A Pilot Study of Fluticasone Propionate in Untreated Coeliac Disease

260 Gut, 1991, 32, 260-265 A pilot study offluticasone propionate in untreated

coeliac disease Gut: first published as 10.1136/gut.32.3.260 on 1 March 1991. Downloaded from

H C Mitchison, H Al Mardini, S Gillespie, M Laker, A Zaitoun, C 0 Record

Abstract sion of the pituitary-adrenal axis and the authors Although gluten withdrawal is likely to remain concluded that these agents offered no benefit the mainstay of treatment for adult coeliac over prednisolone.S disease, many patients find the diet incon- Fluticasone propionate is a new corticosteroid venient and unpalatable and compliance among with poor systemic absorption after an oral dose asymptomatic patients is often poor. Oral and a high first pass metabolism leading to low corticosteroids have been used for patients bioavailability. Repeated oral doses of up to who seem to be resistant to gluten withdrawal 20 mg/day in volunteers have not been associated but preparations with low systemic bioavail- with low cortisol values, neither have these been ability might be preferable. We have given a a problem in clinical trials in patients with new glucocorticoid (fluticasone propionate) to ulcerative colitis. We have therefore undertaken 12 adults with untreated coeliac disease for six an open trial of fluticasone propionate in un- weeks while they were on a normal diet. One treated coeliac disease, looking for objective patient defaulted and one suffered a relapse in functional and histological improvement in the a pre-existing neoplasm. Excluding these, small bowel and for evidence of adrenal sup- there was an improvement of symptoms, a pression. mean weight gain of 2 kg, and a rise in albumin of5 4 g/l. There was a significant improvement in the lactulose/mannitol excretion ratio Methods (p<005) and in all histological variables Patients with untreated coeliac disease, of either examined in paired biopsy specimens (surface sex and over 18 years of age, were considered. A and crypt intraepithelial lymphocyte/entero- firm diagnosis of coeliac disease including a cyte and goblet cell/enterocyte ratios and duodenal or jejunal biopsy was required. enterocyte height, p<001 or better). In six Patients with contraindications to cortico- http://gut.bmj.com/ paired specimens sucrase and alkaline phos- steroids, lactating mothers, or those with phatase activity increased in all (p<0.05) and evidence of other small bowel disease associated lactase in five of six. No appreciable side with coeliac disease (such as lymphoma) were effects were observed, but two patients had excluded and women of childbearing age were suppressed cortisol values and synacthen only included if using adequate contraception. responses at six weeks. A further three, with normal pretrial results, had a blunted tetra- on September 27, 2021 by guest. Protected copyright. cosactrin response at six weeks. Fluticasone PRELIMINARY INVESTIGATIONS propionate seems worthy of further assess- Baseline symptoms were assessed, particularly ment in the treatment of coeliac disease as an gastrointestinal symptoms of weight loss, adjunct to gluten withdrawal. anorexia, nausea, bowel frequency and consistency, and abdominal discomfort. Physical examination and routine urine analysis were per- Coeliac disease is a condition where exposure to formed. Full blood count, red cell and serum gluten produces abnormalities in the upper small folate and serum iron (except in those patients on bowel that lead to malabsorption. Removal of haematinic drugs), urea and electrolytes. gluten from the diet leads to improvement in glucose, liver function tests (bilirubin, alanine most cases but necessitates life long compliance transaminase and alkaline phosphatase), with a socially inconvenient and unpalatable albumin, protein, immunoglobulin, and gliadin diet. Many patients are non-compliant and thus antibodies were measured. A short tetracosactrin show poor histological healing though symptoms test was performed. may be tolerably well controlled. In a proportion A differential sugar absorption study was Gastroenterology Unit of patients the removal of not H C Mitchison gluten is sufficient undertaken using lactulose and mannitol as H Al Mardini to produce clinical resolution and in these, in probes: after an overnight fast the subjects drank A Zaitoun particular, corticosteroids have been used with a test solution of 5 g lactulose and 2 g mannitol in C O Record improvements both in clinical state' and in 100 ml of tapwater containing 10-3 g glycerol to and Department of jejunal morphology,4 though the benefits do not achieve a hypertonic solution, osmolarity 1500 Clinical Biochemistry, outlive the period of treatment. Adrenal sup- mol/l. They continued to fast until the end of the Royal Victoria Infirmary pression has been a major worry and might be first urine collection. Urine was in and collected two University, avoidable if a Newcastle upon Tyne topically active but non-absorbed consecutive five hour periods and stored in NEI 4LP corticosteroid could be shown to be effective. containers holding 0.2 ml sodium methiolate. S Gillespie Bramble et al used clobetasone butyrate or The total volume was recorded and 20 ml M Laker betamethasone valerate over four months and aliquots stored at -20°C. Analysis was by gas- Correspondence to: showed biochemical and Dr C O Record. histological improve- liquid chromatography as previously described67 Accepted for publication ments in 10 untreated coeliac patients on a except that for mannitol methoxime derivatives 24 April 1990 normal diet but eight of 10 developed suppres- were formed before trimethylsilylation. A pilotstudy offluticavone propionate in untreated coeliac disease 261

Endoscopic duodenal biopsy specimens were three weeks they were reviewed for adverse obtained using a large channel endoscope (3.7 events and the following checked for safety: mm channel). Some of the tissue was fixed in urine analysis and 9 am cortisol, urea, electro- formalin for histological assessment, processed lyte, and glucose concentrations. Gut: first published as 10.1136/gut.32.3.260 on 1 March 1991. Downloaded from in paraffin wax, sectioned at 5 ,um intervals, and stained with haematoxylin and eosin and with alcian blue/periodic acid Schiff. Intraepithelial POSTTREATMENT INVESTIGATIONS lymphocytes were counted in the villous At six weeks all the preliminary assessments epithelium or superficial flat epithelium and also were repeated, full dietary advice on a gluten free in the crypt epithelium. At least 500 enterocytes diet given, and continuing follow up arranged. were counted in each case in sections performed at multiple levels to provide intraepithelial lymphocyte/enterocyte ratios for surface and STATISTICAL METHODS crypt epithelium. Enterocyte height was All paired results have been compared using the measured according to Howdle et aP and de Ritis Wilcoxon signed rank test except for the dif- et aP. At least 50 epithelial cells with basal ferential sugar absorption data where, after log10 centrally located nuclei were measured using transformation, Student's t test was used. All p multiple sections at different levels. Cells were values are two tailed. chosen at random throughout the epithelium of This study was performed in accordance with the villi or superficial flat epithelium. A crossed the Declaration of Helsinki and had ethical micrometer eye piece graticule was used for this committee approval. We had thought that it purpose. Goblet cells in the crypt epithelium would be desirable to perform insulin stress tests were counted and the ratio of goblet cells to to assess adrenal reserve but permission was not enterocytes obtained by counting a minimum of given for this. 500 enterocytes. The biopsy specimens were assessed blind. Intestinal enzyme activities were measured by Results taking a freshduodenal specimenandhomogenis- Twelve patients were entered into the study, and ing this in 1 ml of normal saline in a loose fitting 10 completed it with good compliance. One Potter-Elvehjem glass homogeniser. The speci- patient had a relapse in a pre-existing Hodgkin's men was then frozen until used. Before analysis lymphoma, necessitating withdrawal, and of protein content,'` lactase," sucrase," and remained severely symptomatic throughout. alkaline phosphatase"l activities, specimens were Another, with longstanding, mildly sympto-

defrosted and sonicated three times at 0°C for 10 matic coeliac disease and known to be entirely http://gut.bmj.com/ seconds. The results are expressed as IU/g non-compliant with dietary measures, defaulted. protein. Biopsy specimens were also obtained Except where stated, these patients have not from 12 patients having endoscopies for other been included in paired assessments ofinitial and reasons and in whom routine duodenal histology end of treatment data. The Table gives details of was normal. the patients. The patients were issued with a diary card to

record compliance and stool frequency and con- on September 27, 2021 by guest. Protected copyright. sistency. They received fluticasone propionate 5 CLINICAL EVENTS mg four times a day for six weeks (probably Initial clinical assessments are shown in the equivalent to 40 mg prednisolone a day). After Table. At six weeks seven patients were assessed

Patient details After treatment Cortisol+tetracosactrin Before treatment response at 6 weeks (nmol/l) Clinical Weight Albumin Case Age Duration Reasonfor ratingof change change 30 min after No (years) ofdisease* diagnosis severity (kg) (gil) Baseline tetracosactrin 1 24 2-5 yr Diarrhoea, anaemia Moderate + 1 +5 <30 99 weight loss 2 54 4 mth Diarrhoea, anaemia Severe - -t weight loss 3 42 2-5 yr Diarrhoea Mild +4-4 +9 275 733 weight loss 4 44 33 yr Steatorrhoea Moderate +2 +2 396 519 5 42 6 mth Anaemia Moderate 0 + 1 138 365 6 51 3 yr Dermatitis Mild +0.5 +3 261 699 herpetiformis 7 22 2 mth Diarrhoea Mild +15 +14 <30f <30 weight loss 8 56 55 yr Failure to thrivet Mild -0.3 +3 524 690 9 35 32 yr Diarrhoea Mild - - - - weight loss 10 66 >30 yr Anaemia Moderate -0-2 -1 338t 466 11 67 20yr Anaemia Moderate +0.5 +3 289 598 12 68 3 mth Diarrhoea, anaemia Moderate +2 + 15 261t 465 weight loss *Estimated from history; tdiagnosed in childhood. Normal tetracosactrin test: baseline (9 am) > 140 nmol/l, 30 minute increment > 190 nmolIl, 30 minute value >500 nmol/l. tCortisol response before treatment already abnormal. Case no 2 and 9 did not complete the trial period. 262 Mitchison, Mardini, Gillespie, Laker, Zaitoun, Record

as in remission and three as having mild symp- tion on the first test was 66.2 (14-4) mg/vol toms with an improvement having been noticed (n= 10) and on the second test 60.9 (18-7) mg/vol in bowel frequency (3/3 initially abnormal), stool (n=8) (not significant, normal range consistency (6/6 initially abnormal) and weight 5-31 mg/vol). Values for mannitol excretion Gut: first published as 10.1136/gut.32.3.260 on 1 March 1991. Downloaded from (mean weight gain 2 kg, p<0O05). were 128-8 (34.7) mg/vol (n=10) and 259.9 (73.4) mg/vol (n=8) (p=005, normal range 350-590 mg/vol). Thus, overall, the improve- ADVERSE EVENTS meyt in the lactulose/mannitol ratio (Fig 1, There were no major adverse events that could p<005) occurred because ofincreased mannitol be ascribed to the treatment. One person com- absorption. In one case the ratio fell to within the plained of retrosternal discomfort, another of normal range. The first five hour collection ofthe heartburn, and one of an increase in acne: all test is thought to be the most useful part, the could have been due to steroid treatment. For second half being more likely to be disturbed by other minor events reported any connection with the breaking of the fast and by colonic treatment seemed unlikely. No one developed metabolism of the sugars. In both the cases cushingoid features. where the first collection was missing, after pooling the results for urine obtained through the whole 10 hour period and comparing the first HAEMATOLOGY AND BIOCHEMISTRY and second tests there was a pronounced There was a mean rise of 6 g/l in the haemo- improvement after treatment: the second lac- globin concentration in the nine patients with tulose/mannitol ratios being approximately 25% paired results (not significant) and of 5.4 g/l in ofthe first. the albumin concentration (p<0.01). Liver function tests were initially abnormal in six patients: in five the abnormality was a modest HISTOLOGICAL ASSESSMENT rise in alkaline phosphatase activity (liver v bone There was a significant reduction in the lympho- source not determined) and one had an abnormal cytic infiltrate in the 10 paired biopsy specimens alanine aminotransferase activity (70 IU/1, (Figs 2, 3): in all cases the intraepithelial normal <46). After six weeks all patients still lymphocytes, as a ratio of the surface enterocyte had raised alkaline phosphatase activity but the count, fell (p=0002), and in comparison with transaminase value was normal. One of the the crypt enterocyte count the intraepithelial patients with a raised initial alkaline phosphatase lymphocytes fell in all but two cases (p<002). activity was the patient with Hodgkin's disease: Enterocyte height improved in nine of 10

his liver function tests deteriorated until chemo- (p<001) and the ratio of goblet cells to entero- http://gut.bmj.com/ therapy was introduced and the abnormal tests cytes increased in all cases (p=0.002). were almost certainly due to the lymphoma rather than the coeliac disease. Urea, electrolyte, and glucose concentrations were normal in all, and urine analysis showed only slight abnormalities in 1.4k two ofthe patients on their first visit only.

Morning cortisol concentrations were initially on September 27, 2021 by guest. Protected copyright. normal in all. The criteria for a normal tetracosactrin test are shown in the Table, and by these strict criteria five patients failed to show an adequate increment in cortisol after tetracosactrin and one of these also failed to reach the 30 1.0- minute minimum concentration of 500 nmol/l. At the end of six weeks of treatment this patient and one other had low morning cortisol con- 0

centrations and a very poor response to tetra- 0

cosactrin, and in a further five patients the C response was blunted: two ofthese were patients c whose pretreatment tetracosactrin responses had E been abnormal. o 0.6- t -J IMMUNOLOGY IgG concentrations were normal throughout, IgM was slightly raised in the one patient who later defaulted (2-72 g/l, normal range 0 75-2 g/l) and IgA in one patient was low but became normal (0.22 g/l, normal 0.65-3 g/l). All but one 02 ± patient had a positive gliadin antibody initially. -- -1- J p

Figure 2: Intraepithelial 801 lymphocytelenterocyte percentage for surface and crypt epithelium before and after treatment in the 10 Gut: first published as 10.1136/gut.32.3.260 on 1 March 1991. Downloaded from patients whofinished the 1 trial. Mean (SEM) shown. - 0 U 60- 30- 0 0 a)m 4_ 0 0 Cc: +. 0. 4)

W -c C.,U U0 20 + -C -cna) 0 C.)0. E.

E > 20- ± C ___a) LCc

p=0-002 p < 0-02 0- I l Before After Before After treatment treatment treatment treatment

INTESTINAL ENZYME ACTIVITIES activity rose in five of six cases. Four of the Biopsy specimens from 12 normal patients gave posttreatment results for alkaline phosphatase the following enzyme activities: alkaline phos- were within the range of the normal biopsy phatase: mean (SE) 955 (103) IU/g, range specimens. 325-1520; lactase: 52.7 (6.5) IU/g, range 23-105; sucrase: 103.6 (11-8), range 46-179. Six http://gut.bmj.com/ paired samples from trial patients were available Discussion for comparison (Fig 4). In no case did pretreat- Among 10 untreated coeliac patients with villous ment values fall within the range of the normal atrophy confirmed by biopsy who completed six biopsy specimens (p<0001). There was a mean weeks of treatment with fluticasone propionate improvement in all three enzyme activities while continuing with a normal diet, there was an measured and with respect to alkaline phos- improvement in symptoms, weight, and serum phatase and sucrase the activity increased in albumin concentration, and in three parameters on September 27, 2021 by guest. Protected copyright. every case after treatment (p<005). The lactase of gut damage: differential sugar absorption,

40- 30

a) 0 :c 0 C 20- LC 0 0 + 0 0 0 -o 0-

20- 10. + Figure 3: Enterocyte height andgoblet celllenterocyte percentage before and after p<0.01 p=0-002 treatment in the 10 patients I 1 whofinished the trial. Mean Before After Before After (SEM) shown. treatment treatment treatment treatment 264 Mitchison, Mardini, Gillespie, Laker, Zaitoun, Record

700 351 Gut: first published as 10.1136/gut.32.3.260 on 1 March 1991. Downloaded from

S D 500 13 m CA 'a 25- Q T tn 0 * 0 0 cU IL az0, C.,CU en _ _ -J I C X 300L 9. .L 15~ + . 1 + 100- 5. I a p < 0.05 I p< 0*1 5 p< 0O05 Before After Before After Before After treatment treatment treatment treatment treatment treatment Figure 4: Alkaline phosphatase, sucrase, and lactase activities before and after treatment in six ofthe 10 patients whofinished the trial. Mean (SEM) shown.

small intestinal enzymic activity, and intestinal was associated with an improvement in entero- histology. Even though the number of patients cyte height, and Riecksen et al,'5 using serial was small many of the changes were consistent biopsies in one patient, showed that recovery in enough to be significant. enzyme activities was detectable within two http://gut.bmj.com/ Longterm follow up of these patients to weeks and appreciable within four weeks of establish a definitive diagnosis of coeliac disease gluten withdrawal. - that is, clinical and histological response to In addition to enzyme analyses and detailed gluten withdrawal - has been possible in the 10 histological assessment we used a differential patients who have been largely compliant with a sugar absorption test to assess the efficacy of gluten free diet. All have remained clinically well treatment. This is a more sophisticated version with no recurrence of the symptoms leading to of the simple sugar absorption studies which on September 27, 2021 by guest. Protected copyright. their original diagnosis. Further duodenal depended on the passive absorption of water biopsy specimens, taken at intervals of 9-18 soluble molecules across the gut and their sub- months after the study, have shown normal or sequent renal excretion to quantify gut perme- near normal histology in three, appreciable ability. The absorption of mannitol seems to be villous atrophy in one, while in the remaining transcellular and factors that reduce the entero- six, histological appearances were improved com- cyte area, such as coeliac disease, will reduce pared with the biopsy specimen taken at the end absorption. Lactulose seems to diffuse via para- ofthe study. cellular pathways and diseases that damage the The results are in keeping with those of gut and increase its general 'leakiness' lead to previous studies of steroid use in coeliac increased lactulose absorption. Lactulose disease,4511 all ofwhich showed an improvement behaves in the same way as cellobiose and in intestinal enzyme activity and, in two raffinose, both of which have been used in reports,45 clinical and histological improvement. absorption studies in coeliac disease'617 with The histological improvement shown here closely similar results. In one centre the lac- occurred both in the inflammatory infiltrate tulose/mannitol combination has been favour- (intraepithelial lymphocyte count) and in the ably compared with duodenal biopsy in measur- absorptive surface epithelium (enterocyte height ing response to gluten challenge. 18 The lactulose/ and goblet cell ratio). mannitol ratio clearly improved with treatment, Our findings and those of Wall et a14 and primarily due to an improvement in mannitol Bramble et all are in keeping with the rate of absorption rather than to a reduction in lactulose recovery seen both clinically and in the mucosa absorption, suggesting that gut healing initially of the gut of coeliac patients after withdrawal takes the form of increasing enterocyte area from gluten. It is well recognised that full rather than ofreducing 'leakiness'. recovery of the villous pattern on gluten with- The major problems with the use of oral drawal may take months to occur or, indeed, steroids in coeliac disease have been adrenal may never do so. The clinical recovery seen on suppression'9 and the worry about longterm side gluten withdrawal, however, occurs within days effects such as osteoporosis to which the underly- to weeks. Yardley et al'4 described three patients ing condition increases vulnerability. We found in whom gluten withdrawal for 10 days or less adrenal suppression in two patients after fluti- A pilotstudy offluticasonepropionate in untreated coeliac disease 265

casone treatment, although one had been an unexpected finding in this study was that at abnormal previously, while there was a blunted least two patients were sufficiently impressed by cortisol response in a further five, two of whom the improvement in their health with fluticasone had been abnormal previously. This suggestion propionate that they were motivated to under- Gut: first published as 10.1136/gut.32.3.260 on 1 March 1991. Downloaded from of systemic absorption of fluticasone propionate take a gluten free diet conscientiously, some- is not understood as it has not been seen in thing they had been reluctant to consider. normal volunteers and only once in patients with These considerations, as well as the clear colitis: it would be better clarified by more benefits associated with fluticasone propionate, stringent testing with insulin stress tests. The make it reasonable to suggest that the drug is same observations concerning clobetasone buty- worthy of further longterm assessment in coeliac rate were made by Bramble et al.5 Presumably disease, in a controlled trial v gluten with- the greater 'leakiness' of the damaged gut - as drawal. Such a trial would have to incorporate shown by the greater than normal absorption of stringent observations for adrenal suppression. lactulose - encourages absorption of the steroid, This study was undertaken with the aid of Glaxo Group Research but this is not seen with prednisolone where Ltd, who kindly supplied the fluticasone propionate. blood concentrations after oral doses were the same in coeliac patients and in normal subjects.20 ADDENDUM . Ifso, as the gut heals a lessening ofcorticosteroid The morphological aspects of this study have now been extended using quantitative computerised image analysis. (Zaitoun A, absorption and adrenal suppression would be Record CO. Alimentary Pharmacology and Therapeutics, in press.) expected. This is partially supported by Bramble et all: 9 am cortisol concentrations were at their 1 Adlersberg D, Colcher H, Drachman SR. Studies on the lowest the months treatment, effects of cortisone pituitary adrenocorticotrophic hormone during four of (ACTH) in the sprue syndrome. Gastroenterology 1951; 19: while by the end ofthe treatment period they had 674-97. actually risen slightly. Thus their conclusion that 2 Otaki AT, Daly JD, Gill AM. Observations on oral betamethasone 17 valerate in the treatment of idiopathic steatorrhoea. the two steroids they were studying had nothing Gut 1967; 8: 458-62. to add to prednisolone treatment may have been 3 Cooke WT, Holmes GKT. Coeliac disease. Edinburgh: Churchill Livingstone, 1984. unduly severe. The question of longterm side 4 Wall AJ, Douglas AP, Booth CC, Pearse AGE. Response ofthe effects would only be answered by longer jejunal mucosa in adult coeliac disease to oral prednisolone. Gut 1970; 11: 7-14. studies - corticosteroid osteoporosis is not neces- 5 Bramble MG, Watson AJ, Scott J, Peters TJ, Record CO. sarily circumvented by avoiding adrenal sup- Clinical, biochemical and morphological responses of patients with villous atrophy to oral betamethasone valerate pression. and clobetasone butyrate. Digestion 1981; 22: 281-8. The use of corticosteroids in coeliac disease 6 Laker MF. Estimation ofdisaccharides in plasma and urine by gas-liquid chromatography. J7 Chromatogr 1979; 163: 9-18. seems to relate to three different patient groups. 7 Laker MF, Mount JN. Mannitol estimation in biological fluids

Firstly, there are the patients who are resistant to by gas-liquid chromatography. Clin Chem 1980; 26: 441-3. http://gut.bmj.com/ 8 Howdle PD, Corazza GR, Bullen AW, Losowsky MS. Gluten gluten withdrawal (estimated to be 10% of all sensitivity of small intestinal mucosa in vitro: quantitative coeliac assessment of histologic change. Gastroenterology 1981; 80: patients), in whom prednisolone has been 442-50. used with gratifying response and where the 9 de Ritis G, Auricchio S, Jones HW, Lew E J-L, Bernadin JE, benefits the but Kasarda DD. In vitro (organ culture) studies of the toxicity clearly outweigh disadvantages of specific A gliadin peptides in coeliac disease. Gastro- where substitution with a corticosteroid with enterology 1988; 94: 41-9. lower systemic bioavailability must be theoreti- 10 Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ. Protein measurement with the folinphenol reagent. J Biol Chem cally preferable. The second group of patients 1951; 193: 265-75. on September 27, 2021 by guest. Protected copyright. are those who are clearly non-compliant. It is 11 Dahlqvist A. Assay ofintestinal disaccharidases. Anal Biochem 1968; 22: 99-107. important to recognise that corticosteroid treat- 12 Hausamen TU, Hegler R, Rick W, Cross W. An optimised ment cannot be in these as an method for the determination of alkaline phosphatase in justified patients serum. Clin Chim Acta 1967; 15: 241-5. easy alternative to a gluten free diet: removing 13 Peters TJ, Jones PE, Jenkins WJ, Wells G. Analytical the allergen must always be preferable to sup- subcellular fractionation of jejunal biopsy specimens: enzyme activities, organelle pathology and response to pressing the body's response. Among non-com- corticosteroids in patients with non-responsive coeliac and ill small there an disease. Clinical Science and Molecular Medicine 1978; 55: pliant patients (a group) is 293-300. obvious role for steroid use, but there is also an 14 Yardley JH, Bayles TM, Norton JH, Hendrix TR. Celiac argument for steroid use among disease: a study of the jejunal epithelium before and after a non-compliant gluten free diet. NEnglJ Med 1962; 267: 1173-9. and well patients now that compliance has been 15 Riecksen EO, Stewart JS, Booth CC, Pearse AGE. A histo- shown to reduce the longterm risks of small chemical study on the role of lysosomal enzymes in idiopathic steatorrhoea before and during a gluten free diet. Gut bowel neoplasia,2' presumably by encouraging 1966; 7: 317-32. normalisation of the small bowel mucosa. If a 16 Cobden I, Dickinson RJ, Rothwell J, Axon AT. Intestinal permeability assessed by excretion ratios of two molecules: safe corticosteroid could be found then treat- results in coeliac disease. BMJ 1978; ii: 1060. ment 17 Dawson DJ, Lobley RW, Burrows PC, Notman JA, Mahon of well but non-compliant patients M, Holmes R. Changes in jejunal permeability and passive becomes a valid consideration. Even here corti- permeation of sugars in intestinal biopsies in coeliac disease costeroids are not an alternative to a and Crohn's disease. Clin Sci 1988; 74: 427-31. easy gluten 18 Juby LD, Rothwell J, Axon ATR. Gluten challenge using free diet as it cannot be assumed that suppression lactulose mannitol (LA/MA) test. Gut 1989; 30: A720. to would have the same 19 Hamilton JD, Chambers RA, Wynn-Williams A. Role of of the reaction gluten gluten, prednisolone and azathioprine in non-responsive beneficial effect on the incidence of neoplasia as coeliac disease. Lancet 1976; i: 1213-6. are 20 Pickup ME, Farah F, Lowe JR, Dixon JS, Record CO. gluten removal. The third group of patients Prednisolone absorption in coeliac disease. Europ J Drug the newly diagnosed in whom the addition of Metab Pharmacokinet 1979; 2: 87-9. 21 Holmes GKT, Prior P, Lane MR, Pope D, Allan RN. steroids for a short period might hasten healing Malignancy in coeliac disease - effect of a gluten free diet. and well being and improve dietary compliance: Gut 1989; 30: 333-8.