Development and validation of a nomogram to predict non-response to 5-aminosalicylic acid in patients with ulcerative colitis

Background: there are some patients with ulcerative colitis (UC) who have non-response (NR) to 5-aminosalicylic acid (5-ASA). To promote individualized treatment in UC patients, it is crucial to identify valid predictors to estimate NR to 5-ASA. Therefore, this study aimed to identify the predictive value of clinical and biochemical markers and to construct a nomogram model predicting NR to 5-ASA in patients with UC. Methods: data of patients diagnosed with UC in the First Hospital of China Medical University between January 2012 and December 2020 were retrospectively analyzed. Primary outcome was the proportion of NR to 5-ASA. Multivariable logistic regression was used to construct prediction models. Area under the curve (AUC), calibration and decision curve analyses (DCA) were assessed in the validation cohort. Results: of 284 UC patients who were treatment-naive, 86 (30.3 %) had NR to 5-ASA. Univariate regression analysis showed that disease classification (DC) (p = 0.008), monocytes (MONO) (p = 0.041), platelet distribution width (PDW) (p = 0.027), serum total cholesterol (TC) (p = 0.031) and α1 globulin (p < 0.001) were strongly associated with NR to 5-ASA. Receiver operating characteristics (ROC) analysis indicated the AUC was 0.852, it showed that this model has a good degree of discrimination. The DCA curve showed that the predicted probability is 0.0-96.0 %. Conclusion: this study developed a predictive model with good discrimination and calibration, and high clinical validity, which can effectively estimate the risk of NR to 5-ASA. DC, MONO, PDW, TC and α1 globulin can be used as predictors for NR to 5-ASA in UC patients. (AU)

Molecular mechanism of the TGF­ß/Smad7 signaling pathway in ulcerative colitis.

Aberrant TGF­ß/Smad7 signaling has been reported to be an important mechanism underlying the pathogenesis of ulcerative colitis. Therefore, the present study aimed to investigate the effects of a number of potential anti­colitis agents on intestinal epithelial permeability and the TGF­ß/Smad7 signaling pathway in an experimental model of colitis. A mouse model of colitis was first established before anti­TNF­α and 5­aminosalicyclic acid (5­ASA) were administered intraperitoneally and orally, respectively. Myeloperoxidase (MPO) activity, histological index (HI) of the colon and the disease activity index (DAI) scores were then detected in each mouse. Transmission electron microscopy (TEM), immunohistochemical and functional tests, including Evans blue (EB) and FITC­dextran (FD­4) staining, were used to evaluate intestinal mucosal permeability. The expression of epithelial phenotype markers E­cadherin, occludin, zona occludens (ZO­1), TGF­ß and Smad7 were measured. In addition, epithelial myosin light chain kinase (MLCK) expression and activity were measured. Anti­TNF­α and 5­ASA treatments was both found to effectively reduce the DAI score and HI, whilst decreasing colonic MPO activity, plasma levels of FD­4 and EB permeation of the intestine. Furthermore, anti­TNF­α and 5­ASA treatments decreased MLCK expression and activity, reduced the expression of Smad7 in the small intestine epithelium, but increased the expression of TGF­ß. In mice with colitis, TEM revealed partial epithelial injury in the ileum, where the number of intercellular tight junctions and the expression levels of E­cadherin, ZO­1 and occludin were decreased, all of which were alleviated by anti­TNF­α and 5­ASA treatment. In conclusion, anti­TNF­α and 5­ASA both exerted protective effects on intestinal epithelial permeability in an experimental mouse model of colitis. The underlying mechanism may be mediated at least in part by the increase in TGF­ß expression and/or the reduction in Smad7 expression, which can inhibit epithelial MLCK activity and in turn reduce mucosal permeability during the pathogenesis of ulcerative colitis.

5­Aminosalicylic acid attenuates paraquat­induced lung fibroblast activation and pulmonary fibrosis of rats.

Pulmonary fibrosis is one of the most important pathological processes associated with paraquat (PQ) poisoning. 5­Aminosalicylic acid (5­ASA) has been shown to be a promising agent against fibrotic diseases. In the present study, the alleviating role of 5­ASA was evaluated in a rat model of pulmonary fibrosis induced by PQ intragastric poisoning (80 mg/kg). Wistar rats were divided into control, PQ, 5­ASA (30 mg/kg daily, 14 days) and PQ + 5­ASA groups. Histological examination revealed congestion, edema and inflammatory cell infiltration in the bronchial and alveolar walls at 3 days after PQ exposure. Alveolar septum thickening with alveolar lumen narrowing was observed at 14 days, while fibroblast proliferation, increase in collagen fiber number and fibrous thickening of the alveolar walls were observed at 28 day. All the aforementioned pulmonary injury changes in the PQ group were attenuated in the PQ + 5­ASA group. Hydroxyproline (HYP) content increased in the lung tissues of the rats at 14 days after PQ treatment and reached a peak at 28 days. Compared with the PQ group, HYP contents of lung tissue decreased at 14 and 28 days after PQ + 5­ASA treatment. Masson's trichrome staining revealed that the increase in the amount of collagen fibers in the lung tissues of rats in the PQ group was inhibited by 5­ASA treatment, further confirming the alleviating effect of 5­ASA on fibrosis. In addition, the results showed that 5­ASA attenuated the upregulation of transforming growth factor­ß1 and phosphorylated­SMAD3, and the reduction of peroxisome proliferator activated receptor γ induced by PQ in lung tissue of rats and human lung fibroblast WI­38 VA13 cells. In conclusion, the results suggested that 5­ASA had an alleviating effect on PQ­induced pulmonary fibrosis, partly by suppressing the activation of the TGF­ß1 signaling pathway.

Ustekinumab as the First Biological Agent for Crohn's Disease in a 10-Year-Old Girl.

Pediatric inflammatory bowel disease is associated with growth failure due to chronic inflammation, nutrient disorder, and the side effects of drugs, such as corticosteroids. Biological agents are therapeutic drugs that significantly improve the prognosis of patients with inflammatory bowel disease. The effectiveness of ustekinumab has been reported in the management of adult patients with inflammatory bowel disease. There are very few reports regarding the effectiveness and safety of ustekinumab in pediatric patients with inflammatory bowel disease, especially those who are biologically naive. A 10-year-old girl presented with chronic abdominal pain, diarrhea, and weight loss. Colonoscopy showed a longitudinal ulcer and cobblestone appearance in the ileum and discontinuous inflammation of the colon; therefore, she was diagnosed with Crohn's disease. She was prescribed a fat-restricted diet, elemental diet, 5-aminosalicylic acid, transient prednisolone, and ustekinumab. She achieved clinical and endoscopic remission based on the weighted Pediatric Crohn's Disease Activity Index, fecal calprotectin, and colonoscopy findings at week 75. This patient developed no adverse events, such as infusion reaction or susceptibility to infection over the 75 weeks. The use of ustekinumab as the first biological agent may be an effective and safe treatment for pediatric Crohn's disease.

Predictive factors of relapse after dose reduction of oral 5-aminosalicylic acid in patients with ulcerative colitis in the remission phase.

OBJECTIVES: Useful indices to determine whether to reduce the dose of 5-aminosalicylic acid (5-ASA) in patients with ulcerative colitis (UC) during remission remain unclear. We aimed to analyze the rate and risk factors of relapse after reducing the dose of oral 5-ASA used for maintenance therapy of UC. METHODS: UC patients whose 5-ASA dose was reduced in clinical remission (partial Mayo score of ≤ 1) at our institution from 2012 to 2017 were analyzed. Various clinical variables of patients who relapsed after reducing the dose of oral 5-ASA were compared with those of patients who maintained remission. Risk factors for relapse were assessed by univariate and multivariate logistic regression analyses. Cumulative relapse-free survival rates were calculated using the Kaplan-Meier method. RESULTS: A total of 70 UC patients were included; 52 (74.3%) patients maintained remission and 18 (25.7%) patients relapsed during the follow-up period. Multivariate analysis indicated that a history of acute severe UC (ASUC) was an independent predictive factor for clinical relapse (p = 0.024, odds ratio: 21, 95% confidence interval: 1.50-293.2). Based on Kaplan-Meier survival analysis, the cumulative relapse-free survival rate within 52 weeks was 22.2% for patients with a history of ASUC, compared with 82.0% for those without. the log-rank test showed a significant difference in a history of ASUC (p < 0.001). CONCLUSIONS: Dose reduction of 5-ASA should be performed carefully in patients who have a history of ASUC.

Systemic mesalazine treatment prevents spontaneous skin fibrosis in PLK2-deficient mice.

Skin fibrosis is a complex biological remodeling process occurring in disease like systemic sclerosis, morphea, or eosinophilic fasciitis. Since the knowledge about the underlying pathomechanisms is still incomplete, there is currently no therapy, which prevents or reverses skin fibrosis sufficiently. The present study investigates the role of polo-like kinase 2 (PLK2) and the pro-fibrotic cytokine osteopontin (OPN) in the pathogenesis of cutaneous fibrosis and demonstrates the antifibrotic effects of systemic mesalazine treatment in vivo. Isolated primary dermal fibroblasts of PLK2 wild-type (WT) and knockout (KO) mice were characterized in vitro. Skin thickness and histoarchitecture were studied in paraffin-embedded skin sections. The effects of mesalazine treatment were examined in isolated fibroblasts and PLK2 KO mice, which were fed 100 µg/g mesalazine for 6 months via the drinking water. Compared to WT, PLK2 KO fibroblasts displayed higher spontaneous myofibroblast differentiation, reduced proliferation rates, and overexpression of the fibrotic cytokine OPN. In vitro, 72 h of treatment with 10 mmol/L mesalazine induced phenotype conversion in PLK2 KO fibroblasts and attenuated OPN expression by inhibiting ERK1/2. In vivo, dermal myofibroblast differentiation, collagen accumulation, and skin thickening were prevented by mesalazine in PLK2 KO. Plasma creatinine levels indicated good tolerability of systemic long-term mesalazine treatment. The current study reveals a spontaneous fibrotic skin phenotype and ERK1/2-dependent OPN overexpression in PLK2 KO mice. We provide experimental evidence for the antifibrotic effectiveness of systemic mesalazine treatment to prevent fibrosis of the skin, suggesting further investigation in experimental and clinical settings.

Mesalazine and inflammatory bowel disease - From well-established therapies to progress beyond the state of the art.

Inflammatory bowel disease incidence has been constantly rising for the past few decades. Current therapies attempt to mitigate its symptoms since no cure is established. The most commonly prescribed drug for these patients is 5-aminosalicylic acid (5-ASA). Due to the low rate and seriousness of side effects compared to other therapies, 5-ASA is still largely prescribed in many stages of inflammatory bowel disease, including scenarios where evidence suggests low effectiveness. Although commercialized formulations have come a long way in improving pharmacokinetics, it is still necessary to design and develop novel delivery systems capable of increasing effectiveness at different stages of the disease. In particular, micro- and nano-sized particles might be the key to its success in Crohn's disease and in more serious disease stages. This review provides an overview on the clinical significance of 5-ASA formulations, its limitations, challenges, and the most recent micro- and nanoparticle delivery systems being designed for its controlled release. Emergent alternatives for 5-ASA are also discussed, as well as the future prospects for its application in inflammatory bowel disease therapies.

Chemoprevention with low-dose aspirin, mesalazine, or both in patients with familial adenomatous polyposis without previous colectomy (J-FAPP Study IV): a multicentre, double-blind, randomised, two-by-two factorial design trial.

BACKGROUND: The only established treatment for preventing colorectal cancer in patients with familial adenomatous polyposis (FAP) is colectomy, which greatly reduces patient quality of life. Thus, an alternative method is warranted. In this trial, we aimed to clarify the individual and joint effects of low-dose aspirin and mesalazine on the recurrence of colorectal polyps in Japanese patients with FAP. METHODS: This was a randomised, double-blind, placebo-controlled, multicentre trial with a two-by-two factorial design done in 11 centres in Japan. Eligible patients were aged 16-70 years and had a history of more than 100 adenomatous polyps in the large intestine, without a history of colectomy. Before the study, patients underwent endoscopic removal of all colorectal polyps of at least 5·0 mm in diameter. Randomisation was done with a minimisation method with a random component to balance the groups with respect to the adjustment factors of sex, age (<30 years vs ≥30 years), or smoking status at the time of entry. Patients and researchers were masked to the treatment group. There were four groups: aspirin (100 mg per day) plus mesalazine (2 g per day), aspirin (100 mg per day) plus mesalazine placebo, aspirin placebo plus mesalazine (2 g per day), or aspirin placebo plus mesalazine placebo. Treatment was continued until 1 week before 8 month colonoscopy. The primary endpoint was the incidence of colorectal polyps of at least 5·0 mm at 8 months and was assessed in the intention-to-treat population. Safety was assessed in the ITT population. We also did a per-protocol analysis including only patients who took at least 70% of the allocated study drug. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000018736, and is complete. FINDINGS: Between Sept 25, 2015, and March 13, 2017, 104 patients were randomly assigned to receive either aspirin or aspirin placebo (n=52) or mesalazine or mesalazine placebo (n=52). Two patients withdrew from the aspirin plus mesalazine placebo group. 26 (50%) of 52 patients who received no aspirin had colorectal polyps of at least 5·0 mm at 8 months, as did 15 (30%) of the 50 patients who received any aspirin, 21 (42%) of the 50 patients who received no mesalazine, and 20 (38%) of the 52 patients who received any mesalazine. The adjusted odds ratio for polyp recurrence was 0·37 (95% CI 0·16-0·86) in the patients who received any aspirin and 0·87 (95% CI 0·38-2·00) in any who received mesalazine. The most common adverse events were grade 1-2 upper gastrointestinal symptoms in three (12%) of 26 patients who received aspirin plus mesalazine, one (4%) of 24 patients who received aspirin plus mesalazine placebo, and one (4%) of 26 patients who received mesalazine plus aspirin placebo. There was one grade 4 event in the mesalazine plus aspirin placebo group, but not related to the treatment. INTERPRETATION: Low-dose aspirin safely suppressed the recurrence of colorectal polyps larger than 5·0 mm in patients with FAP. These results suggest an effect of low-dose aspirin for FAP and could be an alternative method for preventing colorectal cancer in FAP. FUNDING: Japan Agency for Medical Research and Development.

Research on Preparation of 5-ASA Colon-Specific Hydrogel Delivery System without Crosslinking Agent by Mechanochemical Method.

PURPOSE: This study aims to overcome the challenges of the current oral targeted drug delivery system, such as the complex preparation process, poor biocompatibility, and delayed drug release. METHODS: Here, a non-covalent polymer hydrogel was prepared using the mechanochemical method, and the solid phase loading of 5-amino salicylic acid (5-ASA) was realized. RESULTS: The results obtained from the thermodynamics study, particle size analysis, and electron microscopy show that chitosan (CS) and sodium alginate (SA) form a pH-sensitive hydrogel under the mechanochemical force and also maintain good stability in aqueous solution. Fluorescent tracers study showed that the pH-sensitive hydrogel could achieve the targeted drug release in the colon and the retention time was over 12 h. Next, in vivo efficacy studies, change in mice body weight, DAI (disease activity index) score, thymus, and spleen index, and the diseased state of the mice colon revealed that the pH-sensitive hydrogel is an improved drug delivery system over 5-ASA API commercial preparations as observed in the efficacy and toxicological studies. CONCLUSION: This method uses an innovative preparation technology that without the need of cross-linking agent to produce an efficient colon-targeted drug delivery system for the treatment of ulcerative colitis.

Histological Remission in Ulcerative Colitis in Deep Remission under Treatment with Adalimumab.

BACKGROUND AND AIMS: Histological remission (HR) has been recently demonstrated as the last therapeutic goal in ulcerative colitis (UC), but it is unknown whether and how it may occur. Our aim was to assess the histology during the follow-up of an UC population in deep remission under treatment with adalimumab (ADA). METHODS: We performed a retrospective study on 22 UC patients who were in deep remission and followed-up while receiving therapy with ADA. Colonoscopy in those patients was performed every year. Four-quadrant biopsies every 10 cm were obtained during each colonoscopy and assessed by hematoxylin and eosin stain. Histological activity was classified using the Geboes scale. RESULTS: A total of 22 patients were enrolled in the study. The mean follow-up of those patients was 28±7 months, and 2,592 biopsy specimens in total were taken during 108 colonoscopies performed during the follow-up. At the beginning of the follow-up, histological inflammation was found in 15/22 (68.2%) of patients in deep remissio while receiving maintenance ADA therapy, 8/22 (36.4%) of them with Geboes score ≥3.1. At the end of the follow-up, when patients were still in deep remission while receiving maintenance ADA therapy, only 4 patients (18.2%) had at least one biopsy specimen with evidence of any histological inflammation during the follow-up; only two patients (9.1%) had Geboes score ≥3.1. CONCLUSIONS: Our study shows for the first time that UC patients in deep remission under ADA may reach HR, but it seems slower than other clinical or endoscopic goals.

Kidney function monitoring to prevent 5-aminosalicylic acid nephrotoxicity: What the gastroenterologist should know.

BACKGROUND: The kidney function monitoring is recommended in routine practice to detect 5-aminosalicylic acid (5-ASA) related nephrotoxicity, although is not standardized. The optimal monitoring is unknown, especially the best timing and which tests to perform. We summarized why, how, and when to perform the monitoring for patients treated with 5-ASA and provided an overview of the current guidelines on this topic. METHOD: Relevant studies on this topic were searched in PubMed, Embase, and Web of Science databases from July to August 2020. RESULTS: Serum creatinine, the estimated glomerular filtration rate, and 24-h proteinuria are the 3 main tests used for the monitoring in daily practice. Regarding the timing, several monitoring strategies have been proposed and guidelines are available too, but they provide conflicting information. To date, there is no medical evidence-based that one strategy is better than another. Comorbidities, chronic renal disease, use of nephrotoxic drugs or concomitant steroid therapy also impact the nephrotoxicity risk. Based on the literature review we proposed a kidney function monitoring strategy to guide physicians in clinical practice. CONCLUSION: A baseline assessment should be performed in all patients treated with 5-ASA. The monitoring should be carried out according to the other nephrotoxic factors. A tight monitoring may reduce morbidity and mortality of drug nephrotoxicity.

Effect of Kangfuxin Liquid enema combined with mesalazine on gestational outcomes and quality of life in child-bearing female with active ulcerative colitis: A protocol for randomized, double-blind, controlled trial.

BACKGROUND: In recent years, the incidence of ulcerative colitis (UC) is on the rise, and most of them are young adults. As the peak of the disease overlaps with the childbearing age, it has a great impact on the fertility of female patients. We, therefore, conduct a randomized and controlled trial to evaluate the efficacy and safety of mesalazine enteric-coated tablets combined with Kangfuxin Liquid (KFX) enema for the child-bearing period female with active UC. METHODS: In this randomized controlled study, a total of 236 eligible patients will be assigned to the experimental group (n = 118) or the control group (n = 118) in a 1:1 ratio. The control group will be taken mesalazine enteric-coated tablets combined with placebo enema and the experimental group will be taken mesalazine enteric-coated tablets combined with KFX enema. Participants will receive 8 weeks of intervention treatment and 3 months of maintenance treatment before pregnancy. The primary assessment is the Mayo score. Secondary outcomes include mucosal healing, faecal calprotectin (FC), Inflammatory Bowel Disease Quality (IBDQ), and pregnancy outcome. DISCUSSION: This study will provide evidence regarding the efficacy and safety of KFX enema used before pregnancy on halting active UC, reducing the relapse rate during pregnancy, improving pregnancy outcome, and the quality of life. TRIAL REGISTRATION: Chinese Clinical Trials Register identifier, ChiCTR2000039161, registered on October 20, 2020.

Efficacy of Oral, Topical, or Combined Oral and Topical 5-Aminosalicylates, in Ulcerative Colitis: Systematic Review and Network Meta-analysis.

BACKGROUND: 5-Aminosalicylates [5-ASAs] are the mainstay of treatment for ulcerative colitis [UC]. The optimum preparation, dose, and route of administration for UC remain unclear. We conducted a network meta-analysis to examine this issue. METHODS: We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register of controlled trials from inception to December 2020. We included randomised controlled trials [RCTs] comparing oral, topical, or combined oral and topical 5-ASAs, with each other or placebo for induction of remission or prevention of relapse of UC. Results were reported as pooled relative risks [RRs] with 95% confidence intervals [CIs] to summarise effect of each comparison tested, with treatments ranked according to P-score. RESULTS: We identified 40 RCTs for induction of remission and 23 for prevention of relapse. Topical mesalazine [P-score 0.99], or oral and topical mesalazine combined [P-score 0.87] ranked first and second for clinical and endoscopic remission combined. Combined therapy ranked first in trials where ≥50% of patients had left-sided/extensive disease, and topical mesalazine first in trials where ≥50% of patients had proctitis/proctosigmoiditis. High-dose [≥3.3 g/day] oral mesalazine ranked third in most analyses, with the most trials and most patients. For relapse of disease activity, combined therapy and high-dose oral mesalazine ranked first and second, with topical mesalazine third. 5-ASAs were safe and well tolerated, regardless of regimen. CONCLUSIONS: Our results support previous evidence; however, higher doses of oral mesalazine had more evidence for induction of remission than combined therapy and were significantly more efficacious than lower doses. Future RCTs should better establish the role of combined therapy for induction of remission, as well as optimal doses of oral 5-ASAs to prevent relapse.

Targeting IL-10, ZO-1 gene expression and IL-6/STAT-3 trans-signaling by a combination of atorvastatin and mesalazine to enhance anti-inflammatory effects and attenuates progression of oxazolone-induced colitis.

Ulcerative colitis (UC) is a chronic inflammatory disease characterized by diffused inflammation of the colon and rectum mucosa. The pathogenesis of UC is multifactorial, and the exact underlying mechanisms remain poorly understood. This study aims to investigate the effect of mesalazine and atorvastatin combination in enhancing anti-inflammatory effects and attenuates progression of oxazolone colitis in rats. In the present study, male albino rats (N = 60) were divided into six groups (10 rats each), the first two groups served as normal control and a control saline group. Colitis was induced by intra-rectal administration of oxazolone in the 5th and 7th days after pre-sensitization. Then, rats were divided into untreated group, groups treated with mesalazine or atorvastatin or their combination. Colitis was assessed by colon length, body weight, and incidence of diarrhea, rectal bleeding, and histopathology of colon tissue. Colon tissues were used for measuring interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), IL-13, signal transducer and activator of transcription-3 (STAT-3), myeloperoxidase activity (MPO), reduced glutathione(GSH), and tissue expression of IL-10, tight junction protein zonula occludens (ZO-1), and caspase-3 genes. The combination therapy significantly attenuated progression of UC by decreasing incidence of diarrhea, rectal bleeding, weight loss, IL-13, IL-6, TNF-α, STAT-3, caspase-3, and MPO activity and significantly increased IL-10, ZO-1, colon length, and GSH content, and these effects were more superior to single drugs. These findings showed that combination therapy was able to ameliorate progression of UC and enhance anti-inflammatory effects possibly by restoring IL-10 and ZO-1 levels and limiting IL-6/STAT-3 trans-signaling.

Multicenter survey on mesalamine intolerance in patients with ulcerative colitis.

BACKGROUND AND AIM: Although oral mesalamine is the first-choice drug for treating mild-to-moderate ulcerative colitis (UC), some patients show symptoms of intolerance, including exacerbation of diarrhea and abdominal pain. The present study clarified the current state and clinical courses of patients with mesalamine intolerance. METHODS: Patients who were diagnosed with UC and administered oral mesalamine at eight hospitals in Japan with a follow-up period exceeding 1 year were analyzed. RESULTS: Sixty-seven (11%) of 633 patients showed intolerance to at least one formulation of oral mesalamine. The frequency of mesalamine intolerance has increased in recent years, rising from 5.3% in 2007-2010 to 9.1% in 2011-2013 and 16.2% in 2014-2016. The most common complications were the exacerbation of diarrhea (n = 29), a fever (n = 25), and abdominal pain (n = 22). Readministration of mesalamine/sulfasalazine was attempted in 43 patients, mostly with other types of formulation of mesalamine, and more than half of these patients proved to be tolerant. The risk factors for mesalamine intolerance were female gender (odds ratio [OR] = 1.83; 95% confidence interval [CI], 1.08-3.12), age < 60 years old (OR = 2.82; CI, 1.19-8.33), and pancolitis (OR = 2.09; 95% CI, 1.23-3.60). There were no significant differences in the use of anti-tumor necrosis factor-α agents, colectomy, or steroid-free remission at the last visit between patients with and without mesalamine intolerance. CONCLUSIONS: Mesalamine intolerance is not rare, and its frequency has been increasing recently. The prognosis of patients with mesalamine intolerance did not differ significantly from that of those without intolerance.

Intestinal protozoa and helminths in ulcerative colitis and the influence of anti-parasitic therapy on the course of the disease.

PURPOSE: The aim of this study is to determine the prevalence of intestinal helminths and protozoa in patients with ulcerative colitis (UC) and to estimate the influence of the anti-parasitic therapy on the course of the disease. METHODS: The study was conducted at the Research Institute of Epidemiology, Microbiology and Infectious Diseases and Coloproctology Department of the Republic Clinical Hospital №1 of the Ministry of Health of the Republic of Uzbekistan. One hundred UC patients and 200 healthy individuals were examined by triple coproscopy. Additionally, 20, 25 and 22 UC patients with Blastocystis infection were treated with nitazoxanide (1.0 g/day), mesalazine (1.5-2 g/day) or a combination of nitazoxanide (1.0 g/day) and mesalazine (≥1.5-2 g/day) for 14 consecutive days, respectively. Parasitological, clinical and endoscopic examinations were conducted before therapy, immediately after and 6 and 12 weeks after therapy completion. RESULTS: The overall prevalence of helminths in UC patients and control individuals was not significantly different: 14±3.4% and 8.5±1.9%, respectively (OR: 1.7524; 95% CI: 0.8258 to 3.7186; P=0.1). Giardia lamblia was the most prevalent parasite in both groups, but the difference compared to the control was insignificant (OR: 0.4565; 95% CI: 0.2020 to 1.0318; P=0.05). A significantly higher prevalence of Blastocystis sp., Chilomastix mesnili and Iodamoeba butschlii in UC patients compared to control individuals was found (P<0.0005): 65.0%, 14.0% and 22.0%, respectively. During all follow-up periods, the clinical response and clinical remission were not statistically different between the groups (P>0.05). Mucosal healing immediately and 6 weeks after therapy with a combination of nitazoxanide with mesalazine was significantly better than with a monotherapy of nitazoxanide, respectively (P<0.05). UC patients treated with a combination of nitazoxanide with mesalazine showed better mucosal healing than in patients treated with a monotherapy of mesalazine (P>0.05). CONCLUSIONS: Diagnosis of Blastocystis sp. should be introduced in the complex examination of UC patients. Further clinical studies are necessary for assessment of the efficiency of anti-Blastocystis therapy in UC patients.

Chemically modified inulin for intestinal drug delivery - A new dual bioactivity concept for inflammatory bowel disease treatment.

This study investigates a novel preparation technique for pellets made from acetylated inulin and their characterization focusing on specific intestinal delivery of 5-aminosalicylic acid. By means of acetylation the hydrophobicity of four native inulins was increased yielding materials with selected degrees of acetylation. The acetylated inulins were insoluble in water, which was confirmed by the log P-values ranging from 1.30 to 1.58. 5-Aminosalicylic acid loading capacity of the pellets was up to 60 % and high enough to match the therapeutic range of the anti-inflammatory drug. Depending on the 5-aminosalicylic acid content and the type of acetylated inulin, up to 80 % of the entrapped drug was released within 24 h in intestinal environment under in-vitro conditions. Here we successfully prepared chemically modified and profoundly characterized inulin to provide innovative formulations and to open up a promising new strategy for treatment of Morbus Crohn and ulcerative colitis.

Concomitant 5-Aminosalicylate Therapy in Moderate-to-Severe Ulcerative Colitis Patients Escalated to Infliximab Is Not Beneficial.

BACKGROUND AND AIMS: While there is recent literature to support the discontinuation of 5-aminosalicylate (5-ASA) upon the initiation of biologics, continuing 5-ASA after treatment failure is relatively common. We aimed to assess the impact of concomitant 5-ASA therapy on clinical outcomes in ulcerative colitis (UC) patients escalated to infliximab. METHODS: This is a retrospective chart review of patients with moderate-to-severe UC started on infliximab between January 2012 and December 2017 at the University of Alberta. The primary outcome was clinical remission (partial Mayo score < 2) at 6 and 12 months. Secondary outcomes included endoscopic (endoscopic Mayo < 2) and deep remission (combined clinical and endoscopic remission) as well as the need for rescue therapy, hospitalization or colectomy. Univariate and multivariate logistic regression models were used to estimate the odds ratios and 95% CI for the outcomes. RESULTS: One hundred and twenty-one patients were followed over a period of 47 (SD = 34) months. Patients on 5-ASA had increased concomitant immunomodulator use (73.3% vs. 54.1%, p = 0.03). There was no difference in clinical remission at 6 (aOR 2.59, p = 0.07) or 12 months (aOR 0.43, p = 0.06). At 12 months, patients on concomitant 5-ASA were less likely to achieve endoscopic (aOR 0.08, p = 0.01) and deep remission (aOR 0.07, p = 0.02). Adverse outcomes such as need for rescue therapy, hospitalization, and colectomy did not differ between the groups. CONCLUSIONS: Our data suggest that 5-ASA may be stopped in patients with moderate-to-severe UC who have been escalated to infliximab therapy as it has no additional benefit to control inflammation.

Mesalazine allergy and an attempt at desensitization therapy in patients with inflammatory bowel disease.

Mesalazine is a key drug used for remission induction and maintenance therapy in inflammatory bowel disease (IBD). We sometimes encounter patients who develop allergic reactions to the drug and inevitably discontinue treatment. Of 692 patients who received mesalazine for IBD between 2014 and March 2020, 33 diagnosed with mesalazine allergy (43 episodes) were included, and their clinical manifestations were evaluated. For ten patients undergoing desensitization therapy, therapeutic outcomes were evaluated. The incidence of mesalazine allergy was 4.8%. The time from the start of oral medication to allergy onset was 10 ± 5 days for the first allergic attack and 2 ± 1 days for the second and subsequent allergic attacks. The observed clinical symptoms included fever (93%), diarrhea (26%), abdominal pain (23%), and bloody stool (12%). Drug-induced lymphocyte stimulation test was performed in 85% of the patients (28/33), and the sensitivity was 51%. Desensitization therapy with a time-dependent mesalazine granule formulation was successful in nine of the ten patients (90%), allowing them to receive 2000 mg or more of the drug. Fever was a common allergic symptom, and its presence appeared to be useful for distinguishing mesalazine allergy from exacerbation of the primary disease. Desensitization therapy was useful in patients with mesalazine allergy.

Histologic remission does not offer additional benefit for ulcerative colitis patients in endoscopic remission.

BACKGROUND: Histologic remission in ulcerative colitis (UC) patients may be associated with positive outcomes. It is unclear whether UC patients in endoscopic remission obtain additional benefit from achieving histologic remission. AIM: To evaluate the relationship between time to relapse and histological activity among UC patients in endoscopic remission. METHODS: In this retrospective study using an observational database, we identified UC patients who had achieved endoscopic remission (Mayo endoscopic subscore 0). Index colonoscopy was the first colonoscopy when endoscopic remission was achieved. Histologic activity was classified as normal, inactive or active colitis. The primary outcome was time to relapse. Secondary outcomes included reasons for relapse and the association between baseline variables and risk of relapse. A Cox proportional hazards model evaluated baseline factors and the outcome of relapse. RESULTS: We included 269 patients. The Kaplan-Meier survival curve showed no significant difference between the presence or absence of histologic activity and time to relapse (log rank P = 0.85). There was no difference in time to clinical relapse of patients with histologically active colitis compared to inactive colitis (adjusted hazard ratio [AHR] 1.17, 95% CI 0.58-2.32, P = 0.67]). 5-aminosalicylate use (AHR 0.42, 95% CI 0.21-0.82, P = 0.011), pancolitis (AHR 0.32, 95% CI 0.13-0.75, P = 0.008), left-sided colitis (AHR 0.46; 95% CI 0.22-0.98; P = 0.044) and older age (AHR 0.96, 95% CI 0.94-0.99, P = 0.002) were significantly associated with reduced time to clinical relapse. CONCLUSION: Histologic remission did not influence time to relapse in UC patients who had achieved endoscopic remission.