Ole Østergaard Thomsen

A comparison of budesonide with prednisolone for active Crohn's disease

BACKGROUND Patients with active Crohns disease are often treated with corticosteroids, but the treatment has many side effects. Budesonide is a potent, well-absorbed corticosteroid, but because of a high rate of first-pass metabolism in the liver, its systemic bioavailability is low. METHODS We conducted a randomized, double-blind, 10-week trial comparing the efficacy and safety of an oral controlled-release form of budesonide with the efficacy and safety of prednisolone in 176 patients with active ileal or ileocecal Crohns disease (88 patients in each treatment group). The dose of budesonide was 9 mg per day for eight weeks and then 6 mg per day for two weeks. The dose of prednisolone was 40 mg per day for two weeks, after which it was gradually reduced to 5 mg per day during the last week. RESULTS At 10 weeks, 53 percent of the patients treated with budesonide were in remission (defined as a score < or = 150 on the Crohns disease activity index), as compared with 66 percent of those treated with prednisolone (P = 0.12). The mean score on the Crohns disease activity index decreased from 275 to 175 in the budesonide group and from 279 to 136 in the prednisolone group (P = 0.001). Corticosteroid-associated side effects were significantly less common in the budesonide group (29 vs. 48 patients, P = 0.003). Two patients in the prednisolone group had serious complications (one had intestinal perforation and one an abdominal-wall fistula). The mean morning plasma cortisol concentration was significantly lower in the prednisolone group than in the budesonide group after 4 weeks (P < 0.001) and 8 weeks (P = 0.02) of therapy, but not after 10 weeks. CONCLUSIONS Among patients with active Crohns disease, both controlled-release budesonide and prednisolone are effective in inducing remission. In this trial, prednisolone reduced scores on the Crohns disease activity index more, whereas with budesonide there were fewer glucocorticoid-associated side effects and less suppression of pituitary-adrenal function.

A Placebo-Controlled, Double-Blind, Randomized Trial of Cyclosporine Therapy in Active Chronic Crohn's Disease

We randomly assigned 71 patients with active chronic Crohns disease who were resistant to or intolerant of corticosteroids to treatment with oral cyclosporine (5 to 7.5 mg per kilogram of body weight per day) or placebo for three months. Disease activity was assessed on a clinical grading scale without knowledge of the treatment given. At the end of the treatment period, 22 of the 37 cyclosporine-treated patients (59 percent) had improvement, as compared with 11 of the 34 placebo-treated patients (32 percent) (P = 0.032). During cyclosporine treatment, there was significant improvement in plasma orosomucoid levels (P = 0.0025) and the Crohns Disease Activity Index (P = 0.00012). The effect of treatment became evident after two weeks. In the subsequent three months, during which the patients were gradually withdrawn from treatment, the improvement continued in 14 of the 37 patients (38 percent) in the cyclosporine group and in 5 of the 34 (15 percent) in the placebo group (P = 0.034). No serious adverse events were observed. We conclude that cyclosporine has a beneficial therapeutic effect in patients with active chronic Crohns disease and resistance to or intolerance of corticosteroids.

Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during the last 5 decades: A population‐based study from Copenhagen, Denmark

Background: It remains uncertain whether the increasing incidence of inflammatory bowel disease (IBD) during the last decades has been accompanied by an alteration in the presentation, course, and prognosis of the disease. To answer this question, 3 consecutive population‐based IBD cohorts from Copenhagen, Denmark (1962–2005), were assessed and evaluated. Methods: Phenotype, initial disease course, use of medications, cumulative surgery rate, standardized incidence ratio of colorectal cancer (CRC), and standardized mortality ratio (SMR) were compared in the 3 cohorts, which had a total of 641 patients with Crohns disease (CD) and 1575 patients with ulcerative colitis (UC). Results: From 1962 to 2005, the proportion of IBD patients suffering from CD increased (P < 0.001), time from onset of symptoms to diagnosis of CD decreased (P = 0.001), and median age at diagnosis of UC increased (P < 0.01). The prevalence of upper gastrointestinal involvement and pure colonic CD varied significantly between cohorts. UC patients diagnosed in the 1990s had a higher prevalence of proctitis, received more medications, and had a milder initial disease course than did previous patients. The surgery rate decreased significantly in CD but not in UC. The risk of CRC in IBD was close to expected over the entire period, whereas the mortality of patients with CD increased (overall SMR, 1.31; 95% CI, 1.07–1.60). Conclusions: Despite variations in the presentation and initial course of IBD during the last 5 decades, its long‐term prognosis remained fairly stable. Treatment of IBD changed recently, and future studies should address the effect of these changes on long‐term prognosis.

A COMPARISON OF BUDESONIDE AND MESALAMINE FOR ACTIVE CROHN'S DISEASE

Background Crohns disease is often treated with glucocorticoids or mesalamine. We compared the efficacy and safety of controlled-ileal-release budesonide capsules and slow-release mesalamine tablets in patients with active Crohns disease affecting the ileum, the ascending colon, or both. Methods In a double-blind, multicenter trial, we enrolled 182 patients with scores of 200 to 400 on the Crohns Disease Activity Index (with higher scores indicating greater disease activity) and randomly assigned 93 to receive 9 mg of budesonide once daily and 89 to receive 2 g of mesalamine twice daily for 16 weeks. The primary efficacy variable was clinical remission, defined as a score of 150 or less on the Crohns Disease Activity Index. Results In the analysis of all patients who received at least one dose of study drug, the rates of remission after 8 weeks of treatment were 69 percent in the budesonide group and 45 percent in the mesalamine group (P=0.001); the respective rates after 16 weeks of treatment were 62...

World Gastroenterology Organization Practice Guidelines for the Diagnosis and Management of IBD in 2010

Inflammatory bowel disease (IBD) represents a group of idiopathic, chronic, inflammatory intestinal conditions. Its two main disease categories are: Crohns disease (CD) and ulcerative colitis (UC), which feature both overlapping and distinct clinical and pathological features. While these diseases have, in the past, been most evident in the developed world, their prevalence in the developing world has been gradually increasing in recent decades. This poses unique issues in diagnosis and management which have been scarcely addressed in the literature or in extant guidelines. Depending on the nature of the complaints, investigations to diagnose either form of IBD or to assess disease activity will vary and will also be influenced by geographic variations in other conditions that might mimic IBD. Similarly, therapy varies depending on the phenotype of the disease being treated and available resources. The World Gastroenterology Organization has, accordingly, developed guidelines for diagnosing and treating IBD using a cascade approach to account for variability in resources in countries around the world.

Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial

Objective Although the reasons for secondary loss of response to infliximab (IFX) maintenance therapy in Crohn’s disease vary, dose intensification is usually recommended. This study investigated the cost-effectiveness of interventions defined by an algorithm designed to identify specific reasons for therapeutic failure. Design Randomised, controlled, single-blind, multicentre study. 69 patients with secondary IFX failure were randomised to IFX dose intensification (5 mg/kg every 4 weeks) (n=36) or interventions based on serum IFX and IFX antibody levels using the proposed algorithm (n=33). Predefined co-primary end points at week 12 were proportion of patients responding (Crohns Disease Activity Index (CDAI) decrease ≥70, or ≥50% reduction in active fistulas) and accumulated costs related to treatment of Crohn’s disease, expressed as mean cost per patient, based on the Danish National Patient Registry for all hospitalisation and outpatient costs in the Danish healthcare sector. Results Costs for intention-to-treat patients were substantially lower (34%) for those treated in accordance with the algorithm than by IFX dose intensification: €6038 vs €9178, p<0.001. However, disease control, as judged by response rates, was similar: 58% and 53%, respectively, p=0.81; difference 5% (−19% to 28%). For per-protocol patients, treatment costs were even lower (56%) in the algorithm-treated group (€4062 vs €9178, p<0.001) and with similar response rates (47% vs 53%, p=0.78; difference −5% (−33% to 22%)). Conclusions Treatment of secondary IFX failure using an algorithm based on combined IFX and IFX antibody measurements significantly reduces average treatment costs per patient compared with routine IFX dose escalation and without any apparent negative effect on clinical efficacy. Trial Registration No NCT00851565.

Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn's disease

Abstract Introduction. Reasons for infliximab failure in Crohns disease and ulcerative colitis are debated. Serum levels of infliximab and anti-infliximab antibodies have been associated with loss of response. We aimed at determining cut-off levels for infliximab and anti-infliximab antibody concentrations associated with clinical response to infliximab maintenance therapy. Methods. Patients with inflammatory bowel disease (n = 106) were retrospectively classified as having maintained response or loss of response to infliximab maintenance therapy. Trough concentrations were measured by fluid-phase radioimmunoassays. Results. Infliximab levels were significantly lower, and anti-infliximab antibody levels significantly higher, in Crohns disease patients with loss of response (median infliximab 0 μg/ml, median anti-infliximab antibodies 35 U/ml) compared to patients with maintained response (median infliximab 2.8 μg/ml, median anti-infliximab antibodies 0 U/ml; p < 0.0001). Receiver operating characteristic (ROC) analysis identified optimal cut-off values: infliximab <0.5 μg/ml, which was associated with loss of response with sensitivity 86% [64–97] and specificity 85% [72–94]; and anti-infliximab antibodies ≥10 U/ml yielding a sensitivity of 81% [61–93] and specificity 90% [79–96]. Combined measurements of infliximab and anti-infliximab antibodies using these cut-off values had higher accuracy yielding a sensitivity of 81% [57–94] and specificity 94% [82–98]. Similar pattern was observed in a smaller cohort of patients with ulcerative colitis. Conclusions. Combined measurements of infliximab and anti-infliximab antibodies using cut-off levels provided high accuracy for discriminating between clinical response types to infliximab maintenance therapy. Cut-off levels are considered a prerequisite to further investigations of clinical usefulness of measurements of infliximab and anti-infliximab antibodies in patients failing infliximab therapy.

Individual medicine in inflammatory bowel disease: monitoring bioavailability, pharmacokinetics and immunogenicity of anti-tumour necrosis factor-alpha antibodies.

Antibody constructs targeting tumour necrosis factor-alpha (TNF) have become important in the management of several chronic immunoinflammatory diseases. Four recombinant anti-TNF drugs are currently approved for clinical use in patients with various chronic inflammatory diseases, three of which are effective in chronic inflammatory bowel disease. These proteins can dramatically lower disease activity and, in some patients, induce remission. Unfortunately, however, not all patients respond favourably to anti-TNF antibodies. For example, patients suffering from Crohns disease do not benefit from etanercept, and some patients treated with the other anti-TNF constructs either do not respond at all (primary response failure), or they respond initially but have later relapses (secondary response failure) despite increased dosage and/or more frequent administration of the drugs. The reason(s) for these response failures are not clear but inter-individual and even intra-individual differences in bioavailability and pharmacokinetics may contribute. Furthermore, immunogenicity of the drugs, causing patients to develop anti-drug antibodies (ADAs), contributes to treatment failure. Monitoring patients for circulating levels of functional anti-TNF drugs and ADAs is therefore warranted so that treatment can be tailored to the individual patient (individual medicine or personal medicine) in order that effective and economical long-term therapy can be given with minimal risks to the patients.

Severe infusion reactions to infliximab: aetiology, immunogenicity and risk factors in patients with inflammatory bowel disease

Aliment Pharmacol Ther 2011; 34: 51–58

Continuous Therapy With Certolizumab Pegol Maintains Remission of Patients With Crohn's Disease for up to 18 Months

BACKGROUND & AIMS The safety and efficacy of maintenance therapy with the anti-tumor necrosis factor certolizumab pegol has not been reported beyond 6 months. We assessed the long-term efficacy, safety, and immunogenicity of continuous versus interrupted maintenance therapy with subcutaneous certolizumab pegol in patients with Crohns disease. METHODS Patients who responded to induction therapy at week 6 of the PEGylated Antibody Fragment Evaluation in Crohns Disease: Safety and Efficacy (PRECiSE) 2 trial were assigned randomly to groups given certolizumab pegol (continuous) or placebo (drug-interruption) during weeks 6 to 26. Patients who completed PRECiSE 2 were eligible to enter PRECiSE 3, an ongoing, prospective, open-label extension trial in which patients have received certolizumab pegol (400 mg) every 4 weeks for 54 weeks to date, and were not offered the option to increase their dose. Disease activity was measured by the Harvey-Bradshaw Index. RESULTS Harvey-Bradshaw Index responses at week 26 for the continuous and drug-interruption groups were 56.3% and 37.6%, respectively; corresponding remission rates were 47.9% and 32.4%, respectively. Of patients responding at week 26, response rates at week 80 after the start of PRECiSE 2 in the continuous and drug-interruption groups were 66.1% and 63.3%, respectively; among patients in remission at week 26, week 80 remission rates were 62.1% and 63.2%, respectively. More patients in the drug-interruption group developed antibodies against certolizumab pegol (and had lower plasma concentrations of certolizumab pegol) than the continuously treated group. CONCLUSIONS Certolizumab pegol effectively maintains remission of Crohns disease for up to 18 months. Continuous therapy is more effective than interrupted therapy.