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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 1Medicine and 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.
INTRODUCTION
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-test.
Duodenal biopsies for all patients were reviewed and de- Table 2. 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 Table 1. 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
Table 3. Budesonide and Concomitant Medication Use in Relation
Table 4. 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 DISCUSSION
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 = 0.37).
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.
Table 5. 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- STUDY HIGHLIGHTS
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 r Budesonidecanbeusedalongwithotherimmunomod- 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. (26).
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 REFERENCES
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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.
Financial support: None.
21. Dickey W, Hughes DF. Histology of the terminal ileum in Potential competing interests: None.
coeliac disease. Scand J Gastroenterol 2004;39:665–7.

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