Budesonide Is Effective in Treating Lymphocytic Colitis: A Randomized Double-Blind Placebo-Controlled Study
Article Outline
Background & Aims
Budesonide is effective in treating collagenous colitis, but no treatment is established for lymphocytic colitis. We performed a randomized, double-blind, placebo-controlled study to evaluate the effects of budesonide in patients with lymphocytic colitis.
Methods
Forty-two patients (median age, 61 years) with lymphocytic colitis and chronic diarrhea were randomly assigned to groups that were given oral doses of budesonide (9 mg/d) or placebo for 6 weeks. Nonresponders at week 6 were given open-label budesonide (9 mg/d) for 6 additional weeks. A complete colonoscopy and histologic and quality-of-life analyses were performed at baseline and at week 6. The primary end point was clinical remission at 6 weeks, with last observation carried forward (LOCF). All patients who left the study in clinical remission were followed for relapse.
Results
At week 6, 86% of patients given budesonide were in clinical remission (with LOCF) compared with 48% of patients given placebo (P = .010). Furthermore, open-label budesonide therapy induced clinical remission in 7 of 8 patients given placebo. Histologic remission was observed in 73% of patients given budesonide compared with 31% given placebo (P = .030). Only 1 patient discontinued budesonide therapy prematurely. During a mean follow-up period of 14 months, 15 patients (44.1%) experienced a clinical relapse (after a mean of 2 months); 8 of the relapsing patients were retreated with and responded again to budesonide.
Conclusions
Budesonide effectively induces clinical remission in patients with lymphocytic colitis and significantly improves histology results after 6 weeks. Clinical relapses occur but can be treated again with budesonide.
Abbreviations used in this paper: AE, adverse event, IEL, intraepithelial lymphocyte, ITT, intention-to treat, LOCF, last observation carried forward, NSAID, nonsteroidal anti-inflammatory drug, PP, per protocol, QoL, quality of life, SF-36, Short Form-36 Health Survey, SIBDQ, short inflammatory bowel disease questionnaire
Lymphocytic colitis is a distinct form of microscopic colitis, characterized by chronic or recurrent nonbloody watery diarrhea, normal radiologic and endoscopic findings, and microscopic abnormalities in the colon. In addition to lymphocytic colitis the entity microscopic colitis includes collagenous colitis. Both diseases cannot be distinguished clinically and differ only by specific histopathologic features of the colon mucosa: lymphocytic colitis shows a characteristic increase of intraepithelial lymphocytes (IELs; ≥20 IEL/100 epithelial cells) and a chronic inflammation in the lamina propria.1 In contrast to collagenous colitis, the subepithelial collagenous layer is normal (<10 μm) in lymphocytic colitis.
The cause of lymphocytic colitis remains unclear. Mucosal responses to noxious luminal agents or associations with coexistent autoimmune disorders are discussed.1, 2 Some cases might be associated with celiac disease, the use of drugs (eg, lansoprazole, nonsteroidal anti-inflammatory drugs [NSAIDs], ticlopidine, ranitidine, carbamazepine, simvastatin) or with infections (eg, immune responses after infectious triggers).1, 3, 4 A seasonal incidence patterns has been reported.5
Epidemiologic investigations showed a much higher incidence of lymphocytic colitis than previously presumed. The incidence and prevalence are likely to be underestimated because microscopic colitis might be the underlying disease in some cases diagnosed as irritable bowel syndrome6, 7 or as chronic diarrhea.8 A recent US study found a mean annual incidence of 5.5 per 100,000 inhabitants together with a pronounced increase during the past 10–15 years and calculated a prevalence rate of 64/100,000 at the end of 2001.9 Similar incidence rates have been reported from Europe.10, 11
Currently, no established treatment of lymphocytic colitis exists. A recent Cochrane review identified only one randomized placebo-controlled trial investigating bismuth subsalicylate in 5 patients with lymphocytic colitis and 9 patients with collagenous colitis.12, 13 Because of the small number of patients with lymphocytic colitis, no conclusions about the efficacy of bismuth subsalicylate in lymphocytic colitis can be drawn from this trial. Retrospective and uncontrolled case series reported response rates between 37% and 94% with various drugs, including antidiarrheals, aminosalicylates, and corticosteroids.14 However, retrospective or uncontrolled studies might be inappropriate for efficacy assessment of pharmacologic treatment options because of the variable course of disease, including spontaneous remissions.15
The hypothesis of the presented study was based on the treatment data in collagenous colitis. A recent Cochrane analysis identified 7 randomized placebo-controlled trials: 3 trials studied budesonide, 1 study each investigated bismuth subsalicylate, Boswellia serrata extract, probiotics, and prednisolone.16 Budesonide showed the most promising results, with clinical responses in 73%–100% of patients with collagenous colitis.17, 18, 19 Histologic improvements were reported in 54%–100% of patients. Each study showed a statistically superior treatment effect of budesonide compared with placebo.
Budesonide is a locally acting anti-inflammatory substance. Its systematic activity is very limited because ≤90% are metabolized during the first pass effect in the liver.20 On the basis of the experiences in collagenous colitis, we considered it important to investigate the effect of budesonide in the treatment of lymphocytic colitis and conducted a double-blind placebo-controlled study. Our primary objective was to investigate whether oral budesonide 9 mg/d for 6 weeks is effective for the induction of clinical remission in lymphocytic colitis.
Materials and Methods
This study was designed as a randomized, double-blind, placebo-controlled, multicenter clinical study. It was performed in various centers throughout Germany which submitted their biopsy specimen to one of the study pathologists. The study was approved by the independent ethics committee of the Dresden University Hospital. All study participants were given a detailed description of the study, and their written informed consent was obtained. The study was conducted in accordance with good clinical practice and the Declaration of Helsinki. The study was registered at www.clinicaltrials.gov (Identifier: NCT00180050).
Patients
Men and women between 18 and 80 years of age with histologically confirmed lymphocytic colitis (>20 IEL/100 epithelial cells), and >3 watery or loose stools/d within 7 days before random assignment were eligible for inclusion into this trial. Patients with the following conditions were not allowed to participate: Other types of bowel disease, eg, infectious colitis (proved by stool culture or rectal biopsy), collagenous colitis, Crohn's disease, ulcerative colitis or ischemic colitis, celiac disease (ruled out by duodenal biopsy or serum antibodies or both), malignancy or any severe concomitant disease, partial colonic resection, intolerance to budesonide, as well as pregnancy and lactation. In addition, patients treated with budesonide, aminosalicylates, steroids, or antibiotics during the past 4 weeks before random assignment were excluded.
Treatment
Patients with lymphocytic colitis were randomly assigned centrally by a computer-generated random list to receive either budesonide (Budenofalk) at a dose of 9 mg/d (3 capsules) orally or matching placebo (3 capsules/d). Budesonide was supplied as enteric-coated, pH-dependent release granules in capsules and packed in neutral blisters and boxes. Each capsule contained 3 mg budesonide or placebo. Placebo was supplied and formulated in the same way as budesonide except it contained no budesonide. The study medication was manufactured by Dr Falk Pharma GmbH, Freiburg, Germany. All capsules were swallowed whole without chewing and with plenty of fluid. The study treatment period lasted for 6 weeks. Patients evaluated as nonresponders at the end of the 6-week treatment were treated with open-label budesonide 9 mg/d for a further 6 weeks.
Clinic visits were scheduled for 3 and 6 weeks after the start of treatment. If patients discontinued from the study prematurely, a full final visit was performed if possible. Documentation of all assessments occurred at all visits. Patients regarded as nonresponders after 6 weeks of treatment had a further visit after 12 weeks.
Concomitant medications involved in the treatment of inflammatory bowel diseases, including aminosalicylates (eg, mesalamine), antidiarrheals, antibiotics, immunosuppressants, NSAIDs, and all steroids (eg, budesonide, prednisolone) were not allowed. In the case of abdominal pain, butylscopolaminbromid was allowed. Loperamide was allowed during the first 2 weeks of the study. To prevent interactions between loperamide and the efficacy evaluation at the end of the treatment period, loperamide was not allowed thereafter.
Objectives and Outcomes
We tested the hypothesis that budesonide can reduce the frequency of watery or loose stools in patients with lymphocytic colitis. The primary objective was to determine the clinical remission from lymphocytic colitis after 6 weeks of treatment (with last observation carried forward [LOCF]). Secondary objectives were to determine the clinical remission from lymphocytic colitis after 3 weeks of treatment and to assess histopathology of the colon, quality of life (QoL), as well as safety and tolerability of the treatment.
Examinations
Patient's history was assessed at baseline by a standardized questionnaire. Stool frequency and consistency were recorded at baseline and at weeks 3 and 6 (and at week 12 in patients treated open label) by asking the patient for the average number of stools per day within the past 7 days and for the dominant type of stool consistency. Symptoms (occurrence of diarrhea) and QoL (Short Form-36 Health Survey [SF-36]) were assessed at baseline and after 6 weeks. Each patient completed 18-point QoL (SF-36) questionnaires for physical and mental well-being at baseline and after 6 weeks.
Complete colonoscopies were performed before randomization and at week 6. At each colonoscopy 2 biopsy specimens each were taken from the ascending, transverse, descending, and sigmoid colon as well as from the rectum for histologic assessment. In addition, one particle each was taken from the 3 distal colon segments for microbiologic examinations.
Biopsy specimens were fixed in 10% formalin and embedded in paraffin. Sections (5-μm thick) were stained with hematoxylin and eosin. A central, blinded pathologist (M.S.) assessed the absolute number of IELs per 100 epithelial cells and the inflammation of the lamina propria in a semiquantitative manner. Additional stainings (van-Gieson, tenascin) were performed to rule out collagenous colitis.
Patients were monitored for the occurrence of adverse events (AEs) throughout the study. Standard laboratory tests were performed at each visit. Compliance with study medication was checked by counting the medication returned at the follow-up visits.
Evaluations
The primary end point was clinical remission at 6 weeks (LOCF), predefined as ≤3 stools/d on average within the preceding 7 days before assessment and a reduction of ≥1 stool compared with screening. Patients were also evaluated for the change in stool consistency and number of stools produced. A secondary end point was clinical remission at week 3 according to the above-mentioned definition.
The histologic results were examined at each visit after baseline and classified as remission (reduction in the number of IEL ≤20 IEL/100 epithelial cells plus a reduction in lamina propria inflammation), response (>20 IEL/100 epithelial cells but reduction of ≥50% compared with baseline or reduction in lamina propria inflammation or both), or nonresponse (no significant change in IEL numbers, no change in lamina propria inflammation).
The data from 18-point QoL (SF-36) scales for physical and mental well-being were analyzed for changes in individual items and summed to obtain the overall scores in a descriptive manner.
All patients who achieved clinical remission either after initial or subsequent open-label budesonide or after placebo treatment entered an open follow-up phase. Patients were asked to present to their physician in case of recurrence of symptoms for reevaluation. In addition, standardized questionnaires were used to address stool frequency and consistency, past or present medications, and medication for treatment of relapse at the discretion of the physician. According to the inclusion criteria of the clinical trial, a clinical relapse was defined as >3 watery or loose stools/d on average per week.
Study Populations
All clinical efficacy analyses were performed for the intention-to treat (ITT) population. The ITT population included all patients who received ≥1 dose of study medication and had 1 evaluation after baseline. The primary outcome was also analyzed for the per protocol (PP) population (patients from the ITT population without major protocol deviations). The analyses of histology were based on the patients with histopathologic examinations after 6 weeks and the analyses of QoL data on the PP population. All safety data were analyzed in the safety population (patients who received ≥1 dose of study medication).
Sample Size Calculation, Statistical Analysis
Twenty patients were to be included in each of the 2 treatment groups.
On the basis of the assumption that approximately 10% of the patients (ie, 2 patients per treatment group) had to be excluded because of a lack of compliance, 36 patients were expected to be suitable for the statistical analysis. The hypothesis was based on the assumption of an efficacy of placebo treatment of maximally 30% and an efficacy of budesonide treatment of approximately 80%.
The probability of a first-order error (risk of false-positive results) was set to 5% (α = 0.05), the probability of a second-order error (risk of false-negative results) was set to 10% (β = 0.1). The proposed number of 18 evaluable patients per treatment group was expected to be sufficient to provide statistical evidence of the efficacy of budesonide.
The treatment effects about clinical remission as well as histologic remission were analyzed with the one-sided Fisher's exact test. Median stool frequencies were analyzed with the Wilcoxon signed rank test. For the comparison of mean IEL numbers, the 2-sample t test (interindividual comparison) and the 1-sample t test (intraindividual comparison) and covariate analysis with factors ‘treatment group’ and ‘baseline value’ were used. In addition, the correlation (Spearman correlation coefficient) between clinical and histologic remission and response was determined. For comparison of SF-36 domains, the 2-sample t test and the 1-sample t test were used. The statistical software package SAS 9.1.3 for Windows (SAS Institute, Cary, NC) was used.
Results
Study Population
A total of 42 patients with lymphocytic colitis were randomly assigned in 31 German study centers between June 2002 and March 2006. Patients in both groups had well-matched demographic and baseline characteristics (Table 1). The majority of patients (67%) were women; the median age was 61 years in both treatment groups. The median stool frequency was approximately 5 per day, and virtually all patients had watery or loose stools. Previous use of antidiarrheal medications (mostly loperamide) was reported by 20 patients (48%). None of the patients had been previously exposed to budesonide. None of the patients had a history of cholecystectomy, colonic or ileum resections, or abdominal radiation. All patients completed the double-blind phase at the 6-week end point except 3 from the budesonide group and 1 from the placebo group. A nonregular intake of the study medication during the double-blind phase was documented in 1 patient of both treatment groups.
Table 1. Demographic and clinical characteristics
| Budesonide 9 mg (n = 21) | Placebo (n = 21) | |
|---|---|---|
| Sex | ||
 Male, n (%) | 8(38) | 6(29) |
| Female, n (%) | 13(62) | 15(71) |
| Age, median (range), y | 61(36–80) | 61(23–76) |
| Patients with weight loss, n (%) | 9(43) | 14(67) |
| Weight loss in 6 mo, mean (range), kg | 2.2(0–16) | 2.6(0–10) |
| Smoking, n (%) | 9(43) | 8(38) |
| Stool frequency, mean (95% CI), number/d | 5.3(3.9–6.7) | 5.8(5.0–6.6) |
| Stool consistency, n (%) | ||
| Watery | 12(57) | 9(43) |
| Loose | 6(29) | 3(14) |
| Watery/loose | 2(10) | 6(29) |
| Loose/solid | 1(5) | 3(14) |
| Stool components (mucus, blood, food remnants), n (%) | 6(29) | 7(34) |
| Duration of symptoms, median (range), mo | 4(1–72) | 4(4–72) |
| Abdominal pain, n (%) | ||
| Regularly | 6(29) | 3(14) |
| Sometimes | 13(62) | 10(48) |
| Family history of diarrhea, n (%) | 3(14) | 2(10) |
Clinical Efficacy: Double-Blind Treatment
In the ITT population, clinical remission (≤3 stools/d and a reduction of ≥1 stool compared with screening) was observed in 67% of patients in the budesonide group after 3 weeks of treatment compared with 29% of patients in the placebo group (P = .015; Figure 1). At the primary end point of 6 weeks (LOCF), 86% of patients (n = 18) in the budesonide group had clinical remission compared with 48% (n = 10) in the placebo group (P = .010). The results of the PP population were of a similar magnitude and clinical and statistical significance. After treatment with budesonide the median (lower and upper quartile) daily stool frequency decreased from 4.5 (4, 5) to 2 (1, 3.8) at 3 weeks (P < .001) and to 1 (1, 2) at 6 weeks (P < .001). The stool consistency improved also from baseline to week 6 (LOCF). At baseline, 57% and 43% of the patients in the budesonide and placebo groups, respectively, had watery stools, whereas at week 6 (LOCF) only 5% in the budesonide group (P = .0009, McNemar test) and 14% in the placebo group (P = .0339, McNemar test) had watery stools. Moreover, 48% of patients in the budesonide group, but only 10% in the placebo group, had formed stools after 6 weeks (LOCF; P = .0063; chi-square test). None of the patients used loperamide rescue medication during the double-blind treatment phase.
Figure 1.
Proportion of patients in clinical remission at 3 and 6 weeks LOCF. ITT indicates intention-to-treat population; PP, per protocol population. *P = .015, **P = .006, ***P = .010.
Histology
A total of 28 patients (15 with budesonide, 13 with placebo) were available for histologic analysis at 6 weeks. At 6 weeks, 73% of patients in the budesonide group showed histologic remission compared with 31% in the placebo group (P = .030; Figure 2). A further 13% in the budesonide group showed a histologic response (>20 IEL/100 epithelial cells and a reduction of IEL > 50%), but this was not significantly different from placebo (15%). In contrast, the proportion of nonresponders was significantly greater in the placebo group than in the budesonide group (P = .029).
Figure 2.
Proportion of patients with histologic remission, response, and nonresponse at 6 weeks, *P = .030, **P = .029.
The mean (±SD) number of IEL/100 epithelial cells decreased significantly from 73 ± 14 IEL/100 at baseline to 20 ± 9 IEL/100 after 6 weeks of budesonide treatment (P < .001; Figure 3). Patients in the placebo group also showed a significant decrease from 72 ± 20 IEL/100 at baseline to 38 ± 21 IEL/100 epithelial cells at 6 weeks (P = .001). However, the mean number of IEL/100 epithelial cells at week 6 was significantly lower in the budesonide group than in the placebo group (P = .013). Covariate analysis showed that treatment group (P = .0079) but not baseline value (P = .9119) are significant covariate factors. Further analysis showed a weak positive correlation between the clinical and histologic response (Spearman correlation coefficient, 0.21; Table 2).
Figure 3.
Mean number of IEL/100 epithelial cells at baseline and at 6 weeks. *P < .001 compared with baseline, **P = .013 compared with placebo, +P = .001 compared with baseline.
Table 2. Correlation between clinical remission and histologic remission and response (patients with histopathologic examinations after 6 weeks)
| Budesonide 9 mg (n = 15) | Placebo (n = 13) | |||
|---|---|---|---|---|
| Clinical remission (n = 13) | No clinical remission (n = 2) | Clinical remission (n = 8) | No clinical remission (n = 5) | |
| Histology | ||||
| Remission, n (%) | 10(77) | 1(50) | 2(25) | 2(40) |
| Response, n (%) | 2(15) | 0 | 2(25) | 0 |
| No response, n (%) | 1(8) | 1(50) | 4(50) | 3(60) |
Open-Label Treatment
A total of 10 of the 13 patients who were nonresponders in the double-blind study (8 with placebo, 2 with budesonide) received open-label budesonide 9 mg/d for a further 6 weeks. Of the 8 treated nonresponders from the placebo group, 7 (88%) achieved clinical remission. Of the 2 nonresponders from the budesonide group, 1 (50%) achieved clinical remission. Eight patients underwent another colonoscopy with histology. Of those, 6 showed histologic remission (all in clinical remission) and 2 had histologic nonresponse.
Quality of Life
Complete SF-36 questionnaires were available from 22 (13 budesonide, 9 placebo) patients included in the PP population and from 24 (14 budesonide, 10 placebo) patients at 6 weeks. Analyses were performed only for patients with questionnaires at both time points. At baseline, SF-36 analysis showed a substantial effect of lymphocytic colitis on QoL, indicated by reduced physical (43.0) and mental (47.4) sum scores compared with the general population (50.2 and 51.5, respectively) and similar to other chronic gastrointestinal diseases (42.6 and 43.0, respectively). Female patients had a lower mean physical sum score than did male patients (41.2 compared with 48.8).
With budesonide, the mean physical sum score increased from 43.5 to 51.6, whereas the mental sum score remained unchanged (46.0 at baseline, 47.1 at week 6). With the placebo group, the physical sum score slightly increased from 42.5 to 47.1, whereas the mental sum score remained unchanged as well (48.8 at baseline, 46.8 at week 6). With respect to individual SF-36 domains, both budesonide and placebo recipients showed significant improvements in the domains “physical functioning” (budesonide: from 76.0 to 89.7, P = .0159; placebo: from 70.3 to 78.3, P = .0086) and “bodily pain” (budesonide: from 54.9 to 80.5, P = .0014; placebo: from 57.8 to 75.3, P = .028). The domain “vitality” improved significantly with budesonide (from 45.7 to 62.7, P = .0034) but not with placebo (from 55.0 to 54.3, P = .71). In the remaining domains, no significant differences were observed between baseline and week 6 or between treatment groups.
Tolerability and Safety
Tolerability of budesonide during the double-blind phase was judged as very good/good by 17 patients (3 missing values) and 17 investigators (4 missing). One patient judged tolerability as moderate. In the placebo group, tolerability was judged as very good/good by 14 patients (6 missing values) and 14 investigators (7 missing values). One patient judged tolerability as moderate.
No deaths occurred in the study. Serious AEs were reported in 2 patients in the placebo group (nausea, abdominal pain, and hyperhidrosis in one patient; headache, neck pain, and abdominal discomfort in another patient). During the double-blind phase, 6 AEs occurred in 2 patients (10%) taking budesonide 9 mg/d, and 9 AEs occurred in 3 patients (14%) taking placebo. During the open-label phase, 2 AEs were reported in 2 patients. All AEs were graded as mild or moderate in intensity. The most common AE was headache. One AE led to withdrawal of the study drug in one patient each in the budesonide and placebo groups. No clinically relevant pathologic findings were observed in laboratory serum and urine tests.
Long-Term Follow-Up
Patients who achieved clinical remission either with budesonide (n = 26; 18 with initial budesonide, 8 with open-label budesonide) or with placebo (n = 7; one missing value) entered the open clinical follow-up. During a mean follow-up of 14 months (range, 3–41 months), a total of 15 clinical relapses (44.1%) occurred after a mean time of 2 months. Age and sex were not associated with clinical relapse. Twelve relapses occurred after budesonide-induced remission (46.2%) and 3 occurred after placebo-induced remission (42.8%). A total of 8 patients with relapse (7 after budesonide, 1 after placebo) were treated and responded to budesonide. The other 7 patients received alternative antidiarrheal or no medication at the discretion of the investigator.
Discussion
This was the first randomized, placebo-controlled trial investigating the efficacy of oral budesonide in lymphocytic colitis. We showed that budesonide induces effective clinical and histologic remission in patients with lymphocytic colitis. After 6 weeks of treatment with budesonide 9 mg/d, the clinical remission rates were 86% compared with 48% with placebo (P = .010). In addition, treatment with budesonide was safe, and the rate of AEs was low.
In lymphocytic colitis no established treatment has been developed so far.1, 12 The available data generated by case reports and retrospective analyses have limited value because the natural course of the disease is characterized by variations in disease activity and spontaneous remissions. As a consequence, the efficacy of specific therapies cannot be assessed by uncontrolled trials. A single randomized placebo-controlled study that included just 5 patients with lymphocytic colitis has been conducted so far.13 That study showed a tendency toward better clinical remission in patients on bismuth subsalicylate (only 3) compared with placebo. Histologic improvement did not differ between treatment and placebo. It is obvious that no conclusions can be drawn from that very small study.
In the past, we and others compared budesonide with placebo in patients with collagenous colitis in randomized controlled trials and were able to show a high efficacy of budesonide in collagenous colitis.17, 18, 19 In our previous study, we achieved a clinical remission rate of 77% after 6 weeks of budesonide treatment compared with 12% of placebo patients.19 Here, we were able to show that with budesonide a comparable therapeutic effect can be achieved in lymphocytic colitis. Note that in the present study the placebo response at 6 weeks was somewhat higher in comparison of the placebo response rates observed in collagenous colitis, suggesting that spontaneous remissions might occur more often in lymphocytic colitis. Nevertheless, the therapeutic benefit of budesonide over placebo in lymphocytic colitis is evident and clinically relevant.
In addition to the clinical effect, we observed a significant effect of budesonide on the histopathology in lymphocytic colitis which appears particularly important for a disease that can only be diagnosed by histology. In the absence of defined criteria for histologic response or remission we defined histologic remission as normalization of IEL numbers (≤20 IEL/100 epithelial cells) plus a reduction in lamina propria inflammation. By this definition, >70% of patients were found to have histologic remission after 6 weeks of budesonide treatment compared with only 31% of placebo recipients (P = .030). This magnitude of histologic response seems quite comparable to that observed in collagenous colitis whereby we and others found histologic improvement in >60% of patients.17, 18, 19
In the present study biopsies were obtained from multiple colonic sites both at baseline and at follow-up to minimize the risk of sampling error; however, biopsies were subsequently pooled for further histologic examination. Therefore, we were not able to compare the distribution of baseline histopathology or the effect of treatment on histopathology between the right-sided and the left-sided colon.
However, on the basis of our previous experience in collagenous colitis whereby we observed that both the histopathology and the effect of budesonide on histopathology was homogenously distributed throughout the entire colon,19 we speculate that the anti-inflammatory effect of budesonide in lymphocytic colitis might also be similar in both parts of the colon. However, we would like to point out that in the present study a considerable number of patients were lacking histologic data. Therefore, the results of the histologic analyses should be regarded as “observational,” and no firm conclusions should be drawn until these findings are confirmed by other studies.
The findings of the open-label phase of the present study further support the results from the double-blind phase. Approximately 90% of previous placebo nonresponders achieved clinical remission with budesonide, whereas histologic remission was also evident in most cases. In addition, 1 of the 2 patients who did not respond to budesonide during the double-blind phase responded to further open-label treatment with budesonide, suggesting that a treatment duration of >6 weeks might be beneficial in individual cases. At present, however, the optimal duration of budesonide treatment in lymphocytic colitis remains unclear. Previous experience in collagenous colitis suggest that, although most patients respond early to budesonide treatment, the rate of clinical remissions is higher after 6 weeks compared with that after 2 or 4 weeks.21 Although most patients with lymphocytic colitis were in clinical remission at 3 weeks, we would recommend a treatment duration of 6–8 weeks, as in collagenous colitis, followed by cessation of treatment and clinical follow-up. Note that there were no safety or tolerability issues arising from budesonide treatment. Only one patient discontinued budesonide treatment because of an AE of nausea and headache.
We have recently shown that QoL, assessed by the Gastrointestinal Quality of Life Index is considerably reduced in collagenous colitis.22 Although it can be assumed that lymphocytic colitis may also have an effect on the patient's QoL, it has not been formally investigated so far. When we started our present trial, we decided to use the generic SF-36,23 because we were interested to investigate the effect of lymphocytic colitis on the general QoL. Our findings suggest that lymphocytic colitis may affect on general QoL similar to other chronic gastrointestinal diseases.23 However, only the physical sum score of the SF-36 improved after 6 weeks of treatment with budesonide, whereas the mental sum score did not. A possible reason for this observation might be that the SF-36 is not disease specific and, therefore, not sensitive enough to detect treatment effects. Meanwhile, we have shown that the SF-36 is comparable to the short inflammatory bowel disease questionnaire (SIBDQ) to detect impaired QoL in collagenous colitis, and it appears to be inferior in the detection of improvement after budesonide treatment.24 Therefore, we suggest the SIBDQ/IBDQ to be more suitable for future studies addressing QoL in microscopic colitis. Finally, we would like to point out that a considerable number of patients were lacking SF-36 data; thus, the results of the present QoL analysis must be interpreted with caution.
Which mechanisms may be responsible for the beneficial effect of budesonide in lymphocytic colitis? One hypotheses could be that in lymphocytic colitis, the histopathology may be more pronounced in the right colon25 and may also affect the ileum to some extent,26 anatomical regions where budesonide exerts its anti-inflammatory properties most. In addition, there may also be mucosal uptake of budesonide in the left colon, if the colonic mucosa is inflamed, as it has been shown in ulcerative colitis.27 Moreover, oral budesonide (Budenofalk) capsules have also been shown to be efficacious in Crohn's disease patient with ileocolonic inflammation.28
In addition, bile acid malabsorption might contribute to diarrhea in ≤60% of patients with lymphocytic colitis which also mostly respond to cholestyramine.29 In collagenous colitis, budesonide treatment has been shown to virtually normalize decreased bile acid absorption,30 presumably by an transactivation of the bile acid transporter in the terminal ileum.31 Thus, improvement of bile acid malabsorption may be another hypothesis underlying the beneficial effect of budesonide in lymphocytic colitis.
Previous studies in collagenous colitis have shown considerable clinical relapse rates in the range of 60%–80% after termination of budesonide treatment,17, 18, 32 underlining the chronic course of disease in most patients. In our present study we performed an open follow-up of all patients who left the trial in clinical remission to assess the natural course of the disease. Similar to collagenous colitis, most clinical relapses occurred early after cessation of budesonide treatment, whereas the cumulative relapse rate appears to be somewhat lower (40%) than in collagenous colitis. Interestingly, we observed no difference in the clinical relapse rates between patients with budesonide-induced or placebo-induced remission, suggesting that short-term budesonide treatment may not affect the long-term course of lymphocytic colitis. Therefore, the ideal long-term management of lymphocytic colitis should be specifically addressed by further controlled clinical trials.
In addition, the role of other potentially useful drugs for the treatment of lymphocytic colitis such as bismuth or mesalazine should also be further evaluated in randomized, controlled trials.
In summary, we conclude that oral budesonide (Budenofalk, 3-mg capsules) is effective and safe in the treatment of lymphocytic colitis. It induces clinical and histologic remission after 6 weeks of treatment and is well tolerated.
Acknowledgments
All authors contributed to interpretation of the study findings and in the writing of the manuscript. Medical writing support was provided by Christoph Müller–Löbnitz, Forchheim (Germany) and Margaret Bray, Ashford (United Kingdom), with funding from Dr Falk Pharma GmbH.
The statistical analysis of the entire data sets pertaining to efficacy (specifically primary and major secondary efficacy end points) and safety was independently conducted by a biostatistician (E.K.) who is not employed by the study sponsor.
The corresponding author had full access to all of the data and takes full responsibility for the veracity of the data and analysis.
Appendix
We thank the following investigators for their participation in this study: N. Ahmadiar, Engelskirchen; T. Blankenstein, Düsseldorf; St. Blomer, Goslar; N. Bockelmann, Gedern; B. Bokemeyer, Minden; G. Börsch and M. Mertens, Essen; V. Deinert, Düsseldorf; V. Ernst, Aschaffenburg; R. Glosemeyer, Osnabrück; H. Gutgesell, Lichtenfels; R. Haarmann and B. Ewert, Meschede; M. Jolowicz, Salzgitter; H.–U. Kellner, Kassel; J. Keymling, Wedemark; M. Khoury, Hof; R. Kurowski, Bad Segeberg; J. Labenz, Siegen; R. Laubscher, Heppenheim; W. Lupberger, E. Kraus and W. v. Finkenstein, Augsburg; R. de Mas, Neuwied; E. Meier, Amberg; H. Mazloum, Eisenach; M. Neumeyer, Oldenburg; H. Reike and Dr. Völkel, Werl; J. Rintelmann, Bad Nenndorf; M. Schmidt-Lauber, Oldenburg; A. Schirmer, Hamm; C. Schöll, Vaihingen; K. Steisslinger, Böblingen; and G. Wilhelms, Goslar.
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Conflicts of interest The authors disclose the following: S.M. has received honoraria from Dr Falk Pharma GmbH for oral presentations and consultancies and research grant support from Dr Falk Pharma GmbH. A. Madisch has received honoraria from Dr Falk Pharma GmbH for oral presentations and research grant support from Dr Falk Pharma GmbH. A. Morgner has received honoraria from Dr Falk Pharma GmbH for oral presentations. M.S. has received honoraria from Dr Falk Pharma GmbH for oral presentations and research grant support from Dr Falk Pharma GmbH. R.M. and R.G. are employees of Dr Falk Pharma GmbH. The remaining authors disclose no conflicts.
Funding The study was supported by Dr Falk Pharma GmbH, Freiburg, Germany.
PII: S0016-5085(09)00365-5
doi:10.1053/j.gastro.2009.02.078
© 2009 AGA Institute. Published by Elsevier Inc. All rights reserved.
