[Show abstract][Hide abstract] ABSTRACT: Obesity is a risk factor for inflammatory diseases such as nonalcoholic steatohepatitis, pancreatitis, and Crohn's disease. The effect of being overweight or obese on the severity and clinical course of ulcerative colitis (UC) was assessed in a retrospective analysis of data from 2000-2006.
International Journal of Colorectal Disease 11/2014; · 2.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In 1977, 5-aminosalicylic acid (5-ASA) was discovered as a therapeutically active moiety of sulfasalazine (SASP) and was launched for topical and oral therapy of ulcerative colitis (UC) in 1984. As a first-step, delivery systems had to be developed to protect 5-ASA against absorption in the upper gastrointestinal tract, resulting in different and competing strategies (azo compounds, controlled release, and pH-dependent release). In a second step, at the beginning of the new century, coinciding with the expiration of patent protection for the first 5-ASA formulations, two component composite release mechanisms (pH-dependent and controlled release) were developed. Furthermore, the drug was formulated as granules instead of tablets, allowing higher unit strengths compared with tablets. Neither Salofalk Granu-Stix®, nor MMX 5-ASA, nor Pentasa® granules have initially been developed for once-daily (OD) dosing. A review of the achievements of 20 years of 5-ASA development has demonstrated that 5-ASA has equal efficacy compared with SASP at best, that there are no measurable differences in efficacy between various 5-ASA preparations, and that in a group of patients tolerating SASP, adverse event profiles of SASP and 5-ASA did not differ significantly, with SASP being the far cheaper substance. Therefore, drug adherence came into focus as a new goal for improving UC therapy. Although adherence is a complex and multifactorial construct, a simple dosing schedule may contribute to higher drug adherence and better efficacy of treatment. Simultaneously, the US 5-ASA market, estimated to be worth US$1.4 billion, is expected to grow continuously. Naturally, this very competitive market is not only driven by scientific progress but also by commercial interests. Thus, patents for minor changes to the formulation may serve as protection against drug companies trying to launch generic versions. Randomized controlled trials performed on OD dosing in induction of remission have demonstrated that OD administration of 5-ASA is as effective as conventional dosing in mild to moderate active UC. The three 5-ASA products MMX, Salofalk®, and Pentasa® employed in those studies so far have not shown differences in efficacy between OD and conventional dosing. No differences regarding safety outcomes have been detected between OD and conventional dosing, including incidence of adverse events, serious adverse events, or withdrawal from treatment due to an adverse event. Although the majority of patients prefer OD dosing to conventional dosing, it was not possible to detect differences in adherence between OD and multiple dose regimens in the clinical trial setting. Well-designed and controlled large-scale community-based studies are necessary to further investigate and prove the point of improved long-term adherence and treatment efficacy in OD dosing.
[Show abstract][Hide abstract] ABSTRACT: The consistency of endoscopic and histologic findings in patients with ulcerative colitis (UC) has not been elucidated. Choice of assessment may affect study outcomes.
Post hoc analyses were performed using data from 2 randomized, controlled multicenter trials: (1) SAG-26, mesalazine granules for induction of remission in UC (n = 380), and (2) SAG-27, mesalazine granules for maintenance of UC remission (n = 647). Assessments included Clinical Activity Index, Endoscopic Index, modified Disease Activity Index, and Histology Index.
In SAG-26, 52 of 380 patients (13.7%) with clinically (Clinical Activity Index >4) and endoscopically (Endoscopic Index ≥4) active UC showed no histological signs of active inflammation (Histology Index ≤1) at baseline. Among endoscopically and histologically active patients, 246 of 327 (75.2%) reached clinical remission versus 48 of 52 patients (92.3%) with active endoscopy but no inflammation on histology (difference, 17.1%; P = 0.006). The difference in the proportion of patients achieving clinical remission according to endoscopy and histology in clinically inactive (Clinical Activity Index ≤4) patients was 30.8% in SAG-26 (at the study end) and 28.1% in SAG-27 (at baseline). In SAG-27, clinical relapse occurred in 21.2% of patients with endoscopic and histologic remission at baseline and 27.1% of patients with some histological inflammation at baseline (P = 0.111). Using the modified Disease Activity Index ≤1 (mucosal healing) instead of the Endoscopic Index score, the difference was similar (21.2% versus 28.0%, P = 0.073).
Endoscopic and histologic assessments differ in both active and inactive UC. Overdiagnosis of inflammation using endoscopy versus histology can significantly affect outcomes, at least in studies using induction of clinical remission as an endpoint. The assessment criteria for trials in UC should be reconsidered.
[Show abstract][Hide abstract] ABSTRACT: Robust evidence regarding medical intervention for symptomatic uncomplicated colonic diverticular disease (DD) is sparse.
To investigate mesalazine (Salofalk granules) in this setting.
In a double-blind, placebo-controlled, multicentre, 6-week trial, patients were randomised to mesalazine 1000 mg three times daily or placebo. Primary efficacy endpoint was change in lower abdominal pain to week 4 (baseline defined using pain score from 7 days pre-treatment).
Median change in lower abdominal pain with mesalazine vs. placebo was -37 (n = 56) vs. -33 (n = 61) [P = 0.374; 95% CI (-11; 4)] in the intent-to-treat (ITT) population, and -41 (n = 40) vs. -33 (n = 51) [P = 0.053; 95% CI (-18; 0)] in the per-protocol (PP) population, i.e. the primary endpoint was not significantly different. Post hoc adjustment for confounding factors ('baseline pain intensity', 'baseline symptom score (Brodribb)', and 'localisation of diverticula in the descending colon') resulted in P = 0.111 [ITT, 95% CI (-15.4; 1.6)] and P = 0.005 [PP, 95% CI (-19.7; -3.5)]. Between-group differences increased using pain score on day 1 as baseline, and reached significance for the PP population [mesalazine -42, placebo -26, P = 0.010; 95% CI (-25; -3)]. Median change in combined symptom score from baseline to week 4 was 257 mm with mesalazine vs. 198 mm with placebo [P = 0.064; 95% CI (-3; 105)]. More placebo-treated patients received analgesic/spasmolytic concomitant medication (34.4% vs. mesalazine 21.4%), indicating improved pain relief with mesalazine (P = 0.119). Safety was comparable.
A daily dose of 3.0 g mesalazine may relieve pain during a symptomatic flare of uncomplicated DD. In this, the first placebo-controlled double-blind trial in acute uncomplicated DD, mesalazine showed promising therapeutic efficacy.
[Show abstract][Hide abstract] ABSTRACT: Appendicitis and diverticulitis are very common entities that show some similarities in diagnosis and course of disease. Both are widely believed to be simple clinical diagnoses, which is in contrast to scientific evidence. An accurate diagnosis has to describe not only the initial detection, but particularly the severity of the disease. It is based mainly on cross-sectional imaging by ultrasound (US) and computed tomography (CT). Appendectomy is the standard treatment for acute appendicitis and is mandatory in complicated cases. Antibiotic therapy is similarly effective in uncomplicated appendicitis, but long-term results are not sufficiently known. Treatment of diverticulitis is related to the disease status. Complications such as perforation and bleeding require intervention. Uncomplicated diverticulitis as graded by US or CT are subject to conservative management, in the form of outpatient or hospital care. It is an unresolved debate as to whether antibiotic treatment offers benefits. Mesalazine seems at least to improve pain. The real challenge is treatment of recurrent diverticulitis. Lifestyle measures such as nutritional habits and physical activity are found to influence diverticular disease. Besides immunosuppression, obesity is a significant risk factor for complicated diverticulitis. Whether any medication such as chronic antibiotics, probiotics or mesalazine offers benefits is unclear. The indication for sigmoid resection has changed; it is no longer given by the number of attacks, but rather by structural changes as depicted by cross-sectional imaging.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Predictive factors for a mild course of Crohn's disease (CD) may have therapeutic consequences, but as yet have not been identified. AIMS: To identify baseline factors that predict mild CD and design a predictive scoring system. METHODS: A retrospective, multicenter study of newly diagnosed CD patients allocated to mild CD (no therapy, mesalazine only, or mesalazine with a single initial short course of low-dose prednisone) or moderate CD (all other patients including resected patients). RESULTS: 162 patients (median follow-up 43months) were analyzed: 47 mild CD and 115 moderate CD. For mild CD versus moderate CD, mean age at first diagnosis was higher (41.1 versus 33.9years, p=0.02), mean C-reactive protein (CRP) concentration was lower (1.6 versus 3.6mg/L, p<0.01), and perianal lesions were less frequent (0% versus 10.4%, p=0.02). The combined incidence of complications (stenosis, any type of fistula, extraintestinal complications or fever) was 21.3% in mild CD versus 35.7% in moderate CD (p=0.07). A scoring system based on age, CRP, endoscopic severity (adapted Rutgeert's score), perianal lesions and combined incidence of complications was developed which can predict a mild prognosis at the initial diagnosis, giving patients the chance of simplified therapy and accelerated step-up in the event of treatment failure. CONCLUSIONS: Approximately a third of CD patients experience a mild disease course and require only basic therapy. A possible scoring system to predict mild CD which may avoid overtreatment and unnecessary risks for the patient and costs is suggested.
Journal of Crohn s and Colitis 11/2012; · 3.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite advances in immunosuppressive therapy, up to 10% of patients with severe Crohn's disease (CD) remain refractory to conventional treatment. Limited evidence from pilot trials suggests that high-dose immunosuppression and autologous peripheral blood stem cell transplantation (autoPBSCT) may induce remission in these patients, but there is substantial controversy regarding the safety and efficacy of this approach.
To address this issue, a monocentre phase I/II trial of autoPBSCT was performed in patients with refractory CD in our hospital.
Here, we report on the outcome of 12 patients with refractory CD treated with autoPBSCT. Briefly, CD34(+) -selected PBSCs were harvested after mobilisation therapy with cyclophosphamide and granulocyte-colony stimulating factor. Later, immunoablative conditioning therapy with high-dose cyclophosphamide followed by autoPBSCT was applied and clinical and endoscopic responses were analysed after a mean follow-up of 3.1 years (range 0.5-10.3 years).
PBSC harvest following mobilisation chemotherapy was successful in 11/12 patients and resulted in a clinical and endoscopic improvement in 7/12 patients. Subsequent conditioning and autoPBSCT were performed in nine patients and were relatively well tolerated. Among those, five patients achieved a clinical and endoscopic remission within 6 months after autoPBSCT. However, relapses occurred in 7/9 patients during follow-up, but disease activity could be controlled by low-dose corticosteroids and conventional immunosuppressive therapy.
Immunoablation by cyclophosphamide and autologous peripheral blood stem cell transplantation is safe and effective to induce remission of refractory Crohn's disease, and should be further evaluated in randomised controlled trials.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND AIMS: The optimal mesalazine dosing strategy for ulcerative colitis (UC) continues to evolve. The current study aimed to explore whether documenting drug use could prompt changes in prescribing habits. METHODS: In a multicenter, prospective, observational study, outpatients with active or quiescent UC were enrolled if they were receiving, or were planned to receive, sustained release mesalazine microgranules (Pentasa®). Clinical and prescribing data were collected at study entry, after 2 and 8weeks. Physician-reported influences on prescribing decisions were recorded at study entry. RESULTS: 360 patients were analyzed (203 active UC, 157 remission). Prior to study entry, the range of oral mesalazine doses was 0.50-6.00g/day in active UC patients, and 0.50-4.00g/day for patients in remission. These changed to 1.50-5.00g/day and 1.00-4.00g/day, respectively, at study entry with little change thereafter. Use of a single daily mesalazine dose increased from 16.7% to 58.0% of active cases during the study, and from 5.9% to 46.8% in remission cases. Gastroenterologists reported that their basis for prescription decision-making was most frequently medical experience (80.8%), followed by guidelines (67.2%), further education or colleagues' recommendations (50.0%) and current study results (20.0%). CONCLUSION: In this analysis of mesalazine dosing in routine clinical practice, there was an improvement in adherence to European Crohn's and Colitis Organisation (ECCO) guidelines and in use of once-daily dosing, consistent with recent trial results, following documentation of dosing regimens. Written reporting of drug dosing schedules should be considered fundamental for chronic, complex diseases such as UC.
Journal of Crohn s and Colitis 08/2012; · 3.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The treatment of patients with inflammatory bowel disease has become more complex in recent years through the introduction of various immunosuppressive agents as well as the approval of monoclonal antibodies. Patients receiving such treatment must be carefully monitored. National and international guidelines define a diagnostic and therapeutic context for the practitioner, but can only partially respond to specific questions on the procedure for individual patients. Within the framework of a project initiated by Abbott entitled "IBD ahead" 34 German IBD experts have elaborated concrete proposals for the utility of clinical symptom assessment, endoscopy and the use of laboratory parameters including foecal markers of inflammation. Furthermore, we discuss the significance of conventional X-rays, computed tomography, ultrasound and magnetic resonance tomography. These recommendations are illustrated by case studies from everyday practice in the participating centres.
Zeitschrift für Gastroenterologie 07/2012; 50(7):684-93. · 1.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Irritable bowel syndrome (IBS) is common in western Europe and North America, and many aspects of its epidemiology, risk factors, and natural history have been described in these regions. Recent data suggest, however, that IBS is also common in the rest of the world and there has been some evidence to suggest some differences in demographics and presenting features between IBS in the west and as it is experienced elsewhere. The World Gastroenterology Organization, therefore, established a Task Force comprising experts on the topic from all parts of the world to examine IBS from a global perspective. IBS does, indeed, seem to be common worldwide though with some significant variations in prevalence rates between regions and countries and there may well be some potentially interesting variations in presenting symptoms and sex distribution. The global map of IBS is far from complete; community-based prevalence data is not available from many areas. Furthermore, while some general trends are evident in terms of IBS impact and demographics, international comparisons are hampered by differences in diagnostic criteria, study location and methodology; several important unanswered questions have been identified that should form the basis for future collaborative research and have the potential to shed light on this challenging disorder.
Journal of clinical gastroenterology 05/2012; 46(5):356-66. · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Toxic megacolon is a rare and life-threatening complication of severe colitis, defined as a dilatation of the colon > 6 cm in the absence of distal obstruction in combination with signs of systemic toxicity (major criteria: fever, tachycardia, leukocytosis, anaemia). Various triggers are known and the most common causes are underlying ulcerative colitis and Clostridium difficile. Diagnosis can easily be made by clinical examination, routine laboratory parameters and a plain X-ray of the abdomen. Much more difficult is to decide between non-surgical treatment including intensive care treatment or surgery (mostly subtotal colectomy with terminal ileostomy). Non-surgical therapy includes balancing of electrolytes and fluid volumes, broad-spectrum antibiotics including metronidazole, positioning of patients and probably careful intermittent decompression. In case of ulcerative colitis immunosuppression should be started with corticosteroids and potentially with calcineurin inhibitors. In pseudomembranous colitis vancomycin should be given orally and metronidazole should be given intravenously. As far as possible the patient should be treated in a centre with experience in the field.
Zeitschrift für Gastroenterologie 03/2012; 50(3):316-22. · 1.41 Impact Factor