Doses Of Mesalamine Research Articles

P571 The Nordic diet as a tool to improve the activity of disease and psycho-emotional wellbeing in patients with mild and moderate Ulcerative Colitis – the pilot study

Abstract Background The Nordic diet (ND) has been associated with reduced inflammatory markers and improved anxiety and stress symptoms. Our aim was to evaluate the effect of the ND on the activity of ulcerative colitis (UC), symptoms of anxiety, depression, and fatigue. Methods Patients (N=12) with mild and moderate UC were included (excluding severe UC, UC proctitis, infections). The activity of UC was evaluated with partial Mayo score (pMS) and fecal calprotectin (FC), psycho-emotional wellbeing – using hospital anxiety and depression scale (HADS) and inflammatory bowel disease – fatigue (IBD-F) questionnaire. The patients were evaluated at 3 consecutive visits at week 0, 6 and 10. During the first visit, the patients were consulted by a nutritionist to adjust their diets, received written recommendations and were able to contact the nutritionist later. At every visit HADS, IBD-F scores, and BMI, pMS and FC were registered. The ND score was calculated as described by Bjørnarå et al., 2015. Patients were considered compliant if the ND score increased by at least 2 points and unhealthy snacks were absent or almost excluded. Related samples Wilcoxon signed rank test and independent samples Kruskal-Wallis test were used to assess statistical significance. The ND score was described as low (0–3), medium (4–5) or high (6–10). Results The characteristics of all patients are summarised in Table 1. One patient had mild exacerbation of UC during the study managed with increased dose of mesalamine. Changes of the ND score (Fig.1) differed significantly in visit 2 (p=0.01). After exclusion of non-compliant patients, the data of 8 patients was analysed. The pMS, FC, HADS, IBD-F (level and impact) did not show significant changes at visit 2. BMI was significantly reduced at visit 2 (p=0.018), median at visit 1 was 28.55 (IQR: 24.16 – 32), visit 2 - 27.65 (23.2 – 30.16) kg/m2. We also found lower FC levels in patients with high ND score, but the difference was not statistically significant (Fig. 2). No significant differences were found regarding the psycho-emotional wellbeing but the impact of fatigue on everyday life was higher in low ND score group (Fig. 3). Conclusion We were not able to show improved FC nor psycho-emotional symptoms after 6 weeks of the ND. The adherence decreased after visit 2, therefore another consultation with the nutritionist could be beneficial to improve the understanding and motivation of the patients. Compliance with the ND reduced BMI and high adherence might be associated with lower FC levels. Further studies with larger patient groups would improve reliability of the results. This pilot study is part of the project financed by BIOCODEX MICROBIOTA FOUNDATION 2020.

Retrospective investigation of mesalamine intolerance in patients with ulcerative colitis.

Mesalamine is a key drug in the treatment of ulcerative colitis (UC) for both induction and maintenance therapy. On the other hand, it is known that there are some cases of mesalamine intolerance that are difficult to distinguish from symptoms due to aggravation of UC. The aim of this study is to investigate the clinical characteristic of mesalamine intolerance in UC. A retrospective, observational study was conducted. We enrolled 31 patients who were diagnosed as mesalamine intolerance between April 2015 to March 2020. We examined clinical features, time to onset, drug types of mesalamine, DLST positive rate, colonoscopy findings, disease activity, and clinical course after diagnosis. The average dose of mesalamine was 3.69 g and DLST-positive was 57.1%. Within the first 2 weeks from the start of mesalamine, 51.6% showed symptoms of intolerance. The serum CRP level was relatively high at ≥10.0 mg/dl in 53.6% of the cases. There was no difference in clinical background, symptoms, or laboratory findings between patients with DLST-positive and negative. In this study, we clarified the clinical characteristics of mesalamine intolerant patients, and found no difference in the clinical background or success rate of desensitization therapy between positive and negative DLST cases.

Novel Bioenhanced Curcumin With Mesalamine for Induction of Clinical and Endoscopic Remission in Mild-to-Moderate Ulcerative Colitis: A Randomized Double-Blind Placebo-controlled Pilot Study.

The aim of this study was to assess the efficacy and safety of a novel, hydrophilic, bioenhanced curcumin (BEC) as add-on therapy in inducing clinical and endoscopic remission in mild to moderately active ulcerative colitis (UC). Mild to moderately active UC patients (partial Mayo score 2 to 6 with endoscopic Mayo score >1) on standard dose of mesalamine were randomized to either 50 mg twice daily BEC or an identical placebo. Clinical response (≥2 reduction of partial Mayo score), clinical remission (partial Mayo score ≤1), and endoscopic remission (endoscopic Mayo score of ≤1) were evaluated at 6 weeks and 3 months. Responders were followed-up at 6 and 12 months for assessing maintenance of remission. Sixty-nine patients were randomly assigned to BEC (n=34) and placebo (n=35). At 6 weeks, clinical and endoscopic remission occurred in 44.1% (15/34) and 35.3% (14/34) patients, respectively, compared with none in the placebo group (P<0.01). Clinical response was also significantly higher in the BEC group (18/34, 52.9%) compared with placebo (5/35, 14.3%) (P=0.001). The clinical remission, clinical response, and endoscopic remission rates at 3 months were 55.9% (19/34), 58.8% (20/34), 44% (16/34) and 5.7% (2/35), 28.6% (10/35), 5.7% (2/35) in BEC and placebo groups, respectively. At 6 and 12 months, 95% (18/19) and 84% (16/19) of the responders to BEC maintained clinical remission. None of the responders to placebo maintained clinical remission at 6 months. BEC appeared safe with no significant side effects. A low-dose BEC as add-on therapy was superior to placebo in inducing sustained clinical and endoscopic remission in patients with mild-to-moderately active UC on maximal dose of mesalamine (ClinicalTrials.gov: NCT02683733).

P735 Comparative assessment of probiotics and standard therapies for mild to moderate ulcerative colitis: A systematic review and network meta-analysis

Abstract Background We performed a systematic review and network meta-analysis to compare probiotics to current therapies in the induction and maintenance of remission in ulcerative colitis (UC). Methods We systematically searched Medline, Embase, CENTRAL up to November 2018. We included randomised controlled trials (RCTs) in patients with mild to moderate UC that compared probiotics, sulfasalazine, mesalamine (low dose &amp;lt;2 g/day, standard dose ≥ 2 g/day), olsalazine, balsalazide, budesonide, budesonide MMX and beclomethasone either alone or in combination with topical therapy, to each other or placebo. We excluded trials where &amp;lt;50% of the population had extensive or left-sided colitis. Outcomes were remission (induction studies), relapse (maintenance studies) and discontinuation due to adverse events (tolerability). We conducted random-effects network meta-analysis and ranked treatments based on the surface under the cumulative ranking (SUCRA) probabilities. Results Forty-eight trials (probiotics 6 trials) of induction therapy and 30 trials (probiotics 6 trials) of maintenance therapy were included in the analysis. In studies with probiotics concomitant treatment, mainly mesalamine, were allowed. At induction, probiotics were not superior to placebo (OR 1.43; 95%CI 0.84–2.42) and they were inferior to combined oral and topical mesalamine therapy (OR 0.28; 95%CI 0.12–0.66) and combined mesalamine and beclomethasone therapy (OR 0.27; 95%CI 0.09–0.83). On SUCRA analysis, combination therapies (SUCRA 0.92 and 0.93) were ranked the highest followed by balsalazide (SUCRA 0.71), budesonide ΜΜΧ (SUCRA 0.68), standard dose mesalamine (SUCRA 0.52), beclomethasone (SUCRA 0.50), olsalazine (SUCRA 0.41), probiotics (SUCRA 0.29), low dose mesalamine (SUCRA 0.26) and sulfasalazine (SUCRA 0.23) in terms of inducing remission. Probiotics were well tolerated. At maintenance, probiotics (OR 0.35; 95%CI 0.19–0.62) and their combination with mesalamine (OR 0.38; 95%CI 0.15–0.99) had lower rate of relapse compared with placebo, but there were no differences when compared with other treatments. On SUCRA analysis, probiotics either alone or combined with mesalamine had comparable SUCRA values to standard dose mesalamine (SUCRA 0.59) and sulfasalazine (SUCRA 0.68). The combination of oral and rectal mesalamine was superior to placebo (OR 0.10; 95%CI 0.04–0.26) and all other treatments and it was ranked highest (SUCRA 0.99). Probiotics were ranked the best tolerated option in terms of discontinuation due to adverse events (SUCRA 0.80). Conclusion Probiotics are well tolerated but they are not effective in inducing remission in active UC. They may be effective when added to mesalamine therapy in preventing relapse of quiescent UC, but large, well-designed RCTs are needed.

2053 Mesalamine-Induced Myocarditis in a Patient With Newly Diagnosed IBD

INTRODUCTION: Mesalamine, a 5-ASA agent, is used as first line treatment in mild to moderate IBD. Adverse reactions include GI symptoms and often do not require discontinuation of therapy. Inflammation of the myocardium (myocarditis) is a rare but potentially lethal complication of mesalamine treatment. Early recognition and intervention is vital to prevent progression of inflammation and adverse patient outcomes. CASE DESCRIPTION/METHODS: A 62-year-old woman presented with an 8 month history of GI symptoms. Colonoscopy demonstrated patchy colonic inflammation which was biopsy confirmed. She was treated with mesalamine 500 mg PO OD. At a 6-week follow up visit, she had mild dyspnea and chest discomfort, but a direct causal relationship with mesalamine was not delineated. Due to persistent GI symptoms, her mesalamine dose was increased to 2 g PO BID. After 9 days her cardiorespiratory symptoms worsened. She was advised to discontinue mesalamine and seek emergency care. She was admitted to the CCU where an echocardiogram demonstrated an EF of 15%. Ischemic heart disease was ruled out with cardiac catheterization. Cardiac MRI was consistent with myocarditis. She was started on prednisone 20 mg OD. Following discontinuation of mesalamine with prednisone treatment, her cardiorespiratory symptoms improved. Follow-up echocardiogram showed minimal improvement (EF 20%). DISCUSSION: Mesalamine associated myocarditis is a rare phenomenon that presents 2-4 weeks after initiation of therapy. It is associated with severe clinical sequelae including myocardial dysfunction and death. Early case reports suspected the cause was the sulfapyridine group of sulfasalazine. There have been subsequent case reports of myocarditis from 5-ASA alone. The mechanism is believed to be a hypersensitivity reaction rather than direct cardiotoxicity. Supporting this theory are reports of return of symptoms when a 5-ASA agent is reintroduced. Clinical presentation is variable, and patients may present with normal laboratory and imaging studies. Myocarditis can rarely represent an extra intestinal manifestation of IBD. The improvement of this patient’s symptoms with discontinuation of mesalamine, and the temporal relationship between symptom onset and initiation of mesalamine favors mesalamine induced myocarditis. Given the significant consequences of this rare adverse reaction, dyspnea and chest discomfort in a patient on mesalamine should evoke prompt and permanent discontinuation of the drug. Delayed recognition can lead to patient morbidity.

Oral 5-aminosalicylic acid for maintenance of surgically-induced remission in Crohn's disease.

Background The prevention of relapse is a major issue in the management of Crohn's disease. Corticosteroids, the mainstay of treatment of acute exacerbations, are not effective for maintenance of remission and its chronic use is limited by numerous adverse events. Randomised controlled trials assessing the efficacy of oral 5-aminosalicylic acid (5-ASA) agents for maintenance of medically-induced remission in Crohn's disease have produced conflicting results. Objectives To conduct a systematic review to evaluate the efficacy and safety of oral 5-ASA agents for the maintenance of medically-induced remission in Crohn's disease. Search methods We searched MEDLINE, EMBASE, CENTRAL and the IBD Group Specialized Register from inception to 8 June 2016. We also searched reference lists and conference proceedings. Selection criteria We included randomised controlled trials that compared oral 5-ASA agents to either placebo or sulphasalazine in patients with quiescent Crohn's disease. The trials had to have a treatment duration of at least six months. Data collection and analysis Two authors independently extracted data and performed the risk of bias assessment. Any disagreements were resolved by discussion and consensus. The primary outcome measure was the occurrence of relapse as defined by the primary studies. Secondary outcomes included time to relapse, adverse events, withdrawal due to adverse events and serious adverse events. We calculated the pooled risk ratio (RR) and corresponding 95% confidence interval (95% CI) using a fixed-effect model. All data were analysed on an intention-to-treat basis and drop-outs were considered to be relapses. Sensitivity analyses included an available case analysis where drop-outs were ignored and using a random-effects model. We evaluated the overall quality of the evidence supporting the outcomes using the GRADE criteria. Main results Twelve studies (2146 participants) that compared 5-ASA to placebo were included. We did not identify any studies that compared sulphasalazine to placebo. Seven studies were judged to be at low risk of bias. The other studies were judged to have an unclear risk of bias for various items due to insufficient details to allow for a judgement. There was no statistically significant difference in relapse rates at 12 months. Fifty-three per cent (526/998) of 5-ASA patients (dose 1.6 g to 4 g/day) relapsed at 12 months compared to 54% (544/1016) of placebo patients (RR 0.98, 95% CI 0.91 to 1.07; 11 studies; 2014 patients; moderate-quality evidence). Sensitivity analyses based on an available case analysis and a random-effects model had no impact on the results. One study found no difference in relapse rates at 24 months. Fifty-four per cent (31/57) of 5-ASA patients (dose 2 g/day) relapsed at 24 months compared to 58% (36/62) of placebo patients (RR 0.94, 95% CI 0.68 to 1.29, 119 patients; low-quality evidence). One paediatric study found no statistically significant difference in relapse rates at 12 months. Sixty-two per cent (29/47) of paediatric 5-ASA patients (dose 50 mg/kg/day) relapsed at 12 months compared to 64% (35/55) of paediatric placebo patients (RR 0.97, 95% CI 0.72 to 1.31; 102 patients; moderate-quality evidence). There was no statistically significant difference in the proportion of patients who experienced an adverse event, withdrawal due to adverse events or serious adverse events. Thirty-four per cent (307/900) of 5-ASA patients had at least one adverse event compared to 33% (301/914) of placebo patients (RR 1.05, 95% CI 0.95 to 1.17; 10 studies; 1814 patients). Fourteen per cent (127/917) of 5-ASA patients withdrew due to adverse events compared to 13% (119/916) of placebo patients (RR 1.11, 95% CI 0.88 to 1.38; 9 studies; 1833 patients). One per cent (3/293) of 5-ASA patients had a serious adverse event compared to 0.7% (2/283) of placebo patients (RR 1.43, 95% CI 0.24 to 2.83; 3 studies; 576 patients). Common adverse events reported in the studies included diarrhoea, nausea and vomiting, abdominal pain, headache and skin rash. Authors' conclusions We found no evidence in this review to suggest that oral 5-ASA preparations are superior to placebo for the maintenance of medically-induced remission in patients with Crohn's disease. Additional randomised trials may not be justified.

Endoscopic Remission of Ulceratie Pancolitis Induced by Qing-Dai After Biologic Therapy Failure

Introduction: Advancements in treatment of inflammatory bowel disease have provided remission for many patients who previously suffered on prolonged courses of steroids. Even with new biologic and small molecule agents, patients are still wary about these medications due to concerns over infection or malignancy. In cases where mesalamine have failed, patients can explore alternative medicines in hopes of avoiding these ‘stronger’ medications. Qing-Dai, also known as indigo naturalis, is a herbal medication prescribed in China for ulcerative colitis. The exact mechanism of how Qing-Dai promotes mucosal healing is unknown. There is limited data on the use of this herbal medication in the United States, especially patients who failed biologic therapy. We present a case of a patient who discontinued adalimumab due to persistent symptoms and started Qing-Dai with clinical and endoscopic remission. Case Description: 31 y/o M with a history of ulcerative pancolitis previously treated with maximum dose mesalamine without significant improvement. He was subsequently started on adalimumab and had partial response after induction that was lost even on weekly dosing of 80 mg. His initial colonoscopy showed Mayo 2 pancolitis and repeat colonoscopies during this time continued to show active disease (Image 1). The patient reports that out of frustration and due to concerns over long term biologic therapy, he discontinued adalimumab on his own and researched alternative treatments. He then started taking Qing-Dai 2 grams daily along with mesalamine 4.8 gram daily. He noticed symptomatic improvement over the course of the first week (going from 5-6 intermittently blood stools to 1-2 formed BMs/day). He presented for a scheduled colonoscopy three months later and revealed this change in regimen. Colonoscopy revealed no evidence of disease activity and biopsies showed mild architectural distortion (Image 2). Patient reports no other dietary or medication changes except the exchange of Qing-Dai for adalimumab.Discussion: Presented here is a patient who started alternative therapy (Qing-Dai) with disease that was not responding to increased doses of adalimumab and mesalamine. While the mechanism of his treatment failure for adalimumab is unclear, the clinical and endoscopic improvement on Qing-Dai compared to prior scopes is noteworthy. The safety profile of Qing-Dai (especially with concurrent mesalamine) is not well known and requires further investigation.2068_A Figure 1. Colonoscopy prior to initiation of Qing-dai supplementation. Patient on mesalamine and biologics for greater than 1 year at this point with continued symptoms.2068_B Figure 2. Colonoscopy 3 months after patient discontinued biologic therapy and started Qing-dai supplement in addition to mesalamine.

Clinical Vignettes/Case Reports - Inflammatory Bowel Disease.

Mesalamine (5-aminosalycilic acid) is a first line anti-inflammatory agent used for treatment of inflammatory bowel disease. Mesalamine is thought to reduce colonic inflammation by inhibiting the cyclooxygenase pathway and the γ-form of peroxisomal proliferator-activated receptors (PPAR-γ) signaling pathway. A 30-year-old male with a medical history significant for ulcerative colitis diagnosed 1 year prior, presented with chest pain, fever, chills, and generalized weakness. His symptoms began spontaneously six hours prior to coming to the Emergency room. The patient described a localized chest pain to his mid-sternum, that was sharp, non-radiating, and unalleviated by over-the-counter analgesics. He denied pleurisy, shortness of breath, diaphoresis, palpitations. His chest pain resolved after aspirin 325 mg and 0.5 inch topical nitroglycerin at the emergency department. The patient gave a history of starting budesonide 9 mg QD and an increase in his mesalamine dose from 800 mg to 1600 mg TID, 6 weeks prior. These medication regimen change occurred after an ulcerative colitis flair which developed after the patient had stopped taking his mesalamine for 2 weeks. His initial electrocardiogram showed normal variant study. Chest xray was negative. The case was discussed with his primary gastroenterologist and on-call cardiologist. Considering the strong association of the patients' recent symptoms with increase in his mesalamine dose, only budesonide was continued at admission. Subsequently, TEE showed grade II left ventricular dysfunction and left ventricular ejection fraction of 61 %. After thorough clinical evaluation, the patient was diagnosed with mesalamine-induced-myocarditis, and cardiac catherization was deferred, with recommendations for supportive care. Mesalamine induced-myocarditis is rare. The exact mechanism of which is unclear, but is thought to be secondary to a hypersensitivity reaction rather than direct myocardiotoxicity. This ideology of hypersensitivity myocarditis is supported by cases of acute recurrence of pleuropericarditis with re-exposure to mesalamine. Mesalamine-induced myocarditis has been associated with chronic use, often more than not with a recent increase in dosage in patients who are also concomitantly taking steroids as exemplified in our case. We hope that this report will further increase the awareness of prescribers to myocarditis caused by an increased dosage of mesalamine and with its chronic use.

Comparative Effectiveness of Mesalamine, Sulfasalazine, Corticosteroids, and Budesonide for the Induction of Remission in Crohn's Disease: A Bayesian Network Meta-analysis: Republished.

Induction treatment of mild-to-moderate Crohn's disease is controversial. To compare the induction of remission between different doses of mesalamine, sulfasalazine, corticosteroids, and budesonide for active Crohn's disease. We identified randomized controlled trials from existing Cochrane reviews and an updated literature search in Medline, EMBASE, and CENTRAL to November 2015. We included randomized controlled trials (n = 22) in adult patients with Crohn's disease that compared budesonide, sulfasalazine, mesalamine, or corticosteroids with placebo or each other, for the induction of remission (8-17 wks). Mesalamine (above and below 2.4 g/d) and budesonide (above and below 6 mg/d) were stratified into low and high doses. Our primary outcome was remission, defined as a Crohn's Disease Activity Index score <150. A Bayesian random-effects network meta-analysis was performed on the proportion in remission. Corticosteroids (odds ratio [OR] = 3.64; 95% credible interval [CrI]: 2.16-6.19), high-dose budesonide (OR = 2.99; 95% CrI: 1.83-4.90), and high-dose mesalamine (OR = 1.87; 95% CrI: 1.14-3.15) were superior to placebo. Corticosteroids were similar to high-dose budesonide (OR = 1.21; 95% CrI: 0.79-1.89), but more effective than high-dose mesalamine (OR = 1.95; 95% CrI: 1.14-3.25). Sulfasalazine was not significantly superior to any therapy including placebo. Randomized controlled trials that use a strict definition of induction of remission and disease severity at enrollment to assess effectiveness in treating mild-to-moderate Crohn's disease are limited. Corticosteroids and high-dose budesonide were effective treatments for inducing remission in mild-to-moderate Crohn's disease. High-dose mesalamine maybe an option among patients preferring to avoid steroids.

Comparative Effectiveness of Mesalamine, Sulfasalazine, Corticosteroids, and Budesonide for the Induction of Remission in Crohn's Disease: A Bayesian Network Meta-analysis.

Induction treatment of mild-to-moderate Crohn's disease is controversial. To compare the induction of remission between different doses of mesalamine, sulfasalazine, corticosteroids, and budesonide for active Crohn's disease. We identified randomized controlled trials from existing Cochrane reviews and an updated literature search in Medline, EMBASE, and CENTRAL to November 2015. We included randomized controlled trials (n = 22) in adult patients with Crohn's disease that compared budesonide, sulfasalazine, mesalamine, or corticosteroids with placebo or each other, for the induction of remission (8-17 wks). Mesalamine (above and below 2.4 g/d) and budesonide (above and below 6 mg/d) were stratified into low and high doses. Our primary outcome was remission, defined as a Crohn's Disease Activity Index score <150. A Bayesian random-effects network meta-analysis was performed on the proportion in remission. Corticosteroids (odds ratio [OR] = 3.80; 95% credible interval [CrI]: 2.48-5.66), high-dose budesonide (OR = 2.96; 95% CrI: 2.06-4.30), and high-dose mesalamine (OR = 2.29; 95% CrI: 1.58-3.33) were superior to placebo. Corticosteroids were similar to high-dose budesonide (OR = 1.21; 95% CrI: 0.84-1.76), but more effective than high-dose mesalamine (OR = 1.83; 95% CrI: 1.16-2.88). Sulfasalazine was not significantly superior to any therapy including placebo. Randomized controlled trials that use a strict definition of induction of remission and disease severity at enrollment to assess effectiveness in treating mild-to-moderate Crohn's disease are limited. Corticosteroids and high-dose budesonide were effective treatments for inducing remission in mild-to-moderate Crohn's disease. High-dose mesalamine is an option among patients preferring to avoid steroids.

A Novel Two Day Desensitization Protocol to Oral Mesalamine

Ulcerative proctosigmoiditis is a chronic inflammatory condition that is initially treated with mesalamine, a preferred treatment to steroids and immunomodulators. Hypersensitivity reactions to mesalamine have been reported and a limited number of desensitization protocols have been published taking between 3 days to weeks. We present a case of a patient with ulcerative proctosigmoiditis and aspirin allergy with adverse reactions to mesalamine who failed an oral mesalamine challenge. She subsequently underwent successful mesalamine desensitization with a rapid 2 day protocol. The desensitization took place in the intensive care unit. The starting dose of mesalamine was 1mg. On day 1, incremental doses were given every 30 minutes up to 500mg. On day 2, the patient received a total of 2.5 grams of mesalamine, which was her targeted daily dose. The patient was successfully desensitized after 2 days with one hypersensitivity reaction. She developed mild shortness of breath with a drop in FEV1 from 450 to 350 on day 1 of the desensitization, which resolved with nebulized albuterol and fexofenadine. Since discharge from the hospital, she continued mesalamine 2.4 grams daily without adverse reactions. This case demonstrates a patient with mesalamine hypersensitivity can be safely offered a rapid 2 day oral desensitization protocol, and maintained on the medication for long term management of ulcerative proctosigmoiditis.

Aminosalicylates for induction of remission or response in Crohn's disease.

Aminosalicylates for induction of remission or response in Crohn's disease.

Casein glycomacropeptide for active distal ulcerative colitis: a randomized pilot study.

In ulcerative colitis (UC), dietary supplements may have anti-inflammatory properties and improve disease course. We investigated the effects of casein glycomacropeptide (CGMP), a fraction of bovine whey protein, in active UC. In a randomized open-label intervention study, 24 patients with active UC involving 10-40cm of the distal colon were randomized in a 2:1 ratio into two groups. The first group was administered their usual treatment plus a daily supplement of CGMP 30g, and the second group was administered a dose escalation to 4800mg oral mesalamine daily (standard treatment) for 4weeks. Clinical, endoscopic, mucosal and circulating disease activity markers were monitored. Acceptance of and adherence to CGMP up to 8weeks were documented. After 4weeks of treatment, 10 of 16 (63%) patients who received CGMP had an unchanged or decreased Simple Clinical Colitis Activity Index (SCCAI), which was similar to the four of eight (50%) (P=0·67) patients on the standard treatment. The number of patients in which SCCAI decreased by three or more did not differ between the two groups: nine of 16 (56%) in the CGMP group vs. four of eight (50%) in the standard treatment group (P=0·77). Changes in disease extent and severity were similar between the two groups. CGMP was well tolerated and accepted by the patients. The addition of CGMP as a nutritional therapy to standard treatment was safe and accepted by patients with active distal UC. The disease-modifying effect of CGMP was similar to that of the mesalamine dose escalation.

Efficacy and safety of two pH-dependent-release mesalamine doses in moderately active ulcerative colitis: a multicenter, randomized, double-blind, parallel-group study.

Background/AimsThe therapeutic effect of mesalamine is considered to be dose-dependent; however, no consensus has been reached regarding the optimal doses for individual patients. This study aimed to provide new insight for dose optimization using two doses of pH-dependent release mesalamine for induction of remission of moderately active ulcerative colitis (UC).MethodsIn a multicenter, double-blind, randomized study, 110 patients with moderately active UC were assigned to two groups after treatment with a constant dose of mesalamine. Fifty-five patients were treated with a pH-dependent release formulation of 3.6 or 4.8 g/day for 8 weeks. The primary endpoint was a decrease in the UC disease activity index (UCDAI) adjusted by covariates.ResultsIn the full analysis set (n=110), the mean decrease in UCDAI was 3.1 in the 3.6 g/day group and 3.4 in the 4.8 g/day group (P>0.05). In a subgroup analysis, the effectiveness of the 4.8 g/day dose was greater in particular populations, such as those who had been previously treated with a lower dose of mesalamine and those with more severe disease. The safety was comparable between the two groups.ConclusionsThe results suggest that treatment with pH-dependent release mesalamine at either 3.6 or 4.8 g/day was effective and safe for the induction of remission in patients with moderately active UC. However, the patients receiving mesalamine at 2.4 g/day but in whom the therapeutic effect is not sufficient and having more severe symptoms (UCDAI 9-10), benefit from higher doses of mesalamine compared to others.

Pulmonary Manifestations of Inflammatory Bowel Disease (IBD) in Patients With Late-Onset IBD

Background: pulmonary manifestations are uncommon in IBD. We report 3 different pulmonary manifestations in patients with late onset IBD to show that they may be more prone to pulmonary complications. Patient #1: A 45 year old male developed frequent loose stools with streaks of blood. Colonoscopy demonstrated diffuse colitis extending from the distal colon to the distal ascending colon. Biopsy demonstrated chronic active colitis with extensive ulceration and inflammation. The patient was diagnosed with Ulcerative Colitis and started Mesalamine. Over a 3 month period the patients symptoms continue to worsen despite increased doses of Mesalamine and a trial of oral corticosteroids. The patient was started Azathioprine. Two weeks later the patient presented for dyspnea and was diagnosed with a pulmonary embolus. He was discharged from the hospital on Warfarin. He continued Warfarin therapy for 12 months with no further reported evidence of thrombus formation. Patient # 2: A 71 year old male developed hematochezia. 71. A flexible sigmoidoscopy demonstrated ulcerated mucosa concerning for IBD. He was started on mesalamine for 3 months without benefit, so it was stopped. He then developed a perianal fistula, requiring fistulotomy 14 months later. Colonoscopy showed segmental colitis in the sigmoid. The patient developed dyspnea and was referred to the pulmonary clinic. Pulmonary function tests showed mild restrictive disease and a CT chest showed bibasilar and right middle lobe honeycombing. The patient remained off medications for colitis and had spontaneous symptomatic improvement of his shortness of breath. A chest x-ray 16 months later showed no evidence of interstitial disease. Patient #3: A 51 year old male, with ulcerative colitis, was on prednisone and mesalamine for approximately for 7 years with good control. Because of a flare he was started on azathioprine, but developed fever and dyspnea. A chest x-ray showed bibasilar consolidation and a CT chest showed extensive ground glass opacities bilaterally in the upper lobes. He underwent broncho-alveolar lavage (BAL) and transbronchial biopsies. The BAL cultures showed Staph aureus without symptoms; the transbronchial biopsies showed cryptogenic organizing pneumonia. Azathioprine was stopped, prednisone and mesalamine were continued. Prednisone was tapered and follow up CT chest showed a near resolution of his organizing pneumonia Discussion: Patients #1 and #2 developed pulmonary symptoms close to diagnosis. Patient #3 developed symptoms nearly 7 years after diagnosis, during a flare. These cases demonstrate the importance of looking for pulmonary symptoms in older patients diagnosed with IBD, especially during onset and acute flares.

862 A Randomized Controlled Trial of Mesalamine Dose Escalation for Ulcerative Colitis in Remission

marker levels included sex and inflammation. Phase 2: Among 10 BE cases and 10 controls, median age was 64 (59-70) and 66 (49, 71) and men comprised 80 and 30% respectively. Median BE length was 2 cm (range 1-4). Discrimination of BE by markers was extraordinary with AUC of 1.0 for NDRG4 and 0.99 for BMP3; levels were >100 times higher in cases than controls (Figure). Conclusions: Selected methylated DNA markers highly discriminate BE from normal GC and SE, both in biopsy and brushed specimens, and hold promise for non-endoscopic screening applications. Further research and development are warranted. Table 1

Mesalamine Dose Escalation Reduces Fecal Calprotectin in Patients With Quiescent Ulcerative Colitis

Among patients with quiescent ulcerative colitis (UC), lower fecal concentrations of calprotectin are associated with lower rates of relapse. We performed an open-label, randomized controlled trial to investigate whether increasing doses of mesalamine reduce concentrations of fecal calprotectin (FC) in patients with quiescent UC. We screened 119 patients with UC in remission on the basis of Simple Clinical Colitis Activity Index scores, FC >50 μg/g, and intake of no more than 3 g/day mesalamine. Participants taking mesalamine formulations other than multimatrix mesalamine were switched to multimatrix mesalamine (2.4 g/day) for 6 weeks; 52 participants were then randomly assigned (1:1) to a group that continued its current dose of mesalamine (controls, n= 26) or a group that increased its dose by 2.4 g/day for 6 weeks (n= 26). The primary outcome was continued remission with FC <50 μg/g. Secondary outcomes were continued remission with FC <100 μg/g or <200 μg/g (among patients with pre-randomization values above these levels). The primary outcome was achieved by 3.8% of controls and 26.9% of the dose escalation group (P= .0496). More patients in the dose escalation group reduced FC to below 100 μg/g (P= .04) and 200 μg/g (P= .005). Among the patients who were still in remission after the randomization phase, clinical relapse occurred sooner in patients with FC >200 μg/g compared with those with FC <200 μg/g (P= .01). Among patients with quiescent UC and increased levels of FC, increasing the dose of mesalamine by 2.4 g/day reduced fecal concentrations of calprotectin to those associated with lower rates of relapse. Clinicaltrials.gov number: NCT00652145.

Antibiotics, probiotics and prebiotics in IBD.

The dysbiosis theory of inflammatory bowel disease (IBD) posits that there is an alteration in the gut microbiome as an important underpinning of disease etiology. It stands to reason then, that administering agents that could impact on the balance of microbes on the gut could be impactful on the course of IBD. Herein is a review of the controlled trials undertaken to assess the use of antibiotics that would kill or suppress potentially injurious microbes, probiotics that would overpopulate the gut with potentially beneficial microbes or prebiotics that provide a metabolic substrate that enhances the growth of potentially beneficial microbes. With regard to antibiotics, the best data are for the use of nitroimadoles postoperatively in Crohn's disease (CD) to prevent disease recurrence. Otherwise, the data are limited with the regard to any lasting benefit of antibiotics sustaining remission in either CD or ulcerative colitis (UC). A recent meta-analysis concluded that antibiotics are superior to placebo at inducing remission in CD or UC, although the meta-analysis grouped a variety of antibiotics with different spectra of activity. Despite the absence of robust clinical trial data, antibiotics are widely used to treat perineal fistulizing CD and acute and chronic pouchitis. Probiotics have not been shown to have a beneficial role in CD. However, Escherichia coli Nissle 1917 has comparable effects to low doses of mesalamine in maintaining remission in UC. VSL#3, a combination of 8 microbes, has been shown to have an effect in inducing remission in UC and preventing pouchitis. Prebiotics have yet to be shown to have an effect in any form of IBD, but to date controlled trials have been small. The use of antibiotics should be balanced against the risks they pose. Even probiotics may pose some risk and should not be assumed to be innocuous especially when ingested by persons with a compromised epithelial barrier. Prebiotics may not be harmful but may cause gastrointestinal side effects. Finally, the timing of ingestion of antibiotics and other dietary factors that may function as prebiotics, especially in early childhood, may be critical in shaping the gut microbiome and ultimately predisposing to or preventing IBD. Finding ways to impact on the gut microbiome to alter the course of IBD makes good sense, but should be undertaken in the setting of rigorously performed controlled trials to ensure that the interventions are truly effective and well tolerated.

Long-Term Mesalamine Maintenance in Ulcerative Colitis

There are limited data about the long-term follow-up of patients with ulcerative colitis (UC) maintained on high versus low doses of mesalamine. We evaluated the best long-term average daily dose that would keep the disease in remission. Nationwide ulcerative colitis data were obtained from the Veterans Affairs health care system for the period 2001 to 2011. Those who started mesalamine maintenance during this period were included. Average daily dose and the level of adherence were assessed for the period between the first mesalamine dispense and the date of first flare defined as the first filling of 40 mg/day or more of oral prednisone or any dose of intravenous steroids. Patients with ulcerative colitis maintained on an average daily dose 2.4 to 2.8 g/day (low dose) were compared with 4.4 to 4.8 g/day (high dose). Adherence was assessed using continuous single interval medication availability indicator. We included 4452 patients with a median follow-up of 6 years. There was no significant reduction in the risk of flares when comparing high versus low average mesalamine dose among patients with high [hazard ratio = 0.96, P = 0.8)] and medium (hazard ratio = 0.74, P = 0.17) adherence. However, there was a significant reduction in the risk of flares with high dose of mesalamine among patients with low adherence (hazard ratio = 0.28, P = 0.003). Our data show that when starting a patient on mesalamine, there is no difference in the long-term flare risk between low versus high average daily dose as long as the patients have a high to moderate level of adherence.

Tu1122 Optimal Dosing of Mesalamine for Maintenance of Clinical Remission in Patients With Distal Ulcerative Colitis and Residual Endoscopic Activity: A Subgroup Analysis of a Double-Blind, Double-Dummy, Randomized, Controlled, Dose-Ranging Study

Introduction: Proctosigmoiditis is the most frequent phenotype of ulcerative colitis (UC). Recently, it has been shown that 3 g oral mesalamine (Salofalk® granules) once daily (OD) showed higher rates for maintaining remission compared to lower doses of mesalamine, especially in patients with residual signs of endoscopic inflammatory activity at the start of the treatment.1 But, whether patients with proctosigmoiditis and residual endoscopic inflammation might profit from a higher dose is unclear. Aims: To study optimal dosing of mesalamine for maintenance of remission in proctosigmoiditis with residual endoscopic activity at the start of treatment. Methods: This was a stratified subgroup analysis of a double-blind, double-dummy, randomized, multicenter, comparative phase III study, in which the clinical outcome (i.e., clinical remission at wk 52) was analyzed in patients with proctosigmoiditis according to the presence of residual endoscopic inflammation at the start of maintenance treatment. Patients with active UCwho had recently achieved clinical (Clinical Activity Index [CAI] ,= 4) and an endoscopic index (EI) ,= 3 were randomized to mesalamine (Salofalk® granules) 3g OD, 1.5g OD, or 0.5g TID for 12 months. Remission at study end was defined as a CAI of ,= 4 with no increase of .=3 points from baseline. Results: A total of 647 patients who came into remission within the last 12 weeks prior to baseline were randomized and treated; 217 patients with 3g OD, 212 with 1.5g OD, and 218 with 0.5g TID mesalamine. All three treatment regimens were efficacious in maintaining clinical remission of UC over 1 year. A subgroup analysis in patients with vs. without residual mucosal damage showed that 3g OD performed best in the subgroup with residual inflammation at start of treatment. A further subgroup analysis of patients with residual mucosal damage according to extent of UC revealed that 3g OD performed best independently from the extent (see table below). Conclusions: A dosage of 3g mesalamine (Salofalk® granules) once daily showed the best efficacy for prevention of relapse in UC compared to a daily dose of 1.5g mesalamine, especially in patients with residual signs of inflammation, even in the distal colon. Reference: (1) Kruis W, Jonaitis L, Pokrotnieks J, Mikhailova TL, Horynski M, Batovsky M, et al. Aliment Pharmacol Ther. 2011;33(3):313-22. Support: Dr. Falk Pharma GmbH, Freiburg, Germany Clinical remission by mucosal damage and extent of mucosal damage (ITT):