensures a power of 80% 18 for detecting an odds ratio of 2.18 (o~ = 0.05) in a standard case control study. Because this is a matched study, detecting an even lower odds ratio value may be expected. Moreover, in four disease groups (UC and CD in studies I and II) and two control groups, the percentages of nonsmokers were similar and comparable to the general Israeli population. Thus, the overall power should be much larger than calculated above. Discussion One of the first reports on the association between nonsmoking and UC was accompanied by an editorial questioning the biological significance and possible fortuitous coincidence of the finding. 19 However, the observation that patients with UC are less likely to be current smokers and patients with CD are more likely to be current smokers seems to be well established by over fourteen studies from various parts of the world. 5-14'2-24 Similarly, patients with UC are more frequently past smokers. There have also been some reports of a dose-response effect, 5'&23'24 Table 5. Matched Analysis: Odds Ratios for Smoking (Study I) A a B b C c Odds P Odds Odds Group Control ratio value ratio ratio UC Clinic NS 1.29 UC Population NS 1,33 CD Clinic NS CD Population NS ~Odds ratio for smoking of patients with UC and patients with CD vs. each control group separately, ~Odds ratio for subjects older than 16 years of age only. COdds ratio for patients vs. both control groups together,

4 1686 REIF ET AL. GASTROENTEROLOGY Vol. 108, No. 6 and recently, a double-blind study has suggested the potential usefulness of transdermal nicotine in patients with UC. 25 In view of the above, our findings are somewhat surprising. Several potential sources of error have to be considered. The number of newly diagnosed patients with IBD in study I was not large, only 87 patients. However, when both studies were combined, there were 174 patients with CD and 159 with UC, and a total of 475 study subjects, which is more than in many other studies. <7'9-14 The number of smokers in study I was rather small. However, the numbers in study II were larger. In addition, the percentages of nonsmokers in all study groups were very similar and close to those found in the general population of Israel (63%-68%)) 7 Statistical analysis by groups for each of the two studies as well as a matched analysis for subjects in study I gave similar results. The odds ratios (Table 5) for smoking were minimally >1.000 in patients with UC and < for patients with CD. Thus, the matched analysis was in full accord with the results of group analyses in our study. When only patients older than 16 years of age were analyzed (to exclude possible bias because of age interaction), this tendency was even more pronounced (in patients with UC). The findings in study I were similar to those in study II, although these were two different groups of patients who were questioned by two different and independent investigators unaware of each other's findings. There is little possibility for methodological error. The questions relating to nonsmokers or to current smokers are straightforward. In addition, each patient and control was individually interviewed by an experienced interviewer, not via a questionnaire sent by mail. Thus, the possibility has to be entertained that the association between smoking and IBD is not found in some populations. If a similar lack of association will be found in other populations, this would be a more generalized phenomenon. Alternatively, this phenomenon may be confined to Jews. It has to be remembered that in numerous population studies, both UC and CD were found 3-4 times more frequently in Jews than in non-jews in a defined geographic area. 26-2s The reasons for this high prevalence are not known. Because it was found in various geographic areas and in variable environmental conditions, genetic factors are likely This higher prevalence was also found in areas in which Jews were assimilated and had dietary and social habits similar to the local population and did not observe traditional dietary and other habits. 3'2s-28 This strengthens the case for the existence of genetic predisposing factors in Jews. Thus, one possible explanation for our results would be that in the presence of strong genetic predisposition, smoking has no effect on IBD. If further studies confirm that the lack of association between smoking and IBD is not found in other populations and is confined to Jews, it would strengthen the above hypothesis. References 1. Mayberry JR. Some aspects of the epidemiology of ulcerative colitis. Gut 1985;26: Mayberry JF, Mayberry JR. Epidemiological aspects of Crohn's disease: a review of the literature. Gut 1984;25: Gilat T, Langman MJS, Rozen P. Environmental factors in inflammatory bowel disease. Front Gastrointest Res 1986;11: Person PG, Ahlbom A, Hellers G. Crohn's disease and ulcerative colitis: a review of dietary studies with emphasis on methodologic aspects. Scand J Gastroenterol 1987;22: Harries AD, Baird A, Rhodes J. Non-smoking: a feature of ulcerative colitis. BMJ 1982;284: Bures J, Fisa B, Komarkova O, Fingedand A. Non-smoking: a feature of ulcerative colitis. BMJ 1982;285: Jick H, Walker AM. Cigarette smoking and ulcerative colitis. N Engl J Med 1983;308: Logan RFA, Edmond M, Somerville KW, Langman MJS. Smoking and ulcerative colitis. BMJ 1984;288: Boyko JB, Koepsell TD, Perera DR, Inui TS. Risk of ulcerative colitis among former and current cigarette smokers. N Engl J Med 1987; 316: Franceschi S, Panza E, Lavecchia C, Parazinni F, Decarli A, Porto GB. Nonspecific inflammatory bowel disease and smoking. Am J Epidemiol : Somerville KW, Logan RFA, Langman MJS. Smoking and Crohn's disease. BMJ 1984;289: Tobin MV, Logan RFA, Langman MJS, McConell RB, Gilmore IT. Cigarette smoking and inflammatory bowel disease. Gastroenterology 1987; 93: Thorton JR, Emmett PM, Heaton KW. Smoking, sugar, and inflammatory bowel disease. BMJ 1985;290: Vessey M, Jewell D, Smith A, Yeates D, McPherson K. Chronic inflammatory bowel disease, cigarette smoking, and use of oral contraceptives: findings in a large cohort study of women of childbearing age. BMJ 1986;292: Sokal RR, Rohlf FJ. Biometry. New York: Freeman, 1981: Breslow NE, Day NE. Statistical methods in cancer research I: IARC scientific publication no. 32. Volume 1. The analysis of case control studies. 1980: Ben Sira Z. Smoking! Follow up of trends cessation and continuation. Survey no Jerusalem: The Lewis Gutman Israel Institute of Applied Social Research, Israel government publications no. 5/2BS/1171/H, January Schlesselman JJ. Sample size in case-control studies: design, conduct, analysis. Monographs in epidemiology and biostatistics. New York: Oxford University, 1982: Bailar CB. Cigarettes, ulcerative colitis, and interferences from uncontrolled data. N Engl J Med 1983;308: Lindberg E, Tysk C, Andersson K, Gamerot G. Smoking and inflammatory bowel disease: a case control study. Gut 1988;29: Parsson PG, Ahlbom A, Hellers G. Inflammatory bowel disease and tobacco smoke. A case control study. Gut 1990; 31: Tobin MV, Logan RFA, Langman MJS, McConnell RB, Gilmore IT.

5 June 1995 SMOKING AND IBD IN JEWS 1687 Cigarette smoking and inflammatory bowel disease. Gastroenterology 1987;93: Motley R J, Rhodes J, Ford GA. Time relationship between cessation of smoking and onset of ulcerative colitis. Digestion 1987; 37: Motley R J, Rhodes J, Kay S, Morris TJ. Late presentation of ulcerative colitis in ex-smokers. IntJ Colorectal Dis 1988;3: Pullan RD, Rhodes J, Ganesh S, Mani V, Morris JS, Williams GT, Newcombe RG, Russell MAH, Feyerabend C, Thomas GAO, S~we U. Transdermal nicotine for active ulcerative colitis. N Engl J Med 1994; 330: Gilat T, Grossman A, Fireman Z, Rozen P. inflammatory bowel disease in Jews. Front Gastrointest Res 1986; 11: Grossman A, Fireman Z, Lilos P, Novis B, Rozen P, Gilat T. Epide- miology of ulcerative colitis in the Jewish population of central Israel Hepatogastroentrology 1989;3: Fireman Z, Grossman A, Lilos P, Eshchar Y, Theodor E, Gilat T. Epidemiology of Crohn's disease in the Jewish population of central israel, Am J Gastroentero11989;84: Received July 12, Accepted February 17, Address requests for reprints: Tuvia Gilat, M.D., Department of Gastroenterology, Tel Aviv Sourasky Medical Center, 6 Weizmann Street, Tel Aviv 64239, Israel. Fax: (972) Part of these data are included in the Master of Science thesis of Y. Klein, Tel Aviv University, Tel Aviv, Israel. The authors thank Hannan Farbstein and Motti Farbstein of the Israel Cancer Research Fund for very valuable statistical help and Flora Lubin for her valuable contributions to the study design and in performing the investigation.