Long-term safety and efficacy of certolizumab pegol in the treatment of Crohn's disease: 7-year results from the PRECiSE 3 study.

BACKGROUND: The efficacy and safety of certolizumab pegol (CZP) in moderate-to-severe Crohn's disease were demonstrated in two 26-week double-blind studies (PRECiSE 1 & 2). AIM: To report the safety and efficacy outcomes of long-term, CZP therapy from PRECiSE 3, in which patients received treatment up to 7 years treatment. METHODS: Patients completing PRECiSE 1 or 2 were eligible to enter PRECiSE 3 in which they received CZP 400 mg, open-label, every 4 weeks (without additional induction therapy) for up to 7 years, for up to 91 doses from study start. Safety (adverse events, including infections and malignancies) and efficacy (Harvey-Bradshaw Index, faecal calprotectin, C-reactive protein) were prospectively monitored. Remission was analysed using observed cases, last observation carried forward imputation and nonresponder imputation. RESULTS: A total of 595 patients entered the study; 117 (20%) completed 7 years. Discontinuation rates were 29.2%, 13.6%, 16.1%, 7.9%, 5.0%, 4.5% and 3.9% (years 1-7 respectively). During 1920 patient-years of exposure to CZP, no new safety signals were observed. Incidence rates (new cases/100 patient-years) for serious infections and malignant neoplasms were 4.37 and 1.06 respectively. No lymphoproliferative malignancies were reported. Clinical remission rates were ≥68% at each year (observed cases); rates by last observation carried forward and nonresponder imputation were 58% and 45% at year 1, 56% and 26% at year 3 and 55% and 13% at year 7 respectively. CONCLUSION: Certolizumab pegol was well tolerated in the long-term treatment of Crohn's disease, with sustained remission in some patients continuing in the study for up to 7 years. ClinicalTrials.gov identifier NCT00552058.

Mesalazine granules 1.5 g once-daily maintain remission in patients with ulcerative colitis who switch from other 5-ASA formulations: a pooled analysis from two randomised controlled trials.

BACKGROUND: Mesalazine (mesalamine) granules (MG) were shown to be effective for the maintenance of remission of ulcerative colitis (UC) in two double-blind placebo-controlled trials. AIM: To evaluate the efficacy of once-daily MG for maintenance of remission in patients with UC who switched from other 5-aminosalicylic acid (5-ASA) formulations. METHODS: Data from two independent multicenter, randomised, double-blind, placebo-controlled, 6-month trials evaluating patients with UC in remission were combined for analysis of a subpopulation of patients who switched from other 5-ASA formulations to MG 1.5 g or placebo upon randomisation. The primary endpoint was the percentage of patients who remained relapse-free at Month 6 or end of treatment. Relapse was defined as a Sutherland Disease Activity Index (SDAI) rectal bleeding score ≥1 and mucosal appearance score ≥2, a UC flare or medication used to treat a UC flare. RESULTS: Of the 487 patients who received 5-ASA maintenance therapy at enrolment, 322 were in the MG group and 165 were in the placebo group. The percentage of patients who remained relapse-free (based on Sutherland Disease Activity Index scores) after 6 months was significantly higher with MG than placebo (78.3% vs. 58.8%, P < 0.001). Rectal bleeding, stool frequency and the physician's rating of disease activity remained unchanged after 6 months in a higher percentage of patients using MG compared with those on placebo (P < 0.004 for each endpoint). CONCLUSION: Mesalazine granules 1.5 g once-daily is effective for maintenance of remission in UC patients who switch from other 5-ASA formulations. ClinicalTrials.gov identifiers NCT00744016, NCT00767728.

Early symptomatic response and mucosal healing with mesalazine rectal suspension therapy in active distal ulcerative colitis--additional results from two controlled studies.

BACKGROUND: Rapid resolution of symptoms and endoscopic inflammation in ulcerative colitis (UC) represent important treatment goals. AIMS: To establish times to bleeding cessation and endoscopic healing for topical and oral mesalazine in active distal UC, a post hoc analysis of two published studies was performed. METHODS: Study I (Sutherland 1987) compared mesalazine rectal suspension to placebo, while Study II (Safdi 1997) compared topical suspensions, either alone or in combination with oral mesalazine, and oral alone. Cessation of rectal bleeding (RB) was defined as absence of bleeding on four consecutive days. Endoscopic remission was defined as DAI mucosal healing (MH) subscore=0 and clinical remission as MH subscore =0-1 and ≥ 1-point improvement, plus RB subscore = 0. RESULTS: Study I: By Day 2, 31.4% of subjects using topical monotherapy reported no RB vs. 5.5% in the placebo arm (P<0.0006); median time to RB cessation was 8 days. Significantly higher rates of endoscopic (25.0% vs. 7.8%, P<0.005) and clinical remission (48.6% vs. 9.6%, P<0.0001) were observed at Week 3. Study II: A significantly higher proportion of subjects achieved RB cessation with combination therapy vs. oral therapy, commencing by Day 8. By Week 3, a significantly higher proportion of subjects using combination therapy achieved clinical remission compared to oral therapy alone (57.9% vs. 18.2%, P<0.05). CONCLUSIONS: Topical mesalazine suspension, either alone or in combination with oral mesalazine, led to earlier rectal bleeding cessation and mucosal healing. These data support use of topical therapy for more rapid treatment benefit in active distal ulcerative colitis.

Review article: delivery and efficacy of topical 5-aminosalicylic acid (mesalazine) therapy in the treatment of ulcerative colitis.

BACKGROUND: The use of topical therapy in the treatment of ulcerative colitis has declined in recent years despite evidence of good efficacy. AIMS: To review US prescription trends for 5-aminosalicylic acid (5-ASA) since the US approval of Asacol extended-release oral mesalazine (mesalamine) in 1992; to estimate the optimal level of 5-ASA exposure in the distal colon; to determine factors influencing distal colonic exposures; and to compare the effectiveness of different 5-ASA formulations (oral, topical suspension, foam, suppositories) in clinical trials. METHODS: Review of clinical trials, physiologic studies and prescription trends of various mesalazine formulations for treatment of distal ulcerative colitis. RESULTS: Between 1992 and 2009, prescriptions for oral mesalazine increased sixfold, whereas topical suspensions declined by 10%. In clinical trials, topical therapy resulted in higher remission and clinical response rates than oral therapy, with trends to earlier improvement. The mucosal concentrations of 5-ASA achieved by topical agents in the distal colon were up to 200-fold higher than those achieved by oral administration alone. Despite active colitis, over 40% of a topically administered 4 g 5-ASA suspension (equal to 1.6 g) reached the sigmoid colon. This likely represents a therapeutic exposure of 5-ASA. Although topical therapies are less convenient than oral medications, treatment algorithms have failed to take into account quality of life improvements resulting from more rapid and complete treatment response. CONCLUSIONS: Topical mesalazine therapy is superior to oral therapy in distal ulcerative colitis for both therapeutic response and drug delivery. Practice patterns should be re-evaluated in light of this information.

Randomised clinical trial: delayed-release oral mesalazine 4.8 g/day vs. 2.4 g/day in endoscopic mucosal healing--ASCEND I and II combined analysis.

BACKGROUND: Recent studies have focused on the importance of mucosal healing in ulcerative colitis (UC). However, it was still unclear whether higher doses of delayed-release mesalazine (mesalamine) could provide additional benefit. AIM: To examine how two doses of delayed-release mesalazine (4.8 g/day and 2.4 g/day) from ASCEND I and II compare in their relative ability to heal colonic mucosa over time. METHODS: Primary data from two prospective 6-week, double-blind, randomised studies in patients with mildly to moderately active UC were pooled and analysed retrospectively. The mucosal healing analysis focuses on moderately active UC patients (n=391), comprising a majority of patients (84%). Additional analyses examined the relationship between mucosal healing and dose, clinical response to therapy and patient quality of life (Inflammatory Bowel Disease Questionnaire, IBDQ). RESULTS: At week 3, mucosal healing (endoscopy subscore of 0 or 1) was achieved in 65% of moderately active UC patients on 4.8 g/day and 58% of patients on 2.4 g/day (P=0.219). At week 6, this increased to 80% for 4.8 g/day and 68% for 2.4 g/day (P=0.012). Healing rates with the higher dose were also greater across all extents of disease and in patients with prior steroid use. At 6 weeks, clinical response to therapy and mucosal healing were found to be well correlated (kappa=0.694). Likewise, the change in IBDQ at week 6 showed a significant relationship with mucosal healing (P<0.0001). CONCLUSION: Mucosal healing rates in UC achieved at 6 weeks were statistically significantly higher with delayed-release mesalazine at 4.8 g/day vs. 2.4 g/day.

Clinical trial: once-daily mesalamine granules for maintenance of remission of ulcerative colitis - a 6-month placebo-controlled trial.

BACKGROUND: Ulcerative colitis (UC) is a chronic relapsing and remitting idiopathic inflammatory bowel disorder. AIM: To evaluate once-daily mesalamine (mesalazine) granules (MG) for maintenance of remission of UC. METHODS: Randomized, double-blind, placebo-controlled trial of patients (n=209 MG, n=96 placebo) with UC in remission [revised Sutherland Disease Activity Index (SDAI) rectal bleeding=0, mucosal appearance <2] who took MG 1.5 g or placebo once-daily for up to 6 months. Primary efficacy endpoint: the percentage of patients who remained relapse-free at month 6/end of treatment. Relapse was defined as SDAI rectal bleeding score ≥1 and a mucosal appearance score ≥2, a UC flare, or initiation of medication to treat a UC flare. RESULTS: The percentage of relapse-free patients at month 6/end of treatment was higher with MG than placebo (78.9% vs. 58.3%, P < 0.001) in the intent-to-treat analysis. Significant differences (P ≤ 0.025) favouring MG were observed for most secondary endpoints including improvement in rectal bleeding, physician's disease activity rating, stool frequency, the SDAI at month 6/end of treatment, patients classified as a treatment success and relapse-free duration. The incidence of adverse events was similar between groups. CONCLUSIONS: Once-daily mesalamine (mesalazine) was effective in maintaining remission of UC for 6 months.

An approach to the management of refractory ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology associated with dysregulation of the gastrointestinal mucosal immune system. It is characterized by a waxing and waning course and approximately 15% of UC patients will experience a severe episode. The first line treatment for severe colitis includes IV corticosteroids, however, 40% of patients are non-responsive to corticosteroid therapy and may require either colectomy, intravenous infliximab or intravenous cyclosporine within 3-5 days of presentation. This review focuses on the management and treatment approaches to refractory UC.

Clinical trial: benefits and risks of immunomodulators and maintenance infliximab for IBD-subgroup analyses across four randomized trials.

BACKGROUND: Benefits and risks of concomitant immunomodulators and maintenance infliximab in inflammatory bowel disease (IBD) patients have not been adequately evaluated. AIM: To assess the effect of concomitant immunomodulator and infliximab maintenance therapy using data from four prospective, randomized Phase 3 trials in IBD patients. METHODS: Overall, 1383 patients from ACCENT I and ACCENT II [luminal and fistulizing Crohn's disease trials] and ACT 1 and ACT 2 [ulcerative colitis trials] were analysed. Patients were treated with placebo or infliximab 5 or 10 mg/kg at weeks 0, 2 and 6 followed by every-8-week maintenance therapy. Clinical response, clinical remission, fistula response, complete fistula response, infection and infusion reaction rates; serum infliximab concentrations and immunogenicity were summarized by baseline concomitant immunomodulator subgroup (use or non-use). RESULTS: Overall, almost 40% of evaluated IBD patients received concomitant immunomodulators. Efficacy, infection, and serious infection rates were generally similar in patients who received maintenance therapy with or without concomitant immunomodulators. There were no consistent differences in serum infliximab concentrations with or without immunomodulators in patients who received scheduled maintenance therapy. Concomitant immunomodulators reduced infusion reactions and immunogenicity. CONCLUSION: Concomitant immunomodulators did not improve efficacy or pharmacokinetics in IBD patients who received maintenance infliximab.

Oral budesonide for maintenance of remission of Crohn's disease: a pooled safety analysis.

BACKGROUND: Budesonide exhibits similar efficacy to systemic glucocorticosteroids (GCSs) in Crohn's disease (CD), but with fewer adverse events (AEs). Aim To evaluate budesonide's safety profile in CD patients, in particular, incidences of clinically important AEs known to be associated with systemic GCSs. METHODS: Five 1-year, double-blind, placebo-controlled trials evaluating budesonide for mild-to-moderate CD were pooled for analysis. RESULTS: The highest incidence rates of AEs were gastrointestinal- and endocrine systems-related in both groups (budesonide 6 mg/day, n = 208; placebo, n = 209). Incidence rates were similar, except for higher incidence of endocrine disorders in budesonide versus placebo patients (P = 0.0042) caused by a higher overall occurrence of cutaneous GCS symptoms (P = 0.0036) in the budesonide group; differences in individual symptoms were nonsignificant. Percentage of patients with normal adrenal function was significantly lower at 13 weeks (three of five studies), but not at 52 weeks (two studies) in the budesonide versus placebo groups. Occurrence of clinically important or serious AEs associated with systemic GCSs, including sepsis, cataracts, adrenal insufficiency was rare and similar between groups. CONCLUSIONS: Budesonide treatment for up to 1 year is well-tolerated in CD patients, with an AE profile similar to placebo and only rare occurrences of clinically important AEs associated with systemic GCSs.

Review article: 5-aminosalicylate formulations for the treatment of ulcerative colitis--methods of comparing release rates and delivery of 5-aminosalicylate to the colonic mucosa.

BACKGROUND: Many oral 5-aminosalicylic acid (5-ASA) formulations are designed to maximize 5-ASA release in the colon where it acts topically on the colonic mucosa. Delayed-release formulations and azo-prodrugs minimize 5-ASA absorption in the upper gastrointestinal (GI) tract. AIMS: To review methods for assessing 5-ASA release and colonic distribution from oral formulations, and the potential use of this information for guiding clinical decisions. METHODS: PubMed and recent conference abstracts were searched for articles describing techniques used to assess 5-ASA release from ulcerative colitis (UC) therapies. RESULTS: In-vitro GI models, although unable to simulate more complex aspects of GI physiology, can provide useful data on 5-ASA release kinetics and bioaccessibility. Gamma-scintigraphy is useful for investigating GI disintegration of different formulations, but may not accurately reflect 5-ASA distribution. Plasma pharmacokinetic studies provide data on systemic exposure, but not on colonic distribution or mucosal uptake. Mucosal biopsies provide direct evidence of colonic distribution and may predict clinical efficacy, but must be interpreted cautiously because of considerable inter-subject variability and other confounding factors. CONCLUSION: While assessment of 5-ASA release is important, limitations of individual measurement techniques mean that randomized clinical studies in UC patients remain the best guide for dosing and treatment regimen decisions.

Meta-analysis: factors predicting post-operative recurrence with placebo therapy in patients with Crohn's disease.

BACKGROUND: The use of placebo in randomized clinical trials (PC-RCTs) is often required to evaluate drug efficacy in maintenance of Crohn's disease (CD). AIM: To determine pooled estimates of placebo rates of maintaining clinical remission and endoscopic recurrence following surgery for CD and identify factors that influenced placebo outcomes. METHODS: We performed a systematic review and meta-analysis of PC-RCTs evaluating post-operative maintenance therapies for CD identified from MEDLINE from 1966 to 2005. RESULTS: Twelve studies met our inclusion criteria. The pooled placebo rate of maintaining clinical remission was 56% (95% CI 47-64%; range 34-89%) during a median follow-up of 52 weeks (range 12-156 weeks), but significant heterogeneity existed among the studies (P < 0.001). Prior steroid therapy was the only factor found to be associated with maintaining remission (P = 0.04). The pooled placebo endoscopic recurrence rate was 58% (95% CI 51-65%; range 36-80%) during a median follow-up of 52 weeks (range 12-156 weeks), with significant heterogeneity noted (P = 0.0003). Prior surgery, concomitant small bowel and colonic disease, fistulizing phenotype, or prior immunomodulator therapy influenced endoscopic recurrence (P < 0.05). CONCLUSION: Placebo rates in PC-RCTs evaluating post-operative clinical and endoscopic recurrence demonstrate significant variability, which is influenced by specific study characteristics.

MMX mesalazine for the induction of remission of mild-to-moderately active ulcerative colitis: efficacy and tolerability in specific patient subpopulations.

BACKGROUND: Two phase III studies have evaluated mesalazine (mesalamine) with MMX (Multi Matrix System) technology in patients with active mild-to-moderate ulcerative colitis. AIM: To determine the efficacy of MMX mesalazine for the induction of clinical and endoscopic remission in specific subgroups of patients with active, mild-to-moderate ulcerative colitis. METHODS: Data from two double-blind, placebo-controlled trials were analysed (517 out-patients). Patients were randomized to receive MMX mesalazine [2.4 g/day (once daily or 1.2 g twice daily) or 4.8 g/day (once daily)] or placebo for 8 weeks. RESULTS: The percentages of patients treated with MMX mesalazine, 2.4 or 4.8 g/day, in clinical and endoscopic remission at week 8 were similar and significantly (P < 0.05) greater than placebo in subgroups stratified by disease extent, disease severity and gender and among patients not previously receiving low-dose 5-aminosalicylic acid. Among patients transferring directly from prior low-dose oral 5-aminosalicylic acid, MMX mesalazine 4.8 g/day was significantly (P = 0.018) more effective than placebo in inducing clinical and endoscopic remission. Efficacy over placebo did not reach significance in patients transferring directly to MMX mesalazine 2.4 g/day. CONCLUSION: MMX mesalazine is effective in active UC regardless of disease extent, disease severity, gender and previous, low-dose, 5-ASA therapy.

Randomised trial of once- or twice-daily MMX mesalazine for maintenance of remission in ulcerative colitis.

AIM: Maintenance treatment in ulcerative colitis should be as convenient as possible, to increase the chance of compliance. MMX mesalazine is a once-daily, high-strength (1.2 g/tablet) formulation of 5-aminosalicylic acid. This study evaluated the safety and efficacy of MMX mesalazine dosed once or twice daily as maintenance therapy in patients with ulcerative colitis. METHODS: This multicentre, randomised, open-label trial enrolled patients with strictly defined clinical and endoscopic remission, immediately following an episode of mild to moderate ulcerative colitis. Patients were randomised to MMX mesalazine 2.4 g/day as a single (2x1.2 g tablet) or divided dose (1x1.2 g tablet twice daily) for 12 months. RESULTS: 174 patients (37.9%; safety population n = 459) experienced 384 adverse events, the majority of which were mild or moderate in intensity. Eighteen patients (3.9%), nine in each group, experienced a total of 22 serious adverse events (10 in the once-daily and 12 in the twice-daily group). Most serious adverse events were gastrointestinal, experienced by 5 patients in the once-daily and 4 in the twice-daily group. At month 12, 64.4% (efficacy population, n = 451) of patients in the once-daily and 68.5% of patients in the twice-daily group were in clinical and endoscopic remission (p = 0.351). At month 12, 88.9% and 93.2% in each group, respectively, had maintained clinical remission (were relapse free). CONCLUSIONS: MMX mesalazine 2.4 g/day administered as a single or divided dose demonstrated a good safety profile, was well tolerated and was effective as maintenance treatment. High clinical and endoscopic remission rates can be achieved with once-daily dosing. TRIAL REGISTRATION NUMBER: NCT00151944.

Clinical trial: sodium phosphate tablets are preferred and better tolerated by patients compared to polyethylene glycol solution plus bisacodyl tablets for bowel preparation.

BACKGROUND: Patient acceptance of bowel preparation can affect colon cancer screening compliance. Aim To compare patient acceptance, preference and tolerability of 32-sodium phosphate tablets vs. 2L polyethylene glycol solution plus 4 bisacodyl tablets for bowel preparation. METHODS: A prospective, randomized, investigator-blinded, multicentre trial was performed. Results were based on responses to a patient questionnaire. RESULTS: 411 patients (205 sodium phosphate; 206 polyethylene glycol plus bisacodyl) completed the study preparation and patient questionnaire prior to colonoscopy. More patients receiving sodium phosphate vs. polyethylene glycol plus bisacodyl found it easy to take (77% vs. 42%), reported it to be without taste (47% vs. 6%), found it easy to take with respect to volume of liquid prescribed (72% vs. 27%) and indicated they would take the same preparation again in the future (96% vs. 74%, P < 0.0001 for all). Fewer patients receiving sodium phosphate vs. polyethylene glycol plus bisacodyl had to take time off work or change ordinary activities to take the study preparation (18% vs. 52%, P < 0.0001). Nausea, vomiting, bloating and abdominal pain were reported less frequently with sodium phosphate (P < 0.0013). CONCLUSION: The 32-tablet sodium phosphate dosing regimen was easier to take and better tolerated, when compared to 2L polyethylene glycol plus bisacodyl tablets for bowel preparation.

Medical management of mild to moderate Crohn's disease: evidence-based treatment algorithms for induction and maintenance of remission.

BACKGROUND: Patients with Crohn's disease alternate between periods of active, symptomatic disease and periods of remission. The treatment goal for Crohn's disease is to induce and then maintain remission of symptoms. AIM: To review evidence from randomized, controlled, clinical trials on medical therapies for inducing and maintaining remission in patients with mild-to-moderate Crohn's disease, and to suggest the best evidence-based approaches for induction and maintenance therapies. METHODS: PubMed search using the following terms: sulfasalazine or salicylazosulfapyridine or aminosalicylate or aminosalicylic acid or mesalamine or mesalazine or corticosteroid or prednisone or prednisolone or methylprednisolone or budesonide or antibiotic or metronidazole or ciprofloxacin or immunosuppressive or azathioprine or mercaptopurine or thiopurine or methotrexate and Crohn's disease. RESULTS: Randomized, controlled trials demonstrated that sulfasalazine, budesonide, and conventional corticosteroids are effective for inducing remission of mild-to-moderate Crohn's disease when administered for a period of 8-16 weeks. An ideal maintenance therapy does not currently exist. CONCLUSIONS: Selection of maintenance therapy is based on a combination of evidence from controlled trials and patient features including disease severity and location, co-morbidities, previous response to treatment, and previous surgical resection. The options for maintenance therapy include therapy cessation and patient observation following successful induction, budesonide, or immunosuppressive therapy.

Review article: Bowel preparation for colonoscopy--the importance of adequate hydration.

BACKGROUND: Patient compliance with screening recommendations for colorectal cancer remains low, despite a 90% survival rate achieved with early detection. Bowel preparation is a major deterrent for patients undergoing screening colonoscopy. More than half of patients taking polyethylene glycol electrolyte lavage solution and sodium phosphate preparations experience adverse events, such as nausea and abdominal pain. Many adverse events may be associated with dehydration, including rare reports of renal toxicity in patients taking sodium phosphate products. Addressing dehydration-related safety issues through patient screening and education may improve acceptance of bowel preparations, promote compliance and increase the likelihood of a successful procedure. AIM: To evidence safety issues associated with bowel preparation are generally related to inadequate hydration. RESULTS: Dehydration-related complications may be avoided through proper patient screening, for example, renal function and comorbid conditions should be considered when choosing an appropriate bowel preparation. In addition, patient education regarding the importance of maintaining adequate hydration before, during and after bowel preparation may promote compliance with fluid volume recommendations and reduce the risk of dehydration-related adverse events. CONCLUSIONS: Proper patient screening and rigorous attention by patients and healthcare providers to hydration during bowel preparation may provide a safer, more effective screening colonoscopy.

MMX Multi Matrix System mesalazine for the induction of remission in patients with mild-to-moderate ulcerative colitis: a combined analysis of two randomized, double-blind, placebo-controlled trials.

BACKGROUND: MMX mesalazine [LIALDA (US), MEZAVANT XL (UK and Ireland) MEZAVANT (elsewhere)] utilizes MMX Multi Matrix System (MMX) technology which delivers mesalazine throughout the colon. Two phase III studies have already evaluated MMX mesalazine in patients with active, mild-to-moderate ulcerative colitis. Aim To provide more precise estimates of the efficacy of MMX mesalazine over placebo by combining the patient populations from the two phase III studies. Methods Combined data from two 8-week, double-blind, placebo-controlled trials were analyzed. Patients randomized to MMX mesalazine 2.4 g/day (once daily or 1.2 g twice daily), 4.8 g/day (once daily) or placebo were reviewed. The primary end point was clinical and endoscopic remission (modified Ulcerative Colitis-Disease Activity Index of /=1-point reduction in sigmoidoscopy score from week 0). Results Data from 517 patients were analysed. 8-week remission rates were 37.2% and 35.1% in the MMX mesalazine 2.4 g/day and 4.8 g/day groups, vs. 17.5% on placebo (P < 0.001, both comparisons). 8-week complete mucosal healing rates were 32% in both MMX mesalazine groups compared with 16% on placebo. Adverse event frequency was similar in all groups. Conclusion MMX mesalazine is effective and generally well tolerated for inducing clinical and endoscopic remission of active, mild-to-moderate ulcerative colitis.

Review article: monitoring of immunomodulators in inflammatory bowel disease.

The armamentarium of medications for the treatment of inflammatory bowel disease is growing and becoming more complicated to use. Immunomodulators are a class of medications that have found a niche for the treatment of Crohn's disease and ulcerative colitis. Because of the mounting supporting evidence for efficacy, the most commonly-used immunomodulators are azathioprine, mercaptopurine, methotrexate and ciclosporin. These medications are being used more often due to their steroid-sparing and potentially surgery-sparing effects. Immunomodulators are also known for a significant side-effect profile and require careful monitoring. This review provides the latest information for clinicians on efficacy, side-effects, dosing and monitoring of these medications for treatment of inflammatory bowel disease.

A randomized, double-blind, placebo-controlled trial of CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, in patients with corticosteroid-dependent Crohn's disease.

AIM: To evaluate CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, for the treatment of corticosteroid-dependent Crohn's disease. METHODS: Patients with corticosteroid-dependent Crohn's disease (use of prednisolone 15-40 mg/day or budesonide 9 mg/day for at least 8 weeks, a previous failed attempt to discontinue corticosteroids within 8 weeks, and Crohn's Disease Activity Index score 150 points or less) were enrolled in a 16-week, randomized, double-blind, placebo-controlled trial. The patients received intravenous CDP571 (20 mg/kg at week 0 and 10 mg/kg at week 8) or placebo. Corticosteroid therapy was decreased following a predefined schedule. The primary efficacy end-point was the percentage of patients with corticosteroid-sparing [i.e. no disease flare (Crohn's Disease Activity Index score > or =220 points) and no longer requiring corticosteroid therapy] at week 10. The major secondary efficacy end-point was corticosteroid-sparing at week 16. RESULTS: Seventy-one patients received treatment. Corticosteroid-sparing was achieved by 19 of 39 (48.7%) CDP571 patients and 13 of 42 (40.6%) placebo patients (P = 0.452) at week 10, and by 18 of 39 (46.2%) CDP571 patients and seven of 32 (21.9%) placebo patients (P = 0.032) at week 16. CDP571 therapy was well-tolerated and the incidence of serious adverse events was similar to placebo. CONCLUSIONS: The CDP571 was effective for corticosteroid-sparing at week 16 but not week 10, and was well-tolerated in patients with corticosteroid-dependent Crohn's disease.