An Investigation into the Validity of the Present Classification of Inflammatory Bowel Disease

Quarterly Journal of Medicine, New Series 54, No. 214,pp. 183 190, February 1985 An Investigation into the Validity of the Present Classification of Inflammatory Bowel Disease G. HOLDSTOCK, D. SAVAGE, M. HARMAN and RALPH WRIGHT From the Professorial Medical Unit, Level D, S Laboratory and Pathology Block, Southampton General Hospital, Southampton SO9 4XY Accepted 19 July 1984 SUMMARY To assess the validity of the present subdivision of patients with inflammatory bowel disease into those with Crohn's disease of the small bowel or of the colon and those with ulcerative colitis, 252 patients with inflammatory bowel disease have been studied by questionnaire and case note review. One hundred and seventy-two variables concerning the nature and frequency of symptoms in remission and relapse, the incidence of complications and results of investigation have been analysed by computer. As expected, there were many highly significant variables between patients with ulcerative colitis and those with Crohn's disease of the small bowel. The latter showed evidence of a more severe disease course with more complications. There were similar, although less marked, differences between patients with Crohn's disease of the colon and those with Crohn's disease of the small bowel. There were very few differences in disease course between patients with Crohn's disease of the colon and those with ulcerative colitis. The results suggest that while separate classification of patients with Crohn's disease of the small bowel is justified on clinical grounds, the present separation of patients with disease confined to the colon into groups labelled ulcerative colitis or Crohn's disease of the colon is not. Alternative methods of classification should therefore be investigated. INTRODUCTION The present classification of patients with inflammatory bowel disease has largely arisen for historical reasons. Ulcerative colitis was the first to be described (1) and subsequently inflammatory bowel disease involving the small bowel was reported and given the eponym of Crohn's disease (2). These patients behaved differently from those with ulcerative colitis, thereby justifying the eponym. Later it was realised that patients with small bowel disease could also have colonic disease (3) and that some patients in whom there was only colonic disease had pathological features similar to those of Crohn's disease of the small bowel (4). These patients were then labelled as having Crohn's colitis, and early studies suggested that they had a rather worse prognosis than those patients with ulcerative colitis (5, 6). Recently there have been considerable advances in diagnostic methods, particularly the advent of colonoscopy, which allows the whole colon to be directly viewed with the facility for

184 G. Holdstock and others multiple biopsies. Although there may have been real changes in the epidemiology of the two conditions, with an increasing incidence of Crohn's disease (7, 8) it is likely that at least some of these new diagnostic techniques have resulted in patients who previously would have been labelled as having ulcerative colitis being reclassified for Crohn's disease of the colon, for example with the finding of granulomas in biopsy material. Because of this, we felt it important to reassess the clinical course of patients with these various forms of inflammatory bowel disease diagnosed on present criteria to see whether the different subgroups did indeed behave differently. To do this, we assessed the disease course in a large number of patients and compared the clinical course of patients in the various subgroups. PATIENTS AND METHODS A total of 252 consecutive patients attending medical outpatient clinics of the three gastroenterologists in Southampton because of inflammatory bowel disease between 1 November 1982 and 30 April 1983 were interviewed and their casenotes reviewed. Details of the frequency of relapse, the nature and severity of symptoms in relapse and remission, medication, disease extent as assessed radiologically and colonoscopically, the incidence of complications and the number of hospital admissions and surgical interventions for each patient were recorded. The questionnaire was designed on similar lines to those of a recent computer survey (9). The mean of the three most recent haemoglobin, w.b.c, ESR platelet and albumin levels taken were recorded. The data for each patient were transferred on to computer cards and the total of 172 variables per patient were investigated. Analysis was carried out on an ICL 2970 computer using the Statistical Package for the Social Services (SPSS). The chi-squared test with Yates' correction factor where appropriate was used for all cross-correlations of coded variables. Continuous variables were analysed using the two-tailed Student's r-test and the Mann-Whitney test. Probability values of less than 5 per cent were considered to be significant. The patients were divided into four groups, depending on the diagnosis designated by the gastroenterologist in charge of the patient. Group 1 consisted of patients with ulcerative colitis, Group 2 of patients with Crohn's disease of the colon and Group 3 of patients with Crohn's disease of the small bowel. Patients who did not fulfil either category and had features of both groups formed a separate group (intermediate colitis (10)). Patients with Crohn's disease with both small bowel and colonic features were only included in the small bowel group. The diagnosis recorded was that made by the consultant in charge of the individual case. This depended on a combination of clinical, radiological and histological features with perhaps more emphasis on the last. Histological features considered to be diagnostic of Crohn's disease were the presence of granulomas, rectal sparing, skip lesions and full thickness of inflammation in resected specimens. RESULTS A comparison of patients with ulcerative colitis and those with Crohn's disease of the small bowel is shown in Table 1. There were many differences between these two groups, including, from the patient questionnaire, symptoms in relapse and remission and in the incidence of complications, most notably a history of anal problems which occured in 16 per cent of ulcerative colitis patients compared with 37 per cent of those with Crohn's disease of the small bowel (p < 0.005). Anal fistulas were recorded in two patients with ulcerative colitis and eight with Crohn's disease of the small bowel (p < 0.005). In general, the latter had a more severe disease course, best illustrated by the frequency of relapse (p < 0.02), the frequency of hospital admission (p ) and surgical intervention (p ).

The Present Classification of Bowel Disease 185 TABLE 1. Significant differences between patients with ulcerative colitis (UC) and small bowel Crolm s disease (SBC)* Number Symptoms in relapse Severity of pain (0 10 visual analogue scale) Blood (per rectum) Mucus Nausea Fever Weight loss Anorexia Symptoms in remission Tenesmus Diarrhoea Complications (on history) Anal problems Anaemia Complication (on casenote review) Anal fistula Investigations ESR Albumin UC 102 73 (72) 5.2 ±2.4 92(91) 92(91) 31 (30) 19(19) 47(46) 38(37) 2(2) 13(13) 22(22) 16 (16) 34(33) 2(2) 1 5.3 ± 1 5 41+4.4 0. 7± 1 1. 9± 2.3 67. 5± 12 SBC 54 48(89) 7 ±2.4 23(43) 36(67) 28(52) 26(48) 36(67) 37(69) 7(13) 18(33) 23 (43) 20(37) 29 (54) 8(15.8) 22.9 ± 19 39 + 4.3 1.9 + 1.8 4 + 5.2 52 + 11 P < 0.024 < 0.014 < 0.0002 < 0.022 < 0.0004 < 0.01 5 < 0.004 < 0.01 < 0.005 < 0.022 < 0.005 < 0.013 < 0.011 Number undergoing surgery for inflammatory bowel disease (IBD) 4(3.9) 27(50) Mean number hospital admissions for IBD Average number of relapses per year Mean body weight (kg) *Percentages in parentheses. <0.0001 <0.018 <0.006 A comparison of patients suffering Crohn's disease of the colon and those with Crohn's disease of the small bowel is shown in Table 2. Again the latter had evidence of a more severe disease course with more frequent relapses (p<0.02), more frequent hospital admissions (p) and surgical intervention (p ). Perhaps the most interesting results emerged from a comparison of patients with ulcerative colitis and those with Crohn's disease of the colon (Table 3). In relapse, the former were less likely to pass mucus (p < 0.05) or to be incontinent (p < 0.03) but were more likely to complain of anorexia (p < 0.02). The latter were more likely to have erythema nodosum (p < 0.03) and anal abscesses (p < 0.008), but less likely to have sacral ileitis (p < 0.05). The ESR (p < 0.002) and w.b.c. (p< 0.04) were higher in patients with Crohn's disease of the colon, and these were also more likely to have undergone surgery (p < 0.05). There were also striking differences in smoking habits (p < 0.002). Smoking habits were found to differ considerably between all groups. Only 8 per cent of ulcerative colitis patients were current smokers, 32 per cent ex-smokers and 60 per cent were non-smokers. Respective figures for Crohn's disease of the colon were 26, 36 and 48 per cent,

186 G. Holdstock and others TABLE 2. Significant differences between patients with Crohn's disease of the colon (CC) and Crohn 's disease of the small bowel (SBC)* Number Symptoms in relapse Severity of pain (0 10 visual analogue scale) Blood pressure Fever CC 66 47(73) 5.7 ± 2.5 51 (77) 18(27) SBC 55 48(89) 7 ±2.5 23 (43) 26(48) P < 0.04 < 0.01 1 < 0.0004 < 0.03 Symptoms in remission Complications (on history) Anaemia Number undergoing surgery for inflammatory bowel disease (IBD) Mean number hospital admissions Average number of relapses per year Mean body weight (kg) 15 (23) 19(28) 9(14) 8 ±0.8 1.8 ±1.8 67+11.8 23 (43) 29 (54) 27(50) 1.9±1.8 4±5.2 62 ± 1.5 < 0.031 < 0.0098 < 0.027 < 0.027 *Percentages in parentheses. TABLE 3. Significant differences between patients with ulcerative colitis (UC) and Crohn 's disease of the colon (CC)* Number Symptoms in relapse Mucus Anorexia Incontinence Incidence of complications Erythema nodosum Sacroileitis Anal abscess Investigations: w.b.c. ESR Number undergoing surgery for inflammatory bowel disease (IBD) UC 102 92 (91) 38(37) 39(38) 1 (1) 8(8) 2 (2) 7.87±2.9 1 5.3 ±15 4 (3.9) CC 66 20(30) 38(58) 14(21) 6(9.1) 0 9 (14)+ 8.9 ±3.0 24.4 ± 19 9 (13.6)+ P 0.003 0.015 0.03 0.03 0.05 0.008 0.04 0.002 0.05 *Percentages in parentheses. t Four patients labelled as CC with evidence of anal abscess on review were found to have features of UC rather than CC. If it is assumed that the diagnosis has been unjustifiably influenced by the presence of this finding, which is typically associated with CC, and these patients omitted, there would then be no difference between groups in these respects (see text). and for Crohn's disease of the small bowel 52, 13 and 35 per cent. Thus, taking these three groups of patients, significantly fewer patients with ulcerative colitis were current or ex-smokers (p < 0.02). On the other hand, significantly more patients with Crohn's disease of the small bowel are current smokers, compared to those with Crohn's disease of the colon (p < 0.02) or those with ulcerative colitis (p ).

The Present Classification of Bowel Disease 187 TABLE 4. Similarities between patients with ulcerative colitis (UC) and Crolm 's disease of the colon (CCj* Number Male/female ratio Symptoms in relapse Severity of pain (0 10 scale) Blood pressure Fever Nausea Weight loss Fatigue Tenesmus Symptoms in remission Diarrhoea Complications (on history) Joint pains Skin problems Mouth ulcers Anal problems Anaemia Eye disease Liver disease Complications (on casenote review) Sclerosing cholangitis Pyoderma gangrenosus Arthritis Ankylosing spondylitis Anal fissures Anal fistulae Investigations Hb Platelets Albumin UC 102 41/66 73(72) 5.2±2.5 92 (91) 19 (19) 31 (30) 47 (46) 85 (83) 58(57) 22(22) 13(13) 34(33) 32 (31) 33(32) 16(16) 34(33) 14(14) 3 (3) 1 (1) 2(2) 12(12) 5 (5) 7 (7) 2 (2) 12.9 + 1.8 321±102 41 ±4.4 CC 66 22/44 47(73) 5.7±2.5 51(77) 18(27) 25 (39) 38(56) 54(82) 33(50) 15 (23) 12(18) 26(35) 15(24) 20(30) 14(21) 19(29) 9(14) 4(6) 1 (1.5) 0 10(15) 2(3) 6 (9) 5 (7.6) 13.1 ±1.3 359 ± 131 40±4.0 Number of out patient department visits in last 12 months 5.3 ±3 4.9 ±2.4 Number of hospital admissions for inflammatory bowel disease (IBD) 0.7 ± 1 0.8±0.8 Average number of relapses per year 1.9 ±2.3 1.8 ±1.8 Duration of disease 7.3 ±4.1 7.8 ±4.8 *Percentages in parentheses. Similarities in the two groups are shown in Table 4, and notably there was no difference between the average number of relapses per year, outpatient visits or hospital admissions between the two groups. Haemoglobin, platelet counts and albumin levels were not significantly different. There was no marked difference in the severity, character or position of pain, and most extragastrointestinal complications occurred equally in both groups. The nine patients with Crohn's disease of the colon and anal fissure were reviewed to see on what grounds diagnosis had been made. Four of them were found to have features otherwise typical of ulcerative colitis, but to have been recorded as having Crohn's disease of the colon

188 G. Holdstock and others because of the development of this complication and the recognition that it was a feature of the latter rather than the former. If these patients were removed from the analysis, there was then no significant difference between the incidence of the complications of Crohn's disease of the colon and ulcerative colitis. This illustrates the difficulty of diagnosis in these conditions. These four patients also accounted for the difference in the number of surgical operations, as they had all undergone surgery for their anal problem. Again, if these were removed, there was no increased frequency of surgery in patients with Crohn's disease of the colon. Current and previous therapy was significantly different between groups, with ulcerative colitis patients much more likely to be taking sulphasalazine and Crohn's patients more likely to be on steroids, metronidazole or azothiaprine. However, these difficulties clearly result as sequelae to diagnosis and do not necessarily indicate differences between groups. As expected, there were no relevant differences between patients with intermediate colitis and either ulcerative colitis or Crohn's disease of the colon, but numbers were small. DISCUSSION The retrospective nature of this study, together with the large number of variables assessed, result in some difficulties in interpretation. However, we believe the results do give a reasonably accurate picture of the disease course. We have shown major differences in the disease course between patients with Crohn's disease of the small bowel and those with ulcerative colitis. Similar but less marked differences were found between patients with Crohn's disease of the small bowel and those with Crohn's disease of the colon. However, there were few clinically important differences between patients with ulcerative colitis and Crohn's disease of the colon. Furthermore, those which were present were minor and their very presence may have had unjustifiable influence on the diagnostic label attached to the patient since certain features are traditionally associated with particular diagnoses. Furthermore, a small proportion of patients with Crohn's disease of the colon may have undetected small bowel disease, thereby accounting for some of the differences that did emerge between these patients and those with ulcerative colitis. We believe that these findings are important as they suggest that assumptions made early in the history of the disease can no longer be held to be correct with modern diagnostic criteria. Thus, the importance of the more subtle histological evidence of Crohn's disease which emerged from the greater use of colonoscopy remains to be defined. Most gastroenterologists at present believe in subgrouping patients with inflammatory bowel disease into the groups discussed (11, 12), although there is a minority view that this is unnecessary (13) as it may not influence immediate management. It appears to us that subgrouping is warranted only should there be significant differences in the disease course between the groups. Our results would favour the use of a subgroup for patients with Crohn's disease of the small bowel, as these patients behave differently from those with only colonic involvement. On the other hand, subdividing patients with disease apparently confined to the colon does not seem justified in view of the very minor differences between the groups. The eponym of'crohn's disease' carries with it the suggestion of a poorer prognosis. It may therefore cause unnecessary alarm to the doctor and the patient withcrohn's disease of the colon who might understandably consider the prognosis to be that of a patient with small bowel disease. It is clear that there does appear to be a small subgroup of patients with Crohn's colitis with a poor prognosis because they develop the abscesses and fistulas so characteristic of patients with small bowel disease. This study has shown that the present criteria for diagnosis do not adequately separate these patients from those likely to run a more benign course. There is therefore a need to reassess individual criteria for diagnosis prospectively, taking into account

The Present Classification of Bowel Disease 189 modern diagnostic techniques, to see whether a better distinction can be made. For example, we and others have shown that granulomas are of no clinical relevance in this respect (14-16). It is possible that other variables, such as the nature of the inflammation or the accurately assessed anatomical extent of the disease, might be more useful in this respect. Indeed, it is well recognised that patients discovered to have ileocolic disease at laparotomy are more likely to undergo further surgery than those with disease confined to the colon or the small bowel (17). Some follow-up studies of patients with either ulcerative colitis or Crohn's disease confined to the colon after surgery have shown that there is little difference in the recurrence rate or requirement for further surgery between these two groups (18 20). Thus, some authors claim that in patients with disease confined to the colon, surgical decisions should not be influenced by the fear that those patients with features of Crohn's disease may be more likely to develop recurrent disease. Although these studies did not assess disease progress in such detail and only concentrated on surgical recurrence rates, they do demonstrate the similarity between the two conditions. Furthermore, any differences that occur might be related to disease of the small bowel which was undetected by standard radiological techniques. Therefore it may be that the most important feature, both in terms of prognosis and surgical management, is the presence of small bowel disease. In this regard, further study of non-invasive methods of investigating the presence or absence of small bowel disease such as the absorption of bile salts (21, 22), absorption of inert substances (23) or white cell labelling (24) are important. It cannot be denied that other studies on patients with Crohn's colitis undergoing colectomy have suggested that recurrence is common, perhaps as high as 50 per cent at 10 years (25 27). We believe that the lack of agreement between these studies and those discussed above may well result because of differences in diagnostic criteria. Also, results inevitably depend on how carefully patients with small bowel involvement are excluded, and those points are not fully discussed. It is possible that we are labelling patients as having Crohn's disease of the colon whom others would diagnose as suffering from ulcerative colitis. We cannot deny this possibility, but suggest that it further supports the need to search for better prognostic markers and clearly defined criteria of diagnosis, including the value of colonoscopic findings. The relevance of the differences in smoking habits is unclear and is discussed elsewhere (28). In conclusion, this study shows that established criteria of diagnosis need to be revised in view of recent developments in diagnostic techniques. The results indicate the prognostic significance of small bowel involvement in inflammatory bowel disease, but do not support the subclassification of patients with disease confined to the colon into those with ulcerative colitis or Crohn's disease of the colon. The study highlights the difficulties in comparing studies from different centres, as diagnostic criteria are not well defined. REFERENCES 1. Wilks S, Moxon W. Lectures on Pathological Anatomy, 2nd edn, 408 409. Philadelphia: Lindsay and Blakiston, 1875. 2. Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis: a pathological and clinical entity. JAMA 1932; 99: 1323-1329. 3. Wells C. Ulcerative colitis and Crohn's disease. Ann R Coll Surg Engl 1952; 11: 105-120. 4. Lockhart-Mummery HE, Morson BC. Crohn's disease (regional enteritis) of the large intestine and its distinction from ulcerative colitis. Gut 1960; 1: 87-105. 5. Allan R, Steinberg DM, Alexander-Williams J, Cooke WJ. Crohn's disease involving the colon: an audit of clinical management. Gastroenterology 1977; 73: 723 732. 6. Fanner RG, Hawk WA, Turnbull RB. Regional enteritis of the colon: a clinical and pathological comparison with ulcerative colitis. Am J Dig Dis 1968; 13: 501-514. 7. Miller DS, Keighley AC, Irangman MJS. Changing patterns in epidemiology of Crohn's disease. Lancet 1974; 2: 691-693.

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