Mesalazine Treatment Research Articles

Recurrence of Myocarditis After Mesalazine Treatment for Ulcerative Colitis

Recurrence of Myocarditis After Mesalazine Treatment for Ulcerative Colitis

Questions about mesalazine and the irritable bowel syndrome

Sirs, Andrews et al. reported the effect of mesalazine (mesalamine) on symptoms and faecal bacterial profiles in patients with IBS.1 Fourteen patients were included and treated with mesalazine, two dropped out due to worsening diarrhoea, and eight reported satisfactory relief from symptoms. Data analyses were performed only on patients without worsening symptoms. The summary states that 8 of 12 (67%) responded favourably to mesalazine, which is not correct; 8 of 14 (57%) responded favourably and 2 of 14 (14%) unfavourably. Correspondingly, the conclusion that mesalazine treatment is associated with a decrease in faecal bacteria abundance was based on analyses of patients without worsening symptoms. Correct handling of missing data is challenging, but to report the treatment effect without mentioning that all patients with aggravation of symptoms were excluded from the analyses is unacceptable.2 Inclusion of patients, irrespective of response to treatment could have changed the conclusions. Authors and editors are responsible for conscientious and correct data analyses and reporting. Declaration of personal and funding interests: None.

Mesalazine (5‐aminosalicylic acid) alters faecal bacterial profiles, but not mucosal proteolytic activity in diarrhoea‐predominant irritable bowel syndrome

Imbalances in gut luminal bacteria may contribute to the pathogenesis of irritable bowel syndrome (IBS). To explore select bacteriological and anti-inflammatory effects of mesalazine (mesalamine; 5-aminosalicylic acid or 5ASA) and their relation to potential therapeutic effects in IBS. Prospective pilot study of 12 women with diarrhoea-predominant IBS. Patients received oral mesalazine (1.5 g b.d.) for 4 weeks followed by a 4-week washout phase. Molecular profiling of stool bacterial communities and IBS symptoms were assessed before, during and after mesalazine treatment. Colonic mucosal biopsies were assessed for proteolytic activity. Qualitative and quantitative effects of mesalazine on stool microbiota, mucosal proteolytic activity and IBS symptoms were assessed. Faecal bacteria decreased by 46% on mesalazine treatment (P = 0.014), but returned to baseline during washout. Firmicutes and Bacteroidetes represented 95% of identified phylotypes, with a trend towards an increase in the proportion of Firmicutes at week 4 in symptomatic responders [median (IQR) 14% (49) increase] compared with nonresponders [median 5% (11) decrease, P = 0.088]. Rectosigmoid mucosal proteolytic activity did not change between baseline and treatment [median 23.2 (17.9) vs. 19.5 (46.7) mU activity/mg tissue, P = 0.433]. Eight of 12 (67%) patients responded favourably to mesalazine based on a global relief questionnaire, with significant decreases in days with discomfort and increases in bowel movement satisfaction. Mesalazine treatment is associated with a decrease in faecal bacteria abundance and rebalancing of the major constituents of the microbiota. Further study of the bacteriological and anti-inflammatory properties of mesalazine in IBS is warranted.

The Efficacy of the Combination Therapy with Oral and Topical Mesalazine for Patients with the First Episode of Radiation Proctitis

Radiation proctitis is a common complication of pelvic radiation for which an optimal treatment remains undetermined. We assessed the efficacy of oral and topical mesalazine combination therapy for patients with naive radiation proctitis. A total of 23 patients with radiation proctitis were enrolled in the study over a period of 2 years. Three of these patients were excluded due to severe bleeding during the study. Twenty patients (mean age 60.3 years; two males, 18 females) were treated with oral mesalazine (3 × 1 g per day) plus a daily mesalazine suppository (1 g per day at bedtime) for 4 weeks. The efficacy of treatment was assessed according to the Subjective Objective Management Analytic (SOMA) scale for alleviation of clinical symptoms of rectal toxicity and sigmoidoscopic findings. The mean bleeding score improved significantly from 2.10 to 1.70 (p = 0.002) with mesalazine treatment. However, scores were not improved for pain (0.30-0.20, p = 0.163), tenesmus (0.50-0.45, p = 0.577), or stool frequency (0.35-0.30, p = 0.577). The improvements in the mean telangiectasia score (1.80-1.45, p = 0.005), bleeding point score (1.60-1.05, p < 0.001), and friable mucosa score (1.35-1.00, p = 0.005) were all statistically significant. No side-effects were noted in any of the patients. The combination of oral and topical mesalazine therapy for radiation proctitis may be a safe and effective treatment for naive radiation proctitis, especially for hemorrhagic proctitis. A large, randomized controlled trial is required to confirm the results of this pilot study.

High-dose mesalazine treatment for ulcerative colitis patients who relapse under low-dose maintenance therapy

Background Mesalazine is often used to maintain remission in patients with ulcerative colitis. Aim To investigate if increasing the dose of mesalazine is safe and effective for patients with ulcerative colitis who relapse under low-dose maintenance therapy. Methods Ninety consecutive patients who relapsed during maintenance therapy with oral mesalazine at 1.5–2.25 g/day were included. All patients had mildly or moderately active ulcerative colitis at entry, and were treated with oral mesalazine at 4.0 g/day for the following 8 weeks. At entry and week 8, endoscopic examinations were carried out to assess the severity of endoscopic inflammation. The primary as well as the secondary endpoints were clinical and endoscopic improvements at week 8. Results No patient experienced any serious side effect, and the treatment with 4.0 g/day mesalazine over the 8 week period was well tolerated by all patients. Fifty-nine patients (66%) achieved clinical improvement in stool frequency and/or rectal bleeding including 40 (44%) with clinical remission (normal stool frequency and no rectal bleeding). Forty-three patients (48%) showed endoscopic improvement including 25 (28%) with endoscopic remission. Conclusions Increasing the dose of mesalazine up to 4.0 g/day appeared to be safe and effective for patients who relapsed under low-dose, 1.5–2.25 g/day maintenance therapy.

Prolonged MMX® mesalazine therapy in patients with acute, mild-to-moderate ulcerative colitis who fail initial mesalazine treatment may prevent a requirement for therapeutic escalation

Introduction: MMX® mesalazine (Mezavant®, Shire Pharmaceuticals Inc., USA; MMX; Cosmo Technologies Ltd, Ireland) has been observed to successfully induce remission in patients with mild-to-moderate ulcerative colitis (UC) in two, phase III, placebo-controlled (parent) studies by Lichtenstein et al. (SPD476–301) and Kamm et al. (SPD476–302).

Mesalazine-Induced Multi-Organ Hypersensitivity

Mesalazine therapy for ulcerative colitis has been reported to be effective and safe. Rare cases of mesalazine-induced renal, pancreatic, myo-pericardial, pleuro-pulmonary and haematological toxicity have been described separately. We report a case characterized by the simultaneous presence of fever, pericarditis, peripheral eosinophilia, eosinophilic pneumonia, anaemia and haematuria (together with proteinuria and leukocyturia) due to mesalazine treatment in a patient with ulcerative colitis. No clinical response had been obtained with corticosteroids and various antibacterial agents. When mesalazine treatment was suspended, all symptoms rapidly and totally disappeared, confirming the direct responsibility of this drug in causing these adverse events. We conclude that mesalazine can induce multi-organ hypersensitivity, which must always be considered as a possible adverse effect during treatment with this drug. To resolve this adverse event it is essential to discontinue mesalazine treatment.

A comparison of physician-rated disease severity and patient reported outcomes in mild to moderately active ulcerative colitis

Background and aimsThe aim was to derive health state utility scores in ulcerative colitis (UC) by establishing the relationship between the physician-rated ulcerative colitis disease activity index (UCDAI) and a patient reported EQ-5D by statistically mapping the two instruments. MethodsIn a randomised controlled trial comparing oral plus enema mesalazine treatment with oral mesalazine treatment alone (PINCE), UCDAI and EQ-5D scores were collected in parallel from patients with active UC. From these data, multinomial logistic regression was used to estimate response probabilities to each of the five domains of the EQ-5D index from assessment of UC disease severity using original and abbreviated (no endoscopy) versions of the UCDAI. Predicted EQ-5D responses were converted by Monte Carlo simulation to the EQ-5D index for predicting health-related quality of life (HRQoL). The reliability of the algorithm was tested using UCDAI scores from a second mesalazine RCT (PODIUM). ResultsThe abbreviated-UCDAI showed comparable explanatory performance to the full UCDAI. For patients in remission, mean utility was 0.939, 0.944, and 0.940U for PINCEestimated, PINCEobserved, and PODIUM, respectively. Mild/moderate and relapsing cases showed mean utilities of 0.801, 0.811, and 0.775, respectively; whilst for those in severe relapse, the mean utilities were 0.630, 0.700 and 0.660units, respectively. The mean squared error between actual and predicted utilities from observations in PINCE was 0.019. ConclusionResponse mapping of UC activity to EQ-5D domains produced reliable estimates of patient-rated health state utility consistent with UCDAI rated severity. Comparing abbreviated-UCDAI and full UCDAI suggests that inclusion of endoscopy scores has limited predictive value in estimating patient HRQoL.

Maintenance effect of polyglycosides of Tripterygium wilfordii on remission in postoperative Crohn disease

To observe the maintenance effect of polyglycosides of Tripterygium wilfordii (GTW) on remission in postoperative Crohn disease (CD). From 2005 to 2007, 45 adult cases of postoperative Crohn disease were randomly divided into two groups, GTW group and mesalazine group, which received GTW and mesalazine treatment respectively. CD activity index (CDAI) and clinical markers were collected at 0, 3, 6, 12 months or at the onset of symptoms. Ileocolonoscopy was performed at the end of the trial (1 year after operation) or at the onset of symptoms, and recurrence score were recorded. No clinical recurrence was ascertained in both groups at 3 months. Four patients (18.2%) in GTW group relapsed and 5 (21.7%) in mesalazine group relapsed at 6 months (P=0.530). Seven patients (31.8%) in GTW group and 9 (39.1%) in mesalazine group relapsed at one year (P=0.421). Ten patients (45.5%) in GTW group had endoscopic recurrence compared with 14 (60.9%) in mesalazine group at one year(P=0.231). There were no significant differences between two groups. GTW is similar to mesalazine in maintenance of remission of postoperative Crohn disease.

Hypereosinophilia Due to Mesalazine Treatment

Hypereosinophilia Due to Mesalazine Treatment

The cost‐utility of high dose oral mesalazine for moderately active ulcerative colitis

Mesalazine (mesalamine) is standard first line treatment for moderately active ulcerative colitis (UC). Recently, doubling the mesalazine dose (Asacol 4.8 g/day) was shown to improve efficacy with no increase in adverse events. The cost-effectiveness of this strategy remains unknown. To assess the cost-utility of high dose (HD) mesalazine (Asacol 4.8 g/day) compared with standard dose (SD) mesalazine (Asacol 2.4 g/day) as first line treatment for moderately active UC. The costs and benefits associated with a treatment pathway beginning with HD or SD mesalazine were determined over 12 weeks using a decision tree analytical model. A 12-week treatment pathway starting with HD mesalazine cost an average of 2382 pounds per patient compared with 2474 pounds for SD mesalazine and generated 0.0016 more quality adjusted life years (QALYs). HD mesalazine dominated SD mesalazine, being both more effective and less costly. HD mesalazine treatment resulted in fewer patients requiring surgery or hospitalization for intensive pharmacological treatment. Probabilistic sensitivity analysis indicated a 72% chance that HD mesalazine was cost effective, based on a cost/QALY threshold of 30,000 pounds. This study suggests that HD mesalazine represents a cost-effective alternative to SD mesalazine for moderately active UC, while potentially reducing the need for hospitalization.

T1146 Maintenance Therapy with Once-Daily 2g Mesalazine (Pentasa) Treatment Improves Remission Rates in Subjects with Ulcerative Colitis Compared to Twice Daily 1g Mesalazine: Data from a Randomised Controlled Trial

T1146 Maintenance Therapy with Once-Daily 2g Mesalazine (Pentasa) Treatment Improves Remission Rates in Subjects with Ulcerative Colitis Compared to Twice Daily 1g Mesalazine: Data from a Randomised Controlled Trial

T1394 Mesalazine Treatment for Intestinal Immune Activation in Patient with Irritable Bowel Syndrome: A Randomized Controlled Pilot Trial

T1394 Mesalazine Treatment for Intestinal Immune Activation in Patient with Irritable Bowel Syndrome: A Randomized Controlled Pilot Trial

Review article: increasing the dose of oral mesalazine therapy for active ulcerative colitis does not improve remission rates

Oral mesalazine (mesalamine, 5-aminosalicylic acid) formulations are effective in the treatment of active ulcerative colitis. All formulations contain the same active drug but differ with regard to mechanisms to deliver the drug to the colon. Patients who fail to respond to initial therapy are often administered higher doses of the same formulation. To review published trials of oral mesalazine formulations in treating active ulcerative colitis and to examine the effect of dose escalation on remission rates. Increasing the doses of oral mesalazine formulations does not result in higher remission rates, although increasing the doses of some formulations has been effective in increasing symptomatic improvement and/or response to treatment. Because oral mesalazine formulations do not demonstrate a significant dose response with regard to induction of remission of active ulcerative colitis, simple dose escalation may not be the most effective course for patients who fail to respond to initial mesalazine treatment.

Atypical Lung Changes in a 19-Year-Old Woman with Crohn’s Disease

A 19-year-old woman with a history of Crohn’s disease presented with a three-week history of fever, nonproductive cough, and migrating arthralgias. She had been treated with mesalazine and budesonide and was free of any recent intestinal symptoms. A chest radiograph revealed bilateral multiple rounded densities and a chest CT showed that the densities were also subpleural and varied in size (Fig. 1). Lung biopsy was performed (video-assisted thoracoscopy, VATS) and histopathologic examination was consistent with organizing pneumonia (OP). The most characteristic feature was areas of necrosis surrounded by intra-alveolar organization of fibrinoid inflammatory cell buds with formation of abortive granulomas consisting of epithelioid and giant cells and accompanying active neutrophillic infiltrations (Fig. 2). Because of the possible relationship of these lung changes to mesalazine treatment, the drug was withdrawn but the symptoms returned within two weeks. She was then treated with prednisone (0.5 mg/kg) followed by rapid improvements in radiographic signs and respiratory symptoms. Physical and radiologic symptoms, histopathologic examination, and good response to steroids are consistent with organizing pneumonia accompanying Crohn’s disease [1, 2]. Lung metastases, Wegener’s granuloma, and pulmonary emboli were considered in differential diagnosis. The lung changes in inflammatory bowel disease (IBD, i.e., Crohn’s disease and ulcerative colitis) can be grouped into three categories: (1) destructive inflammation at various levels of conductive airways, most frequently bronchiectasis and/or obliterative bronchiolitis; (2) various forms of interstitial lung disease [OP, nonspecific interstitial pneumonia (NSIP), or pulmonary eosinophillic infiltrates]; and (3) other rare forms of lung involvement (i.e., sterile necrobiotic nodules, pleuritis) [1]. The real frequency of pulmonary involvement is difficult to define, but the problem seems to be underestimated by most physicians. Both pulmonary function and high resolution computed tomography (HRCT) abnormalities may occur in more than 50% of patients with IBD. Up to 40% of these patients may be free of respiratory symptoms [3]. Patients without clinical evidence of pulmonary involvement may have alveolar lymphocytosis [4] and reduced diffusion capacity (DLCO) [5], which may suggest the presence of latent alveolitis. The common link between colonic and bronchial/alveolar inflammation has not been determined, but it seems probable that the common ancestry (both systems originate from the primitive gut) is important. Extraintestinal manifestations of IBD may represent autoimmune phenomena. The role of infection (i.e., cytomegalovirus) in induction of these processes has been considered. Approximately 20% of patients with pulmonary involvement have inactive W. J. Piotrowski (&) P. Gorski Department of Pneumology and Allergy, Medical University of Lodz, 22 Kopcinskiego St., 90-153, Lodz, Poland e-mail: piotrow@toya.net.pl

Thrombin generation in mesalazine refractory ulcerative colitis and the influence of low molecular weight heparin

In ulcerative colitis (UC), a state of hypercoagulation has frequently been observed. Low molecular weight heparin (LMWH) has shown beneficial effects as an adjuvant treatment of steroid refractory UC in open trials. We assessed potential therapeutic effects of the LMWH reviparin in hospitalised patients with mesalazine refractory UC, as well as its influence on haemostasis factors. Twenty-nine patients with mild-to-moderately active UC were included in a double-blind placebo controlled trial. All patients had a flare-up of disease under mesalazine treatment. Reviparin (Clivarin) 3,436 IU anti-Xa/0.6 ml or placebo s.c. was added, and self-administered twice daily for 8 weeks. Patients were monitored for possible adverse events and changes in clinical symptoms. Endoscopical, histological, biochemical and haemostasis parameters were analysed. Tolerability and compliance were excellent and no serious adverse events occurred. No significant differences were observed on the clinical, endoscopical and histological outcome, as compared to placebo. A high intrinsic and extrinsic thrombin potential was found before LMWH therapy. However, the significant reduction in the thrombin generation by LMWH was not related to the reduction in disease activity. The LMWH reviparine reduces thrombin generation in patients with mild-to-moderately active, mesalazine refractory UC, but is not associated with a reduction in disease activity.

Severe myalgia associated with mesalazine treatment in a child with Crohn’s disease

Severe myalgia associated with mesalazine treatment in a child with Crohn’s disease

A Meta-Analysis of the Placebo Rates of Remission and Response in Clinical Trials of Active Ulcerative Colitis

Knowledge of the placebo outcomes and understanding specific study features that influence these outcomes is important for designing future clinical trials evaluating therapy of ulcerative colitis (UC). The aims of this study were to estimate the placebo rates of remission and response in placebo-controlled, randomized clinical trials for active UC and to identify factors influencing these rates. We performed a systematic review and meta-analysis of placebo-controlled, randomized clinical trials evaluating therapies for active UC identified from MEDLINE from 1966 through 2005. Forty studies met the inclusion criteria. The pooled estimates of the placebo rates of remission and response were 13% (95% confidence interval, 9%-18%; range, 0%-40%; median, 12%) and 28% (95% confidence interval, 23%-33%; range, 0%-67%; median, 30%), respectively, both with significant heterogeneity. Studies that used more stringent definitions of outcomes had lower placebo rates of remission and response. Study duration, number of study visits, disease duration, baseline composite and rectal bleeding scores of the disease activity index, and inclusion of endoscopic mucosal healing as the remission definition all were associated with the placebo remission rate. Rates of remission in the placebo arm of UC clinical trials ranges from 0% to 40%. The placebo remission rates are influenced by the trial length, number of study visits, use of stricter remission definitions, and design features that enroll patients with more active disease. These factors should be considered when designing future placebo-controlled clinical trials in patients with active UC.

Perianal Crohn's Disease Presentation in Infancy Requiring Surgery and Infliximab Treatment

There are only a few case reports on infant presentation of Crohn's disease. Perianal changes are an extremely rare presentation of the disease in infancy and surgical therapy is anecdotal. Infiximab has never been used before in infancy. Our case presentation is the first one with the description of perianal changes, unsuccessful surgical therapy and infliximab treatment performed. Case report: We report a 10 months old infant who presented to a local hospital with bloody diarrhoea, perianal inflammation and fissure at the age of 2 months. The child was referred to our hospital at the age of four months because of loose stools with blood and mucous. Weight and height were within normal limits (75c), because of tenderness of perianal area ultrasound was performed which showed a perianal abscess. Ulcerations, erosions, pseudopolyps were observed along the whole colon on colonoscopy. Histological examination of the colon biopsies showed severe limphocyte infiltrations. Immune deficiencies (including chronic granulomatous disease) were excluded and the diagnosis of Crohn's disease was established. Steroid therapy, azathioprine, mesalazine treatment as well as total parenteral nutrition and antibiotic therapy were introduced with subsequent improvement of endoscopic and histological changes. Still the abscess did not respond to treatment and perianal fistulas complicated the course of the disease. At the age of 5 months ileostomy was performed to obtain bowel rest and abscess heeling. Ileostomy resulted with successful treatment of the abscess, which however reappeared after 6 weeks and then self-evacuated. The child was switched to enteral nutrition and then to nutrition by oral route. However, after steroids were reduced and parenteral nutrition was stopped the child lost appetite and started to vomit a few times a day. The symptoms did not respond to increased doses of steroid. Gastroscopy was performed which showed inflammation of gastric mucosa and heeled ulceration, colonoscopy revealed moderate inflammation throughout the colon. Infliximab was introduced after receiving informed consent of the parents. The first dose 5 mg/kg body weight/day resulted in quick clinical improvement: the child stopped vomiting, started to eat, there were no untoward effects observed. The second Infliximab dose was administered after 2 weeks- the immediate untoward reaction was observed: hypotermia and hypotensia. Intensive fluid therapy resulted with clinical improvement. During the following days parenteral therapy was stopped and the child was discharged home. At the moment 4 weeks after the second Infliximab dose the child is doing well, gaining weight, with no clinical symptoms from the alimentary tract. Conclusions: The severe presentation of Crohn's disease in infancy may be resistant to intensive pharmacotherapy and surgery. Infiximab treatment can be effective even in very small infants, still the risk of complications may limit its use.

Protein phosphatase 2A is required for mesalazine-dependent inhibition of Wnt/ -catenin pathway activity

The rising incidence and poor prognosis of colorectal cancer have aroused substantial interest in novel chemopreventive strategies. Interestingly, treatment of ulcerative colitis with mesalazine, which displays few side effects during long-term treatment, is associated with a reduced incidence of colorectal cancer, but its molecular mechanism is not known. The effect of mesalazine on the Wnt/beta-catenin pathway was studied in colorectal cancer cell lines to find a molecular basis underlying its chemopreventive features. Mesalazine affects the Wnt/beta-catenin pathway in adenomatous polyposis coli mutated cells with intact beta-catenin, judged by luciferase reporter assays. Furthermore, mesalazine treatment reduced expression of nuclear beta-catenin and Wnt/beta-catenin target genes, and increased beta-catenin phosphorylation. This effect on the Wnt/beta-catenin pathway is mediated via protein phosphatase 2A (PP2A): increased phosphorylation of PP2A after mesalazine treatment is observed, which coincides with decreased PP2A enzymatic activity. The inhibition of PP2A enzymatic activity by mesalazine is essential for its effect on the Wnt/beta-catenin pathway, as shown by transient transfection with siPP2A and mutant PP2A. This study shows, using concentrations of mesalazine identical to concentrations seen in patients with inflammatory bowel disease, that mesalazine inhibits the Wnt/beta-catenin pathway via inhibition of PP2A.