Randomised non-inferiority trial: 1600 mg versus 400 mg tablets of mesalazine for the treatment of mild-to-moderate ulcerative colitis.

BACKGROUND: High concentration mesalazine formulations are more convenient than conventional low concentration formulations for the treatment of ulcerative colitis (UC). AIM: To compare the efficacy and safety of 1600 mg and 400 mg tablet mesalazine formulations. METHODS: Patients with mild-to-moderate active UC (Mayo Clinic Score >5; N=817) were randomised to 3.2 g of oral mesalazine, administered as two 1600 mg tablets once, or four 400 mg tablets twice daily. We hypothesised that treatment with the 1600 mg tablet was non-inferior (within a 10% margin) to the 400 mg tablet for induction of clinical and endoscopic remission at week 8. Open-label treatment with the 1600 mg tablet continued for 26-30 weeks based on induction response. Predictors of treatment response were also explored. RESULTS: At week 8, remission occurred in 22.4% and 24.6% of patients receiving the 1600 mg and 400 mg tablets, respectively (absolute difference -2.2%, 95% CI: -8.1% to 3.8%, non-inferiority P=.005). Endoscopic and histopathologic disease activity, leucocyte concentration and age were significantly associated with clinical remission (P=.022, .042, .014 and .023, respectively). At week 38, 43.9% (296/675) of patients who continued treatment with the 1600 mg formulation were in remission, including 70.3% (142/202) of patients who received a reduced dose of mesalazine (1.6 g/d). The overall incidence of serious adverse events was low. CONCLUSIONS: Induction therapy with 3.2 mg mesalazine using two 1600 mg tablets once-daily was statistically and clinically non-inferior to a twice-daily regimen using four 400 mg tablets (NCT01903252).

Review article: infliximab for Crohn's disease treatment--shifting therapeutic strategies after 10 years of clinical experience.

BACKGROUND: Crohn's disease is a progressive condition, with most patients developing a penetrating or stricturing complication over time. A decade ago, treatment goals consisted of immediate symptomatic control. The introduction of anti-tumour necrosis factor (anti-TNF) therapies, however, has changed the way patients with Crohn's disease are treated. Over 10 years of clinical data and experience have demonstrated these therapies to be highly effective in Crohn's disease. AIM: To provide clinicians guidance on optimising treatment with anti-TNF therapies in Crohn's disease by introducing an evidence- and personal opinion-based treatment algorithm using infliximab initial anti-TNF therapy. METHODS: Scientific literature was reviewed using MEDLINE to evaluate data on clinical trials with infliximab in luminal and fistulising Crohn's disease. RESULTS: The data from several landmark infliximab trials have changed clinical practice and led to a readjustment of treatment goals in Crohn's disease, allowing patients to achieve more than just symptomatic relief including sustained steroid-free remission. Infliximab induces complete mucosal healing and reduces the rates of hospitalisation and surgery. Based on disease-related risk factors, a treatment algorithm for infliximab is delineated in favour of a rapid step-up approach in patients at high risk for a disabling course of disease. CONCLUSION: Adopting the suggested treatment algorithm for infliximab into clinical routine is aimed to optimise outcomes for patients with Crohn's disease.

Randomised clinical trial: improvement in health outcomes with certolizumab pegol in patients with active Crohn's disease with prior loss of response to infliximab.

BACKGROUND: Crohn's disease (CD) is associated with impaired health-related quality of life (HRQoL). Certolizumab pegol, administered either every 2 weeks (q2w) or q4w, maintains efficacy in patients previously failing on the anti-TNF agent infliximab (WELCOME study). AIM: To investigate the impact of certolizumab pegol administered q2w and q4w on work productivity and HRQoL in the WELCOME study. METHODS: Patients with loss of response to infliximab received open-label certolizumab pegol induction and were randomised to receive double-blind maintenance treatment with certolizumab pegol 400 mg either q4w or q2w through week 24, with a final evaluation at week 26. Work productivity and HRQoL were assessed using the Work Productivity and Activity Impairment:CD questionnaire and Inflammatory Bowel Disease Questionnaire respectively. RESULTS: Baseline HRQoL burden was representative of moderately to severely active CD. HRQoL, daily activity and work productivity improved in both treatment groups as early as week 6 and were maintained through week 26. Treatment benefits to HRQoL, daily activity and work productivity were similar between the certolizumab pegol q2w vs. q4w groups. CONCLUSIONS: Certolizumab pegol therapy results in meaningful improvements in work productivity, daily activities and HRQoL in patients with active CD who previously responded to but either lost response or could not tolerate infliximab (ClinicalTrials.gov number: NCT00308581).

Review article: the limitations of corticosteroid therapy in Crohn's disease.

Corticosteroids are highly effective in inducing clinical remission in patients with active Crohn's disease. However, the role of corticosteroids in the treatment of this disease is primarily ameliorative because they are ineffective in maintaining remission or healing mucosal lesions. Nearly half of the patients who initially respond to corticosteroid therapy develop a dependency on corticosteroids or have a relapse within 1 year. In addition, use of these agents is often limited by a relatively high risk of serious adverse effects that can involve nearly every major body system. These effects include: bone loss, which can develop with even short-term and low-dose corticosteroid therapy; metabolic complications such as glucose intolerance and diabetes mellitus; increased intraocular pressure and glaucoma; and potentially lethal infections. To minimize the risk of toxicity, corticosteroids are increasingly recommended for short-term use only at the lowest effective dose to induce remission in patients with moderately to severely active Crohn's disease. Corticosteroid formulations with low systemic bioavailability, such as controlled-release budesonide, may be associated with a lower rate of dermatologic adverse effects but appear to be somewhat less effective than conventional corticosteroids in inducing remission in patients with active Crohn's disease. Immunosuppressive agents such as azathioprine, 6-mercaptopurine, and methotrexate have demonstrated corticosteroid-sparing effects, facilitating the withdrawal of corticosteroids when initiated as maintenance therapy. Infliximab can be used as an alternative to corticosteroids.

Infliximab in the treatment of severe, steroid-refractory ulcerative colitis: a pilot study.

We report the experience of 11 patients (of 60 planned patients) enrolled in a double-blind, placebo-controlled clinical trial of infliximab in patients with severe, active steroid-refractory ulcerative colitis. The study was terminated prematurely because of slow enrollment. Patients having active disease for at least 2 weeks and receiving at least 5 days of intravenous corticosteroids were eligible to receive a single intravenous infusion of infliximab at 5, 10, or 20 mg/kg body weight. The primary endpoint used in this study was treatment failure at 2 weeks after infusion. Treatment failure was defined as 1) unachieved clinical response as defined by a modified Truelove and Witts severity score, 2) increase in corticosteroid dosage, 3) addition of immunosuppressants, 4) colectomy, or 5) death. Safety evaluations included physical examination, clinical chemistry and hematology laboratory tests, and occurrence of adverse experiences. Four of 8 patients (50%) who received infliximab were considered treatment successes at 2 weeks, compared with none of 3 patients who received placebo. Improvement in erythrocyte sedimentation rates and serum concentrations of C-reactive protein and interleukin-6 correlated with the clinical response observed in patients receiving infliximab. Infusion with infliximab produced no significant adverse events. Infliximab was well tolerated and may provide clinical benefit for some patients with steroid-refractory ulcerative colitis.

Conventional treatment of Crohn's disease: objectives and outcomes.

Despite conventional medical and/or surgical intervention, endoscopic and symptomatic relapse is common among individuals with Crohn's disease (CD). Treatment goals have therefore been refocused to include achieving control of active disease and maintaining remission with agents associated with a minimum of toxic adverse effects. Conventional treatment regimens have been used with varying success in regard to these therapeutic goals. Traditionally, aminosalicylates have been considered effective in inducing a response in some patients with mild-to-moderate CD but have demonstrated little or no long-term benefit in controlled clinical trials. Glucocorticosteroid therapy is associated with higher rates of response in patients with active CD; however, clinical benefits are frequently offset by the common occurrence of corticosteroid-related toxicity. Oral controlled-release budesonide has demonstrated comparable efficacy to prednisolone with less risk for adverse effects, although many questions remain regarding the long-term use of this agent. Response to standard immunosuppressive agents such as azathioprine and 6-mercaptopurine in patients with active disease may require 3 to 6 months from initiation of treatment. These agents are therefore considered most valuable as maintenance therapy, providing consistent long-term benefit in patients with chronic refractory or corticosteroid-dependent disease. Although the incidence of allergic adverse effects is relatively low with azathioprine/6-mercaptopurine, more serious adverse effects, including bone marrow suppression, hepatotoxicity, pancreatitis, and infectious complications, can occur. Limited success in the treatment of perianal disease has been achieved with antibiotics such as metronidazole and the immunosuppressives cyclosporine and azathioprine/6-mercaptopurine. Although broader use of immunosuppressive agents has allowed improvement in the maintenance of remission in patients with CD, long-term safety data with these agents are lacking, concerns about toxicity and the potential risk for neoplasia remain, and attenuation of response with chronic immunosuppressive use can occur. Therefore, innovative therapeutic approaches are needed to meet key treatment goals often not addressed by conventional therapies.

Medical therapies for ulcerative colitis and Crohn's disease.

This review focuses on data reported in the last year on medical treatment of Crohn's disease and ulcerative colitis. In Crohn's disease, a broad range of cytokine-based therapies are currently being tested. Although all are very exciting, the anti-tumor-necrosis-factor (TNF) approach remains the most effective, with infliximab (a chimeric monoclonal antibody directed against TNF) being the most active agent. With repeated infusions every 8 weeks, remission is induced and can be maintained even in refractory patients with no major apparent side effects. Thalidomide, an oral agent with anti-TNF effects, shows promise in non-controlled experience. Important new data on azathioprine/6-mercaptopurine (6-MP) and its metabolites are also helpful. Methotrexate can induce remissions in 6-MP-allergic or refractory Crohn's patients and has now shown efficacy as a maintenance agent. Beneficial effects are also reported for a variety of new agents: mycophenolate mofetil, tacrolimus (FK506), growth hormone, and granulocyte colony-stimulating factor (G-CSF). Important observations in ulcerative colitis (UC) over the past year include evidence of a protective effect of 5-aminosalicylic acid (5-ASA) with respect to colorectal cancer, negative results from a study for heparin monotherapy, and results from a comparison of mycophenolate mofetil versus azathioprine as maintenance therapy. Epidemiologically, the negative association between appendectomy and UC was corroborated in a meta-analysis, suggesting an immunologic role for this organ. Finally, in chronic pouchitis, probiotic therapy was found to maintain remissions very significantly.

Differences in gastric motor activity in renal transplant recipients treated with FK-506 versus cyclosporine.

BACKGROUND: Little is known concerning gastric motility after renal transplantation and on the impact of immunosuppressants on gastric emptying. METHODS: Gastric emptying was measured in renal transplant recipients, taking different immunosuppressive therapy (steroids and cyclosporine/azathioprine/FK-506), and compared with normal volunteers. RESULTS: After renal transplantation, gastric emptying of liquids was normal, irrespective of the type of immunosuppression. However, solid gastric emptying was significantly faster in FK-506-treated patients compared with patients taking cyclosporine for all measured emptying parameters. Compared with normal volunteers solid gastric emptying was slower in patients taking cyclosporine, comparable in azathioprine treated patients, and characterized by an unusual short lag phase in patients taking FK-506. CONCLUSIONS: In stable renal transplant recipients gastric emptying of solids was significantly faster in patients on FK-506 compared with patients taking cyclosporine. Therefore, FK-506 may be the immunosuppressant of choice after solid organ transplantation in patients with problems related to gastroparesis.

Review article: efficacy of infliximab in Crohn's disease--induction and maintenance of remission.

The primary goals of treating patients with Crohn's disease are to induce a clinical remission, maintain the remission, and prevent associated complications. Various treatment regimens for patients with Crohn's disease induce a response and remission; however, most prove ineffective for maintenance of the clinical effect. A therapeutic agent that can induce and maintain remission, while promoting the restoration of intestinal mucosa, would prove to be most beneficial in such a patient population. Several studies with infliximab have clinically demonstrated that the antitumour necrosis factor-alpha therapy rapidly reduced the signs and symptoms in patients with moderate-to-severe Crohn's disease. In acute studies with the chimeric monoclonal antibody, clinical benefit was associated with healing and reduction of inflammation in the bowel mucosal tissue. In a maintenance study, retreatment with infliximab maintained remission of the active disease. Additionally, treatment with the lowest infusion dose of infliximab (5 mg/kg) provided a high degree of clinical benefit with a long-term outcome.

Gastric emptying in hyperemesis gravidarum and non-dyspeptic pregnancy.

BACKGROUND: Emesis and hyperemesis are significant problems associated with early pregnancy. However, gastric emptying of solids has never been studied during early pregnancy in humans. AIM: To investigate gastric emptying of solids in patients recovering from hyperemesis gravidarum and in non-dyspeptic pregnant women and to compare these results with a group of healthy non-pregnant women. METHODS: Fourteen patients with hyperemesis gravidarum, 10 non-dyspeptic pregnant women and 36 non-pregnant women in the first half of the menstrual cycle underwent a gastric emptying study. Seven non-pregnant women repeated the test in the post-ovulatory period. RESULTS: Gastric emptying of solids was not significantly delayed in non-dyspeptic pregnant women compared with non-pregnant women. The emptying rate tended to be impaired in the post-ovulatory period of the menstrual cycle. Solid emptying was significantly accelerated in patients recovering from hyperemesis gravidarum, correlating well with thyroid function in the latter group. CONCLUSION: Pregnancy in humans is not associated with decreased solid gastric emptying. In subjects recovering from hyperemesis gravidarum, solid emptying is increased, correlating well with thyroid function abnormalities. Nausea and vomiting in hyperemesis are therefore probably not due to upper gastrointestinal disorders.

Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn's ileocolitis.

BACKGROUND & AIMS: Anti-tumor necrosis factor alpha monoclonal antibody treatment (infliximab) reduces clinical signs and symptoms in patients with Crohn's disease. The effects of infliximab on mucosal histopathologic abnormalities in Crohn's ileocolitis were studied. METHODS: Thirteen patients with steroid-refractory Crohn's disease were treated with a single infusion of infliximab (5-20 mg/kg), and 5 were treated with placebo. Ileal and colonic biopsy specimens of all patients were collected before and 4 weeks after therapy. Severity of inflammation was assessed by a histological score. Immunohistochemical stainings with antibodies against HLA-DR, CD68, tumor necrosis factor alpha, intercellular adhesion molecule 1, lymphocyte function-associated antigen, CD4, CD8, and interleukin 4 were performed. RESULTS: Total histological activity score was reduced significantly in both ileitis and colitis after infliximab. This is caused by a virtual disappearance of the neutrophils and a reduction of mononuclear cells. Mucosal architecture returned to normal in 4 patients at 4 weeks. The number of lamina propria mononuclear cells decreased because of a global reduction of CD4(+) and CD8(+) T lymphocytes and CD68(+) monocytes. Aberrant colonic epithelial HLA-DR expression completely disappeared. The percentage of intercellular adhesion molecule 1 and lymphocyte function-associated antigen 1-expressing and interleukin 4- and tumor necrosis factor-positive lamina propria mononuclear cells sharply decreased. CONCLUSIONS: Infliximab dramatically decreases histological disease activity in Crohn's ileocolitis. Signs of active inflammation nearly disappear accompanied by a profound down-regulation of mucosal inflammatory mediators.

Hypertrophic lymphocytic gastritis with a gastric carcinoma.

Lymphocytic gastritis is a recently described gastric inflammation, characterized by an increased intraepithelial lymphocytic infiltrate mainly composed of T-lymphocytes. Endoscopically it correlates mainly with diffuse varioliform gastritis. Ménétrier's disease is a hypertrophic gastropathy with enlarged gastric folds. The histological picture is that of foveolar hyperplasia and glandular cysts of the mucosa. A few small series of lymphocytic gastritis with microscopic and endoscopic features of Ménétrier's disease have been published previously. We describe a similar case associated with a gastric adenocarcinoma.

Gastric emptying flow curves separated from carbon-labeled octanoic acid breath test results.

Recently, we developed the [13/14C]octanoic acid breath test to measure gastric emptying of solids. Although the method has been validated extensively, absorption, metabolism, and excretion of the label in the breath need to be corrected for. In this study a mathematical model was developed that allows for 1) separation of the global CO2 excretion after ingestion of the labeled test meal into the emptying rate of the labeled test meal from mouth to pylorus and the postgastric processing of absorption, metabolism, and excretion of the label, and 2) numerical calculation of the half-emptying time and lag phase of the emptied meal. The model was applied to the gastric emptying results obtained by simultaneous scintigraphic and breath test measurements. An excellent correlation was found between the gastric half-emptying time (r = 0.98) and lag phase (r = 0.85) determined scintigraphically and via breath test. There was also a good agreement between the two methods [mean values and confidence limits for differences: t1/2 = 10 min (-20 to 41) and tlag = -3 min (-39 to 34)]. Moreover, the separated gastric emptying curves, lacking the influence of postgastric processing of the label, showed real patterns of gastric outflow, which changes from moment to moment.

Gastric emptying of the liquid, solid and oil phase of a meal in normal volunteers and patients with Billroth II gastrojejunostomy.

BACKGROUND: The relationship between gastric emptying of different phases of a meal in humans has only been partly studied in normal subjects and in patients with previous gastric surgery. METHODS: In the present study, gastric emptying of the liquid, solid and oil phase and the relationship between the phases was evaluated in 10 normal control subjects and in seven patients with Billroth II gastrojejunostomy using breath test technology. RESULTS: Gastric emptying in normal subjects showed a clear separation between the emptying of the liquid, solid and oil phase. In healthy volunteers, the liquid phase emptied in the same manner in the presence of a solid phase as in the presence of an oil phase. In contrast, the oil phase emptied more slowly with liquids than with solids. The emptying rate of the oil phase was not only inversely related to the amount administered but was also dependent on its chemical composition. Gastric emptying in patients with Billroth II gastroenterostomy was characterized by a complete loss of discrimination between the different phases of the meal, with an extremely fast emptying of the oil phase compared with normal control subjects. CONCLUSION: In normal subjects, the liquid, solid and oil phase of a meal are emptied differently. In patients with Billroth II gastrojejunostomy, dumping of the oil phase is the most pronounced difference from the normal physiology of gastric emptying. This could be one of the reasons why Billroth II gastrectomy may be associated with fat malabsorption.

A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group.

BACKGROUND: Studies in animals and an open-label trial have suggested a role for antibodies to tumor necrosis factor alpha, specifically chimeric monoclonal antibody cA2, in the treatment of Crohn's disease. METHODS: We conducted a 12-week multicenter, double-blind, placebo-controlled trial of cA2 in 108 patients with moderate-to-severe Crohn's disease that was resistant to treatment. All had scores on the Crohn's Disease Activity Index between 220 and 400 (scores can range from 0 to about 600, with higher scores indicating more severe illness). Patients were randomly assigned to receive a single two-hour intravenous infusion of either placebo or cA2 in a dose of 5 mg per kilogram of body weight, 10 mg per kilogram, or 20 mg per kilogram. Clinical response, the primary end point, was defined as a reduction of 70 or more points in the score on the Crohn's Disease Activity Index at four weeks that was not accompanied by a change in any concomitant medications. RESULTS: At four weeks, 81 percent of the patients given 5 mg of cA2 per kilogram (22 of 27 patients), 50 percent of those given 10 mg of cA2 per kilogram (14 of 28), and 64 percent of those given 20 mg of cA2 per kilogram (18 of 28) had had a clinical response, as compared with 17 percent of patients in the placebo group (4 of 24) (p<0.001 for the comparison of the cA2 group as a whole with placebo). Thirty-three percent of the patients given cA2 went into remission (defined as a score below 150 on the Crohn's Disease Activity Index), as compared with 4 percent of the patients given placebo (P=0.005). At 12 weeks, 41 percent of the cA2-treated patients (34 of 83) had had a clinical response, as compared with 12 percent of the patients in the placebo group (3 of 25) (P=0.008). The rates of adverse effects were similar in the groups. CONCLUSIONS: A single infusion of cA2 was an effective short-term treatment in many patients with moderate-to-severe, treatment-resistant Crohn's disease.

Gastric emptying rate of solids in patients with nonulcer dyspepsia.

The underlying role of motility disorders and delayed gastric emptying in nonulcer dyspepsia is still questioned. This study aimed to determine the role of the gastric emptying rate of solids in patients with nonulcer dyspepsia. By means of breath test technology, gastric emptying results of 344 consecutive patients with nonulcer dyspepsia were compared with those of 70 normal healthy volunteers. Although gastric emptying was significantly delayed in patients with nonulcer dyspepsia compared with normal volunteers, there was a great overlap between the two groups. Using 5-95% confidence intervals of the control group in about 30% of the patients with nonulcer dyspepsia gastric emptying was delayed. No correlation was found between gastric emptying rate and age, weight, height, or sex of the subjects in both groups. These findings suggest that, apart from gastric emptying, other mechanisms are very important in the etiology of nonulcer dyspepsia.

Gastric emptying and Helicobacter pylori infection in duodenal ulcer disease.

The pathogenetic link between Helicobacter pylori gastritis and duodenal ulcer is still unknown. Fast gastric emptying of liquids might be important in the pathogenesis of gastric metaplasia of the duodenum and duodenal ulcer through an increased exposure of the duodenum to gastric acid. In H. pylori-infected subjects, an abnormal gastric emptying could affect urea breath test results and correlate with histological gastritis. This study was performed to evaluate the gastric emptying of liquids in duodenal ulcer patients with H. pylori infection and the possible relation between the bacterial load, gastric emptying, and urea breath test results. Seventeen duodenal ulcer patients with H. pylori gastritis and 15 healthy volunteers were studied by a [14C]octanoic acid and [13C]urea breath test to evaluate gastric emptying rate and H. pylori status simultaneously. Endoscopy with antral biopsies were performed in all duodenal ulcer patients. Duodenal ulcer patients with H. pylori infection have a normal liquid gastric emptying that is unrelated with histological severity of gastritis. The urea breath test results and the gastric emptying parameters do not correlate with histology. A significant correlation between the gastric emptying and the urea hydrolysis rate is found. It is concluded that H. pylori infection and duodenal ulcer disease is not associated with abnormally fast liquid gastric emptying, and this finding should be taken into account when a casual link between H. pylori infection and duodenal ulcer disease is searched for. The correlation between gastric emptying and urea hydrolysis rate explains why no conclusions on intragastric bacterial load can be drawn from the urea breath test results.