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Budesonide in the Treatment of Refractory Celiac DiseasePardeep Brar, M.D.,1 Susie Lee, M.D.,1 Suzanne Lewis, M.D.,1 Ikenna Egbuna, M.D.,1 Govind Bhagat, M.D.,2and Peter H.R. Green, M.D.1Departments of
2Surgical Pathology, Columbia University College of Physiciansand Surgeons, New York
Corticosteroids are used in patients with refractory celiac disease. In order to minimize theirsystemic side effects, we assessed the role of a locally active sustained release corticosteroid withminimal systemic bioavailability in patients with refractory celiac disease in an open labelednoncontrolled study.
Patients who received budesonide for refractory celiac disease were classified according to whetherthey were primarily or secondarily unresponsive to the diet, and whether they had a polyclonal(type I) or clonal (type II) expansion of intraepithelial lymphocytes. The response to budesonide wasassessed globally and by reduction in bowel movements.
Patients (N = 29, 72% female) received budesonide for a mean of 6.7 ± 8.5 months, 5 patients(18%) had type II disease (clonal T-cell population); 76% responded to the medication, 55%completely. Response occurred when budesonide was used alone or with oral corticosteroidsand/or azathioprine. There was an objective improvement in the number of bowel movements inthose that responded. Response occurred in those with either primary or secondary refractorydisease and in those with type II disease, irrespective of the presence of microscopic colitis (N = 7).
There was no improvement in the duodenal biopsy over the study period and there were no sideeffects of budesonide.
Budesonide may be of value in the management of refractory celiac disease.
is however limited by systemic side effects. Topically activesteroids are therefore attractive for treating patients who have
Celiac disease is an autoimmune enteropathy triggered by in-
poorly responsive or refractory celiac disease, since they have
gestion of gluten, the storage protein of wheat, and similar
low systemic bioavailability and provide immunosuppressant
proteins in rye and barley (1). A gluten-free diet is the main-
activity in the bowel, avoiding deleterious systemic effects.
stay of treatment; however, up to 7–30% of patients have poor
Budesonide is a synthetic steroid that has high topical glu-
responses to this dietary therapy (2–4). While a systematic ap-
cocorticoid activity, but low systemic bioavailability because
proach to the evaluation of these patients frequently reveals
of high first-pass metabolism primarily by cytochrome P450
a treatable cause for this poorly responsive state, no other
in the liver (2, 11). Entocort EC (controlled-release budes-
disease process is discovered in some patients (1–5). These
onide) is enteric coated and is designed to deliver the active
poorly responsive patients with persistent symptoms and vil-
drug to the distal small intestine and colon (2, 11). However,
lous atrophy on biopsy, despite adherence to a gluten-free diet
studies have revealed that about 30% is released and absorbed
for at least 6–12 months, are determined to have refractory
in the upper small intestine (2, 11). We therefore evaluated
celiac disease (4, 6). Patients with refractory celiac disease
the use of this drug in refractory patients who were compliant
are classified as having either primary refractory disease if
they never responded to a gluten-free diet or secondary iftheir disease relapsed, despite adherence to the diet (4). Analternate classification is based on determining the presence
of clonal proliferations of intraepithelial lymphocytes thathave phenotypic aberrations (6).
Patients with celiac disease responding poorly to dietary re-
Corticosteroids, either alone or in combination with other
striction of gluten, and in whom budesonide was prescribed,
immunosuppressive drugs, are used in refractory patients,
were identified from the database of our university based
especially those with severe persistent or recurrent symptoms
celiac disease center. An experienced dietician assessed di-
despite being on a strict gluten-free diet (3, 6–10); their use
etary compliance, and patients noncompliant to the diet
Brar et al.
were excluded. Data regarding patient’s demographics, mode
small bowel biopsies followed by polyacrylamide gel elec-
of disease presentation, serology profiles (endomysial anti-
trophoresis and heteroduplex analysis (13).
body [EMA] and/or tissue transglutaminase antibody [tTG]),dose and duration of budesonide use, clinical response, and
concomitant medication use were recorded. All poorly re-sponsive patients had undergone extensive evaluation that
A total of 30 refractory celiac disease patients received budes-
included colonoscopy and colon biopsies, CT scans of the
onide between January 2000 and April 2005, one patient was
abdomen and pelvis, imaging of the small intestine either
excluded from the study because she did not come for a
by small bowel series or video capsule endoscopy, and stool
follow-up visit. Twenty-four patients were on a gluten-free
specimens were examined for ova and parasites and breath
diet for at least 6 months, while 5 patients were on the diet
tests performed to exclude bacterial overgrowth. Antijejunal
for less than 6 months, each of the latter group of patients
antibodies, used to exclude autoimmune enteropathy, were
had required hospitalization because of severe disease man-
performed in one patient. Patients had received pancreatic
ifestations. Patient demographics along with histopathology
supplements, bismuth, and antibiotics prior to the use of
and serology results are shown in Table 2. All 29 patients ful-
steroid or immunosuppressants. This study was approved by
filled the criteria for celiac disease with compatible biopsies
and serologic profiles. Only one patient with negative en-
Mode of presentation, at the time of initial celiac disease
domysial antibodies had antijejunal antibodies assessed, they
diagnosis, was classified as classical (diarrhea predominant)
were negative. Our cohort was female predominant (72%)
and atypical (absence of diarrhea). Unresponsiveness to the
and more patients had a classical (90%) compared with atyp-
diet was classified as primary (no response to gluten-free diet
ical (10%) presentation. Unresponsiveness to gluten-free diet
to begin with) or secondary (recurrence of symptoms after
was primary in 55% and secondary in 45% of the patients.
initial response to diet) (4). Based on the results of polymerase
All patients had persistent villous atrophy and intraepithelial
chain reaction (PCR) analysis for T-cell receptor gene (TCR)
lymphocytosis despite the diet. The degree of villous atro-
rearrangement, the cohort was also divided into two groups;
phy was partial in 69% and total in 31%. Antibodies to EMA
type I refractory celiac disease if TCR gene rearrangement
and/or tTG were positive in 31% at the time of assessment
analysis yielded a polyclonal product and refractory celiac
of the refractory state, despite strict adherence to the diet.
disease type II if the TCR gene rearrangement was clonal
These patients had been on the diet for less than 12 months.
All serological tests became negative during the period of this
Budesonide treatment outcomes were globally classified as
study. PCR for TCR-γ
gene rearrangement was performed in
complete response, moderate response, and poor response, a
all except one patient; 23 patients (82%) had type I refractory
modified form of scale used by Chopra et al
. (25) for in-
celiac disease (polyclonal) and 5 patients (18%) had type II
flammatory bowel disease patients (Table 1). The global as-
sessment was based on the patient claiming that they were
Mean age at the start of budesonide therapy was 56 yr,
improved with loss of systemic symptoms such as fatigue
and all patients except 5 had celiac disease for at least
and increased well-being as well as the physician’s assess-
6 months’ duration (range 1–249 months) (Table 2). All pa-
ment of both the laboratory and clinical data. In order to
tients received 9 mg of budesonide per day and it was used
assess the response objectively, the number of bowel move-
for a mean of 7 months (range 1–36 months). During the time
ments for subjects with classical presentation and body mass
period of this study, one patient with type II refractory celiac
index (BMI) for all subjects were recorded before and after
disease died of sepsis and malnutrition.
budesonide treatment. The change in BMI was assessed usingpaired samples t
Duodenal biopsies for all patients were reviewed and de-
Demographic Characteristics (N = 29)
gree of villous atrophy was classified as partial (PVA), subto-
tal (STVA), or total (TVA). Cases with subtotal and total
villous atrophy were combined together (denoted as TVA)
for this study. Histopathology was compared before and after
budesonide treatment. PCR analysis for TCR gene rearrange-
ment was performed on formalin-fixed paraffin-embedded
Classification of Budesonide Treatment Outcome
Resolution of symptoms in patients completely
Resolution of symptoms and systemic steroid dose
Poor response Persistent symptoms despite therapy
CD = celiac disease; PVA = partial villous atrophy; TVA = total villous atrophy;EMA = endomysial antibody; tTG = transglutaminase antibody IgA.
Treatment of Refractory Celiac Disease
Budesonide and Concomitant Medication Use in Relation
Number of Bowel Movements Before and After Budesonide
S = systemic steroids; A = azathioprine.
response in 3 and moderate response in 2). Six patients hadlymphocytic colitis and one had collagenous colitis. The lat-ter patient only had a moderate response to the therapy. No
Use of immunomodulatory medications in addition to
patient had side effects that could be attributed to budesonide
budesonide: the use of prednisone and azathioprine was based
on the severity of symptoms. Some subjects received steroidsor azathioprine before budesonide became available. The ini-tial dosage of prednisone was 20–40 mg daily with efforts to
taper the dosage as the patient responded. Azathioprine wasused in an initial dosage of 50 mg daily; three patients re-
Corticosteroids are used in patients with celiac disease who
ceived 75 mg daily. These therapies were used for a duration
are severely ill, despite a gluten-free diet. They may be used
alone or along with immunomodulatory agents such as aza-
We looked at the use of budesonide along with concomitant
thioprine (7, 9, 14–16), cyclosporine (15, 17), or inflixamab
systemic steroids and other immunomodulators in relation to
(18, 19). With an aim of minimizing the systemic side effects
the three outcome groups (Table 3). Overall, 76% of the pa-
of corticosteroids, we assessed the role of a locally acting
tients had a response to budesonide, considered as complete
controlled-release corticosteroid, budesonide, in 29 patients
response in 55%. The number of bowel movements in the
with poorly responsive celiac disease. A beneficial clinical re-
subjects decreased from six to one in both the complete and
sponse to budesonide either used alone or in combination with
moderate response groups, but it remained the same in the
systemic steroids or azathioprine was observed in 76% of pa-
poor response group (Table 4). Overall, there was a slight
tients. When budesonide was used in combination with oral
improvement in BMI from 20.8 ± 3.9 to 21.1 ± 3.6, but this
steroids and/or azathioprine it is realized that all agents may
was not statistically significant (P
have contributed to improvement in the patients’ condition,
When budesonide was used without other immunomod-
including the effect of a delayed response to the azathioprine.
ulatory agents, 12 patients (80%) had a complete response
Several lines of evidence support the use of locally acting
and only 3 (20%) had a poor response. When budesonide
controlled-released corticosteroids in celiac disease. Firstly,
was used with steroids, azathioprine, or both, a complete re-
celiac disease is a chronic inflammatory small intestinal dis-
sponse was noted in 4, moderate in 6, and a poor response in
ease that primarily involves the proximal small intestine, but
may in some patients involve the entire small intestine (20–
We also looked at the patient characteristics in relation
22). Entocort EC, with its release in the small intestine, allows
to budesonide response Table 5. Among those with primary
delivery of a locally active corticosteroid preparation to the
refractory celiac disease there was an almost equal distribu-
involved tissues (11, 12). Secondly, this class of drug has been
tion among the three outcome groups, whereas patients with
previously been demonstrated to be efficacious in celiac dis-
secondary refractory disease had a complete response in 10
ease. Mitchison et al
. and Bramble et al
. used topically active
(77%), moderate response in 2 (15%), and poor response in
corticosteroids in patients with celiac disease while on a reg-
one. Almost an equal percentage of patients with PVA (55%)
ular diet. Improvement in both histology and parameters of
and TVA (56%) had a complete clinical response. However,
there was no noticeable improvement in the degree of vil-
Experience of the use of budesonide in celiac disease is,
lous atrophy in follow-up duodenal biopsies from any patient.
however, limited. There had been no reports of its use when
Type II refractory patients had persistent clonal proliferation
we started this study. Subsequently, in a study of budesonide
of IELs. Of the nine patients who had positive antibodies
use for inflammatory bowel disease, Chopra et al
. (25) men-
when assessed for the refractory state, a complete response
tioned that the drug was used in two patients with celiac dis-
was noted in 6 and poor response in 3 patients. Patients with
ease, without obvious benefit. The clinical details of these pa-
both type I and II refractory disease responded to budesonide
tients were not included. However, in another study the drug
was considered beneficial in patients with refractory sprue
Seven patients had concomitant microscopic colitis,
syndromes, including 7 with refractory celiac disease, one
5 (71%) responded to budesonide treatment (complete
with autoimmune enteropathy, and another with enteropathy
Brar et al.
Distribution of Subjects’ Characteristics in Relation to
the drug is beneficial in patients with type II refractory dis-
ease. This group, however, needs to be followed closely be-
cause of their poor long-term prognosis (6).
In view of the results demonstrated in this study a prospec-
tive placebo-controlled study is indicated. However, in the in-
terim, we advocate the use of budesonide as first-line therapy
in patients with celiac disease that require immunosuppres-
What Is Current Knowledge
CD = celiac disease; GFD = gluten-free diet; PVA = partial villous atrophy; TVA =
total villous atrophy; EMA = endomysial antibody; tTG = transglutaminase antibody
7–30% of patients with celiac disease have poor re-
IgA; TCR = T-cell receptor gene rearrangements.
r Corticosteroids/immunosuppressants are used in re-
associated T-cell lymphoma (26). We used the method of
r Systemic steroids are associated with systemic side ef-
assessing the response to budesonide that had been devel-
oped by Chopra et al
. at the Mayo Clinic (25), fully awarethat this had been used to assess patients with inflamma-
What Is New Here
tory bowel disease. There is no currently published tool
r Budesonide is useful in the management of refractory
for assessing the severity of illness for patients with celiac
r Response occurred in the presence of aberrant T-cell
Type II refractory celiac disease, as ascertained by the
populations (type II refractory celiac disease) as well
presence of clonally expanded intraepithelial lymphocytes,
presents a difficult management problem. Patients typically
r Response occurred irrespective of the presence of mi-
have a very difficult course, receive immunosuppression, and
often deteriorate despite treatment (27). This was seen in one
of our patients with type II refractory disease who died of sep-
sis and malnutrition during the period of this study. Patients
r Objective improvement in the number of bowel move-
with type II refractory disease are also at an increased risk
for the development of lymphoma (9). However, we noted
r No improvement in the duodenal biopsy over the study
improvement in 4 of 5 patients with type II refractory celiac
disease with the administration of budesonide, supporting the
observations of Daum et al
Overall, despite improvement in clinical symptoms, there
was no change in the duodenal histology on treatment with
Reprint requests and correspondence:
Peter H.R. Green, M.D.,
budesonide. This is probably related to the major site of action
Harkness Pavilion, Suite 956, 180 Fort Washington Ave., New York,
being the more distal small bowel as well as the fact that
morphological improvement in duodenal biopsies lags behind
Received October 25, 2006; accepted April 17, 2007.
Seven of the patients had concomitant lymphocytic colitis,
an indication in itself for budesonide use (30). The majority
of these patients did well on budesonide. However, when weexcluded patients with microscopic colitis from the overall
1. Green PH, Jabri B. Coeliac disease. Lancet 2003;362:383–
analysis, 77% of patients without microscopic colitis ben-
2. Pink IJ, Creamer B. Response to a gluten-free diet of patients
efited from budesonide therapy. Budesonide is therefore of
with the coeliac syndrome. Lancet 1967;1:300–4.
value in the treatment of celiac disease irrespective of coex-
3. O’Mahony S, Howdle PD, Losowsky MS. Review article:
Management of patients with non-responsive coeliac dis-
The major limitation of our study is that it is uncontrolled,
ease. Aliment Pharmacol Ther 1996;10:671–80.
without a placebo arm. Despite this, the analysis of response
4. Ryan BM, Kelleher D. Refractory celiac disease. Gastroen-
to the drug suggests that budesonide is beneficial in patients
5. Abdulkarim AS, Burgart LJ, See J, et al. Etiology of non-
with refractory celiac disease, both in individuals with pri-
responsive celiac disease: Results of a systematic approach.
mary or secondary unresponsiveness to the diet. In addition,
Am J Gastroenterol 2002;97:2016–21.
Treatment of Refractory Celiac Disease
6. Daum S, Cellier C, Mulder CJ. Refractory coeliac disease.
22. Culliford A, Daly J, Diamond B, et al. The value of wire-
Best Pract Res Clin Gastroenterol 2005;19:413–24.
less capsule endoscopy in patients with complicated celiac
7. Hamilton JD, Chambers RA, Wynn-Williams A. Role of
disease. Gastrointest Endosc 2005;62:55–61.
gluten, prednisone, and azathioprine in non-responsive
23. Bramble MG, Watson AJ, Scott J, et al. Clinical, biochem-
coeliac disease. Lancet 1976;1:1213–6.
ical and morphological responses of patients with villous
8. Trier JS. Celiac sprue. N Engl J Med 1991;325:1709–19.
atrophy to oral betamethasone valerate and clobetasone bu-
9. Goerres MS, Meijer JW, Wahab PJ, et al. Azathioprine and
prednisone combination therapy in refractory coeliac dis-
24. Mitchison HC, al Mardini H, Gillespie S, et al. A pilot study
ease. Aliment Pharmacol Ther 2003;18:487–94.
of fluticasone propionate in untreated coeliac disease. Gut
10. Ciclitira PJ, King AL, Fraser JS. AGA technical review
on celiac sprue. American Gastroenterological Association.
25. Chopra A, Pardi DS, Loftus EV, et al. Budesonide in
the treatment of inflammatory bowel disease: The first
11. Edsbacker S, Larsson P, Wollmer P. Gut delivery of
year of experience in clinical practice. Inflamm Bowel Dis
budesonide, a locally active corticosteroid, from plain and
controlled-release capsules. Eur J Gastroenterol Hepatol
26. Daum S, Ipczynski R, Heine B, et al. Therapy with
budesonide in patients with refractory sprue. Digestion
12. Edsbacker S, Bengtsson B, Larsson P, et al. A phar-
macoscintigraphic evaluation of oral budesonide given as
27. Cellier C, Delabesse E, Helmer C, et al. Refractory
controlled-release (Entocort) capsules. Aliment Pharmacol
sprue, coeliac disease, and enteropathy-associated T-cell
lymphoma. French Coeliac Disease Study Group. Lancet
13. Bottaro M, Berti E, Biondi A, et al. Heteroduplex analysis
of T-cell receptor gamma gene rearrangements for diagno-
28. Greco L, Corazza G, Babron MC, et al. Genome search in
sis and monitoring of cutaneous T-cell lymphomas. Blood
celiac disease. Am J Hum Genet 1998;62:669–75.
29. Dickey W, Hughes DF, McMillan SA. Disappearance
14. Maurino E, Niveloni S, Chernavsky A, et al. Azathioprine
of endomysial antibodies in treated celiac disease does
in refractory sprue: Results from a prospective, open-label
not indicate histological recovery. Am J Gastroenterol
study. Am J Gastroenterol 2002;97:2595–602.
15. Rolny P, Sigurjonsdottir HA, Remotti H, et al. Role of im-
30. Olesen M, Eriksson S, Bohr J, et al. Lymphocytic colitis:
munosuppressive therapy in refractory sprue-like disease.
A retrospective clinical study of 199 Swedish patients. Gut
Am J Gastroenterol 1999;94:219–25.
16. Vaidya A, Bolanos J, Berkelhammer C. Azathioprine in re-
fractory sprue. Am J Gastroenterol 1999;94:1967–9.
17. Longstreth GF. Successful treatment of refractory sprue
with cyclosporine. Ann Intern Med 1993;119:1014–6.
CONFLICT OF INTEREST
18. Gillett HR, Arnott ID, McIntyre M, et al. Successful inflix-
imab treatment for steroid-refractory celiac disease: A case
Guarantor of the article:
Peter H.R. Green, M.D.
report. Gastroenterology 2002;122:800–5.
Specific author contributions:
Dr. Peter H.R. Green is
19. Turner SM, Moorghen M, Probert CS. Refractory coeliac
responsible for the entire contents. Dr. Pardeep Brar and
disease: Remission with infliximab and immunomodulators.
Dr. Ikenna Egbuna are the fellows who analyzed and com-
Eur J Gastroenterol Hepatol 2005;17:667–9.
20. Macdonald WC, Brandborg LL, Flick AL, et al. Studies of
piled the data. Dr. Susie Lee, Dr. Suzanne Lewis, and Dr.
celiac sprue IV. The response of the whole length of the small
Peter H.R. Green looked after the patients, while Dr. Govind
bowel to a gluten-free diet. Gastroenterology 1964;47:573–
Bhagat is the pathologist involved in the study.
21. Dickey W, Hughes DF. Histology of the terminal ileum in
Potential competing interests:
coeliac disease. Scand J Gastroenterol 2004;39:665–7.
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