Maintenance Of Remission In Ulcerative Colitis Research Articles

Fecal transplantation for treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic, relapsing disease of the gastrointestinal (GI) tract that is thought to be associated with a complex interplay between the immune system, the GI tract lining, the environment, and the gut microbiome, leading to an abnormal inflammatory response in genetically susceptible individuals. An altered composition of the gut's native microbiota, known as dysbiosis, may have a major role in the pathogenesis of ulcerative colitis (UC) and Crohn disease (CD), two subtypes of IBD. There is growing interest in the correction of this underlying dysbiosis using fecal microbiota transplantation (FMT). To evaluate the benefits and safety profile of FMT for treatment of IBD in adults and children versus autologous FMT, placebo, standard medication, or no intervention. We searched CENTRAL, MEDLINE, Embase, two clinical trial registries, and the reference sections of published trials through 22 December 2022. We included randomized controlled trials that studied adults and children with UC or CD. Eligible intervention arms used FMT, defined as the delivery of healthy donor stool containing gut microbiota to a recipient's GI tract, to treat UC or CD. Two review authors independently screened studies for inclusion. Our primary outcomes were: 1. induction of clinical remission, 2. maintenance of clinical remission, and 3. serious adverse events. Our secondary outcomes were: 4. any adverse events, 5. endoscopic remission, 6. quality of life, 7. clinical response, 8. endoscopic response, 9. withdrawals, 10. inflammatory markers, and 11. microbiome outcomes. We used the GRADE approach to assess the certainty of evidence. We included 12 studies with 550 participants. Three studies were conducted in Australia; two in Canada; and one in each of the following: China, the Czech Republic, France, India, the Netherlands, and the USA. One study was conducted in both Israel and Italy. FMT was administered in the form of capsules or suspensions and delivered by mouth, nasoduodenal tube, enema, or colonoscopy. One study delivered FMT by both oral capsules and colonoscopy. Six studies were at overall low risk of bias, while the others had either unclear or high risk of bias. Ten studies with 468 participants, of which nine studies focused on adults and one focused on children, reported induction of clinical remission in people with UC at longest follow-up (range 6 to 12 weeks) and showed that FMT may increase rates of induction of clinical remission in UC compared to control (risk ratio (RR) 1.79, 95% confidence interval (CI) 1.13 to 2.84; low-certainty evidence). Five studies showed that FMT may increase rates of induction of endoscopic remission in UC at longest follow-up (range 8 to 12 weeks); however, the CIs around the summary estimate were wide and included a possible null effect (RR 1.45, 95% CI 0.64 to 3.29; low-certainty evidence). Nine studies with 417 participants showed that FMT may result in little to no difference in rates of any adverse events (RR 0.99, 95% CI 0.85 to 1.16; low-certainty evidence). The evidence was very uncertain about the risk of serious adverse events (RR 1.77, 95% CI 0.88 to 3.55; very low-certainty evidence) and improvement in quality of life (mean difference (MD) 15.34, 95% CI -3.84 to 34.52; very low-certainty evidence) when FMT was used to induce remission in UC. Two studies, of which one also contributed data for induction of remission in active UC, assessed maintenance of remission in people with controlled UC at longest follow-up (range 48 to 56 weeks). The evidence was very uncertain about the use of FMT for maintenance of clinical remission (RR 2.97, 95% CI 0.26 to 34.42; very low-certainty evidence) and endoscopic remission (RR 3.28, 95% CI 0.73 to 14.74; very low-certainty evidence). The evidence was also very uncertain about the risk of serious adverse events, risk of any adverse events, and improvement in quality of life when FMT was used to maintain remission in UC. None of the included studies assessed use of FMT for induction of remission in people with CD. One study with 21 participants reported data on FMT for maintenance of remission in people with CD. The evidence was very uncertain about the use of FMT for maintenance of clinical remission in CD at 24 weeks (RR 1.21, 95% CI 0.36 to 4.14; very low-certainty evidence). The evidence was also very uncertain about the risk of serious or any adverse events when FMT was used to maintain remission in CD. None of the studies reported data on use of FMT for maintenance of endoscopic remission or improvement in quality of life in people with CD. FMT may increase the proportion of people with active UC who achieve clinical and endoscopic remission. The evidence was very uncertain about whether use of FMT in people with active UC impacted the risk of serious adverse events or improvement in quality of life. The evidence was also very uncertain about the use of FMT for maintenance of remission in people with UC, as well as induction and maintenance of remission in people with CD, and no conclusive statements could be made in this regard. Further studies are needed to address the beneficial effects and safety profile of FMT in adults and children with active UC and CD, as well as its potential to promote longer-term maintenance of remission in UC and CD.

Tofacitinib and newer JAK inhibitors in inflammatory bowel disease-where we are and where we are going.

Inflammatory bowel diseases, comprising ulcerative colitis (UC) and Crohn’s disease, are chronic, immune-mediated and progressive inflammatory disorders affecting the gastrointestinal tract. Tofacitinib is the first oral small-molecule Janus kinase (JAK) inhibitor licensed and approved by the National Institute for Health and Care Excellence (NICE) for use in moderately-to-severely active UC after intolerance, inadequate response, or loss of response to conventional treatment or biologic therapy. The pivotal OCTAVE studies demonstrated the efficacy and safety of tofacitinib for the induction and maintenance of remission in UC. A growing body of evidence from real-world data supports the positive clinical and endoscopic benefits observed with tofacitinib treatment in the OCTAVE trials. This narrative review summarizes the current literature regarding the mechanism of action of tofacitinib, data from registrational trials, emerging real-world evidence, and an overview of the most recent safety evidence. We explore evolving treatment paradigms, including the use of tofacitinib in the COVID-19 era, pregnancy and extraintestinal manifestations, as well as the emerging concept of combining tofacitinib with biological therapy. We will also present a brief overview of the next generation of JAK inhibitors in the pipeline.

Influence of Corticosteroid Use on Short- and Long-Term Outcomes of Biologic Therapy for Inflammatory Bowel Diseases.

Corticosteroids (CS) are widely used to treat Crohn's disease (CD) and ulcerative colitis (UC), but are not recommended as maintenance therapy. Biologic drugs are widely used as an alternative to or in conjunction with CS to induce and maintain remission. This meta-analysis tested the hypothesis that CS use is associated with differential response to biologics. We identified published placebo-controlled clinical trials of biologic drugs approved for the treatment of CD or UC. Pooled estimates of the risk difference (RD) and 95% confidence intervals were derived from random effects models for induction of response and remission and maintenance of remission comparing biologic with CS versus biologic alone. Heterogeneity of response was estimated using I2. Fifteen studies met the inclusion criteria. Pooled estimates of the RD and I2 comparing biologic plus CS versus biologic alone were as follows: induction of UC response 0.15 (0.05, 0.25), I2 = 57.29% and CD response 0.02 (- 0.03, 0.06), I2 = 0.01%; induction of UC remission 0.03 (- 0.01, 0.08), I2 = 0.00% and CD remission 0.08(0.02, 0.14), I2 = 7.81%; and maintenance of UC remission - 0.06 (- 0.13, 0.01), I2 = 0.00% and CD remission - 0.06 (- 0.14, 0.03), I2 = 11.24%. Patients in the placebo arm of CD trials who were receiving CS were less likely to achieve remission during the induction phase (pooled RD - 0.05 (- 0.09, - 0.00), I2 = 0.00%). In this meta-analysis of placebo-controlled trials, CS use was associated with higher biologic response rates for UC and remission rates for CD during the induction phase, but were not associated with improved maintenance of remission.

Long-term, Real-life, Observational Study in Treating Outpatient Ulcerative Colitis with Golimumab

Several studies have found Golimumab (GOL) effective and safe in the short-term treatment of ulcerative colitis (UC), but few long-term data are currently available from real world. Our aim was to assess the long-term real-life efficacy and safety of GOL in managing UC outpatients in Italy. A retrospective multicenter study assessing consecutive UC outpatients treated with GOL for at least 3-month of follow-up was made. Primary endpoints were the induction and maintenance of remission in UC, defined as Mayo score ≤2. Several secondary endpoints, including clinical response, colectomy rate, steroid free remission and mucosal healing, were also assessed during the follow-up. One hundred and seventy-eight patients were enrolled and followed up for a median (IQR) time of 9 (3-18) months (mean time follow-up: 33.1±13 months). Clinical remission was achieved in 57 (32.1%) patients: these patients continued with GOL, but only 6 patients (3.4%) were still under clinical remission with GOL at the 42nd month of follow-up. Clinical response occurred in 64 (36.4%) patients; colectomy was performed in 8 (7.8%) patients, all of them having primary failure. Steroid-free remission occurred in 23 (12.9%) patients, and mucosal healing was achieved in 29/89 (32.6%) patients. Adverse events occurred in 14 (7.9%) patients. Golimumab does not seem able to maintain long-term remission in UC in real life. The safety profile was good.

Treatment of inflammatory bowel diseases: focusing on 5-aminosalicylates and immunomodulators

Background: Recently, the incidence and prevalence rates of inflammatory bowel disease (IBD) have increased worldwide, including in Korea. Although there has been considerable progress in the management of IBD following the discovery of biologic agents, 5-aminosalicylate (5-ASA) and immunomodulators are still considered cornerstones in the management of mild to moderate IBD.Current Concepts: 5-ASA plays a key role in inducing remission in patients with mild to moderate ulcerative colitis. High doses of 5-ASA are more effective in inducing remission in patients with moderate ulcerative colitis, and combination therapy of oral 5-ASA and topical 5-ASA agents is recommended. Although the effect of 5-ASA in patients with Crohn disease is limited, high doses of 5-ASA can be effective for patients with mild disease, inflammatory behavior, and colonic involvement. Maintaining remission is essential for patients with IBD. Good doctor-patient relationships and encouraging drug adherence are recommended. Regarding drug adherence, a once-daily regimen is preferred for patients’ satisfaction. Thiopurines, the most important immunomodulators, show therapeutic benefits, such as steroid-sparing effects and remission maintenance in ulcerative colitis and Crohn disease after induction therapy. However, several side effects, including severe leukopenia, can induce the discontinuation of thiopurines. Close monitoring and management decisions should be individualized according to the risk of relapse and adverse events.Discussion and Conclusion: In conclusion, 5-ASA and immunomodulators are cornerstones in the management of IBD. As such, clinicians should have knowledge of these drugs and patients’ characteristics for proper prescription.

A ‘real‐world’ retrospective multi‐centre cohort study comparing infliximab and adalimumab for the maintenance of remission in ulcerative colitis

Background Anti-tumour necrosis factor therapy is an established treatment for moderate-to-severely active ulcerative colitis (UC). Recent network meta-analyses of controlled trial data have indicated a superiority of intravenous drugs (infliximab) over subcutaneous (adalimumab). We conducted a retrospective multi-centre cohort study to determine the comparative effectiveness of these two drugs. Methods Patients with UC administered infliximab or adalimumab as their first biologic, identified from the therapy databases of five UK hospitals, were included, if they had completed induction and were on maintenance treatment. Patients receiving infliximab as ‘rescue’ therapy for acute severe UC were excluded. The primary end-points for comparison were the number of patients remaining on initial therapy (infliximab or adalimumab) at 52 weeks and the number of patients in clinical remission at 52 weeks (Simple Clinical Colitis Activity [SCCAI] score ≤ 3). Results Seventy-eight infliximab and 63 adalimumab patients were analysed. At 52 weeks, 83% of infliximab patients and 59% of adalimumab patients remained on therapy (P = 0.001). At 52 weeks, 62% of the infliximab group were in clinical remission compared to 32% of the adalimumab group (P = 0.0004). Primary non-response was reported in 24% of adalimumab patients and 5% of infliximab patients (P = 0.001). There were no significant differences in colectomy rates or hospital admission for acute flares at 52 weeks. Conclusions Our real-world results affirm the findings of network meta-analyses of clinical trials, suggesting that infliximab is superior to adalimumab in the maintenance of remission in UC up to 52 weeks.

Prebiotics and Probiotics in Inflammatory Bowel Disease: Where are we now and where are we going?

The incidence, prevalence, and cost of care associated with diagnosis and management of inflammatory bowel disease are on the rise. The role of gut microbiota in the causation of Crohn's disease and ulcerative colitis has not been established yet. Nevertheless, several animal models and human studies point towards the association. Targeting intestinal dysbiosis for remission induction, maintenance, and relapse prevention is an attractive treatment approach with minimal adverse effects. However, the data is still conflicting. The purpose of this article is to provide the most comprehensive and updated review on the utility of prebiotics and probiotics in the management of active Crohn's disease and ulcerative colitis/pouchitis and their role in the remission induction, maintenance, and relapse prevention. A thorough literature review was performed on PubMed, Ovid Medline, and EMBASE using the terms "prebiotics AND ulcerative colitis", "probiotics AND ulcerative colitis", "prebiotics AND Crohn's disease", "probiotics AND Crohn's disease", "probiotics AND acute pouchitis", "probiotics AND chronic pouchitis" and "prebiotics AND pouchitis". Observational studies and clinical trials conducted on humans and published in the English language were included. A total of 71 clinical trials evaluating the utility of prebiotics and probiotics in the management of inflammatory bowel disease were reviewed and the findings were summarized. Most of these studies on probiotics evaluated lactobacillus, De Simone Formulation or Escherichia coli Nissle 1917 and there is some evidence supporting these agents for induction and maintenance of remission in ulcerative colitis and prevention of pouchitis relapse with minimal adverse effects. The efficacy of prebiotics such as fructooligosaccharides and Plantago ovata seeds in ulcerative colitis are inconclusive and the data regarding the utility of prebiotics in pouchitis is limited. The results of the clinical trials for remission induction and maintenance in active Crohn's disease or post-operative relapse with probiotics and prebiotics are inadequate and not very convincing. Prebiotics and probiotics are safe, effective and have great therapeutic potential. However, better designed clinical trials in the multicenter setting with a large sample and long duration of intervention are needed to identify the specific strain or combination of probiotics and prebiotics which will be more beneficial and effective in patients with inflammatory bowel disease.

P002 The use of probiotics in the maintenance of remission in ulcerative colitis: A systematic review

BACKGROUND: Ulcerative colitis (UC) is a chronic relapsing disease characterised by diffuse mucosal inflammation limited to the colon. Current maintenance treatments have multiple adverse events and an effective treatment with minimal adverse events is desired. Several studies have demonstrated the importance of intestinal flora in the pathogenesis of ulcerative colitis. It has been suggested that modifying the bacteria flora with probiotics may attenuate the inflammatory process and prevent relapses in UC. METHODS: Data extraction and risk of bias assessment of included studies were independently performed by 2 authors, data was analysed using Review Manager 5.3, dichotomous and continuous outcomes were expressed as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). The certainty of evidence was assessed using GRADE methodology. RESULTS: Eleven studies (1,204 randomised participants) met the inclusion criteria. The studies compared probiotics to placebo, probiotics to 5-ASA and a combination of probiotics and 5-ASA to 5-ASA. The risk of bias was high in all except 3 studies due to selective reporting, incomplete outcome data and lack of blinding, this results in low to very low rating of the quality of the evidence. There is no clear difference in relapse when probiotics are compared with placebo (RR, 0.86; 95% CI, 0.71–1.04; 341 participants, 5 studies; low quality of evidence). There is no clear difference in maintenance of remission when probiotics are compared with 5-ASA (RR, 1.05; 95% CI, 0.89–1.24; 122 participants; 2 studies; low quality of evidence). There is no clear difference in maintenance of remission when probiotics coupled with—ASA are compared to 5-ASA alone (RR, 1.49; 95% CI, 0.86–2.57; 92 participants; 2 studies; very low quality evidence). CONCLUSION(S): Given the limited data and high risk of bias in the included studies, there is insufficient evidence to make conclusion about the efficacy of probiotics for maintenance of remission in UC. This is based on low to very low quality of evidence. This review highlights the need for further well-designed randomised controlled trials (RCT) to investigate the above objective. Future research should focus on comparing probiotics with 5-ASA as this will reflect clinical practise, patients are unlikely to not be on any treatment to maintain remission. Additionally, length of follow up of most studies in this review is much less than other published reviews, studies looking at 12 months or less are simply too limited in their usefulness to clinical practise. Overall this is the second review for the above objective and it is surprising to see that similar issues exist that did in the first review such as small participants numbers. The issues highlighted in this review should be taken into account for any authors that wish to produce well-designed RTCS looking at the usefulness of probiotics for patients with UC. Some staff received funding from NIHR Cochrane programme.

P053 TARGETED RELEASE ORAL CYCLOSPORINE FORMULATION AS A POTENTIAL NEW THERAPY FOR ULCERATIVE COLITIS

Ulcerative colitis (UC) is a chronic inflammatory disease of the colonic mucosa. Infliximab has long been a standard therapy for moderate to severe UC. IV followed by oral cyclosporine (CsA) has demonstrated similar safety and efficacy to infliximab for the treatment of acute UC; however, prolonged use for the maintenance of remission is limited due to concerns about side effects of systemically available CsA. There remains a need for an oral CsA therapy that controls UC disease activity while minimizing systemic exposure. ST-0529 is a novel, orally administrated, solubilized CsA formulation designed to optimize the delivery of drug to colonic tissue while minimizing systemic absorption. To characterize the whole blood pharmacokinetics of ST-0529 following single and multiple oral doses (ODs), and compare to the pharmacokinetic profile following CsA IV infusion in healthy male subjects. To establish CsA colonic mucosa concentrations following single or twice-daily (BID) ODs and various dosage regimens of ST-0529 for seven days, comparing them to CsA continuous IV infusion. In Stage 1, a total of 24 eligible healthy male subjects received either 2 mg/kg/day of IV CsA over two consecutive 12-hour infusions (per protocol) and a once- or a twice-daily ODs of 75 mg ST-0529 for seven days. The protocol allowed to conduct further investigations with alternative ST-0529 doses and dose frequencies after review of Stage 1 data. Following this review, eight subjects recruited to Stage 2 received 37.5mg ST-0529 once-daily orally for seven days. A further eight subjects recruited to Stage 3 received 150mg ST-0529 BID ODs for seven days. Single dose systemic exposure to CsA was considerably lower (~5%) following treatment with ST-0529 ranging from 37.5 mg to 300 mg daily for seven days compared with 24-hour continuous IV 2 mg/kg/day infusion. All ST-0529 dosage groups tested achieved colon tissue concentrations comparable to or above that attained during IV CsA administration with the 75 mg BID and 150 mg BID groups sustaining the minimum tissue concentrations achieved following IV infusion and being substantially higher than that achieved by 37.5 mg OD and 75 mg OD groups. A total of 26 subjects (54.2%) reported treatment-emergent adverse events (TEAEs) during the study. All were mild or moderate; there were no severe TEAEs reported. The study demonstrated ST-0529 achieved similar or higher colonic tissue concentrations than continuous IV CsA infusion with substantially lower systemic exposure. These data suggest that ST-0529 may provide similar or enhanced efficacy to IV or oral CsA formulations with an improved tolerance profile and thus support further development as a treatment for the induction and maintenance of remission in UC. Mean CsA concentrations and AEs Mean CsA concentrations and AEs

Fecal transplantation for treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic, relapsing disease of the gastrointestinal tract that is thought to be associated with a complex interplay between microbes and the immune system, leading to an abnormal inflammatory response in genetically susceptible individuals. Dysbiosis, characterized by the alteration of the composition of the resident commensal bacteria in a host compared to healthy individuals, is thought to play a major role in the pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD), two subtypes of IBD. There is growing interest to correct the underlying dysbiosis through the use of fecal microbiota transplantation (FMT) for the treatment of IBD. The objective of this systematic review was to assess the efficacy and safety of FMT for the treatment of IBD. We searched the MEDLINE, Embase, Cochrane Library, and Cochrane IBD Group Specialized Register databases from inception to 19 March 2018. We also searched ClinicalTrials.gov, ISRCTN metaRegister of Controlled Trials, and the Conference Proceedings Citation Index. Only randomized trials or non-randomized studies with a control arm were considered for inclusion. Adults or pediatric participants with UC or CD were eligible for inclusion. Eligible interventions were FMT defined as the administration of fecal material containing distal gut microbiota from a healthy donor to the gastrointestinal tract of a someone with UC or CD. The comparison group included participants who did not receive FMT and were given placebo, autologous FMT, or no intervention. Two authors independently screened the titles and extracted data from the included studies. We used the Cochrane risk of bias tool to assess study bias. The primary outcomes were induction of clinical remission, clinical relapse, and serious adverse events. Secondary outcomes included clinical response, endoscopic remission and endoscopic response, quality of life scores, laboratory measures of inflammation, withdrawals, and microbiome outcomes. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes and the mean difference and 95% CI for continuous outcomes. Random-effects meta-analysis models were used to synthesize effect sizes across trials. The overall certainty of the evidence supporting the primary and selected secondary outcomes was rated using the GRADE criteria. Four studies with a total of 277 participants were included. These studies assessed the efficacy of FMT for treatment of UC in adults; no eligible trials were found for the treatment of CD. Most participants had mild to moderate UC. Two studies were conducted in Australia, one study was conducted in Canada, and another in the Netherlands. Three of the included studies administered FMT via the rectal route and one study administered FMT via the nasoduodenal route. Three studies were rated as low risk of bias. One study (abstract publication) was rated as unclear risk of bias. Combined results from four studies (277 participants) suggest that FMT increases rates of clinical remission by two-fold in patients with UC compared to controls. At 8 weeks, 37% (52/140) of FMT participants achieved remission compared to 18% (24/137) of control participants (RR 2.03, 95 % CI, 1.07 to 3.86; I² = 50%; low certainty evidence). One study reported data on relapse at 12 weeks among participants who achieved remission. None of the FMT participants (0/7) relapsed at 12 weeks compared to 20% of control participants (RR 0.28, 95% CI 0.02 to 4.98, 17 participants, very low certainty evidence). It is unclear whether there is a difference in serious adverse event rates between the intervention and control groups. Seven per cent (10/140) of FMT participants had a serious adverse event compared to 5% (7/137) of control participants (RR 1.40, 95% CI 0.55 to 3.58; 4 studies; I² = 0%; low certainty evidence). Serious adverse events included worsening of UC necessitating intravenous steroids or surgery; infection such as Clostridium difficile and cytomegalovirus, small bowel perforation and pneumonia. Adverse events were reported by two studies and the pooled data did not show any difference between the study groups. Seventy-eight per cent (50/64) of FMT participants had an adverse event compared to 75% (49/65) of control participants (RR 1.03, 95% CI 0.81 to 1.31; I² = 31%; moderate certainty evidence). Common adverse events included abdominal pain, nausea, flatulence, bloating, upper respiratory tract infection, headaches, dizziness, and fever. Four studies reported on clinical response at 8 weeks. Forty-nine per cent (68/140) of FMT participants had a clinical response compared to 28% (38/137) of control participants (RR 1.70, 95% CI 0.98 to 2.95, I² = 50%, low certainty evidence). Endoscopic remission at 8 weeks was reported by three studies and the combined results favored FMT over the control group. Thirty per cent (35/117) of FMT participants achieved endoscopic remission compared to 10% (11/112) of control participants (RR 2.96, 95 % CI 1.60 to 5.48, I² = 0%; low certainty evidence). Fecal microbiota transplantation may increase the proportion of participants achieving clinical remission in UC. However, the number of identified studies was small and the quality of evidence was low. There is uncertainty about the rate of serious adverse events. As a result, no solid conclusions can be drawn at this time. Additional high-quality studies are needed to further define the optimal parameters of FMT in terms of route, frequency, volume, preparation, type of donor and the type and disease severity. No studies assessed efficacy of FMT for induction of remission in CD or in pediatric participants. In addition, no studies assessed long-term maintenance of remission in UC or CD. Future studies are needed to address the therapeutic benefit of FMT in CD and the long-term FMT-mediated maintenance of remission in UC or CD.

Cannabis for the treatment of ulcerative colitis.

Cannabis and cannabinoids are often promoted as treatment for many illnesses and are widely used among patients with ulcerative colitis (UC). Few studies have evaluated the use of these agents in UC. Further, cannabis has potential for adverse events and the long-term consequences of cannabis and cannabinoid use in UC are unknown. To assess the efficacy and safety of cannabis and cannabinoids for the treatment of patients with UC. We searched MEDLINE, Embase, WHO ICTRP, AMED, PsychINFO, the Cochrane IBD Group Specialized Register, CENTRAL, ClinicalTrials.Gov and the European Clinical Trials Register from inception to 2 January 2018. Conference abstracts and references were searched to identify additional studies. Randomized controlled trials (RCTs) comparing any form or dose of cannabis or its cannabinoid derivatives (natural or synthetic) to placebo or an active therapy for adults (> 18 years) with UC were included. Two authors independently screened search results, extracted data and assessed bias using the Cochrane risk of bias tool. The primary outcomes were clinical remission and relapse (as defined by the primary studies). Secondary outcomes included clinical response, endoscopic remission, endoscopic response, histological response, quality of life, C-reactive protein (CRP) and fecal calprotectin measurements, symptom improvement, adverse events, serious adverse events, withdrawal due to adverse events, psychotropic adverse events, and cannabis dependence and withdrawal effects. We calculated the risk ratio (RR) and corresponding 95% confidence interval for dichotomous outcomes. For continuous outcomes, we calculated the mean difference (MD) and corresponding 95% CI. Data were pooled for analysis when the interventions, patient groups and outcomes were sufficiently similar (determined by consensus). Data were analyzed on an intention-to-treat basis. GRADE was used to evaluate the overall certainty of evidence. Two RCTs (92 participants) met the inclusion criteria. One study (N = 60) compared 10 weeks of cannabidiol capsules with up to 4.7% D9-tetrahydrocannabinol (THC) with placebo capsules in participants with mild to moderate UC. The starting dose of cannabidiol was 50 mg twice daily increasing to 250 mg twice daily if tolerated. Another study (N = 32) compared 8 weeks of therapy with two cannabis cigarettes per day containing 0.5 g of cannabis, corresponding to 23 mg THC/day to placebo cigarettes in participants with UC who did not respond to conventional medical treatment. No studies were identified that assessed cannabis therapy in quiescent UC. The first study was rated as low risk of bias and the second study (published as an abstract) was rated as high risk of bias for blinding of participants and personnel. The studies were not pooled due to differences in the interventional drug.The effect of cannabidiol capsules (100 mg to 500 mg daily) compared to placebo on clinical remission and response is uncertain. Clinical remission at 10 weeks was achieved by 24% (7/29) of the cannabidiol group compared to 26% (8/31) in the placebo group (RR 0.94, 95% CI 0.39 to 2.25; low certainty evidence). Clinical response at 10 weeks was achieved in 31% (9/29) of cannabidiol participants compared to 22% (7/31) of placebo patients (RR 1.37, 95% CI 0.59 to 3.21; low certainty evidence). Serum CRP levels were similar in both groups after 10 weeks of therapy. The mean CRP in the cannabidiol group was 9.428 mg/L compared to 7.638 mg/L in the placebo group (MD 1.79, 95% CI -5.67 to 9.25; moderate certainty evidence). There may be a clinically meaningful improvement in quality of life at 10 weeks, measured with the IBDQ scale (MD 17.4, 95% CI -3.45 to 38.25; moderate certainty evidence). Adverse events were more frequent in cannabidiol participants compared to placebo. One hundred per cent (29/29) of cannabidiol participants had an adverse event, compared to 77% (24/31) of placebo participants (RR 1.28, 95% CI 1.05 to1.56; moderate certainty evidence). However, these adverse events were considered to be mild or moderate in severity. Common adverse events included dizziness, disturbance in attention, headache, nausea and fatigue. None (0/29) of the cannabidiol participants had a serious adverse event compared to 13% (4/31) of placebo participants (RR 0.12, 95% CI 0.01 to 2.11; low certainty evidence). Serious adverse events in the placebo group included worsening of UC and one complicated pregnancy. These serious adverse events were thought to be unrelated to the study drug. More participants in the cannabidiol group withdrew due to an adverse event than placebo participants. Thirty-four per cent (10/29) of cannabidiol participants withdrew due to an adverse event compared to 16% (5/31) of placebo participants (RR 2.14, 95% CI 0.83 to 5.51; low certainty evidence). Withdrawls in the cannabidiol group were mostly due to dizziness. Withdrawals in the placebo group were due to worsening UC.The effect of cannabis cigarettes (23 mg THC/day) compared to placebo on mean disease activity, CRP levels and mean fecal calprotectin levels is uncertain. After 8 weeks, the mean disease activity index score in cannabis participants was 4 compared with 8 in placebo participants (MD -4.00, 95% CI -5.98 to -2.02). After 8 weeks, the mean change in CRP levels was similar in both groups (MD -0.30, 95% CI -1.35 to 0.75; low certainty evidence). The mean fecal calprotectin level in cannabis participants was 115 mg/dl compared to 229 mg/dl in placebo participants (MD -114.00, 95% CI -246.01 to 18.01). No serious adverse events were observed. This study did not report on clinical remission, clinical response, quality of life, adverse events or withdrawal due to adverse events. The effects of cannabis and cannabidiol on UC are uncertain, thus no firm conclusions regarding the efficacy and safety of cannabis or cannabidiol in adults with active UC can be drawn.There is no evidence for cannabis or cannabinoid use for maintenance of remission in UC. Further studies with a larger number of patients are required to assess the effects of cannabis in UC patients with active and quiescent disease. Different doses of cannabis and routes of administration should be investigated. Lastly, follow-up is needed to assess the long term safety outcomes of frequent cannabis use.

Ethnic and Demographic Differences in Colectomy Rates and Timing for Ulcerative Colitis: 2007-2014

Introduction: Ulcerative Colitis (UC) is a chronic inflammatory disease of the bowel, with one third of patients requiring a colectomy for fulminant disease and tissue dysplasia. In 2007, infliximab was approved for induction and maintenance of remission in UC, with some evidence to suggest a potential reduction in colectomies. The aim of this study is to examine relative colectomy rates for UC among different ethnicities from 2007 to 2014 in order to evaluate for development of new trends or disparities. Methods: The data source was the NIS database, from 2007 to 2014. Patients aged 5 years and older with a primary diagnosis of UC were used. Additional variables included race, age, gender, insurance coverage, region, hospital teaching status, hospital size, elective admission status, and zip code income quartile. Odds ratios for colectomy were calculated via logistic regression. Negative binomial regression modeling was used to observe associations between variables and time to colectomy. Results: Compared to Whites, the odds ratios of colectomy for Blacks (0.63, 95% C.I. 0.53-0.749, p<0.01), Hispanics (0.729, 95% C.I. 0.630-0.844, p< 0.01), and Asians (0.332, 95% C.I. 0.219-0.504, p< 0.01) were all significantly lower. However, Black (2.024, 95% C.I. 1.614-2.537, p< 0.01), Hispanic (1.295, 95% C.I. 1.078-1.557, p< 0.01), and Asian ethnicity (4.293, 95% C.I. 2.632-7.002, p< 0.01) were associated with increasing time until receipt of colectomy. Private insurance was associated with higher colectomy rates (1.545, 95% C.I. 1.325-1.802, p< 0.01), as was increasing hospital zip code income quartile (1.085, 95% C.I. 1.048-1.124, p< 0.01). Conclusion: Discrepancies in colectomy rates and timing are seen in our models which mirror closely findings in a prior study from 1999-2003 (Nguyen GC, et al. Racial and Geographic Variations in Colectomy Rates Among Hospitalized Ulcerative Colitis Patients. Clinical Gastroenterology and Hepatology 2006; 4: 1507-1513.e1). The consistency between our findings suggests that the availability of infliximab has not altered the relative differences in surgical management of inpatients of different ethnicities with UC flares. Closer study of utilization and response to UC therapy across ethnic and demographic lines is needed to better elucidate whether such practices are based on true phenotypic differences in disease or bias, as it appears white, wealthier patients continue to more readily and rapidly receive colectomies.598_A Figure 1. Number of Colectomies by Variable.598_B Figure 2. Colectomy Odds Ratios.598_C Figure 3. Negative Binomial Regression Analysis for Time to Colectomy.

Effectiveness and safety of adalimumab to treat outpatient ulcerative colitis: A real-life multicenter, observational study in primary inflammatory bowel disease centers.

Adalimumab (ADA) was approved in Italy for the treatment of ulcerative colitis (UC) unresponsive to standard treatments in 2014, but no data from real life are currently available. The aim of the present study was to assess the real-life efficacy and safety of ADA in managing UC outpatients in some Italian primary inflammatory bowel disease (IBD) centers after approval of ADA reimbursement.Consecutive UC outpatients with at least 3-month follow-up were retrospectively evaluated. The primary end point was the induction and maintenance of remission in UC, defined as Mayo score ≤2.One hundred seven patients were included. At 3-month follow-up, obtained in 102 (95.3%) patients, 56 (54.9%) patients achieved a clinical remission. At univariate analysis, both Mayo partial score >7 and Mayo subscore for endoscopy = 3 at entry showed to be significantly associated with the lack of remission induction.During a median (95% confidence interval [CI]) follow-up of 18 (12–24) months, 56.6% of patients were under clinical remission; clinical response was achieved in 89.2% of cases. Mucosal healing was achieved in 66 (76.7%) patients, and colectomy occurred in 3 (2.8%) patients. Both C-reactive protein and fecal calprotectin values significantly decreased during follow-up. Steroids discontinuation occurred in 67 (66.7%) patients, and ADA dose escalation was adopted in 9 (16.1%) patients under remission. No factor was significantly related to the maintenance of clinical remission.This first Italian experience found ADA safe and effective to induce and maintain remission in real-life UC outpatients.

Effectiveness and Safety of Golimumab in Treating Outpatient Ulcerative Colitis: A Real-Life Prospective, Multicentre, Observational Study in Primary Inflammatory Bowel Diseases Centers.

Golimumab (GOL) has been recently approved in Italy for the treatment of ulcerative colitis (UC) unresponsive to standard treatments. Our aims were to assess the real-life efficacy and safety of GOL in managing UC outpatients in Italian primary Inflammatory Bowel Diseases (IBD) centres. Consecutive UC outpatients with at least 3-months follow-up were enrolled. Primary end-point was the induction and maintenance of remission in UC, defined as Mayo score </=2, at 6-month follow-up. Ninety-three patients were enrolled. At 6-month follow-up, remission was obtained in 34 (36.5%) patients. Shorter duration of disease was the only significant predictive factor of remission. Clinical response was achieved in 60 (64.5%) patients, while mucosal healing (MH) was obtained in 18 (19.3%) patients. Sixteen (47.0%) patients under remission were still under therapy with steroids. C-reactive protein and fecal calprotectin significantly dropped during the follow-up (plt;0.001 for both proteins). Adverse events occurred in 4 (4.3%) patients and 3 of them stopped treatment. Colectomy was performed in only one patient (1.1%). Golimumab seems to be safe and effective in inducing and maintaining remission in real life UC outpatients.

Fecal transplantation for treatment of inflammatory bowel disease

Background Inflammatory bowel disease (IBD) is a chronic, relapsing disease of the gastrointestinal tract that is thought to be associated with a complex interplay between microbes and the immune system, leading to an abnormal inflammatory response in genetically susceptible individuals. Dysbiosis, characterized by the alteration of the composition of the resident commensal bacteria in a host compared to healthy individuals, is thought to play a major role in the pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD), two subtypes of IBD. There is growing interest to correct the underlying dysbiosis through the use of fecal microbiota transplantation (FMT) for the treatment of IBD. Objectives The objective of this systematic review was to assess the efficacy and safety of FMT for the treatment of IBD. Search methods We searched the MEDLINE, Embase, Cochrane Library, and Cochrane IBD Group Specialized Register databases from inception to 19 March 2018. We also searched ClinicalTrials.gov, ISRCTN metaRegister of Controlled Trials, and the Conference Proceedings Citation Index. Selection criteria Only randomized trials or non-randomized studies with a control arm were considered for inclusion. Adults or pediatric participants with UC or CD were eligible for inclusion. Eligible interventions were FMT defined as the administration of fecal material containing distal gut microbiota from a healthy donor to the gastrointestinal tract of a someone with UC or CD. The comparison group included participants who did not receive FMT and were given placebo, autologous FMT, or no intervention. Data collection and analysis Two authors independently screened the titles and extracted data from the included studies. We used the Cochrane risk of bias tool to assess study bias. The primary outcomes were induction of clinical remission, clinical relapse, and serious adverse events. Secondary outcomes included clinical response, endoscopic remission and endoscopic response, quality of life scores, laboratory measures of inflammation, withdrawals, and microbiome outcomes. We calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI) for dichotomous outcomes and the mean difference and 95% CI for continuous outcomes. Random-effects meta-analysis models were used to synthesize effect sizes across trials. The overall certainty of the evidence supporting the primary and selected secondary outcomes was rated using the GRADE criteria. Main results Four studies with a total of 277 participants were included. These studies assessed the efficacy of FMT for treatment of UC in adults; no eligible trials were found for the treatment of CD. Most participants had mild to moderate UC. Two studies were conducted in Australia, one study was conducted in Canada, and another in the Netherlands. Three of the included studies administered FMT via the rectal route and one study administered FMT via the nasoduodenal route. Three studies were rated as low risk of bias. One study (abstract publication) was rated as unclear risk of bias. Combined results from four studies (277 participants) suggest that FMT increases rates of clinical remission by two-fold in patients with UC compared to controls. At 8 weeks, 37% (52/140) of FMT participants achieved remission compared to 18% (24/137) of control participants (RR 2.03, 95 % CI, 1.07 to 3.86; I² = 50%; low certainty evidence). One study reported data on relapse at 12 weeks among participants who achieved remission. None of the FMT participants (0/7) relapsed at 12 weeks compared to 20% of control participants (RR 0.28, 95% CI 0.02 to 4.98, 17 participants, very low certainty evidence). It is unclear whether there is a difference in serious adverse event rates between the intervention and control groups. Seven per cent (10/140) of FMT participants had a serious adverse event compared to 5% (7/137) of control participants (RR 1.40, 95% CI 0.55 to 3.58; 4 studies; I² = 0%; low certainty evidence). Serious adverse events included worsening of UC necessitating intravenous steroids or surgery; infection such as Clostridium difficile and cytomegalovirus, small bowel perforation and pneumonia. Adverse events were reported by two studies and the pooled data did not show any difference between the study groups. Seventy-eight per cent (50/64) of FMT participants had an adverse event compared to 75% (49/65) of control participants (RR 1.03, 95% CI 0.81 to 1.31; I² = 31%; moderate certainty evidence). Common adverse events included abdominal pain, nausea, flatulence, bloating, upper respiratory tract infection, headaches, dizziness, and fever. Four studies reported on clinical response at 8 weeks. Forty-nine per cent (68/140) of FMT participants had a clinical response compared to 28% (38/137) of control participants (RR 1.70, 95% CI 0.98 to 2.95, I² = 50%, low certainty evidence). Endoscopic remission at 8 weeks was reported by three studies and the combined results favored FMT over the control group. Thirty per cent (35/117) of FMT participants achieved endoscopic remission compared to 10% (11/112) of control participants (RR 2.96, 95 % CI 1.60 to 5.48, I² = 0%; low certainty evidence). Authors' conclusions Fecal microbiota transplantation may increase the proportion of participants achieving clinical remission in UC. However, the number of identified studies was small and the quality of evidence was low. There is uncertainty about the rate of serious adverse events. As a result, no solid conclusions can be drawn at this time. Additional high-quality studies are needed to further define the optimal parameters of FMT in terms of route, frequency, volume, preparation, type of donor and the type and disease severity. No studies assessed efficacy of FMT for induction of remission in CD or in pediatric participants. In addition, no studies assessed long-term maintenance of remission in UC or CD. Future studies are needed to address the therapeutic benefit of FMT in CD and the long-term FMT-mediated maintenance of remission in UC or CD.

Adherence in ulcerative colitis: an overview.

Medication adherence is an important challenge while treating chronic illnesses, such as ulcerative colitis (UC), that require a long-term management to induce and maintain clinical remission. This review provides an overview of the role that medication adherence plays in the routine management of UC, with a focus on the results of a recent Italian study reporting the perception of patients with UC regarding adherence to treatment. A literature analysis was conducted on topics, such as measurement of adherence in real practice, causes, risk factors and consequences of non-adherence and strategies, to raise patients’ adherence. Most of the data refer to adherence to 5-aminosalicylic acid, and standard of care for the induction and maintenance of remission in UC. The adherence rate to 5-aminosalicylic acid is low in clinical practice, thus resulting in fivefold higher risk of relapse, likely increased risk of colorectal cancer, reduced quality of life and higher health care costs for in- and outpatient settings. There are various causes affecting non-adherence to therapy: forgetfulness, high cost of drugs, lack of understanding of the drug regimen – which are sometimes due to insufficient explanation by the specialist – anxiety created by possible adverse events, lack of confidence in physicians’ judgment and complex dosing regimen. The last aspect negatively influences adherence to medication both in clinical trial settings and in real-world practice. Regarding this feature, mesalamine in once-daily dosage may be preferable to medications with multiple doses per day because the simplification of treatment regimens improves adherence.

P-054 Probiotics for Maintenance of Remission in Ulcerative Colitis

Background: Ulcerative colitis (UC) is a chronic relapsing disease characterised by diffuse mucosal inflammation of the colon. Current maintenance treatments have multiple adverse events and an effective treatment with minimal adverse events is desired. Several studies have demonstrated the importance of intestinal flora in the pathogenesis of ulcerative colitis. It has been suggested that modifying the bacterial flora with probiotics may attenuate the inflammatory process and prevent relapses in ulcerative colitis. Five years ago, a Cochrane review found only 4 studies and no evidence regarding the efficacy of probiotics, but much work has been published in recent years. An up to date Cochrane systematic review was performed to determine the efficacy and safety of probiotics for the maintenance of remission in ulcerative colitis. Methods: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL and the Cochrane Inflammatory Bowel Disease Group Specialised Trial Register were searched (Inception-January 2015). Manufacturers of probiotics were contacted to identify any unpublished trials. References of trials were also searched for any additional trials. Abstracts were considered for inclusion if full details to judge inclusion and risk of bias were offered or available from the authors. Randomised controlled trials (RCTs) that compared probiotics against placebo or any other intervention for the maintenance of remission in ulcerative colitis were eligible for inclusion. Data extraction and assessment of methodological quality of included studies were independently performed by 2 authors. The main outcome measure was the occurrence of clinical or endoscopic relapse. Results: The search yielded 1006 results, with 34 papers screened in full. Seven studies (n = 887) met the inclusion criteria and were included in the review. Four trials compared probiotics to mesalazine and 3 trials compared probiotics with placebo. The studies ranged in length from 3 to 12 months. The risk of bias was low for randomisation and allocation concealment in one study and unclear in the others. One study was open label, the rest rated as low risk for blinding as double-blinded double dummy trials. The risk of bias was high in one study due to incomplete outcome data and 2 studies due to selective reporting, all the remaining studies low risk. There was no statistically significant difference between probiotics and placebo for maintenance of remission in UC, although there were just 2 small studies with 92 participants (Odds Ratio 0.56; 95% CI 0.22-1.40). Meta-analysis of 4 studies (n = 638) found no statistically significant difference between probiotics and mesalazine (OR 1.29; 95% CI 0.92-1.80). There was no statistically significant difference in the incidence of adverse events (OR 1.16; 95% CI 0.79-1.71). Conclusions: There was no statistically significant difference between probiotics and placebo, although there were just 2 small studies in the pooled analysis at some risk of bias. There was no difference in efficacy found between probiotics and mesalazine on pooled analysis and no difference in adverse events. Further research is proposed to investigate the role of probiotics to maintain remission in UC.

Systematic review of randomized controlled trials of probiotics, prebiotics, and synbiotics in inflammatory bowel disease.

BackgroundProbiotics are microorganisms that are ingested either in combination or as a single organism in an effort to normalize intestinal microbiota and potentially improve intestinal barrier function. Recent evidence has suggested that inflammatory bowel disease (IBD) may result from an inappropriate immunologic response to intestinal bacteria and a disruption in the balance of the gastrointestinal microbiota in genetically susceptible individuals. Prebiotics, synbiotics, and probiotics have all been studied with growing interest as adjuncts to standard therapies for IBD. In general, probiotics have been shown to be well-tolerated with few side effects, making them a potential attractive treatment option in the management of IBD.AimTo perform a systematic review of randomized controlled trials on the use of probiotics, prebiotics, and synbiotics in IBD.ResultsIn our systematic review we found 14 studies in patients with Crohn’s disease (CD), 21 studies in patients with ulcerative colitis (UC), and five studies in patients with pouchitis. These were randomized controlled trials using probiotics, prebiotics, and/or synbiotics. In patients with CD, multiple studies comparing probiotics and placebo showed no significant difference in clinical outcomes. Adding a probiotic to conventional treatment improved the overall induction of remission rates among patients with UC. There was also a similar benefit in maintaining remission in UC. Probiotics have also shown some efficacy in the treatment of pouchitis after antibiotic-induced remission.ConclusionsTo date, there is insufficient data to recommend probiotics for use in CD. There is evidence to support the use of probiotics for induction and maintenance of remission in UC and pouchitis. Future quality studies are needed to confirm whether probiotics, prebiotics, and synbiotics have a definite role in induction or maintenance of remission in CD, UC, and pouchitis. Similar to probiotics, fecal microbiota transplantation provides an alternate modality of therapy to treat IBD by influencing the intestinal flora.

Effect of MMX® mesalamine coadministration on the pharmacokinetics of amoxicillin, ciprofloxacin XR, metronidazole, and sulfamethoxazole: results from four randomized clinical trials.

BackgroundMMX® mesalamine is a once daily oral 5-aminosalicylic acid formulation, effective in induction and maintenance of ulcerative colitis remission. Patients on long-term mesalamine maintenance may occasionally require concomitant antibiotic treatment for unrelated infections.AimTo evaluate the potential for pharmacokinetic interactions between MMX mesalamine and amoxicillin, ciprofloxacin extended release (XR), metronidazole, or sulfamethoxazole in four open-label, randomized, placebo-controlled, two-period crossover studies.MethodsIn all four studies, healthy adults received placebo once daily or MMX mesalamine 4.8 g once daily on days 1–4 in one of two treatment sequences. In studies 1 and 2, subjects also received a single dose of amoxicillin 500 mg (N=62) or ciprofloxacin XR 500 mg (N=30) on day 4. In studies 3 and 4, subjects received metronidazole 750 mg twice daily on days 1–3 and once on day 4 (N=30); or sulfamethoxazole 800 mg/trimethoprim 160 mg twice daily on days 1–3 and once on day 4 (N=44).ResultsMMX mesalamine had no significant effects on systemic exposure to amoxicillin, ciprofloxacin, or metronidazole; the 90% confidence intervals (CIs) around the geometric mean ratios (antibiotic + MMX mesalamine: antibiotic + placebo) for maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) fell within the predefined equivalence range (0.80–1.25). Sulfamethoxazole exposure increased by a statistically significant amount when coadministered with MMX mesalamine; however, increased exposure (by 12% in Cmax at steady state; by 15% in AUC at steady state) was not considered clinically significant, as the 90% CIs for each point estimate fell entirely within the predefined equivalence range. Adverse events in all studies were generally mild.ConclusionMMX mesalamine may be coadministered with amoxicillin, ciprofloxacin, metronidazole, or sulfamethoxazole, without affecting pharmacokinetics or safety of these antibiotics.ClinicalTrials.gov identifiersNCT01442688, NCT01402947, NCT01418365, and NCT01469637.

Probiotic treatments for induction and maintenance of remission in inflammatory bowel diseases: a meta-analysis of randomized controlled trials.

Probiotics have been used for the treatment of inflammatory bowel diseases (IBD). However, the effects of probiotics on the induction and maintenance of remission in ulcerative colitis (UC) or Crohn's disease (CD) still remain controversial. This systematic review verified the findings of high-quality randomized controlled trials (RCTs) which investigated the therapeutic effects of probiotics on IBD. After the quality assessment, 20 RCTs which investigated the effects of probiotics on the induction or maintenance of remission in IBD were identified. From the results of the validation of these RCTs, beneficial effects of probiotic treatments to improve the response rate and remission rate on the remission induction therapies [risk ratio (RR) 1.81; 95 % confidence interval (CI) 1.40-2.35 and RR 1.56; 95 % CI 0.95-2.56, respectively] were verified. Furthermore, probiotic treatments exhibited effects equal to mesalazine on the maintenance of remission in UC (RR 1.00; 95 % CI 0.79-1.26). In contrast, no significant effect of probiotic treatments was shown in either the induction or maintenance of remission in CD. Because there were many variations in the conditions among these studies, a further analysis evaluating the effects of probiotic treatments in IBD is needed to clarify the optimal probiotics and treatment regimens for each condition or population in IBD patients.