Aliment Pharmacol Ther 2003; 17 (Suppl. 2): 11–17.

Review article: Crohn’s disease: monitoring disease activity R. SOSTEG NI, M. DAPERNO, N. SCAGLIONE, A . LAVAG NA, R. ROCCA & A. PERA UOA Gastroenterologia, Ospedale Mauriziano Umberto I, Torino, Italy

SUMMARY

A global measurement of Crohn’s disease activity, comprising clinical, endoscopic, biochemical and pathological features is not available yet and perhaps is unobtainable. In this review we analyse the most used and validated clinical indices (Crohn’s Disease Activity Index [CDAI], Perianal Disease Activity Index [PDAI], fistula drainage assessment), quality of life scores (Inflammatory Bowel Disease Questionnaire [IBDQ]), sub-clinical markers (C-reactive protein, faecal

INTRODUCTION

Various features can be taken into account in measuring activity in Crohn’s disease, depending on different perspectives. A basic laboratory scientist would use cytokines; a clinical laboratory investigator C-reactive protein, intestinal permeability, calprotectin; a clinical trialist Crohn’s Disease Activity Index (CDAI), Perianal Disease Activity Index (PDAI), fistula drainage assessment; a health administrator would consider costs; and a patient would focus on quality of life (Inflammatory Bowel Disease Questionnaire [IBDQ]).1 In the last 25 years many disease-specific instruments to measure activity have been created but none of these has been widely adopted by practicing gastroenterologists in their everyday work. Generally the clinicians prefer to use global medical judgement rather than numeric activity indices, which are often complex and time-consuming. Correspondence to: Dr A. Pera, UOA Gastroenterologia, Ospedale Mauriziano Umberto I, Largo Turati 62, I-10128 Torino, Italy. E-mail: [email protected]  2003 Copyright Blackwell Publishing Ltd

calprotectin, intestinal permeability) and endoscopic indices (Crohn’s Disease Endoscopic Index of Severity [CDEIS] ⁄ Simple Endoscopic Score for Crohn’s Disease [SES-CD], Rutgeeerts’ score for postsurgical recurrence). We also review the main advantages and disadvantages of each of these scoring systems. All these indices are rather complex and time-consuming, therefore their use is limited to clinical trials. In everyday clinical practice most gastroenterologists rely on their global clinical judgement, which is less reproducible, but simpler for decision-making.

Measures of activity in Crohn’s disease, however, are very useful in clinical trials in order to enrol homogeneous groups of patients and to evaluate their response to treatment; activity indices have to be simple and easily reproducible. CLINICAL ACTIVITY SCORES

Before 1979 very few clinical trials were performed to evaluate new treatments for Crohn’s disease and no score of disease activity was used. The Crohn’s Disease Activity Index CDAI2 was developed and validated before the beginning of the National Cooperative Crohn’s Disease Study.3 The investigators identified 18 potential predictor variables that were prospectively collected in 187 visits. A multivariate regression analysis was performed in order to develop an equation that best predicted the investigator’s overall rating for each patient. Eight variables were identified for CDAI (Table 1). 11

12

R. SOSTEGNI et al.

Table 1. Crohn’s Disease Activity Index (CDAI)2 Variable

Description

Multiplier ·2

Number liquid stools

Sum of 7 days

Abdominal pain

Sum of 7 days ratings

General well being

Sum of 7 days ratings

Extraintestinal complications

Number of listed complications

Antidiarrhoeal drugs

Use in the previous 7 days

Abdominal mass

Hematocrit

Expected–observed Hct

Body weight

Ideal ⁄ observed ratio

0 ¼ none 1 ¼ mild 2 ¼ moderate 3 ¼ severe 0 ¼ generally well 1 ¼ slightly under par 2 ¼ poor 3 ¼ very poor 4 ¼ terrible Arthritis ⁄ arthralgia, iritis ⁄ uveitis, erythema nodosum, pyoderma gangrenosum, aphtous stomatitis, anal fissure ⁄ fistula ⁄ abscess, fever > 37.8 C 0 ¼ no 1 ¼ yes 0 ¼ no 2 ¼ questionable 5 ¼ definite Males: 47-observed Females: 42-observed [1 ) (ideal ⁄ observed)] · 100

CDAI scores range from 0 to approximately 600. In order to identify the limit between remission and active disease, the investigators believed that various cut-off values between 100 and 200 points could be selected such that most patients rated by physicians as ‘very well’ would fall below and most others would fall above. They chose 150 points as a reasonable compromise. The limit between active and very severe disease was defined as a cut-off value of 450 points. Subsequently, some investigators have arbitrarily labelled CDAI scores of 150–219 as mildly active disease and scores of 220– 450 as moderately active disease. The CDAI system has some limitations: 1 interobserver variability;4 2 relevant weight for scores of ‘general well being’ and ‘intensity of abdominal pain’ items, which are subjective and reflect patients’ perceptions of their disease; 3 the calculation of the CDAI is based on a diary filled in by the patient for 7 days before evaluation. This requirement precludes the use of the CDAI in everyday practice; 4 it is not accurate in patients with fistulizing and stenosing behaviour;

·5

·7

·20

·30 ·10

·6 ·1 (NOT < )10)

5 it is not useful in patients with previous extensive ileo-colonic resections or stoma. Up to the present time, however, CDAI is the most frequently used index for clinical trials and must be considered the gold standard for evaluation of disease activity. Other clinical activity indices In the past other activity indices have been proposed: the Simple index (or Harvey Bradshaw index),5 the Organization Mondiale de Gastroenterologie (OMGE) index,6 and the Cape Town index.7 These three validated clinical indices all correlate with each other and with the CDAI. Another index that has been prospectively validated is the van Hees or Dutch index,8 a combined clinical and laboratory index that correlates poorly with the CDAI and with the other mentioned indices, probably as a result of its extensive use of laboratory-based items. Studies are needed in order to simplify the CDAI, possibly including only patients symptoms. Several authors recommend that CDAI be used as a disease activity index only in patients with inflammatory behaviour.

 2003 Copyright Blackwell Publishing Ltd, Aliment Pharmacol Ther 17 (Suppl. 2), 11–17

REVIEW: MONITORING CROHN’ S DISEASE ACTIVITY

probably be considered at present the gold standard for evaluating severity of perianal disease.

Perianal Crohn’s Disease Activity Index In patients with fistulizing disease the CDAI may score very low and does not represent an accurate instrument to assess the activity of perianal Crohn’s disease or of Crohn’s disease with other fistulas. In 1995 Irvine et al.9 reported a scoring system to evaluate the severity of perianal Crohn’s disease called PDAI (Table 2). The PDAI includes five items: 1 2 3 4 5

discharge, pain, restriction of sexual activity, type of perianal disease, degree of induration.

Each category is graded on a 5-point Likert scale ranging from no symptoms (score of 0) to severe symptoms (score of 4); a higher score indicates more severe disease. PDAI has been validated in patients undergoing treatment with metronidazole and has been used as a secondary endpoint in a placebo-controlled trial of infliximab for the closure of perianal fistulas.10 This instrument should Table 2. Perianal Disease Activity Index (PDAI)9 Categories affected by fistulae

Score

Discharge

0 1 2 3 0 1 2

No discharge Minimal mucous discharge Moderate mucous or purulent discharge Gross faecal soiling Pain ⁄ restriction No activity restriction of activities Mild discomfort, no restriction Moderate discomfort, some limitations of activity Marked discomfort, marked limitations Severe pain, severe limitations Restriction of No restriction of sexual activity sexual activity Slight restriction of sexual activity Moderate limitations of sexual activities Marked limitations of sexual activities Unable to engage in sexual activities Type of No perianal disease ⁄ skin tags perianal disease Anal fissure ⁄ mucosal tear < 3 perianal fistulae ‡ 3 perianal fistulae Anal sphincter ulcerations or fistulae with significant undermining of skin Degree of No induration induration Minimal induration Moderate induration Substantial induration Gross fluctuance ⁄ abscess

13

3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

Fistula Drainage Assessment Recently a Fistula Drainage Assessment (Table 3) has been developed and used in order to classify enterocutaneous or perianal fistulae as being either open and actively draining or closed. This instrument has been used as the primary end-point for a placebo-controlled trial of infliximab for abdominal and enterocutaneous fistulae that led to regulatory approval of the drug in the United States and Europe.10 QUALITY OF LIFE MEASURES

Another parameter to monitor disease activity (which is widely used in clinical trials) is quality of life. In patients with Crohn’s disease there are two validated instruments to measure quality of life: the Rating Form of Inflammatory Bowel Disease Patient Concerns11 and the IBDQ.12 The most used in clinical trials as a secondary endpoint (up to the present time it is the gold standard) is the IBDQ, a 32-item questionnaire with four dimensions: 1 2 3 4

bowel function, emotional status, systemic symptoms, social function.

The total score on this index ranges from 32 to 224, with higher scores indicating better quality of life. The score of patients in remission usually is between 170 and 190. A relatively good correlation has been shown between IBDQ and CDAI (r ¼ )0.67; P ¼ < 0.001).13 Studies on IBDQ have been performed in patients with inflammatory behaviour, but there are no data in patients with primarily fistulizing Crohn’s disease. An alternative instrument, the Rating Form of Patients Concerns, quantifies disease-related patients’ concerns, but little experience exists using this measure as a parameter of outcome in randomized controlled trials. PROGNOSTIC SCORES AND BIOCHEMICAL (SUB-CLINICAL) MARKERS OF ACTIVITY

In 1986 Brignola et al.14 identified a laboratory index for predicting relapse in asymptomatic patients with

 2003 Copyright Blackwell Publishing Ltd, Aliment Pharmacol Ther 17 (Suppl. 2), 11–17

14

R. SOSTEGNI et al.

Table 3. Fistulae drainage assessment10 Endpoints

Definition

Improvement

Improvement defined as a decrease from baseline in the number of open draining fistulae of ‡ 50% for at least two consecutive visits (at least 4 weeks) Remission defined as closure of all fistulae that were draining at baseline for at least two consecutive visits (at least 4 weeks)

Remission

Closure of individual fistulae defined as no fistula drainage despite gentle finger compression.

Crohn’s Disease. In this study, disease activity was monitored by CDAI calculation and by measurement of erythrocyte sedimentation rate, white blood cell count, haemoglobin, albumin, a2-globulin, serum iron, C-reactive protein, a1-glycoprotein and a2-antitrypsin. At the beginning of the study the patients who later relapsed showed a remarkable alteration of acid a1glycoprotein, a2-globulin and erythrocyte sedimentation rate when compared to the patients who remained in remission. By discriminant analysis a prognostic index with these laboratory investigations provided a high accuracy (88%) in predicting the 18-month outcome. Biochemical markers C-reactive protein, faecal calprotectin and intestinal permeability are sub-clinical markers of activity commonly used in clinical practice and ⁄ or in clinical trials. C-reactive protein levels are usually increased in patients with active disease, with a significant (although loose) correlation to CDAI values. It has been proposed that systematic assessment of C-reactive protein during remission is also prognostically relevant, giving the possibility of predicting clinical relapse. A longitudinal assessment of C-reactive protein in 101 Crohn’s patients (48 of whom were in remission at the beginning of the study) gave different results: the 1-year relapse rate did not differ between patients with increased C-reactive protein compared to those with normal C-reactive protein; patients with persistent elevated C-reactive protein levels had a significantly higher relapse rate than other patients at 2 years.15 The prognostic role of C-reactive protein levels seems to be even more relevant in children. Faecal calprotectin is a calcium-binding neutrophil protein and is stable during intestinal transit; it represents up to 60% of total cytosol proteins of neutrophils and it is stable for 7 days at room temperature. It can be easily assessed in stools by means of

commercial ELISA tests and increased levels of calprotectin (> 50 mg ⁄ L) during remission were shown to be a good predictor of relapse within 1 year; the sensitivity and specificity of calprotectin in predicting relapse are 90% and 83%, respectively, with a relative risk of relapse of 10.6 in patients with calprotectin levels higher than 50 mg ⁄ L.16 Intestinal permeability, measured either with 51CrEDTA or by selective sugar permeability tests, is a surrogate marker of intestinal inflammation. It has been shown that intestinal permeability is increased in active Crohn’s disease and significantly decreases 4 weeks after infliximab infusion to values within the range found in normal volunteers.17 Also zinc supplementation has been shown to reverse permeability alterations in Crohn’s disease and may contribute to reduced relapse rates.18 In patients in remission increased intestinal permeability has been reported to have a significant prognostic role in Crohn’s disease relapse. In three different studies, sensitivity and specificity in the prediction of Crohn’s disease relapse at 1 year were 84% and 61%16 and 89% and 76%,19 while for relapse at 4 months were 53 and 85%, respectively.20 ENDOSCOPIC ACTIVITY SCORES IN CROHN’S DISEASE

The endoscopic pattern of Crohn’s disease has been characterized and it is based on a number of mucosal lesions: erythema, cobblestoning, aphtoid ulcerations and ulcers of variable size and depth, fistulas, and stenosis.21 Although such lesions show an extremely uneven distribution and degree of expression, in the past they have been found to be reliably reproducible.22 Crohn’s Disease Endoscopic Index of Severity (CDEIS) To measure the endoscopic activity of Crohn’s disease in 1989 the French group of GETAID (Groupe d’Etude

 2003 Copyright Blackwell Publishing Ltd, Aliment Pharmacol Ther 17 (Suppl. 2), 11–17

REVIEW: MONITORING CROHN’ S DISEASE ACTIVITY

Therapeutique des Affections Inflammatoires Digestive) developed the CDEIS.23 The CDEIS has been proposed and validated in a large multicentre trial, and after the first study it was used as marker of mucosal healing in a number of therapeutic trials.24–27 At present it represents the gold standard for evaluation of endoscopic activity (Table 4). The correlation of CDEIS with clinical activity, however, seems to be poor,26 and steroid-induced clinical remission shows little or no evidence of a relationship to mucosal healing;24, 25, 28 other studies have shown endoscopic healing under long-term azathioprine29, 30 and with infliximab anti-TNF treatment.27 There are initial reports of a longer remission and of a lower number of disease events in patients achieving endoscopic remission after infliximab treatment.31, 32 Endoscopic healing is becoming one of the goals of novel biologic therapies. The CDEIS, although reliable and reproducible, is rather time consuming and elaboration of the score requires analogue scale transformation. These characteristics make this endoscopic score unsuitable for everyday clinical practice and also its use can be complex in clinical trials.

15

Endoscopic Crohn’s Disease Index (SES-CD) Recently SES-CD has been proposed33 to simplify endoscopic activity assessment. SES-CD is based on four endoscopic variables to score 0–3 in the same five ileocolonic segments considered in the CDEIS (Table 5). Interobserver agreement (kappa values range 0.770– 1.000 for the different items) was good to excellent, and the resulting score was (Table 6): SES-CD ¼ sum of all variables  1:4  ðnumber of affected segmentsÞ

Reproducibility of the SES-CD results were as good as, if not better than, CDEIS. Nevertheless the clinical correlations of SES-CD results were weak although significant (SES-CD to CDAI r ¼ 0.371; SES-CD to C-reactive protein r ¼ 0.453). The SES-CD represents the answer to two of the aims of an ideal endoscopic score: it is easier and faster to score and calculate than CDEIS, and its results are reproducible and reliably correlating with the present standard. The role of everyday endoscopic assessment of activity is still not known, but endoscopic healing has become

Table 4. Scoring system for Crohn’s Disease Endoscopic Index of Severity (CDEIS)23 Rectum

Sigmoid and left colon

Transverse colon

Right colon

Ileum

Deep ulcerations (12 if present) Superficial ulcerations (12 if present) Surface involved by disease (cm) Surface involved by ulcerations (cm) Total 1 + Total 2 + Total 3 + Total 4 ¼ Number of segments totally or partially explored Total A ⁄ n ¼ If an ulcerated stenosis is present anywhere add 3 ¼ If a nonulcerated stenosis is present anywhere add 3 ¼ Total B + C + D ¼

Total Total 1 Total 2 Total 3 Total 4 Total A n Total B C D CDEIS

Table 5. Definitions of the Simple Endoscopic Score for Crohn’s Disease (SES-CD) variables33 SES-CD score Variable

0

1

2

3

Presence of ulcers

None

Ulcerated surface Affected surface Presence of narrowings Number of affected segments

None Unaffected segment None All variables ¼ 0

Aphtous ulcers (B 0.1–0.5 cm) < 10% < 50% Single, can be passed At least one variable ‡ 1

Large ulcers (B 0.5–2 cm) 10–30% 50–75% Multiple, can be passed

Very large ulcers (B > 2 cm) > 30% > 75% Cannot be passed

 2003 Copyright Blackwell Publishing Ltd, Aliment Pharmacol Ther 17 (Suppl. 2), 11–17

16

R. SOSTEGNI et al.

Ileum

Right colon

Transverse colon

Left colon

Table 6. Scoring sheet for E-CDI33 Rectum

Presence of ulcers Ulcerated surface Affected surface Presence of narrowings Affected segments

h

Sum of all variables h h h h TOT – 1.4 · (number of affected segments) ¼

Table 7. Rutgeerts’ score35

+ + + ¼ TOT E-CDI

The best comment on this issue are probably Sachar’s words:1

Grade

Endoscopic findings

i0 i1 i2

No lesions in the distal ileum £ 5 apthous lesions > 5 apthous lesions with normal mucosa between the lesions, or skip areas of larger lesions or lesions confined to ileocolonic anastomosis Diffuse apthous ileitis with diffusely inflamed mucosa Diffuse inflammation with already larger ulcers, nodules, and ⁄ or narrowing

i3 i4

SUM

‘…Perhaps it is for all these reasons, as well as on account of the heterogeneity of Crohn’s disease and the unpredictability of the human condition that our quest for the Holy Grail of one ‘‘best measure of disease activity’’ still remains today, in Korelitz’s words of 15 years ago, ‘‘a need unfulfilled’’…’

REFERENCES

one of the goals for monitoring treatment outcome in clinical trials. Rutgeerts’ score After a curative resection for Crohn’s disease the cumulative rate of symptomatic recurrence at 3 years is about 50%. Endoscopic examination has been shown to reveal signs of endoscopic recurrence in up to 60–70% of patients at 6–12 months.34 Even more importantly, however, it has been shown35 that the severity of the endoscopic recurrence is predictive of the subsequent clinical course; if there is no recurrence or only mild endoscopic recurrence (less than five aphtous ulcers) is present within the first year after resection, the symptomatic relapse rate at 7 years is 9%, while all patients with severe endoscopic recurrence had a symptomatic relapse within 4 years. At present Rutgeerts’ score is the gold standard for endoscopical post-surgical recurrence evaluation (Table 7). CONCLUSIONS

Many open issues and unanswered questions still remain concerning indices to assess Crohn’s disease activity.

1 Sachar DB. Defining clinical activity in Crohn’s disease In: Hanauer SB, Jewell DP, Rachmilewitz D, Scholmerich J, eds. Inflammatory Bowel Disease. Dordrecht: Kluwer Academic Publishers, 2002: 32–9. 2 Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology 1976; 70: 439–44. 3 Winship DH, Summers RW, Singleton JW, et al. National Cooperative Crohn’s Disease Study: study design and conduct of the study. Gastroenterology 1979; 77: 829–42. 4 de Dombal FT, Softley A. IOIBD report no. 1: Observer variation in calculating indices of severity and activity in Crohn’s disease. International Organisation for the Study of Inflammatory Bowel Disease. Gut 1987; 28: 474–81. 5 Harvey RF, Bradshaw JM. A simple index of Crohn’s disease activity. Lancet 1980; 1: 514. 6 Myren J, Bouchier IA, Watkinson G, et al. Multinational Inflammatory Bowel Disease Survey 1976–82. A further report on 2,657 cases. Scand J Gastroenterol Suppl 1984; 95: 1–27. 7 Wright JP, Marks IN, Parfitt A. A simple clinical index of Crohn’s disease activity—the Cape Town index. S Afr Med J 1985; 68: 502–3. 8 van Hees PA, van Elteren PH, van Lier HJ, van Tongeren JH. An index of inflammatory activity in patients with Crohn’s disease. Gut 1980; 21: 279–86. 9 Irvine EJ. Usual therapy improves perianal Crohn’s disease as measured by a new disease activity index. McMaster IBD Study Group. J Clin Gastroenterol 1995; 20: 27–32. 10 Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med 1999; 340: 1398–405.

 2003 Copyright Blackwell Publishing Ltd, Aliment Pharmacol Ther 17 (Suppl. 2), 11–17

REVIEW: MONITORING CROHN’ S DISEASE ACTIVITY 11 Drossman DA, Leserman J, Li ZM, Mitchell CM, Zagami EA, Patrick DL. The rating form of IBD patient concerns: a new measure of health status. Psychosom Med 1991; 53: 701–12. 12 Guyatt G, Mitchell A, Irvine EJ, et al. A new measure of health status for clinical trials in inflammatory bowel disease. Gastroenterology 1989; 96: 804–10. 13 Irvine EJ, Feagan B, Rochon J, et al. Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Canadian Crohn’s Relapse Prevention Trial Study Group. Gastroenterology 1994; 106: 287–96. 14 Brignola C, Campieri M, Bazzocchi G, Farruggia P, Tragnone A, Lanfranchi GA. A laboratory index for predicting relapse in asymptomatic patients with Crohn’s disease. Gastroenterology 1986; 91(6): 1490–4. 15 Boirivant M, Leoni M, Taricotti D, Fais S, Squarcia O, Pallone F. The clinical significance of serum C reactive protein levels in Crohn’s disease. J Clin Gastroenterol 1988; 10: 401–5. 16 Tibble JA, Sigthorsson G, Bridger S, Fagerhol MK, Bjarnason I. Surrogate markers of intestinal inflammation are predictive of relapse in patients with inflammatory bowel disease. Gastroenterology 2000; 119(1): 15–22. 17 Suenaert P, Bulteel V, Lemmens L, et al. Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease. Am J Gastroentrol 2002; 97(8): 1867–8. 18 Sturniolo GC, Di Leo V, Ferronato A, D’Odorico A, D’Inca R. Zinc supplementation tightens ‘leaky gut’ in Crohn’s disease. Inflamm Bowel Dis 2001; 7(2): 94–8. 19 Arnott IDR, Drummond H, Gosh S. Gut mucosal secretion of interleukin 1b and interleukin-8 predicts relapse in clinically inactive Crohn’s disease. Dig Dis Sci 2001; 46: 402–9. 20 D’Inca R, Di Leo V, Corrao G, et al. Intestinal permeability test as a predictor of clinical course in Crohn’s disease. Am J Gastroenterol 1999; 94(10): 2956–60. 21 Waye JD. The role of colonoscopy in the differential diagnosis of inflammatory bowel disease. Gastrointest Endosc 1977; 23(3): 150–4. 22 Modigliani R, Mary JY presenting the GETAID. Reproducibility of colonoscopic findings in Crohn’s disease: a prospective multicenter study of interobserver variation. Groupe d’Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Dig Dis Sci 1987; 32(12): 1370–9. 23 Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn’s disease: a prospective multicentre study. Groupe d’Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif (GETAID). Gut 1989; 30(7): 983–9.

17

24 Modigliani R, Mary JY, Simon JF, et al. Clinical, biological, and endoscopic picture of attacks of Crohn’s disease. Evolution on prednisolone. Groupe d’Etude Therapeutique des Affections Inflammatoires Digestives. Gastroenterology 1990; 98(4): 811–8. 25 Landi B, Anh TN, Cortot A, et al. Endoscopic monitoring of Crohn’s disease treatment: a prospective, randomized clinical trial. The Groupe d’Etudes Therapeutiques des Affections Inflammatoires Digestives. Gastroenterology 1992; 102(5): 1647–53. 26 Cellier C, Sahmoud T, Froguel E, et al. Correlations between clinical activity, endoscopic severity, and biological parameters in colonic or ileocolonic Crohn’s disease. A prospective multicentre study of 121 cases. The Groupe d’Etudes Therapeutiques des Affections Inflammatoires Digestives. Gut 1994; 35(2): 231–5. 27 D’Haens G, Van Deventer S, Van Hogezand R, et al. Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn’s disease: a European multicenter trial. Gastroenterology 1999; 116(5): 1029–34. 28 Olaison G, Sjodahl R, Tagesson C. Glucocorticoid treatment in ileal Crohn’s disease: relief of symptoms but not of endoscopically viewed inflammation. Gut 1990; 31(3): 325–8. 29 D’Haens G, Geboes K, Ponette E, Penninckx F, Rutgeerts P. Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn’s disease. Gastroenterology 1997; 112(5): 1475–81. 30 D’Haens G, Geboes K, Rutgeerts P. Endoscopic and histologic healing of Crohn’s (ileo-) colitis with azathioprine. Gastrointest Endosc 1999; 50(5): 667–71. 31 Colombel JF, Rutgeerts P, Yan S, et al. Infliximab maintenance treatment results in lower hospitalization rate in Crohn’s disease patients. Gastroenterology 2002; 122: A613(Abstract). 32 D’Haens G, Noman M, Baert F, et al. Endoscopic healing after infliximab treatment for Crohn’s disease provides a longer time to relapse. Gastroenterology 2002; 122: A100 (Abstract). 33 Daperno M, Van Assche G, Bulois P, et al. Development of Crohn’s disease endoscopic score (CDES): a simple index to assess endoscopic severity of Crohn’s disease. Gastroenterology 2002; 122: A216(Abstract). 34 Rutgeerts P, Geboes K, Vantrappen G, et al. Natural history of recurrent Crohn’s disease at the ileocolonic anastomosis after curative surgery. Gut 1984; 25: 665–72. 35 Rutgeerts P, Geboes K, Vantrappen G, Beyls J, Koremans R, Hiele M. Predictability of the postoperative course of Crohn’s disease. Gastroenterology 1990; 99(4): 956–63.

 2003 Copyright Blackwell Publishing Ltd, Aliment Pharmacol Ther 17 (Suppl. 2), 11–17