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Appropriateness of immunosuppressive drugs in inflammatory bowel diseases assessed by RAND method: Italian Group for IBD (IG-IBD) position statement
Digestive and Liver Disease 37 (2005) 407–417
Alimentary Tract
Appropriateness of immunosuppressive drugs in inflammatory bowel diseases assessed by RAND method: Italian Group for IBD (IG-IBD) position statement R. Caprilli a,∗ , E. Angelucci a , A. Cocco a , A. Viscido a , V. Annese b , S. Ardizzone b , L. Biancone b , F. Castiglione b , M. Cottone b , G. Meucci b , P. Paoluzi b , C. Papi b , G.C. Sturniolo b , M. Vecchi b a
Promoter Centre, GI Unit, Department of Clinical Science, University of Rome ‘La Sapienza’, Viale del Policlinico 155, 00161 Rome, Italy b Italian Group for IBD (IG-IBD), Italy Received 23 July 2004; accepted 22 December 2004 Available online 9 March 2005 See related commentary on pages 391–393
Abstract Introduction. Despite the explosion of biological therapies, the old immunosuppressants continue to play a pivotal role in the management of inflammatory bowel diseases. Aim. To assess the appropriateness of immunosuppressants—azathioprine, 6-mercaptopurine, methotrexate, cyclosporine A, tacrolimus (FK506), mycophenolate mofetil and thalidomide—in the treatment of inflammatory bowel disease by using RAND/University of California Appropriateness Method. Methods. The RAND method consists of a combination of evidence from the literature and experts’ opinions. Appropriateness has been defined to mean that the expected health benefit exceeds the expected negative consequences by a sufficiently wide margin. A panel of 10 experts from the Italian Group for Inflammatory Bowel Disease has rated, in two rounds, on a scale from 1 to 9, the appropriateness of each indication selected by the Promoter Centre, on the basis of their own clinical experience. An indication was considered appropriate if the median of the panelists’ ratings fell within the area 7–9, inappropriate in the area 1–3 and uncertain in the area 4–6. A total of 2781 indications were grouped into 13 categories (mild to moderate Crohn’s disease; severe Crohn’s disease; fistulizing Crohn’s disease; steroid-dependant and -resistant Crohn’s disease; maintenance of remission induced by medical treatment in Crohn’s disease; maintenance of remission induced by surgery in Crohn’s disease; mild to moderate ulcerative colitis; severe ulcerative colitis; steroid-dependant and -resistant ulcerative colitis; maintenance of remission induced by medical treatment in ulcerative colitis; extra-intestinal manifestations in inflammatory bowel disease; pregnancy and inflammatory bowel disease; azathioprine-resistant or -intolerant inflammatory bowel disease patients). Results. Of the 2781 scenarios, 212 (7.6%) were rated appropriate, 645 (23.2%) uncertain and 1924 (69.2%) inappropriate. The most relevant results were: in steroid-dependant or -resistant Crohn’s disease, azathioprine, 6-mercaptopurine and methotrexate were defined as appropriate in 25 (86.2%) and 14 (48.3%) of the 29 scenarios respectively; in Crohn’s disease, azathioprine and 6-mercaptopurine were defined as appropriate combined with Infliximab (bridge therapy); in steroid-dependant or -resistant ulcerative colitis, azathioprine and 6-mercaptopurine were defined as appropriate in 45 (77.6%) out of 58 scenarios, while methotrexate was defined appropriate only after previous azathioprine failure; in severe ulcerative colitis, cyclosporine A was defined as appropriate only after previous failure with steroids; in azathioprine-intolerant or -resistant inflammatory bowel disease patients, methotrexate was appropriate in 20 (66.7%) out of 30 scenarios; it is inappropriate to stop azathioprine treatment before conception in the presence of active disease. The use of FK506, mycophenolate mofetil and Thalidomide resulted as inappropriate or uncertain.
∗
Corresponding author. Tel.: +39 06 4460009; fax: +39 06 4463737. E-mail address: [email protected] (R. Caprilli).
1590-8658/$30 © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2004.12.013
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Conclusions. Results of this study show that only azathioprine, 6-mercaptopurine and methotrexate are appropriate in the treatment of inflammatory bowel diseases. Cyclosporine A was found to be appropriate only in severe ulcerative colitis after the failure of steroids. FK506, mycophenolate mofetil and Thalidomide resulted as inappropriate but experience with these agents is somewhat limited. © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Azathioprine; Crohn’s disease; Cyclosporine; Immunosuppressive drugs; Inflammatory Bowel diseases; Methotrexate; Mycophenolate mofetil; RAM; RAND method; Tacrolimus; Thalidomide; Ulcerative colitis
1. Introduction
Table 2 Promoter Centre: University of Rome ‘La Sapienza’, Italy
The introduction and rapid diffusion of biological agents in the treatment of inflammatory bowel disease (IBD) has led us to believe that the old immunosuppressive drugs are destined to disappear. However, despite a decade of clinical experience in the use of biological agents, the old immunosuppressive drugs continue to play a pivotal role in the management of IBD. Ideally, immunosuppressive drugs would be used only in clinical situations in which the treatment has been proven to have a favourable impact on patient-management or outcome. There is, however, still considerable uncertainty concerning the appropriateness of immunosuppressive drugs in many situations. When strong evidence of efficacy from the literature is lacking, the next best evidence, on the evidence scale, is expert opinion (Table 1). The aim of this project is to contribute to a better understanding of the clinical situation for which there is still a need to rely on expert opinion. The opinions of several experts taking part in an Italian National Cooperative Study Group on IBD were collected using the RAND Appropriateness Method (RAM), one of the most widespread methods of developing expert opinion. This method was developed at RAND Corporation and University of California (UCLA) to evaluate the appropriateness of diagnostic and/or therapeutic procedures [1,2].
Renzo Caprilli Erika Angelucci Andrea Cocco Angelo Viscido
2. Project and methods Herein are described the results of a Panel of Expert Italian Gastroenterologists which convened in Turin, Italy on March 28–29, 2004. The Panel was organised by Promoter Centre (Table 2) together with the Italian Group for IBD (IG-IBD). The RAM consists of a combination of evidence from the literature and experts’ opinions. It is conducted in two phases. In the first phase, a detailed search is made of the literature by the Promoter Centre in order to identify studies evaluating Table 1 Hierarchy of evidence Meta-analysis and large RCTs/systematic reviews Single RCT Controlled clinical trials (without randomisation) Prospective observational cohort studies Retrospective studies Case reports, opinion of experts
Table 3 Immunosuppressive drugs currently used in IBD AZA 6-MP MTX CyA Tacrolimus (FK506) MMF THAL
the efficacy, safety and side effects of immunosuppressive drugs currently used in IBD (Table 3). The main source of literature database was MEDLINE (1966–2004). The MEDLINE search was conducted combining several MESH and non-MESH words. However, since MEDLINE usually retrieves only about half the relevant studies, we consulted other sources such as Cochrane Library and manual searches using the list of references of the most relevant articles, as well as those of reviews. The review of the literature was made systematically at the beginning of 2004, considering the hierarchy of evidence as set out in Table 1. The used database consists of more than 700 references. Approximately 500 were actually read and 114 were included in the final review of the literature. In the second phase, a list of the possible indications (several hundred) was drawn up for which immunosuppressive drugs were used. A Panel of 10 experts selected from the members of the IG-IBD were invited to take part in the project (Table 4). Table 4 Panelists taking part in the final Turin meeting Vito Annese, S. Giovanni Rotondo (FG), Italy, non-academic Sandro Ardizzone, Milan, Italy, academic Livia Biancone, Rome, Italy, academic Fabiana Castiglione, Naples, Italy, academic Mario Cottone, Palermo, Italy, academic Gianmichele Meucci, Como, Italy, non-academic Paolo Paoluzi, Rome, Italy, academic Claudio Papi, Rome, Italy, non-academic Giacomo Carlo Sturniolo, Padua, Italy, academic Maurizio Vecchi, Milan, Italy, academic
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The Promoter Centre distributed articles from an extensive review of the literature in February 2004, to the experts who were requested to study the material carefully and make additions to or suggestions or comments on it. The initial list of indications (or scenarios), as well as the literature review, were based on the existing literature dealing with these drugs, supplemented with the Panelists’ suggestions. Scenarios were identified by the Promoter Centre on the basis of all the possible situations that may be encountered in clinical practice. Scenarios have then been classified into 16 categories which became the object of the experts’ evaluation. Each expert was requested to rate, on a scale from 1 to 9, the appropriateness of each of the several hundred indications for which immunosuppressive drugs could, in practice or in theory, be used (1 = extremely inappropriate, 5 = uncertain, 9 = extremely appropriate). After having accomplished this task, each independently, the expert forwarded his/her ratings to the Promoter Centre for data entry and analysis. The Panel was convened 5 weeks later. The results of the initial ratings were distributed to all experts, allowing them to compare their own ratings with those of their fellow Panelists. Following an extensive discussion, focused mainly on differences emerging in evaluations, each expert again rated each indication discussed. It is the final result of the second rating-round that is used to determine appropriateness or inappropriateness of each indication and that is also presented in this article. Appropriateness was defined to mean that the expected health benefit exceeded the expected negative consequences (risks) by a sufficiently wide margin. Financial costs had no direct bearing on the appropriateness of the procedures evaluated by this method [1,2]. A scenario for a procedure was considered appropriate if the median of the panelists’ ratings fell within the area 7–9, without disagreement and inappropriate in the area 1–3, without disagreement. Scenarios with a median rating of 4–6, or those revealing disagreement among the Panelists were considered uncertain. Disagreement was defined, as occurring for a 10-member panel, when at least three panelists rated an indication from 1 to 3 on the scale and three others from 7 to 9 [2]. Previous drug failure means both intolerance and no response to treatment.
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Table 5 Categories (CD, UC) Mild to moderate CD: induction of remission Severe CD: induction of remission Fistulizing CD Steroid-dependant and -resistant CD Maintenance of remission induced by medical treatment in CD Maintenance of remission induced by surgery in CD Mild to moderate UC: induction of remission Severe UC: induction of remission Steroid-dependant and -resistant UC Maintenance of remission induced by medical treatment in UC AZA-intolerant and -resistant IBD patients Extra-intestinal manifestations in IBD patients Pregnancy in IBD patients
narios in a similar way both for Crohn’s disease (CD) and UC. 3.2. Number of ratings per category The number of ratings for each broad clinical category was: mild to moderate CD: induction of remission (105); severe CD: induction of remission (126); fistulizing CD (189); steroid-dependant and -resistant CD (210); maintenance of remission induced by medical treatment in CD (63); maintenance of remission induced by surgery in CD (82); extraintestinal manifestations in IBD (756); pregnancy and IBD (105); mild to moderate ulcerative colitis (UC): induction of remission (180); severe UC: induction of remission (216); steroid-dependant and -resistant UC (413); maintenance of remission induced by medical treatment in UC (96); azathioprine (AZA)-intolerant or -resistant and IBD (240). 3.3. Overall degree of appropriateness and agreement A total of 212 (7.6%) of the 2781 scenarios were rated appropriate, 645 (23.2%) uncertain and 1924 (69.2%) inappropriate. Agreement was reached on 1211 scenarios (43.5%), inconclusive agreement on 1432 (51.5%) and disagreement on 138 (5%). Results for each category are reported below. Due to the difficulty in summarising 2781 clinical scenarios, it has been impossible herein to present the full Panel results for all scenarios. The Promoter Centre remains at disposal.
4. Mild to moderate CD: induction of remission 3. Description of overall panel results 4.1. Definition of terms 3.1. Overall number of ratings The first rating round was performed on a total of 3382 scenarios, classified into 16 categories. This number was reduced to 2781 indications, classified into 13 categories (Table 5) since in those categories comprising pregnancy and extra-intestinal manifestations in IBD, panelists rated sce-
Mild to moderate CD: mildly active disease applies clinically to outpatients, patients able to tolerate oral alimentation, without showing signs of dehydratation, toxicity, abdominal tenderness, painful mass, obstruction, or >10% weight loss. Crohn’s Disease Activity Index (CDAI) between 150 and 220 [3].
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Table 6 Appropriateness of immunosuppressants in mild to moderate CD: subgroup analysis AZA/6-MP are appropriate: If previous steroids/new steroids failure If previous AZA/6-MP success MTX is appropriate: If previous AZA/6-MP failure Other immunosuppressants are inappropriate
Remission: clinical remission (CDAI < 150), if possible confirmed by endoscopy, referring to asymptomatic patients and including patients responding to medical treatment [4]. 4.2. Panel results Of the 105 scenarios, 4 (3.8%) were rated appropriate, 3 (2.9%) uncertain and 98 (93.3%) inappropriate. Significant agreement was reached on 94 scenarios (89.5%), inconclusive agreement on 11 (10.5%) and disagreement on none. An outline of the overall statements concerning the appropriateness of the use of immunosuppressants in mild to moderate CD is shown in Table 6.
5. Severe CD 5.1. Definition of terms Severe CD: severe active disease, refers to patients with persisting symptoms despite the introduction of steroids as outpatients, or individuals presenting with high fever, persistant vomiting, rebound tenderness, cachexia or evidence of an abscess. CDAI score > 450–600 [4]. 5.2. Panel results Of the 126 scenarios, 9 (7.1%) were rated appropriate, 26 (20.6%) uncertain and 91 (72.3%) inappropriate. Agreement was reached on 52 scenarios (41.3%), inconclusive agreement on 62 (49.2%) and disagreement on 12 (9.5%). Table 7 Appropriateness of immunosuppressants in severe CD: subgroup analysis AZA/6-MP are appropriate: If previous steroids/new steroids failure If previous AZA/6-MP success If previous Infliximab not given/failure/success
Fig. 1. Appropriateness of immunosuppressants in fistulizing CD.
Statements concerning the appropriateness of the use of immunosuppressants in severe CD are presented in Table 7.
6. Fistulizing CD 6.1. Definition of terms Fistulizing CD indicates a disease characterised by the presence of fistulas and/or abscesses. 6.2. Panel results Of the 189 scenarios, 18 (9.6%) were rated appropriate, 70 (37%) uncertain and 101 (53.4%) inappropriate. Agreement was reached on 47 scenarios (24.9%), inconclusive agreement on 136 (72%) and disagreement on 6 (3.1%). Statements concerning the appropriateness of the use of immunosuppressants in fistulizing CD are given in Fig. 1 and Table 8.
7. Steroid-dependant and -resistant CD 7.1. Definition of terms Steroid-dependance: partial or complete clinical response to treatment with prednisone or equivalent and relapse within 30 days of stopping prednisone treatment or relapse with a Table 8 Appropriateness of immunosuppressants in fistulizing CD: subgroup analysis
MTX is appropriate: If previous AZA/6-MP failure If previous steroids failure If previous Infliximab success
AZA/6-MP are appropriate: If previous antibiotics failure If previous AZA/6-MP not given/success If previous Infliximab not given/failure/success
Other immunosuppressants are inappropriate
Other immunosuppressants are inappropriate
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Table 10 Appropriateness of immunosuppressants in maintenance of remission induced by medical treatment in CD: subgroup analysis AZA/6-MP are appropriate: In maintenance of remission induced by steroids In maintenance of remission induced by AZA/6-MP In maintenance of remission induced by Infliximab MTX is appropriate: In maintenance of remission induced by MTX In maintenance of remission induced by Infliximab Other immunosuppressants are inappropriate
8.2. Panel results
Fig. 2. Appropriateness of immunosuppressants in steroid-dependant and -resistant CD. Table 9 Appropriateness of immunosuppressants in steroid-dependant and -resistant CD: subgroup analysis AZA/6-MP are appropriate: If previous AZA/6-MP not given/success If previous Infliximab not given/failure/success MTX is appropriate: If previous AZA/6MP failure If previous Infliximab failure
Of the 63 scenarios, 6 (9.5%) were rated appropriate, 10 (15.9%) uncertain and 47 (74.6%) inappropriate. Agreement was reached on 49 scenarios (77.8%), inconclusive agreement on 12 (19%) and disagreement on 2 (3.2%). Statements regarding the appropriateness of the use of immunosuppressants in the maintenance of remission induced by medical treatment in CD are given in Table 10.
9. Maintenance of remission induced by surgery in CD 9.1. Definition of terms
Other immunosuppressants are inappropriate
dose reduction of prednisone at doses ≤15–25 mg/day for at least 6 months [5]. Steroid-resistance: failing to respond within 30 days to prednisone treatment at doses of 40–60 mg/day [5].
Recurrence: the reappearance of new lesions after radical surgical resection. Remission: see first category. High risk of recurrence: see Fig. 3 [6]. Two different scenarios were considered: patients with high risk of recurrence and patients at low risk of recurrence. Fig. 3 shows the features of high risk of recurrence.
7.2. Panel results 9.2. Panel results Of the 210 scenarios, 51 (24.3%) were rated appropriate (37%), 39 (18.6%) uncertain and 120 (57.1%) inappropriate. Agreement was reached on 124 scenarios (59%), inconclusive agreement on 83 (39.5%) and disagreement on 3 (1.6%). Statements regarding the appropriateness of the use of immunosuppressants in steroid-dependant or -resistant CD are showed in Fig. 2 and Table 9.
Immunosuppressive drugs in the maintenance of remission induced by surgery in CD were assessed in 82 scenarios in 2 categories: CD patients at high risk of recurrence (41 scenarios) and low risk of recurrence (41 scenarios). Of the 82 scenarios, 3 (3.6%) were rated appropriate, 5 (6.2%) uncertain and 74 (90.2%) inappropriate. Agreement was reached on 62 scenarios (75.6%), inconclusive agreement on 20 (24.4%) and disagreement on none.
8. Maintenance of remission induced by medical treatment in CD 8.1. Definition of terms Relapse: the reappearance of symptoms after clinical remission, spontaneous or drug-induced, independently of the presence of intestinal lesions. Remission: see first category.
Fig. 3. Predicting factors of high risk of recurrence [6].
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Table 11 Appropriateness of immunosuppressants in maintenance of remission induced by surgery in CD: subgroup analysis In CD patients at high risk of recurrence AZA/6-MP are appropriate in prevention of recurrence: If prophylaxis with antibiotics given/not given Other immunosuppressants are inappropriate In CD patients at low risk of recurrence All immunosuppressants are inappropriate in prevention of recurrence
Statements regarding the appropriateness of the use of immunosuppressants in the maintenance of remission induced by surgery in CD are shown in Table 11.
10. Mild to moderate UC: induction of remission Fig. 4. Features of severe UC and prognostic factors of worse outcome.
10.1. Panel results Immunosuppressive drugs, in the induction of remission, in mild to moderate UC were assessed in 180 scenarios within 2 categories: proctosigmoiditis and colitis extended more than 60 cm. Of the 180 scenarios, 2 (1.1%) were rated appropriate, 12 (6.7%) uncertain and 166 (92.2%) inappropriate. Agreement was reached on 160 scenarios (88.9%), inconclusive agreement on 16 (8.9%) and disagreement on 4 (2.2%). Statements regarding the appropriateness of the use of immunosuppressants in mild to moderate UC are presented in Table 12.
11. Severe UC: induction of remission
Table 13 Appropriateness of immunosuppressants in severe UC: subgroup analysis Proctosigmoiditis AZA/6-MP are appropriate: If previous AZA successful CyA is appropriate: If previous steroids failed (Fig. 5) Other immunosuppressants are inappropriate Colitis extended >60 cm AZA/6-MP are inappropriate CyA is appropriate: If previous steroids failed (Fig. 5) If previous AZA failed If previous Infliximab failed Other immunosuppressants are inappropriate
11.1. Definition of terms Severe UC is defined on the basis of the signs listed in Fig. 4 [7–9]. 11.2. Panel results Immunosuppressive drugs, in the induction of remission in severe UC, were assessed in 180 scenarios within 2 categories: proctosigmoiditis and colitis extended >60 cm. Of the 216 scenarios, 11 (5.1%) were rated appropriate, 19 (8.8%) uncertain and 186 (86.1%) inappropriate. AgreeTable 12 Appropriateness of immunosuppressants in mild to moderate UC: subgroup analysis Proctosigmoiditis and colitis extended >60 cm AZA/6-MP are appropriate: If previous steroids failure Other immunosuppressants are inappropriate
ment was reached on 142 scenarios (65.7%), inconclusive agreement on 64 (29.7%) and disagreement on 10 (4.6%). Statements regarding the appropriateness of the use of immunosuppressants in severe UC are presented in Table 13 and Fig. 5.
12. Steroid-dependant and -resistant UC 12.1. Panel results Immunosuppressive drugs in steroid-dependant and resistant UC were assessed in 180 scenarios within 2 categories: proctosigmoiditis and colitis extended >60 cm. Of the 413 scenarios, 49 (11.9%) were rated appropriate, 171 (41.4%) uncertain and 193 (46.7%) inappropriate. Agreement was reached on 109 scenarios (26.4%), inconclusive agreement on 296 (71.7%) and disagreement on 8 (1.9%).
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Table 14 Appropriateness of immunosuppressants in steroid-dependant and -resistant UC: subgroup analysis Proctosigmoiditis and colitis extended more than 60 cm AZA/6-MP are appropriate: If previous AZA not given/success If previous MTX not given/failure MTX is appropriate: If previous AZA failed Other immunosuppressants are inappropriate
Table 15 Appropriateness of immunosuppressants in maintenance of remission induced by medical treatment in UC: subgroup analysis Fig. 5. Appropriateness of immunosuppressants in severe UC after failure of steroids.
Proctosigmoiditis and colitis extended more than 60 cm AZA/6-MP are appropriate: In maintenance of remission induced by MTX In maintenance of remission induced by AZA/6-MP MTX is appropriate: In maintenance of remission induced by MTX Other immunosuppressants are inappropriate
clusive agreement on 30 (31.2%) and disagreement on none. Statements regarding the appropriateness of the use of immunosuppressants in maintenance of remission induced by medical treatment in UC are shown in Table 15.
14. AZA-intolerant or -resistant IBD patients Fig. 6. Appropriateness of immunosuppressants in steroid-dependant and -resistant UC.
Statements regarding the appropriateness of the use of immunosuppressants in steroid-dependant or -resistant UC are presented in Fig. 6 and Table 14.
14.1. Panel results Of the 240 scenarios, 20 (8.3%) were rated appropriate, 77 (32.1%) uncertain and 143 (59.6%) inappropriate. Agreement was reached on 39 scenarios (16.6%), inconclusive agreement on 174 (72.5%) and disagreement on 27 (11.2%). Statements regarding the appropriateness of the use of immunosuppressants in AZA-intolerant or -resistant IBD patients are given in Table 16.
13. Maintenance of remission induced by medical treatment in UC 13.1. Panel results Immunosuppressants in maintenance of remission induced by medical treatment in UC were assessed in 180 scenarios within 2 categories: proctosigmoiditis and colitis extended more than 60 cm. Of the 96 scenarios, 8 (8.8%) were rated appropriate, 16 (16.7%) uncertain and 72 (75%) inappropriate. Agreement was reached on 66 scenarios (68.8%), incon-
Table 16 Appropriateness of immunosuppressants in AZA-intolerant or -resistant IBD patients: subgroup analysis Use of 6-MP is uncertain MTX is appropriate: If previous steroids/new steroids failed If previous MTX not given/successful If previous Infliximab not given/successful/failed Other immunosuppressants are inappropriate
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Table 17 Appropriateness of immunosuppressants in IBD extra-intestinal manifestations: subgroup analysis
Table 18 Appropriateness of immunosuppressants in IBD during pregnancy: subgroup analysis
Articular manifestations AZA/6-MP are appropriate: If previous steroids failure If previous Infliximab success/failure
Before conception/early pregnancy Quiescient disease: all immunosuppressants (start therapy) are inappropriate Active disease: all immunosuppressants (start therapy) are inappropriate
MTX is appropriate: If previous salazopyrine failure If previous AZA/6-MP failure If previous Infliximab success/failure Other immunosuppressants are inappropriate Pyoderma gangrenosum AZA/6-MP are appropriate: If previous steroids failure If previous Infliximab failure CyA is appropriate: If previous AZA/6-MP failure If previous Infliximab failure
Late pregnancy/nursing Quiescient disease: all immunosuppressants are inappropriate Active disease: AZA/6-MP are appropriate (Fig. 7) Stop treatment in the female 12–18 months before conception is inappropriate Stop treatment in the female 6 months before conception: For THAL is appropriate For MTX is uncertain For other immunosuppressants is inappropriate (Fig. 8) Stop treatment in the male 6–12–18 months before conception is inappropriate (Fig. 9) Therapeutic abortion if conception during immunosuppressive treatment is inappropriate
Other immunosuppressants are inappropriate Erythema nodosum AZA/6-MP are appropriate: if previous steroids failure if previous Infliximab failure Other immunosuppressants are inappropriate Ocular manifestations All immunosuppressants are inappropriate
15. Extra-intestinal manifestations in IBD patients 15.1. Panel results Immunosuppressive drugs in extra-intestinal IBD manifestations were assessed in 756 scenarios within 4 categories: articular manifestations in 189, pyoderma gangrenosum in 189, erythema nodosum in 189, and ocular manifestations in 189. Of the 756 scenarios, 28 (3.7%) were rated appropriate, 186 (24.6%) uncertain and 542 (71.7%) inappropriate. Agreement was reached on 209 scenarios (27.6%), inconclusive agreement on 487 (64.4%) and disagreement on 60 (8%). Statements regarding the appropriateness of the use of immunosuppressants in extra-intestinal manifestations in IBD are presented in Table 17.
conception, late pregnancy, nursing, stop treatment in the female (6, 12 or 18 months before conception), stop treatment in the male (6, 12 or 18 months before conception), therapeutic abortion if conception occurs during immunosuppressive treatment. Of the 105 scenarios, 3 (2.9%) were rated appropriate, 11 (10.4%) uncertain and 91 (86.7%) inappropriate. Agreement was reached on 58 scenarios (55.2%), inconclusive agreement on 41 (39.1%) and disagreement on 6 (5.7%). Statements regarding the appropriateness of the use of immunosuppressants in IBD during pregnancy are presented in Table 18 and Figs. 7–9.
16. Pregnancy in IBD patients 16.1. Panel results Immunosuppressive drugs, in pregnancy, were assessed in 105 scenarios within 7 categories: before pregnancy, early
Fig. 7. Appropriateness of immunosuppressants in IBD during pregnancy: late pregnancy and nursing in active disease.
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Fig. 8. Appropriateness of immunosuppressants in IBD during pregnancy: stop treatment in the female 6 months before conception.
Fig. 9. Appropriateness of immunosuppressants in IBD during pregnancy: stop treatment in the male 6–12–18 months before conception.
17. Discussion Results of the present study show that out of the immunosuppressive drugs currently used in the treatment of patients with CD or UC, only AZA, 6-mercaptopurine (6-MP) and methotrexate are appropriate. Cyclosporine A (CyA) was shown to be appropriate only in severe UC after failure of steroids and in the management of some extra-intestinal manifestations. FK506, MMF and THAL were found to be inappropriate, but the experience in the use of these agents is still lacking. Lastly, immunosuppressive drugs are not considered appropriate, as first-line therapy, in the hierarchy of treatments for IBD. 17.1. CD All immunosuppressive drugs were considered inappropriate as first-line treatment in the induction of remission in luminal CD whether mild to moderate, or severe. However,
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there was general consensus that, after failure of the steroids, AZA, 6-MP and MTX were extremely appropriate. These results are in keeping with two previous meta-analyses and a systematic review [10,11]. MTX was also considered appropriate after AZA failure. This observation indicates that MTX could be considered a valid alternative in patients resistant or intolerant to AZA. Furthermore AZA, 6-MP and MTX were considered appropriate in severe luminal CD after Infliximab. It is notable that panelists were in agreement with the current clinical practice of the association of AZA with Infliximab as bridge therapy. The effectiveness of this association has recently been demonstrated by ACCENT studies [12,13]. In fistulizing CD, AZA and 6-MP were appropriate after antibiotics, with or without prior treatment with AZA, 6-MP and Infliximab. AZA and 6-MP, in this setting, were considered uncertain as first-line treatment. These results are in keeping with those of a very well-known meta-analysis, even if the group of fistulizing CD patients was small [10]. In steroid-dependant or -resistant CD, AZA and 6-MP were appropriate independent of whether there is the previous use or not of AZA, 6-MP or Infliximab. MTX was considered appropriate as an alternative to AZA in steroiddependant or -resistant CD, according to evidence from the literature [14]. Considering that most IBD patients need a course of steroids in their life and that AZA and 6-MP were rated appropriate independently of the outcome (response, resistancy, dependency), we can extrapolate that AZA and 6-MP should always be used in patients requiring steroids. In the maintenance of remission, however induced, AZA and 6-MP were always appropriate. These conclusions are in keeping with evidence from RCTs [11]. The panelists also considered MTX appropriate in the maintenance of remission induced by Infliximab (bridge therapy). In the prevention of post-operative recurrence, despite the equivocal evidence of the effectiveness of AZA and 6-MP in this condition, panelists rated these two drugs appropriate in patients at high risk of recurrence. Albeit, even if there is evidence that mesalazine is effective in the prevention or attenuation of post-operative recurrence [15,16], some gastroenterologists limit prophylactic treatment to patients at high risk of recurrence, by using AZA or 6-MP. This strategy needs to be confirmed by large and well- designed RCTs. 17.2. UC As far as UC is concerned UC, the effectiveness of AZA and 6-MP is still controversial. In the induction of remission, AZA and 6-MP were rated inappropriate in patients with mild to moderate UC after the failure of steroids. In severe UC, only CyA was appropriate after failure of steroids. These results confirm the widespread use, in clinical practice, of CyA in severe steroid-resistant colitis [17] and stress the need to investigate the possible role of CyA as first-line treatment in severe UC. In mild to moderate steroid-dependant or -refractory UC, AZA and 6-MP were considered extremely appropri-
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ate, while MTX was appropriate only after AZA failure. Considering that there are fewer data on the effectiveness of AZA and 6-MP in the treatment of UC, in the treatment these results come mainly from the Panelists’ personal experience. In the maintenance of remission, however induced, AZA and 6-MP were rated appropriate. MTX, on the other hand, was rated appropriate only in the maintenance of remission induced by MTX itself, both in proctosigmoiditis and colitis extending <60 cm. Extra-intestinal manifestations and pregnancy scenarios in CD and UC have been grouped together as the panelists have expressed similar rates for both diseases. Extra-intestinal manifestations were considered independently from the underlying disease. In articular manifestations, AZA and 6-MP were rated appropriate after failure of steroids or Infliximab, while MTX was rated appropriate after salazopyrine, AZA, 6MP or Infliximab failure. In pyoderma gangrenosum and erythema nodosum, AZA and 6-MP were rated appropriate after steroids or Infliximab failure while i.v. CyA was rated appropriate after AZA, 6-MP or Infliximab failure. In ocular manifestations, all immunosuppressants were rated inappropriate. As far as pregnancy in IBD patients is concerned, the use of AZA/6-MP was rated appropriate in late pregnancy and during nursing in patients with active disease under treatment while it was considered inappropriate to start immunosuppressive therapy before conception and in early pregnancy. The risks associated with the use of AZA and 6MP in IBD are equivocal [18]. Interruption of AZA and 6-MP therapy is inappropriate in patients (both the female and the male) 6–18 months before conception. Therapeutic abortion is always inappropriate. From these results, it appears that the Panelists consider that immunosuppressive drugs may be given in pregnant IBD patients and that stopping the treatment may be dangerous for the mother and even the child. 17.3. Conclusions and recommendations From the Italian Panel on Appropriateness of Immunosuppressive Drugs in Inflammatory Bowel Diseases assessed using the RAND method, it appears that AZA/6-MP is appropriate in most therapeutic scenarios of patients with IBD, particularly in CD, and that MTX is considered the only appropriate alternative in the case of AZA/6-MP failure. CyA was rated appropriate only in severe UC and in cutaneous manifestations. The inappropriateness of the other immunosuppressants in all scenarios, could result from the lack of evidence and limited experience with these drugs. The RAND method applied in this study gives great power to the experts’ opinion and it is particularly useful in clinical conditions in which there is still little or conflicting evidence. The Panel results concerning the appropriateness of treatment are intended not only to be a generic recommenda-
tion without offering a graduation of its strength but also to assist gastroenterologists in determining the best strategy of treatment in particular circumstances.
Acknowledgment The authors thank Mrs. Marian Shields for reviewing the English style of the manuscript. Conflict of interest statement None declared.
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Alimentary Tract
Appropriateness of immunosuppressive drugs in inflammatory bowel diseases assessed by RAND method: Italian Group for IBD (IG-IBD) position statement R. Caprilli a,∗ , E. Angelucci a , A. Cocco a , A. Viscido a , V. Annese b , S. Ardizzone b , L. Biancone b , F. Castiglione b , M. Cottone b , G. Meucci b , P. Paoluzi b , C. Papi b , G.C. Sturniolo b , M. Vecchi b a
Promoter Centre, GI Unit, Department of Clinical Science, University of Rome ‘La Sapienza’, Viale del Policlinico 155, 00161 Rome, Italy b Italian Group for IBD (IG-IBD), Italy Received 23 July 2004; accepted 22 December 2004 Available online 9 March 2005 See related commentary on pages 391–393
Abstract Introduction. Despite the explosion of biological therapies, the old immunosuppressants continue to play a pivotal role in the management of inflammatory bowel diseases. Aim. To assess the appropriateness of immunosuppressants—azathioprine, 6-mercaptopurine, methotrexate, cyclosporine A, tacrolimus (FK506), mycophenolate mofetil and thalidomide—in the treatment of inflammatory bowel disease by using RAND/University of California Appropriateness Method. Methods. The RAND method consists of a combination of evidence from the literature and experts’ opinions. Appropriateness has been defined to mean that the expected health benefit exceeds the expected negative consequences by a sufficiently wide margin. A panel of 10 experts from the Italian Group for Inflammatory Bowel Disease has rated, in two rounds, on a scale from 1 to 9, the appropriateness of each indication selected by the Promoter Centre, on the basis of their own clinical experience. An indication was considered appropriate if the median of the panelists’ ratings fell within the area 7–9, inappropriate in the area 1–3 and uncertain in the area 4–6. A total of 2781 indications were grouped into 13 categories (mild to moderate Crohn’s disease; severe Crohn’s disease; fistulizing Crohn’s disease; steroid-dependant and -resistant Crohn’s disease; maintenance of remission induced by medical treatment in Crohn’s disease; maintenance of remission induced by surgery in Crohn’s disease; mild to moderate ulcerative colitis; severe ulcerative colitis; steroid-dependant and -resistant ulcerative colitis; maintenance of remission induced by medical treatment in ulcerative colitis; extra-intestinal manifestations in inflammatory bowel disease; pregnancy and inflammatory bowel disease; azathioprine-resistant or -intolerant inflammatory bowel disease patients). Results. Of the 2781 scenarios, 212 (7.6%) were rated appropriate, 645 (23.2%) uncertain and 1924 (69.2%) inappropriate. The most relevant results were: in steroid-dependant or -resistant Crohn’s disease, azathioprine, 6-mercaptopurine and methotrexate were defined as appropriate in 25 (86.2%) and 14 (48.3%) of the 29 scenarios respectively; in Crohn’s disease, azathioprine and 6-mercaptopurine were defined as appropriate combined with Infliximab (bridge therapy); in steroid-dependant or -resistant ulcerative colitis, azathioprine and 6-mercaptopurine were defined as appropriate in 45 (77.6%) out of 58 scenarios, while methotrexate was defined appropriate only after previous azathioprine failure; in severe ulcerative colitis, cyclosporine A was defined as appropriate only after previous failure with steroids; in azathioprine-intolerant or -resistant inflammatory bowel disease patients, methotrexate was appropriate in 20 (66.7%) out of 30 scenarios; it is inappropriate to stop azathioprine treatment before conception in the presence of active disease. The use of FK506, mycophenolate mofetil and Thalidomide resulted as inappropriate or uncertain.
∗
Corresponding author. Tel.: +39 06 4460009; fax: +39 06 4463737. E-mail address: [email protected] (R. Caprilli).
1590-8658/$30 © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2004.12.013
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Conclusions. Results of this study show that only azathioprine, 6-mercaptopurine and methotrexate are appropriate in the treatment of inflammatory bowel diseases. Cyclosporine A was found to be appropriate only in severe ulcerative colitis after the failure of steroids. FK506, mycophenolate mofetil and Thalidomide resulted as inappropriate but experience with these agents is somewhat limited. © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Azathioprine; Crohn’s disease; Cyclosporine; Immunosuppressive drugs; Inflammatory Bowel diseases; Methotrexate; Mycophenolate mofetil; RAM; RAND method; Tacrolimus; Thalidomide; Ulcerative colitis
1. Introduction
Table 2 Promoter Centre: University of Rome ‘La Sapienza’, Italy
The introduction and rapid diffusion of biological agents in the treatment of inflammatory bowel disease (IBD) has led us to believe that the old immunosuppressive drugs are destined to disappear. However, despite a decade of clinical experience in the use of biological agents, the old immunosuppressive drugs continue to play a pivotal role in the management of IBD. Ideally, immunosuppressive drugs would be used only in clinical situations in which the treatment has been proven to have a favourable impact on patient-management or outcome. There is, however, still considerable uncertainty concerning the appropriateness of immunosuppressive drugs in many situations. When strong evidence of efficacy from the literature is lacking, the next best evidence, on the evidence scale, is expert opinion (Table 1). The aim of this project is to contribute to a better understanding of the clinical situation for which there is still a need to rely on expert opinion. The opinions of several experts taking part in an Italian National Cooperative Study Group on IBD were collected using the RAND Appropriateness Method (RAM), one of the most widespread methods of developing expert opinion. This method was developed at RAND Corporation and University of California (UCLA) to evaluate the appropriateness of diagnostic and/or therapeutic procedures [1,2].
Renzo Caprilli Erika Angelucci Andrea Cocco Angelo Viscido
2. Project and methods Herein are described the results of a Panel of Expert Italian Gastroenterologists which convened in Turin, Italy on March 28–29, 2004. The Panel was organised by Promoter Centre (Table 2) together with the Italian Group for IBD (IG-IBD). The RAM consists of a combination of evidence from the literature and experts’ opinions. It is conducted in two phases. In the first phase, a detailed search is made of the literature by the Promoter Centre in order to identify studies evaluating Table 1 Hierarchy of evidence Meta-analysis and large RCTs/systematic reviews Single RCT Controlled clinical trials (without randomisation) Prospective observational cohort studies Retrospective studies Case reports, opinion of experts
Table 3 Immunosuppressive drugs currently used in IBD AZA 6-MP MTX CyA Tacrolimus (FK506) MMF THAL
the efficacy, safety and side effects of immunosuppressive drugs currently used in IBD (Table 3). The main source of literature database was MEDLINE (1966–2004). The MEDLINE search was conducted combining several MESH and non-MESH words. However, since MEDLINE usually retrieves only about half the relevant studies, we consulted other sources such as Cochrane Library and manual searches using the list of references of the most relevant articles, as well as those of reviews. The review of the literature was made systematically at the beginning of 2004, considering the hierarchy of evidence as set out in Table 1. The used database consists of more than 700 references. Approximately 500 were actually read and 114 were included in the final review of the literature. In the second phase, a list of the possible indications (several hundred) was drawn up for which immunosuppressive drugs were used. A Panel of 10 experts selected from the members of the IG-IBD were invited to take part in the project (Table 4). Table 4 Panelists taking part in the final Turin meeting Vito Annese, S. Giovanni Rotondo (FG), Italy, non-academic Sandro Ardizzone, Milan, Italy, academic Livia Biancone, Rome, Italy, academic Fabiana Castiglione, Naples, Italy, academic Mario Cottone, Palermo, Italy, academic Gianmichele Meucci, Como, Italy, non-academic Paolo Paoluzi, Rome, Italy, academic Claudio Papi, Rome, Italy, non-academic Giacomo Carlo Sturniolo, Padua, Italy, academic Maurizio Vecchi, Milan, Italy, academic
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The Promoter Centre distributed articles from an extensive review of the literature in February 2004, to the experts who were requested to study the material carefully and make additions to or suggestions or comments on it. The initial list of indications (or scenarios), as well as the literature review, were based on the existing literature dealing with these drugs, supplemented with the Panelists’ suggestions. Scenarios were identified by the Promoter Centre on the basis of all the possible situations that may be encountered in clinical practice. Scenarios have then been classified into 16 categories which became the object of the experts’ evaluation. Each expert was requested to rate, on a scale from 1 to 9, the appropriateness of each of the several hundred indications for which immunosuppressive drugs could, in practice or in theory, be used (1 = extremely inappropriate, 5 = uncertain, 9 = extremely appropriate). After having accomplished this task, each independently, the expert forwarded his/her ratings to the Promoter Centre for data entry and analysis. The Panel was convened 5 weeks later. The results of the initial ratings were distributed to all experts, allowing them to compare their own ratings with those of their fellow Panelists. Following an extensive discussion, focused mainly on differences emerging in evaluations, each expert again rated each indication discussed. It is the final result of the second rating-round that is used to determine appropriateness or inappropriateness of each indication and that is also presented in this article. Appropriateness was defined to mean that the expected health benefit exceeded the expected negative consequences (risks) by a sufficiently wide margin. Financial costs had no direct bearing on the appropriateness of the procedures evaluated by this method [1,2]. A scenario for a procedure was considered appropriate if the median of the panelists’ ratings fell within the area 7–9, without disagreement and inappropriate in the area 1–3, without disagreement. Scenarios with a median rating of 4–6, or those revealing disagreement among the Panelists were considered uncertain. Disagreement was defined, as occurring for a 10-member panel, when at least three panelists rated an indication from 1 to 3 on the scale and three others from 7 to 9 [2]. Previous drug failure means both intolerance and no response to treatment.
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Table 5 Categories (CD, UC) Mild to moderate CD: induction of remission Severe CD: induction of remission Fistulizing CD Steroid-dependant and -resistant CD Maintenance of remission induced by medical treatment in CD Maintenance of remission induced by surgery in CD Mild to moderate UC: induction of remission Severe UC: induction of remission Steroid-dependant and -resistant UC Maintenance of remission induced by medical treatment in UC AZA-intolerant and -resistant IBD patients Extra-intestinal manifestations in IBD patients Pregnancy in IBD patients
narios in a similar way both for Crohn’s disease (CD) and UC. 3.2. Number of ratings per category The number of ratings for each broad clinical category was: mild to moderate CD: induction of remission (105); severe CD: induction of remission (126); fistulizing CD (189); steroid-dependant and -resistant CD (210); maintenance of remission induced by medical treatment in CD (63); maintenance of remission induced by surgery in CD (82); extraintestinal manifestations in IBD (756); pregnancy and IBD (105); mild to moderate ulcerative colitis (UC): induction of remission (180); severe UC: induction of remission (216); steroid-dependant and -resistant UC (413); maintenance of remission induced by medical treatment in UC (96); azathioprine (AZA)-intolerant or -resistant and IBD (240). 3.3. Overall degree of appropriateness and agreement A total of 212 (7.6%) of the 2781 scenarios were rated appropriate, 645 (23.2%) uncertain and 1924 (69.2%) inappropriate. Agreement was reached on 1211 scenarios (43.5%), inconclusive agreement on 1432 (51.5%) and disagreement on 138 (5%). Results for each category are reported below. Due to the difficulty in summarising 2781 clinical scenarios, it has been impossible herein to present the full Panel results for all scenarios. The Promoter Centre remains at disposal.
4. Mild to moderate CD: induction of remission 3. Description of overall panel results 4.1. Definition of terms 3.1. Overall number of ratings The first rating round was performed on a total of 3382 scenarios, classified into 16 categories. This number was reduced to 2781 indications, classified into 13 categories (Table 5) since in those categories comprising pregnancy and extra-intestinal manifestations in IBD, panelists rated sce-
Mild to moderate CD: mildly active disease applies clinically to outpatients, patients able to tolerate oral alimentation, without showing signs of dehydratation, toxicity, abdominal tenderness, painful mass, obstruction, or >10% weight loss. Crohn’s Disease Activity Index (CDAI) between 150 and 220 [3].
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Table 6 Appropriateness of immunosuppressants in mild to moderate CD: subgroup analysis AZA/6-MP are appropriate: If previous steroids/new steroids failure If previous AZA/6-MP success MTX is appropriate: If previous AZA/6-MP failure Other immunosuppressants are inappropriate
Remission: clinical remission (CDAI < 150), if possible confirmed by endoscopy, referring to asymptomatic patients and including patients responding to medical treatment [4]. 4.2. Panel results Of the 105 scenarios, 4 (3.8%) were rated appropriate, 3 (2.9%) uncertain and 98 (93.3%) inappropriate. Significant agreement was reached on 94 scenarios (89.5%), inconclusive agreement on 11 (10.5%) and disagreement on none. An outline of the overall statements concerning the appropriateness of the use of immunosuppressants in mild to moderate CD is shown in Table 6.
5. Severe CD 5.1. Definition of terms Severe CD: severe active disease, refers to patients with persisting symptoms despite the introduction of steroids as outpatients, or individuals presenting with high fever, persistant vomiting, rebound tenderness, cachexia or evidence of an abscess. CDAI score > 450–600 [4]. 5.2. Panel results Of the 126 scenarios, 9 (7.1%) were rated appropriate, 26 (20.6%) uncertain and 91 (72.3%) inappropriate. Agreement was reached on 52 scenarios (41.3%), inconclusive agreement on 62 (49.2%) and disagreement on 12 (9.5%). Table 7 Appropriateness of immunosuppressants in severe CD: subgroup analysis AZA/6-MP are appropriate: If previous steroids/new steroids failure If previous AZA/6-MP success If previous Infliximab not given/failure/success
Fig. 1. Appropriateness of immunosuppressants in fistulizing CD.
Statements concerning the appropriateness of the use of immunosuppressants in severe CD are presented in Table 7.
6. Fistulizing CD 6.1. Definition of terms Fistulizing CD indicates a disease characterised by the presence of fistulas and/or abscesses. 6.2. Panel results Of the 189 scenarios, 18 (9.6%) were rated appropriate, 70 (37%) uncertain and 101 (53.4%) inappropriate. Agreement was reached on 47 scenarios (24.9%), inconclusive agreement on 136 (72%) and disagreement on 6 (3.1%). Statements concerning the appropriateness of the use of immunosuppressants in fistulizing CD are given in Fig. 1 and Table 8.
7. Steroid-dependant and -resistant CD 7.1. Definition of terms Steroid-dependance: partial or complete clinical response to treatment with prednisone or equivalent and relapse within 30 days of stopping prednisone treatment or relapse with a Table 8 Appropriateness of immunosuppressants in fistulizing CD: subgroup analysis
MTX is appropriate: If previous AZA/6-MP failure If previous steroids failure If previous Infliximab success
AZA/6-MP are appropriate: If previous antibiotics failure If previous AZA/6-MP not given/success If previous Infliximab not given/failure/success
Other immunosuppressants are inappropriate
Other immunosuppressants are inappropriate
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Table 10 Appropriateness of immunosuppressants in maintenance of remission induced by medical treatment in CD: subgroup analysis AZA/6-MP are appropriate: In maintenance of remission induced by steroids In maintenance of remission induced by AZA/6-MP In maintenance of remission induced by Infliximab MTX is appropriate: In maintenance of remission induced by MTX In maintenance of remission induced by Infliximab Other immunosuppressants are inappropriate
8.2. Panel results
Fig. 2. Appropriateness of immunosuppressants in steroid-dependant and -resistant CD. Table 9 Appropriateness of immunosuppressants in steroid-dependant and -resistant CD: subgroup analysis AZA/6-MP are appropriate: If previous AZA/6-MP not given/success If previous Infliximab not given/failure/success MTX is appropriate: If previous AZA/6MP failure If previous Infliximab failure
Of the 63 scenarios, 6 (9.5%) were rated appropriate, 10 (15.9%) uncertain and 47 (74.6%) inappropriate. Agreement was reached on 49 scenarios (77.8%), inconclusive agreement on 12 (19%) and disagreement on 2 (3.2%). Statements regarding the appropriateness of the use of immunosuppressants in the maintenance of remission induced by medical treatment in CD are given in Table 10.
9. Maintenance of remission induced by surgery in CD 9.1. Definition of terms
Other immunosuppressants are inappropriate
dose reduction of prednisone at doses ≤15–25 mg/day for at least 6 months [5]. Steroid-resistance: failing to respond within 30 days to prednisone treatment at doses of 40–60 mg/day [5].
Recurrence: the reappearance of new lesions after radical surgical resection. Remission: see first category. High risk of recurrence: see Fig. 3 [6]. Two different scenarios were considered: patients with high risk of recurrence and patients at low risk of recurrence. Fig. 3 shows the features of high risk of recurrence.
7.2. Panel results 9.2. Panel results Of the 210 scenarios, 51 (24.3%) were rated appropriate (37%), 39 (18.6%) uncertain and 120 (57.1%) inappropriate. Agreement was reached on 124 scenarios (59%), inconclusive agreement on 83 (39.5%) and disagreement on 3 (1.6%). Statements regarding the appropriateness of the use of immunosuppressants in steroid-dependant or -resistant CD are showed in Fig. 2 and Table 9.
Immunosuppressive drugs in the maintenance of remission induced by surgery in CD were assessed in 82 scenarios in 2 categories: CD patients at high risk of recurrence (41 scenarios) and low risk of recurrence (41 scenarios). Of the 82 scenarios, 3 (3.6%) were rated appropriate, 5 (6.2%) uncertain and 74 (90.2%) inappropriate. Agreement was reached on 62 scenarios (75.6%), inconclusive agreement on 20 (24.4%) and disagreement on none.
8. Maintenance of remission induced by medical treatment in CD 8.1. Definition of terms Relapse: the reappearance of symptoms after clinical remission, spontaneous or drug-induced, independently of the presence of intestinal lesions. Remission: see first category.
Fig. 3. Predicting factors of high risk of recurrence [6].
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Table 11 Appropriateness of immunosuppressants in maintenance of remission induced by surgery in CD: subgroup analysis In CD patients at high risk of recurrence AZA/6-MP are appropriate in prevention of recurrence: If prophylaxis with antibiotics given/not given Other immunosuppressants are inappropriate In CD patients at low risk of recurrence All immunosuppressants are inappropriate in prevention of recurrence
Statements regarding the appropriateness of the use of immunosuppressants in the maintenance of remission induced by surgery in CD are shown in Table 11.
10. Mild to moderate UC: induction of remission Fig. 4. Features of severe UC and prognostic factors of worse outcome.
10.1. Panel results Immunosuppressive drugs, in the induction of remission, in mild to moderate UC were assessed in 180 scenarios within 2 categories: proctosigmoiditis and colitis extended more than 60 cm. Of the 180 scenarios, 2 (1.1%) were rated appropriate, 12 (6.7%) uncertain and 166 (92.2%) inappropriate. Agreement was reached on 160 scenarios (88.9%), inconclusive agreement on 16 (8.9%) and disagreement on 4 (2.2%). Statements regarding the appropriateness of the use of immunosuppressants in mild to moderate UC are presented in Table 12.
11. Severe UC: induction of remission
Table 13 Appropriateness of immunosuppressants in severe UC: subgroup analysis Proctosigmoiditis AZA/6-MP are appropriate: If previous AZA successful CyA is appropriate: If previous steroids failed (Fig. 5) Other immunosuppressants are inappropriate Colitis extended >60 cm AZA/6-MP are inappropriate CyA is appropriate: If previous steroids failed (Fig. 5) If previous AZA failed If previous Infliximab failed Other immunosuppressants are inappropriate
11.1. Definition of terms Severe UC is defined on the basis of the signs listed in Fig. 4 [7–9]. 11.2. Panel results Immunosuppressive drugs, in the induction of remission in severe UC, were assessed in 180 scenarios within 2 categories: proctosigmoiditis and colitis extended >60 cm. Of the 216 scenarios, 11 (5.1%) were rated appropriate, 19 (8.8%) uncertain and 186 (86.1%) inappropriate. AgreeTable 12 Appropriateness of immunosuppressants in mild to moderate UC: subgroup analysis Proctosigmoiditis and colitis extended >60 cm AZA/6-MP are appropriate: If previous steroids failure Other immunosuppressants are inappropriate
ment was reached on 142 scenarios (65.7%), inconclusive agreement on 64 (29.7%) and disagreement on 10 (4.6%). Statements regarding the appropriateness of the use of immunosuppressants in severe UC are presented in Table 13 and Fig. 5.
12. Steroid-dependant and -resistant UC 12.1. Panel results Immunosuppressive drugs in steroid-dependant and resistant UC were assessed in 180 scenarios within 2 categories: proctosigmoiditis and colitis extended >60 cm. Of the 413 scenarios, 49 (11.9%) were rated appropriate, 171 (41.4%) uncertain and 193 (46.7%) inappropriate. Agreement was reached on 109 scenarios (26.4%), inconclusive agreement on 296 (71.7%) and disagreement on 8 (1.9%).
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Table 14 Appropriateness of immunosuppressants in steroid-dependant and -resistant UC: subgroup analysis Proctosigmoiditis and colitis extended more than 60 cm AZA/6-MP are appropriate: If previous AZA not given/success If previous MTX not given/failure MTX is appropriate: If previous AZA failed Other immunosuppressants are inappropriate
Table 15 Appropriateness of immunosuppressants in maintenance of remission induced by medical treatment in UC: subgroup analysis Fig. 5. Appropriateness of immunosuppressants in severe UC after failure of steroids.
Proctosigmoiditis and colitis extended more than 60 cm AZA/6-MP are appropriate: In maintenance of remission induced by MTX In maintenance of remission induced by AZA/6-MP MTX is appropriate: In maintenance of remission induced by MTX Other immunosuppressants are inappropriate
clusive agreement on 30 (31.2%) and disagreement on none. Statements regarding the appropriateness of the use of immunosuppressants in maintenance of remission induced by medical treatment in UC are shown in Table 15.
14. AZA-intolerant or -resistant IBD patients Fig. 6. Appropriateness of immunosuppressants in steroid-dependant and -resistant UC.
Statements regarding the appropriateness of the use of immunosuppressants in steroid-dependant or -resistant UC are presented in Fig. 6 and Table 14.
14.1. Panel results Of the 240 scenarios, 20 (8.3%) were rated appropriate, 77 (32.1%) uncertain and 143 (59.6%) inappropriate. Agreement was reached on 39 scenarios (16.6%), inconclusive agreement on 174 (72.5%) and disagreement on 27 (11.2%). Statements regarding the appropriateness of the use of immunosuppressants in AZA-intolerant or -resistant IBD patients are given in Table 16.
13. Maintenance of remission induced by medical treatment in UC 13.1. Panel results Immunosuppressants in maintenance of remission induced by medical treatment in UC were assessed in 180 scenarios within 2 categories: proctosigmoiditis and colitis extended more than 60 cm. Of the 96 scenarios, 8 (8.8%) were rated appropriate, 16 (16.7%) uncertain and 72 (75%) inappropriate. Agreement was reached on 66 scenarios (68.8%), incon-
Table 16 Appropriateness of immunosuppressants in AZA-intolerant or -resistant IBD patients: subgroup analysis Use of 6-MP is uncertain MTX is appropriate: If previous steroids/new steroids failed If previous MTX not given/successful If previous Infliximab not given/successful/failed Other immunosuppressants are inappropriate
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Table 17 Appropriateness of immunosuppressants in IBD extra-intestinal manifestations: subgroup analysis
Table 18 Appropriateness of immunosuppressants in IBD during pregnancy: subgroup analysis
Articular manifestations AZA/6-MP are appropriate: If previous steroids failure If previous Infliximab success/failure
Before conception/early pregnancy Quiescient disease: all immunosuppressants (start therapy) are inappropriate Active disease: all immunosuppressants (start therapy) are inappropriate
MTX is appropriate: If previous salazopyrine failure If previous AZA/6-MP failure If previous Infliximab success/failure Other immunosuppressants are inappropriate Pyoderma gangrenosum AZA/6-MP are appropriate: If previous steroids failure If previous Infliximab failure CyA is appropriate: If previous AZA/6-MP failure If previous Infliximab failure
Late pregnancy/nursing Quiescient disease: all immunosuppressants are inappropriate Active disease: AZA/6-MP are appropriate (Fig. 7) Stop treatment in the female 12–18 months before conception is inappropriate Stop treatment in the female 6 months before conception: For THAL is appropriate For MTX is uncertain For other immunosuppressants is inappropriate (Fig. 8) Stop treatment in the male 6–12–18 months before conception is inappropriate (Fig. 9) Therapeutic abortion if conception during immunosuppressive treatment is inappropriate
Other immunosuppressants are inappropriate Erythema nodosum AZA/6-MP are appropriate: if previous steroids failure if previous Infliximab failure Other immunosuppressants are inappropriate Ocular manifestations All immunosuppressants are inappropriate
15. Extra-intestinal manifestations in IBD patients 15.1. Panel results Immunosuppressive drugs in extra-intestinal IBD manifestations were assessed in 756 scenarios within 4 categories: articular manifestations in 189, pyoderma gangrenosum in 189, erythema nodosum in 189, and ocular manifestations in 189. Of the 756 scenarios, 28 (3.7%) were rated appropriate, 186 (24.6%) uncertain and 542 (71.7%) inappropriate. Agreement was reached on 209 scenarios (27.6%), inconclusive agreement on 487 (64.4%) and disagreement on 60 (8%). Statements regarding the appropriateness of the use of immunosuppressants in extra-intestinal manifestations in IBD are presented in Table 17.
conception, late pregnancy, nursing, stop treatment in the female (6, 12 or 18 months before conception), stop treatment in the male (6, 12 or 18 months before conception), therapeutic abortion if conception occurs during immunosuppressive treatment. Of the 105 scenarios, 3 (2.9%) were rated appropriate, 11 (10.4%) uncertain and 91 (86.7%) inappropriate. Agreement was reached on 58 scenarios (55.2%), inconclusive agreement on 41 (39.1%) and disagreement on 6 (5.7%). Statements regarding the appropriateness of the use of immunosuppressants in IBD during pregnancy are presented in Table 18 and Figs. 7–9.
16. Pregnancy in IBD patients 16.1. Panel results Immunosuppressive drugs, in pregnancy, were assessed in 105 scenarios within 7 categories: before pregnancy, early
Fig. 7. Appropriateness of immunosuppressants in IBD during pregnancy: late pregnancy and nursing in active disease.
R. Caprilli et al. / Digestive and Liver Disease 37 (2005) 407–417
Fig. 8. Appropriateness of immunosuppressants in IBD during pregnancy: stop treatment in the female 6 months before conception.
Fig. 9. Appropriateness of immunosuppressants in IBD during pregnancy: stop treatment in the male 6–12–18 months before conception.
17. Discussion Results of the present study show that out of the immunosuppressive drugs currently used in the treatment of patients with CD or UC, only AZA, 6-mercaptopurine (6-MP) and methotrexate are appropriate. Cyclosporine A (CyA) was shown to be appropriate only in severe UC after failure of steroids and in the management of some extra-intestinal manifestations. FK506, MMF and THAL were found to be inappropriate, but the experience in the use of these agents is still lacking. Lastly, immunosuppressive drugs are not considered appropriate, as first-line therapy, in the hierarchy of treatments for IBD. 17.1. CD All immunosuppressive drugs were considered inappropriate as first-line treatment in the induction of remission in luminal CD whether mild to moderate, or severe. However,
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there was general consensus that, after failure of the steroids, AZA, 6-MP and MTX were extremely appropriate. These results are in keeping with two previous meta-analyses and a systematic review [10,11]. MTX was also considered appropriate after AZA failure. This observation indicates that MTX could be considered a valid alternative in patients resistant or intolerant to AZA. Furthermore AZA, 6-MP and MTX were considered appropriate in severe luminal CD after Infliximab. It is notable that panelists were in agreement with the current clinical practice of the association of AZA with Infliximab as bridge therapy. The effectiveness of this association has recently been demonstrated by ACCENT studies [12,13]. In fistulizing CD, AZA and 6-MP were appropriate after antibiotics, with or without prior treatment with AZA, 6-MP and Infliximab. AZA and 6-MP, in this setting, were considered uncertain as first-line treatment. These results are in keeping with those of a very well-known meta-analysis, even if the group of fistulizing CD patients was small [10]. In steroid-dependant or -resistant CD, AZA and 6-MP were appropriate independent of whether there is the previous use or not of AZA, 6-MP or Infliximab. MTX was considered appropriate as an alternative to AZA in steroiddependant or -resistant CD, according to evidence from the literature [14]. Considering that most IBD patients need a course of steroids in their life and that AZA and 6-MP were rated appropriate independently of the outcome (response, resistancy, dependency), we can extrapolate that AZA and 6-MP should always be used in patients requiring steroids. In the maintenance of remission, however induced, AZA and 6-MP were always appropriate. These conclusions are in keeping with evidence from RCTs [11]. The panelists also considered MTX appropriate in the maintenance of remission induced by Infliximab (bridge therapy). In the prevention of post-operative recurrence, despite the equivocal evidence of the effectiveness of AZA and 6-MP in this condition, panelists rated these two drugs appropriate in patients at high risk of recurrence. Albeit, even if there is evidence that mesalazine is effective in the prevention or attenuation of post-operative recurrence [15,16], some gastroenterologists limit prophylactic treatment to patients at high risk of recurrence, by using AZA or 6-MP. This strategy needs to be confirmed by large and well- designed RCTs. 17.2. UC As far as UC is concerned UC, the effectiveness of AZA and 6-MP is still controversial. In the induction of remission, AZA and 6-MP were rated inappropriate in patients with mild to moderate UC after the failure of steroids. In severe UC, only CyA was appropriate after failure of steroids. These results confirm the widespread use, in clinical practice, of CyA in severe steroid-resistant colitis [17] and stress the need to investigate the possible role of CyA as first-line treatment in severe UC. In mild to moderate steroid-dependant or -refractory UC, AZA and 6-MP were considered extremely appropri-
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ate, while MTX was appropriate only after AZA failure. Considering that there are fewer data on the effectiveness of AZA and 6-MP in the treatment of UC, in the treatment these results come mainly from the Panelists’ personal experience. In the maintenance of remission, however induced, AZA and 6-MP were rated appropriate. MTX, on the other hand, was rated appropriate only in the maintenance of remission induced by MTX itself, both in proctosigmoiditis and colitis extending <60 cm. Extra-intestinal manifestations and pregnancy scenarios in CD and UC have been grouped together as the panelists have expressed similar rates for both diseases. Extra-intestinal manifestations were considered independently from the underlying disease. In articular manifestations, AZA and 6-MP were rated appropriate after failure of steroids or Infliximab, while MTX was rated appropriate after salazopyrine, AZA, 6MP or Infliximab failure. In pyoderma gangrenosum and erythema nodosum, AZA and 6-MP were rated appropriate after steroids or Infliximab failure while i.v. CyA was rated appropriate after AZA, 6-MP or Infliximab failure. In ocular manifestations, all immunosuppressants were rated inappropriate. As far as pregnancy in IBD patients is concerned, the use of AZA/6-MP was rated appropriate in late pregnancy and during nursing in patients with active disease under treatment while it was considered inappropriate to start immunosuppressive therapy before conception and in early pregnancy. The risks associated with the use of AZA and 6MP in IBD are equivocal [18]. Interruption of AZA and 6-MP therapy is inappropriate in patients (both the female and the male) 6–18 months before conception. Therapeutic abortion is always inappropriate. From these results, it appears that the Panelists consider that immunosuppressive drugs may be given in pregnant IBD patients and that stopping the treatment may be dangerous for the mother and even the child. 17.3. Conclusions and recommendations From the Italian Panel on Appropriateness of Immunosuppressive Drugs in Inflammatory Bowel Diseases assessed using the RAND method, it appears that AZA/6-MP is appropriate in most therapeutic scenarios of patients with IBD, particularly in CD, and that MTX is considered the only appropriate alternative in the case of AZA/6-MP failure. CyA was rated appropriate only in severe UC and in cutaneous manifestations. The inappropriateness of the other immunosuppressants in all scenarios, could result from the lack of evidence and limited experience with these drugs. The RAND method applied in this study gives great power to the experts’ opinion and it is particularly useful in clinical conditions in which there is still little or conflicting evidence. The Panel results concerning the appropriateness of treatment are intended not only to be a generic recommenda-
tion without offering a graduation of its strength but also to assist gastroenterologists in determining the best strategy of treatment in particular circumstances.
Acknowledgment The authors thank Mrs. Marian Shields for reviewing the English style of the manuscript. Conflict of interest statement None declared.
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