Ole K. Bonderup

Long-term budesonide treatment of collagenous colitis: a randomised, double-blind, placebo-controlled trial

Objective: To evaluate the efficacy and safety of long-term budesonide therapy for the maintenance of clinical remission in patients with collagenous colitis. Design: Randomised, placebo-controlled study with a 24-week, blinded follow-up period without any treatment. Setting: Three gastroenterology clinics in Denmark. Patients: Forty-two patients with histologically confirmed collagenous colitis and diarrhoea (more than three stools/day). Interventions: Patients in clinical remission after 6 weeks’ open-label therapy with oral budesonide (Entocort CIR capsules, 9 mg/day) received 24 weeks’ double-blind maintenance therapy with budesonide 6 mg/day or placebo. Thereafter, patients entered the 24-week, blinded follow-up period. Main Outcome Measure: The proportion of patients in clinical remission (three or fewer stools/day) at the end of maintenance therapy. Findings: A total of 34 patients in remission at week 6 were randomly assigned to budesonide 6 mg/day (n  =  17) or placebo (n  =  17). After 24 weeks’ maintenance treatment, the proportions of patients in clinical remission were 76.5% (13 of 17) with budesonide and 12% (2 of 17) with placebo (p<0.001). At 48 weeks (the end of the follow-up period, without any treatment) these values were 23.5% (4 of 17) and 12% (2 of 17), respectively (p = 0.6). The median times to relapse after stopping active treatment (6 plus 24 weeks in the budesonide group; 6 weeks in the placebo group) were 39 and 38 days, respectively. Long-term treatment with budesonide was well tolerated. Conclusions: Long-term maintenance therapy with oral budesonide is efficacious and well tolerated for preventing relapse in patients with collagenous colitis. The risk of relapse after 24 weeks’ maintenance treatment is similar to that observed after 6 weeks’ induction therapy.

Budesonide Is More Effective Than Mesalamine or Placebo in Short-term Treatment of Collagenous Colitis

BACKGROUND & AIMS Studies reporting that budesonide is effective for the treatment of collagenous colitis have been small and differed in efficacy measures. Mesalamine has been proposed as a treatment option for collagenous colitis, although its efficacy has never been investigated in placebo-controlled trials. We performed a phase 3, placebo-controlled, multicenter study to evaluate budesonide and mesalamine as short-term treatments for collagenous colitis. METHODS Patients with active collagenous colitis were randomly assigned to groups given pH-modified release oral budesonide capsules (9 mg budesonide once daily, Budenofalk, n = 30), mesalamine granules (3 g mesalamine once daily, Salofalk, n = 25), or placebo for 8 weeks (n = 37) in a double-blind, double-dummy fashion. The study was conducted in 31 centers (hospital clinics and private practices) in Germany, Denmark, Lithuania, Spain, and the United Kingdom. The primary end point was clinical remission at 8 weeks defined as ≤ 3 stools per day. Secondary end points included clinical remission at 8 weeks, according to the Hjortswang-Criteria of disease activity, taking stool consistency into account. RESULTS A greater percentage of patients in the budesonide group were in clinical remission at week 8 than the placebo group (intention-to-treat analysis, 80.0% vs 59.5%; P = .072; per-protocol analysis, 84.8% vs 60.6%; P = .046). Based on the Hjortswang-Criteria, 80.0% of patients given budesonide achieved clinical remission compared with 37.8% of patients given placebo (P = .0006); 44.0% of patients given mesalamine achieved clinical remission, but budesonide was superior to mesalamine (P = .0035). Budesonide significantly improved stool consistency and mucosal histology, and alleviated abdominal pain. The rate of adverse events did not differ among groups. CONCLUSIONS Oral budesonide (9 mg once daily) is effective and safe for short-term treatment of collagenous colitis. Short-term treatment with oral mesalamine (3 g once daily) appears to be ineffective. ClinicalTrials.gov number, NCT00450086.

Drug Exposure and Risk of Microscopic Colitis: A Nationwide Danish Case–Control Study with 5751 Cases

Background:Previous small studies have indicated that commonly prescribed drugs may be associated with microscopic colitis (MC). With an increasing incidence of MC, it is important to explore the association between exposure to proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs, statins, and selective serotonin reuptake inhibitors and MC in a larger setting. Methods:Case–control study based on nationwide Danish registries. The study included all patients with MC diagnosis during the period 2005 to 2011. One hundred sex- and age-matched controls per case were randomly selected among the Danish population. Prescriptions were recorded in a Prescription Register in the year before the first recorded MC diagnosis. Effect measure is the adjusted odds ratio (OR) of collagenous colitis (CC) and lymphocytic colitis (LC) according to prescriptions of PPIs, nonsteroidal anti-inflammatory drugs, statins, and selective serotonin reuptake inhibitors. Within the control group, we identified a subgroup with MC-free colonic biopsies. Results:We identified 3474 patients with CC and 2277 with LC and found a positive association between redemption of prescriptions for PPIs and both CC (OR = 7.04; 95% confidence interval, 6.55–7.56) and LC (OR = 3.37; 95% confidence interval, 3.08–3.69). Among patients with MC-free colon biopsies in the control group, the association between PPIs and CC was strongly positive (OR = 3.47; 95% confidence interval, 3.08–3.89). Adding this parameter to the model attenuated all of the associations, but they remained positive for PPIs versus CC and selective serotonin reuptake inhibitors versus LC. Conclusions:We found positive associations between exposure to all 4 medication classes and MC. Variations in endoscopic frequency by drug category indicate a potential impact of bias.

Neutrophil Extracellular Traps in Ulcerative Colitis: A Proteome Analysis of Intestinal Biopsies

Background:The etiology of the inflammatory bowel diseases, including ulcerative colitis (UC), remains incompletely explained. We hypothesized that an analysis of the UC colon proteome could reveal novel insights into the disease etiology. Methods:Mucosal colon biopsies were taken by endoscopy from noninflamed tissue of 10 patients with UC and 10 controls. The biopsies were either snap-frozen for protein analysis or prepared for histology. The protein content of the biopsies was characterized by high-throughput gel-free quantitative proteomics, and biopsy histology was analyzed by light microscopy and confocal microscopy. Results:We identified and quantified 5711 different proteins with proteomics. The abundance of the proteins calprotectin and lactotransferrin in the tissue correlated with the degree of tissue inflammation as determined by histology. However, fecal calprotectin did not correlate. Forty-six proteins were measured with a statistically significant differences in abundances between the UC colon tissue and controls. Eleven of the proteins with increased abundances in the UC biopsies were associated with neutrophils and neutrophil extracellular traps. The findings were validated by microscopy, where an increased abundance of neutrophils and the presence of neutrophil extracellular traps by extracellular DNA present in the UC colon tissue were confirmed. Conclusions:Neutrophils, induced neutrophil extracellular traps, and several proteins that play a part in innate immunity are all increased in abundance in the morphologically normal colon mucosa from patients with UC. The increased abundance of these antimicrobial compounds points to the stimulation of the innate immune system in the etiology of UC.

Low-dose budesonide for maintenance of clinical remission in collagenous colitis: a randomised, placebo-controlled, 12-month trial

Objective This 1-year study aimed to assess low-dose budesonide therapy for maintenance of clinical remission in patients with collagenous colitis. Design A prospective, randomised, placebo-controlled study beginning with an 8-week open-label induction phase in which patients with histologically confirmed active collagenous colitis received budesonide (Budenofalk, 9 mg/day initially, tapered to 4.5 mg/day), after which 92 patients in clinical remission were randomised to budesonide (mean dose 4.5 mg/day; Budenofalk 3 mg capsules, two or one capsule on alternate days) or placebo in a 12-month double-blind phase with 6 months treatment-free follow-up. Primary endpoint was clinical remission throughout the double-blind phase. Results Clinical remission during open-label treatment was achieved by 84.5% (93/110 patients). The median time to remission was 10.5 days (95% CI (9.0 to 14.0 days)). The maintenance of clinical remission at 1 year was achieved by 61.4% (27/44 patients) in the budesonide group versus 16.7% (8/48 patients) receiving placebo (treatment difference 44.5% in favour of budesonide; 95% CI (26.9% to 62.7%), p<0.001). Health-related quality of life was maintained during the 12-month double-blind phase in budesonide-treated patients. During treatment-free follow-up, 82.1% (23/28 patients) formerly receiving budesonide relapsed after study drug discontinuation. Low-dose budesonide over 1 year resulted in few suspected adverse drug reactions (7/44 patients), all non-serious. Conclusions Budesonide at a mean dose of 4.5 mg/day maintained clinical remission for at least 1 year in the majority of patients with collagenous colitis and preserved health-related quality of life without safety concerns. Treatment extension with low-dose budesonide beyond 1 year may be beneficial given the high relapse rate after budesonide discontinuation. Trial registration numbers http://www.clinicaltrials.gov (NCT01278082) and http://www.clinicaltrialsregister.eu (EudraCT: 2007-001315-31).

The epidemiology of microscopic colitis: a 10-year pathology-based nationwide Danish cohort study

Abstract Objective. Microscopic colitis (MC) includes two main types: collagenous colitis (CC) and lymphocytic colitis (LC). Previous studies have indicated an increasing incidence, but these have mainly been based on regional databases. We found it important to study the epidemiology based on a comprehensive nationwide cohort. Material and methods. We studied the epidemiological data of MC in Denmark from 2002 to 2011. The cohort consisted of all patients with a recorded diagnosis of either CC or LC in the Danish Pathology Register during the study period. Data on all patients with a registered colon biopsy were also included. Results. A total of 7777 patients, 4749 (61%) with CC and 3028 (39%) with LC, were identified. Over the study period, the annual incidence of diagnosed cases of CC increased from 2.9/105 to 14.9/105 and of LC from 1.7/105 to 9.8/105. In 2011, the incidence of MC was 24.7/105 inhabitants. The age-specific incidence showed that the risk of both CC and LC increased with age. The female/male ratio, distribution of the type of colitis and mean age at diagnosis were relatively stable during the study period. The annual number of registered colon biopsies in the pathology register increased from 21.583 in 2002 to 39.733 in 2011, indicating an increased diagnostic activity. Conclusion. In a nationwide cohort study, the incidence of CC and LC continued to increase from 2002 to 2011. An increased diagnostic activity could in part explain the increase in the number of diagnosed cases.

Risk Factors for Symptom Relapse in Collagenous Colitis After Withdrawal of Short-term Budesonide Therapy

Background:Oral budesonide has been proven effective in short- and long-term treatment of collagenous colitis; however, symptom relapse frequently occurs after drug withdrawal. The aim of this study was to identify the risk factors for symptom relapse in patients with collagenous colitis after withdrawal of short-term budesonide therapy. Methods:One hundred twenty-three patients from 4 randomized controlled studies who achieved clinical remission after short-term treatment with budesonide (9 mg/d) were analyzed, including 40 patients receiving subsequent budesonide maintenance therapy (6 mg/d) for 6 months and 83 patients without active maintenance treatment. Variables available for analysis were age, sex, baseline stool frequency, duration of diarrhea, collagenous band thickness, and lamina propria inflammation. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated by Cox proportional hazard model. Results:The overall symptom relapse rate was 61%. By multivariate analysis, a baseline stool frequency >5 per day (HR, 3.95; 95% CI, 1.08–14.39), history of diarrhea >12 months (HR, 1.77; 95% CI, 1.04–3.03), and the absence of budesonide maintenance therapy (HR, 2.71; 95% CI, 1.37–5.38) were associated with symptom relapse. The time to relapse was shorter in patients with a baseline stool frequency >5 per day (56 versus 199 d, P = 0.024), as in those with history of diarrhea >12 months (56 versus 220 d, P = 0.009). Budesonide maintenance therapy delayed the time to relapse (56 versus 207 d, P = 0.005). Conclusions:Our data demonstrate that a high stool frequency at baseline and a long duration of diarrhea are risk factors for symptom relapse in collagenous colitis, whereas budesonide maintenance therapy is a protective factor against symptom relapse.

Proteome analysis of rheumatoid arthritis gut mucosa

Rheumatoid arthritis (RA) is an inflammatory joint disease leading to cartilage damage and ultimately impaired joint function. To gain new insight into the systemic immune manifestations of RA, we characterized the colon mucosa proteome from 11 RA-patients and 10 healthy controls. The biopsies were extracted by colonoscopy and analyzed by label-free quantitative proteomics, enabling the quantitation of 5366 proteins. The abundance of dihydrofolate reductase (DHFR) was statistically significantly increased in RA-patient biopsies compared with controls and correlated with the administered dosage of methotrexate (MTX), the most frequently prescribed immunosuppressive drug for RA. Additionally, our data suggest that treatment with Leflunomide, a common alternative to MTX, increases DHFR. The findings were supported by immunohistochemistry with confocal microscopy, which furthermore demonstrated that DHFR was located in the cytosol of the intestinal epithelial and interstitial cells. Finally, we identified 223 citrullinated peptides from 121 proteins. Three of the peptides were unique to RA. The list of citrullinated proteins was enriched in extracellular and membrane proteins and included known targets of anticitrullinated protein antibodies (ACPAs). Our findings support that the colon mucosa could trigger the production of ACPAs, which could contribute to the onset of RA. The MS data have been deposited to ProteomeXchange with identifiers PXD001608 and PXD003082.

Smoking Status Influences Clinical Outcome in Collagenous Colitis.

BACKGROUND The relationship between clinical and histological parameters in collagenous colitis (CC) is poorly understood. Smoking is a risk factor for CC, whereas its impact on clinical activity and outcome is not well known. METHODS In a post hoc analysis of pooled data from two randomized controlled trials we assessed the association between demographic data (gender, age, smoking habits, family history of inflammatory bowel disease), clinical variables (duration of symptoms, mean number of stools/watery stools per day, abdominal pain, clinical remission) and histological data (thickness of the collagen band, inflammation of the lamina propria, total numbers of intraepithelial lymphocytes, degeneration). Moreover, we analysed the predictive value of baseline parameters for clinical outcome in a logistic regression model. RESULTS Pooled data were available from 202 patients with active CC, of whom 36% were current smokers, 29% former smokers and 35% non-smokers. Smoking status was associated with decreased ability to achieve clinical remission (current smokers vs non-smokers: odds ratio [OR] 0.31, 95% confidence interval [CI] 0.10-0.98, p = 0.045; former smokers vs non-smokers: OR 0.19, 95% CI 0.05-0.73, p = 0.016). Current smokers had an increased mean number of watery stools at baseline compared with non-smokers (p = 0.051) and increased mean number of watery stools per se was associated with decreased likelihood of obtaining clinical remission (OR 0.63, 95% CI 0.47-0.86, p = 0.003). Patient characteristics and histology at baseline had no association with clinical parameters and no predictive value for clinical outcome. CONCLUSION Smoking worsens clinical symptoms in CC and is associated with an increased number of watery stools and decreased likelihood of achieving clinical remission. There is no significant association between histology and clinical data.

Significant association between the use of different proton pump inhibitors and microscopic colitis: A nationwide Danish case-control study

Microscopic colitis causes chronic watery diarrhoea and has previously been associated with the use of proton pump inhibitors.