Treatment of active Crohn's disease by exclusion diet: East Anglian Multicentre Controlled Trial

Articles

Treatment of active Crohn’s disease by exclusion diet: East Anglian Multicentre Controlled Trial

Summary

Introduction

Elemental diet is as effective in producing remission of Crohn’s disease (CD) as is corticosteroid treatment, but most patients relapse soon after resumption of a normal diet. We have investigated the efficacies of dietary modification and oral corticosteroids in maintaining remission achieved with elemental diet. In a multicentre trial, 136 patients with active CD were started on elemental diet and other treatment was withdrawn. 43 (31%) declined to continue elemental diet for 14 days, but 78 (84%) of the remaining 93 achieved remission and were randomly assigned corticosteroids (38) or diet (40). Corticosteroid treatment started at 40 mg prednisolone daily, which was tapered and stopped after 12 weeks; that group received dietary advice on healthy eating. The diet group received "tapered" placebo and were instructed to introduce one new food daily, excluding any that precipitated symptoms. Assessment of progress for up to 2 years was made by physicians unaware of group assignment. Intention-to-treat analysis showed median lengths of remission of 3 8 (interquartile range 5·0) months in the corticosteroid group and 7·5 (15·3) months on diet, and relapse rates at 2 years, adjusted for withdrawals, of 79% and 62%, respectively (p=0·048). Clinical improvement in the diet group was associated with significant changes in plasma albumin and &agr;1-antichymotrypsin concentrations and erythrocyte sedimentation rate. Food intolerances discovered were predominantly to cereals, dairy products, and yeast. Diet provides a further therapeutic strategy in active Crohn’s disease.

The

Lancet 1993; 342: 1131-34

of

Crohn’s

disease (CD) remains unsatisfactory. Many drugs in routine use, such as corticosteroids, azathioprine, and sulphasalazine, have dangerous side-effects and are not always effective. So surgery is necessary in many cases. Elemental diet is as reliable as corticosteroids in producing remission in acute CD, with success rates as high as 90%.1-6 However, most patients relapse shortly after resumption of a normal diet. Although the mechanism of action of elemental diet is poorly understood, it has been claimed that remissions so induced can be prolonged by dietary modification.7,8 However, this suggestion has yet to be proven in a large trial of unselected patients. We have investigated the value of elemental diet in active CD and the efficacies of dietary modification and oral corticosteroids. treatment

Patients and methods All patients with active CD seen in the participating hospitals were considered for inclusion provided that they were permanent residents of the health districts where the hospitals were situated. The diagnosis of CD was confirmed by standard radiological and histological tests within 2 months of entry. Disease activity was confirmed by a Harvey and Bradshaw index (HBI)9 of greater than 6, and the only indications for exclusion were pregnancy, lactation, surgical complications (such as intestinal obstruction, abscesses, and symptomatic fistulae), and severe complications necessitating corticosteroids, such as uveitis. Patients with CD of the rectum only were excluded, as were those with perianal disease more severe than simple fissures or skin tags. Patients unwilling to take part in the study were noted. Patients were treated with elemental diet (E028, Scientific

Hospital Supplies, Liverpool, UK) as inpatients or outpatients, according to the physician’s choice. All other CD treatment was withdrawn. Remission was defined as a fall in the HBI to less than 3. Patients who achieved remission were randomly allocated to treatment with corticosteroids or with diet. Those who did not achieve remission took no further part in the study. Randomisation codes were separate for each participating centre and were stratified for the extent of the disease (small-bowel disease only, colonic disease only, or both small-bowel and large-bowel

Department of Gastroenterology, Addenbrooke’s Hospital, Cambridge (A M Riordan SRD, J O Hunter FRCP, J R Crampton MRCP, G Neale FRCP); Colchester General Hospital (R E Cowan FRCP); Kettering and District General Hospital (A R Davidson FRCP); Hinchingbrooke Hospital, Huntingdon (RJ Dickinson FRCP); Peterborough District Hospital (M W Dronfield FRCP); Norfolk and Norwich Hospital (I W Fellows MRCP, H J Kennedy MRCP); James Paget Hospital, Gorleston (S Hishon FRCP); West Suffolk Hospital, Bury St Edmunds (G N W Kerrigan FRCP); Queen Elizabeth Hospital, Kings Lynn (R C M McGouran FRCP); and Bedford Hospital, UK (J H B Saunders FRCP) Correspondence to: Dr JO Hunter, Gastroenterology Research Unit, Addenbrooke’s Hospital, Cambridge CB2 2QQ, UK

involvement). Patients

in

the

corticosteroid

group

were

prescribed

prednisolone (Prednesol, Glaxo) 40 mg daily. They received general dietary advice from a dietitian. If they remained in remission, the prednisolone dose was reduced to 30 mg after 1

week,

to

20 mg after 1

month, and

to

10 mg after 2

months;

prednisolone was withdrawn after 3 months. Patients in the diet group were instructed to reintroduce a single food each day and to exclude any food that provoked symptoms such as diarrhoea and pain.7 In an attempt to make the trial double-blind they were given placebo tablets identical to the prednisolone and instructed to reduce the dose in the same way. Both groups saw the dietitians at every clinic visit and were free to telephone for advice if necessary. Patients in both groups were told

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ED= elemental diet. ESR erythrocyte sedimentation rate, CRP=C-reactive protein. Table 1: HBI and blood variables before and after elemental diet (ED) In patients randomised to diet or cortlcosteroids

that they had entered a trial of diet in CD and that the tablets might be corticosteroids or a harmless placebo. The group assignment was known to the dietitians who advised the patients but not to the physicians who assessed their progress. Clinic visits were made monthly until 6 months, every 2 months to 1 year, then every 4 months to 2 years, or at any time if severe symptoms developed. Only assessing physicians were allowed to withdraw patients from the trial. An HBI of greater than 6 was taken as a relapse. Other criteria for treatment failure included: unwillingness by the patient to continue; a diet found on computer analysis to be deficient in energy, protein, or any other nutrient that could not be replaced by simple supplements; surgery for CD; serious medical complications; and steroid side-effects severe enough to warrant withdrawal of therapy. Withdrawn patients were subsequently treated at their physicians’ discretion. Blood samples were taken for measurement of erythrocyte sedimentation rate and concentrations of haemoglobin, serum C-reactive protein, o-antichymotrypsin, and albumin at entry to the trial and at each visit. Laboratory tests were done at the local hospitals, except for C-reactive protein and al-antichymotrypsin which were measured at the Department of Biochemistry, Addenbrooke’s Hospital. Data were analysed by the SPSS statistical package (version 5.0.1). Means were compared byt tests for paired or independent samples, as appropriate. Where necessary, non-parametric tests were used. Life-tables were calculated and used to assess the progress of the two groups. We took p < 0-05 to indicate statistical

significance.

Table 2: Demographic and clinical details of corticosteroid and diet groups

There was no significant difference between the patients who responded to the elemental diet and those who did not in severity of disease, age, sex, site or duration of disease,

smoking habits, or previous drug treatment or surgery. Similarly, there were no differences in these variables between the 38 patients assigned corticosteroid treatment and the 40 patients assigned diet treatment (table 2). On reintroduction of normal foods the patients discovered many intolerances (corn [7 patients]; wheat, milk, yeast [6 each]; egg, potato, rye, tea, coffee [4 each]; apples, mushrooms, oats, chocolate [3 each]). 26 patients were

intolerant of more than 3 foods.

patients (66%) were withdrawn from the corticosteroid group because of clinical relapse compared with 12 (30%) in the diet group. In addition, 7 patients from the diet group were withdrawn for non-compliance. They were all counted as failures, even if they were in full remission at the time of withdrawal. 2 patients were withdrawn from the diet group because of intercurrent illness. Withdrawals from the steroid group included 1 patient with intercurrent illness, 2 with steroid side-effects (diabetes mellitus and severe furunculosis), and 2 who became pregnant. All withdrawals (except the pregnant women) were counted as treatment failures in an intention25

to-treat

analysis.

There

was no

significant change in weight during the [SE 88] kg on entry and

study in either the diet group (57-6 Results 224 eligible patients were seen in the participating hospitals during the trial. 88 were not enrolled (35 were unwilling to undergo randomisation or follow the trial protocol, 8 had started on other treatment from their general practitioners, 4 declined for social reasons, 13 were unwilling to try the elemental diet, 11 asked for steroids and 7 for diet, 6 had contraindications to steroid use, 3 required total parenteral nutrition, and 1 was mentally subnormal). 136 patients started on the elemental diet but 43 (31 %) refused to continue for longer than 7 days. After 14 days on the elemental diet 78 (84%) of the remaining 93 patients had achieved remission. There were significant improvements in the group as a whole in erythrocyte sedimentation rate and serum albumin and C-reactive protein concentrations Wilcoxon signed-rank test) but not in (p < 0,01,

haemoglobin or o-antichymotrypsin (table 1). 1132

Figure: Proportion of patients remaining in clinical remission

Table 3: Changes in HBI and blood variables during trial

60[7’4]

kg at 3 months) or the corticosteroid group (59-3 and 63-8 ([122] kg, respectively). The median remission times were 7-5 (interquartile range 15-3) months in the diet group and 3-8 (5-0) months in the steroid group, and the respective relapse rates at 2 years were 62% and 79% (Wilcoxon [Gehan] statistic 3920, df 1, p=0-048, figure). Changes in the clinical state of the patients and in their [11.4] kg

various blood tests are summarised in table 3. Patients in the diet group who remained well until the end of the trial showed significant improvements in albumin, erythrocyte sedimentation rate, and al-antichymotrypsin concentration in comparison with values on entry to the trial. Haemoglobin and C-reactive protein concentrations tended to improve, but the changes did not reach statistical

significance. Discussion This trial confirms the value of elemental diet in acute CD; 84% of patients willing to limit their food intake to elemental diet were symptom-free after 2 weeks. However, the overall success rate was only 57%, since 43 (31%) patients were unwilling to continue elemental diet for more than a week. It seems that the different success rates in previous trialsl-6 relate to patients’ selection, with higher rates reported by groups who are known to believe that elemental diet is valuable in CD and whose patients are referred to them specifically for this treatment. Such patients are more likely to persevere with elemental diet than are unselected patients, such as those in our trial. Despite its proven efficacy, elemental diet is still not used widely, partly because it is not pleasant to ingest. Palatability has improved lately. Earlier forms had to be given by nasogastric tube but most of the patients in our study were able to drink E028 from a cup. Peptide-based and polymeric diets may prove more palatable but seem to be less effective.1o-12 The second difficulty is that many doctors are uncertain how best to manage patients after they have reached remission on elemental diet. The administration of potentially toxic drugs, such as corticosteroids and antimetabolites, seems unwarranted in patients who have become symptom-free and yet most patients relapse rapidly on resumption of normal eating.8,13 Our study shows that in CD patients who have achieved remission on elemental diet, the process of food testing7,8 provides an effective strategy for long-term management.

Food testing and reintroduction is not easy, but even if we take patients who were unwilling to comply as failures, the group treated by diet had a significant advantage over those who received steroids in terms of time of relapse. It is not possible to design a trial of diet that is perfectly double-blind unless artificial foods are used. We have attempted to overcome this difficulty in patients eating every-day foods by ensuring that all were given dietary advice and visited the dietitian with equal frequency. Furthermore, all received indistinguishable medication, with the dose tapered in the same way in both groups. The assessment of a patient’s progress was made, not by the dietitians who were unavoidably aware of his or her treatment, but by the physician, who was not. Although the assessment of the patients made by their physicians at each visit was based on the HBI, which is derived entirely from clincial variables, the changes in the various blood tests provided objective confirmation that the patients were in remission, and that the improvement was

merely symptomatic. Many CD patients report that the course of their illness is affected by what they eat, but this study is the first to demonstrate this association in a large-scale controlled trial of unselected patients. There are many reasons for the difficulty of proving such a simple relation. Many and varied foods were implicated and the resulting diets differed substantially. When a food is eaten daily, it can be difficult to realise that it is provoking symptoms. The process of food testing was slow and difficult and required much skilled dietetic support. Some patients did not have enough determination to continue. Although there was a significant benefit in the group treated with diet, the percentage still in remission at 2 years was nonetheless disappointing. Alun Jones et al8 reported that as many as two-thirds of patients were well at 2 years. The difference in result is probably related to the type of patients studied; self-selected patients inevitably prove more compliant of dietary regimens than an unselected

not

group. Diet provides a further method of treatment for CD that may enable well-motivated and determined patients to avoid unnecessary surgery and the complications of drug therapy. Clearly, however, it does not provide the final answer to the treatment of CD. It is difficult for the patients and requires skilled dietetic support. Also, since staple foods must be avoided by many patients, the diet may be costly and socially inconvenient. Nevertheless, it may well

1133

way to further research. Discovery of the mechanisms underlying food intolerance may lead to more

point the

successful

treatment

of CD in the future.

This study was supported by the East Anglian Regional Health Authority. Prednisolone and matching placebo tablets were provided by Glaxo Ltd. We thank the dietitians, pharmacists, and clinical biochemists of the hospitals involved in the study for their help and support, Dr R Hanka (Medical Informatics Department, University of Cambridge) for statistical advice, and Miss A J Lee for preparation of the paper.

References O’Morain C, Segal AW, Levi AJ. Elemental diet as primary treatment of acute Crohn’s disease: a controlled trial. BMJ 1984; 288: 1859-62. 2 Saverymuttu S, Hodgson HJF, Chadwick VS. Controlled trial comparing prednisolone with an elemental diet plus non-absorbable antibiotics with active Crohn’s disease. Gut 1985; 26: 994-98. 3 Kelly SM, Thuluvath, P Fotherby K, Crampton J, Hunter JO. Elemental diet is an effective treatment of acute Crohn’s disease. Scand J Gastroenterol 1989; 24 (suppl 158): 149. 4 Sanderson IR, Boulton P, Menzie I, Walker-Smith JA. Improvement of abnormal lactulose/rhamnose permeability in active Crohn’s disease of the small bowel by an elemental diet. Gut 1987; 28: 1073-76. 5 Malchow H, Steinhardt HJ, Lorenz-Meyer H, et al. Feasibility and effectiveness of a defined formula diet regimen in treating active 1

Crohn’s disease: European Cooperative Crohn’s disease study III. Scand J Gastroenterol 1990; 25: 235-44. 6 Lochs H, Steinhardt HJ, Klaus-Wentz B, et al. Comparison of enteral nutrition and drug treatment in active Crohn’s disease: results of the European Cooperative Crohn’s disease study IV. Gastroenterology 1991; 101: 881-88. 7 Workman EM, Alun Jones V, Wilson AJ, Hunter JO. Diet in the management of Crohn’s disease. Hum Nutr Appl Nutr 1984; 38A: 469-73. 8 Alun Jones V, Workman E, Dickinson RJ, Wilson AJ, Freeman AH, Hunter JO. Crohn’s disease: maintenance of remission by diet. Lancet 1985; ii: 177-80. 9 Harvey RF, Bradshaw JM. A simple index of Crohn’s disease activity. Lancet 1980; i: 514. 10 Giaffer MH, North G, Holdsworth CD. Controlled trial of polymeric diet in the treatment of active Crohn’s disease. Lancet 1990; 335: 816-19. 11 Rigaud D, Cosnes J, Le Quintrec Y, Rene E, Gendre JP, Mignon M. Controlled trial comparing two types of enteral nutrition in treatment of active Crohn’s disease: elemental vs polymeric diet. Gut 1991; 32: 1492-97. 12 Middleton SJ, Riordan AM, Hunter JO. Peptide based diet: an alternative to elemental diet in the treatment of acute Crohn’s disease. Gut 1991; 32: A578. 13 Teahon K, Bjarnason L, Pearson M, Levi AJ. Ten years experience with an elemental diet in the management of Crohn’s disease,. Gut 1990; 31: 1133-37.

Gene marking to determine whether autologous marrow infusion restores long-term haemopoiesis in cancer patients

Summary The contribution of infused bone marrow cells to long-term haemopoietic recovery in patients undergoing autologous bone marrow transplantation is unknown. Such information would help to clarify the role of this procedure in cancer therapy and would aid in the development of strategies to reduce the risk of subsequent aplasia. By transferring a neomycin resistance marker gene into the marrow cells of 20 patients before transplantation, we were able to trace the pattern of haemopoietic reconstitution postinfusion. The marker gene was present and expressed in all haemopoietic lineages in vivo in 15 of 18 evaluable patients at 1 month post-transplantation, in 8 of 9 patients at 6 months, and in 5 of 5 at 1 year. The marker has remained detectable for up to 18 months—the duration of our study.

Department of Hematology/Oncology, Division of Bone Marrow Transplantation, St Jude Children’s Research Hospital, and Departments of Pediatrics and Medicine, University of Tennessee, Memphis, College of Medicine, Memphis (Prof M K Brenner FRCP, V M Santana MD); Division of Bone Marrow Transplantation, St Jude Children’s Research Hospital (D R Rill BS, M S Holladay BS, H E Heslop MD, M Buschle PhD, R A Krance MD); Genetic Therapy Incorporated, Gaithersburg, MD 20878 (R C Moen MD); USC School of Medicine, Los Angeles, CA 90033 (W F Anderson MD); and Department of Biochemistry, St Jude Children’s Research Hospital (J N Ihle PhD) Correspondence to: Prof Malcolm K Brenner, Division of Bone Marrow Transplantation, St Jude Children’s Research Hospital, Memphis, TN 38105, USA

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Our

findings indicate that harvested bone marrow consistently contributes to long-term multilineage recovery of haemopoiesis after autologous marrow transplantation in cancer patients. These results provide a rationale for the continued exploration of more ablative preparative regimens with single or sequential autologous marrow transplants. Lancet 1993; 342: 1134-37

Introduction

Autologous bone marrow transplantation is widely used to rescue patients from the consequences of ablative cancer therapies, yet little is known about the fundamental biology of autologous marrow graft recovery. 1-3 The marrow infused is usually harvested from individuals who have received intensive cytoreductive therapy, which may eliminate many of the stem cells capable of permanently restoring haemopoiesis. If insufficient stem cells remain in the harvested marrow,4,S the autograft may simply provide temporary replenishment of committed progenitor cells, whereas pluripotent stem cells remaining in the patient after high-dose chemotherapy or radiotherapy could be responsible for full haemopoietic recovery,1,6 If so, combinations of growth factors would be as effective as marrow infusions in stimulating cell regrowth after ablative therapy and would avoid the risk of the return of malignant cells with the infused marrow.2,7 Alternatively, if autologous marrow transplants contribute significantly to long-term multilineage marrow reconstitution, then successive transplantation procedures in the same patient