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Lancet (London, England) Apr 2017Ulcerative colitis is a chronic inflammatory disease affecting the colon, and its incidence is rising worldwide. The pathogenesis is multifactorial, involving genetic... (Review)
Review
Ulcerative colitis is a chronic inflammatory disease affecting the colon, and its incidence is rising worldwide. The pathogenesis is multifactorial, involving genetic predisposition, epithelial barrier defects, dysregulated immune responses, and environmental factors. Patients with ulcerative colitis have mucosal inflammation starting in the rectum that can extend continuously to proximal segments of the colon. Ulcerative colitis usually presents with bloody diarrhoea and is diagnosed by colonoscopy and histological findings. The aim of management is to induce and then maintain remission, defined as resolution of symptoms and endoscopic healing. Treatments for ulcerative colitis include 5-aminosalicylic acid drugs, steroids, and immunosuppressants. Some patients can require colectomy for medically refractory disease or to treat colonic neoplasia. The therapeutic armamentarium for ulcerative colitis is expanding, and the number of drugs with new targets will rapidly increase in coming years.
Topics: Colectomy; Colitis, Ulcerative; Colonoscopy; Diagnosis, Differential; Glucocorticoids; Humans; Immunosuppressive Agents; Mesalamine; Prognosis; Remission Induction
PubMed: 27914657
DOI: 10.1016/S0140-6736(16)32126-2 -
Deutsches Arzteblatt International Aug 2020Ulcerative colitis is a chronic inflammatory bowel disease with an estimated 150 000 patients in Germany alone. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Ulcerative colitis is a chronic inflammatory bowel disease with an estimated 150 000 patients in Germany alone.
METHODS
This review is based on publications about current diagnostic and therapeutic strategies for ulcerative colitis that were retrieved by a selective search in PubMed, and on current guidelines.
RESULTS
The primary goal of treatment is endoscopically confirmed healing of the mucosa. Mesalamine, in various forms of administration, remains the standard treatment for uncomplicated ulcerative colitis. Its superiority over placebo has been confirmed in meta-analyses of randomized, controlled trials. Glucocorticoids are highly effective in the acute treatment of ulcerative colitis, but they should only be used over the short term, because of their marked side effects. Further drugs are available to treat patients with a more complicated disease course of ulcerative colitis, including azathioprine, biological agents, JAK inhibitors (among them TNF antibodies, biosimilars, ustekinumab, vedolizumab, and tofacitinib), and calcineurin inhibitors. Proctocolectomy should be considered in refractory cases, or in the presence of high-grade epithelial dysplasia. Ulcerative colitis beginning in childhood or adolescence is often characterized by rapid progression and frequent comorbidities that make its treatment a special challenge.
CONCLUSION
A wide variety of drugs are now available for the treatment of ulcerative colitis, enabling the individualized choice of the best treatment for each patient. Regular surveillance colonoscopies to rule out colon carcinoma should be scheduled at intervals that depend on risk stratification.
Topics: Adolescent; Algorithms; Biosimilar Pharmaceuticals; Child; Colitis, Ulcerative; Germany; Humans; Mesalamine
PubMed: 33148393
DOI: 10.3238/arztebl.2020.0564 -
Gastroenterology Feb 2019
Review
Topics: Anti-Inflammatory Agents, Non-Steroidal; Colitis, Ulcerative; Disease Management; Female; Humans; Male; Mesalamine; Practice Guidelines as Topic; Prognosis; Remission Induction; Severity of Illness Index; Societies, Medical; Treatment Outcome; United States
PubMed: 30576644
DOI: 10.1053/j.gastro.2018.12.009 -
The Cochrane Database of Systematic... Jul 2016Randomized trials investigating the efficacy of aminosalicylates for the treatment of mildly to moderately active Crohn's disease have yielded conflicting results. A... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Randomized trials investigating the efficacy of aminosalicylates for the treatment of mildly to moderately active Crohn's disease have yielded conflicting results. A systematic review was conducted to critically examine current available data on the efficacy of sulfasalazine and mesalamine for inducing remission or clinical response in these patients.
OBJECTIVES
To evaluate the efficacy of aminosalicylates compared to placebo, corticosteroids, and other aminosalicylates (alone or in combination with corticosteroids) for the treatment of mildly to moderately active Crohn's disease.
SEARCH METHODS
We searched PubMed, EMBASE, MEDLINE and the Cochrane Central Library from inception to June 2015 to identify relevant studies. There were no language restrictions. We also searched reference lists from potentially relevant papers and review articles, as well as proceedings from annual meetings (1991-2015) of the American Gastroenterological Association and American College of Gastroenterology.
SELECTION CRITERIA
Randomized controlled trials that evaluated the efficacy of sulfasalazine or mesalamine in the treatment of mildly to moderately active Crohn's disease compared to placebo, corticosteroids, and other aminosalicylates (alone or in combination with corticosteroids) were included.
DATA COLLECTION AND ANALYSIS
Data extraction and assessment of methodological quality was independently performed by the investigators and any disagreement was resolved by discussion and consensus. We assessed methodological quality using the Cochrane risk of bias tool. The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. The primary outcome measure was a well defined clinical endpoint of induction of remission or response to treatment. Secondary outcomes included mean Crohn's disease activity index (CDAI) scores, adverse events, serious adverse events and withdrawal due to adverse events. For dichotomous outcomes we calculated the pooled risk ratio (RR) and corresponding 95% confidence interval (CI) using a random-effects model. For continuous outcomes we calculated the mean difference (MD) and 95% CI using a random-effects model. Sensitivity analyses based on a fixed-effect model and duration of therapy were conducted where appropriate.
MAIN RESULTS
Twenty studies (2367 patients) were included. Two studies were judged to be at high risk of bias due to lack of blinding. Eight studies were judged to be at high risk of bias due to incomplete outcomes data (high drop-out rates) and potential selective reporting. The other 10 studies were judged to be at low risk of bias. A non-significant trend in favour of sulfasalazine over placebo for inducing remission was observed, with benefit confined mainly to patients with Crohn's colitis. Forty-five per cent (63/141) of sulfasalazine patients entered remission at 17-18 weeks compared to 29% (43/148) of placebo patients (RR 1.38, 95% CI 1.00 to 1.89, 2 studies). A GRADE analysis rated the overall quality of the evidence supporting this outcome as moderate due to sparse data (106 events). There was no difference between sulfasalazine and placebo in adverse event outcomes. Sulfasalazine was significantly less effective than corticosteroids and inferior to combination therapy with corticosteroids (RR 0.64, 95% CI 0.47 to 0.86, 1 study, 110 patients). Forty-three per cent (55/128) of sulfasalazine patients entered remission at 17 to 18 weeks compared to 60% (79/132) of corticosteroid patients (RR 0.68, 95% CI 0.51 to 0.91; 2 studies, 260 patients). A GRADE analysis rated the overall quality of the evidence supporting this outcome as moderate due to sparse data (134 events). Sulfasalazine patients experienced significantly fewer adverse events than corticosteroid patients (RR 0.43, 95% CI 0.22 to 0.82; 1 study, 159 patients). There was no difference between sulfasalazine and corticosteroids in serious adverse events or withdrawal due to adverse events. Olsalazine was less effective than placebo in a single trial (RR 0.36, 95% CI 0.18 to 0.71; 91 patients). Low dose mesalamine (1 to 2 g/day) was not superior to placebo for induction of remission. Twenty-three per cent (43/185) of low dose mesalamine patients entered remission at week 6 compared to 15% (18/117) of placebo patients (RR = 1.46, 95% CI 0.89 to 2.40; n = 302). A GRADE analysis indicated that the overall quality of the evidence supporting this outcome was low due to risk of bias (incomplete outcome data) and sparse data (61 events). There was no difference between low dose mesalamine and placebo in the proportion of patients who had adverse events (RR 1.33, 95% CI 0.91 to 1.96; 3 studies, 342 patients) or withdrew due to adverse events (RR 1.21, 95% CI 0.75 to 1.95; 3 studies, 342 patients). High dose controlled-release mesalamine (4 g/day) was not superior to placebo, inducing a clinically non significant reduction in CDAI (MD -19.8 points, 95% CI -46.2 to 6.7; 3 studies, 615 patients), and was also inferior to budesonide (RR 0.56, 95% CI 0.40 to 0.78; 1 study, 182 patients, GRADE = low). While high dose delayed-release mesalamine (3 to 4.5 g/day) was not superior to placebo for induction of remission (RR 2.02, 95% CI 0.75 to 5.45; 1 study, 38 patients, GRADE = very low), no significant difference in efficacy was found when compared to conventional corticosteroids (RR 1.04, 95% CI 0.79 to 1.36; 3 studies, 178 patients, GRADE = moderate) or budesonide (RR 0.89, 95% CI 0.76 to 1.05; 1 study, 307 patients, GRADE = moderate). However, these trials were limited by risk of bias (incomplete outcome data) and sparse data (small numbers of events). There was a lack of good quality clinical trials comparing sulfasalazine with other mesalamine formulations. Adverse events that were commonly reported included headache, nausea, vomiting, abdominal pain and diarrhea.
AUTHORS' CONCLUSIONS
Sulfasalazine is only modestly effective with a trend towards benefit over placebo and is inferior to corticosteroids for the treatment of mildly to moderately active Crohn's disease. Olsalazine and low dose mesalamine (1 to 2 g/day) are not superior to placebo. High dose mesalamine (3.2 to 4 g/day) is not more effective than placebo for inducing response or remission. However, trials assessing the efficacy of high dose mesalamine (4 to 4.5 g/day) compared to budesonide yielded conflicting results and firm conclusions cannot be made. Future large randomized controlled trials are needed to provide definitive evidence on the efficacy of aminosalicylates in active Crohn's disease.
Topics: Aminosalicylic Acids; Anti-Inflammatory Agents, Non-Steroidal; Budesonide; Crohn Disease; Delayed-Action Preparations; Gastrointestinal Agents; Humans; Induction Chemotherapy; Mesalamine; Randomized Controlled Trials as Topic; Sulfasalazine
PubMed: 27372735
DOI: 10.1002/14651858.CD008870.pub2 -
Clinical Medicine (London, England) Mar 2023A 45-year-old woman presented to the hospital with bloody diarrhoea and significant weight loss over the past 1 month. On admission and evaluation, she was found to have...
A 45-year-old woman presented to the hospital with bloody diarrhoea and significant weight loss over the past 1 month. On admission and evaluation, she was found to have acute ulcerative colitis. She was started on prednisolone and mesalamine therapy. Within 24 hours of initiation of this therapy, the patient complained of giddiness and chest discomfort and was found to have sinus bradycardia on ECG with no acute coronary event. After withdrawing mesalamine, her heart rate normalised within 24 hours and she remained symptom-free. This is a rare case report of severe symptomatic sinus bradycardia due to mesalamine therapy; to our knowledge, only four cases of mesalamine-induced bradycardia have been reported in the literature.
Topics: Female; Humans; Middle Aged; Mesalamine; Anti-Inflammatory Agents, Non-Steroidal; Bradycardia; Colitis, Ulcerative; Prednisolone
PubMed: 36958845
DOI: 10.7861/clinmed.2022-0431 -
Nature Medicine Mar 2023For decades, variability in clinical efficacy of the widely used inflammatory bowel disease (IBD) drug 5-aminosalicylic acid (5-ASA) has been attributed, in part, to its...
For decades, variability in clinical efficacy of the widely used inflammatory bowel disease (IBD) drug 5-aminosalicylic acid (5-ASA) has been attributed, in part, to its acetylation and inactivation by gut microbes. Identification of the responsible microbes and enzyme(s), however, has proved elusive. To uncover the source of this metabolism, we developed a multi-omics workflow combining gut microbiome metagenomics, metatranscriptomics and metabolomics from the longitudinal IBDMDB cohort of 132 controls and patients with IBD. This associated 12 previously uncharacterized microbial acetyltransferases with 5-ASA inactivation, belonging to two protein superfamilies: thiolases and acyl-CoA N-acyltransferases. In vitro characterization of representatives from both families confirmed the ability of these enzymes to acetylate 5-ASA. A cross-sectional analysis within the discovery cohort and subsequent prospective validation within the independent SPARC IBD cohort (n = 208) found three of these microbial thiolases and one acyl-CoA N-acyltransferase to be epidemiologically associated with an increased risk of treatment failure among 5-ASA users. Together, these data address a longstanding challenge in IBD management, outline a method for the discovery of previously uncharacterized gut microbial activities and advance the possibility of microbiome-based personalized medicine.
Topics: Humans; Mesalamine; Gastrointestinal Microbiome; Cross-Sectional Studies; Inflammatory Bowel Diseases; Treatment Outcome
PubMed: 36823301
DOI: 10.1038/s41591-023-02217-7 -
Journal of Crohn's & Colitis Jan 2018Clinically effective therapies now exist for remission maintenance in both ulcerative colitis [UC] and Crohn's Disease [CD]. For each major class of IBD medications... (Review)
Review
Clinically effective therapies now exist for remission maintenance in both ulcerative colitis [UC] and Crohn's Disease [CD]. For each major class of IBD medications [5-aminosalicyclates, immunomodulators, and biologic agents], used alone or in combination, there is a risk of relapse following reduction or cessation of treatment. A consensus expert panel convened by the European Crohn's and Colitis Organisation [ECCO] reviewed the published literature and agreed a series of consensus practice points. The objective of the expert consensus is to provide evidence-based guidance for clinical practice so that physicians can make informed decisions in partnership with their patients. The likelihood of relapse with stopping each class of IBD medication is reviewed. Factors associated with an altered risk of relapse with withdrawal are evaluated, and strategies to monitor and allow early identification of relapse are considered. In general, patients in clinical, biochemical, and endoscopic remission are more likely to remain well when treatments are stopped. Reintroduction of the same treatment is usually, but not always, successful. The decision to stop a treatment needs to be individualized, and shared decision making with the patient should take place.
Topics: Adalimumab; Anti-Inflammatory Agents, Non-Steroidal; Biological Products; Colitis, Ulcerative; Consensus; Crohn Disease; Humans; Immunosuppressive Agents; Infliximab; Mesalamine; Practice Guidelines as Topic; Recurrence; Retreatment; Secondary Prevention; Time Factors; Tumor Necrosis Factor-alpha; Withholding Treatment
PubMed: 28981623
DOI: 10.1093/ecco-jcc/jjx101 -
Revista Espanola de Enfermedades... Jan 2020Microscopic colitis is a common cause of chronic watery diarrhea with a great impact on patient quality of life. Microscopic colitis includes two histological subtypes:... (Review)
Review
Microscopic colitis is a common cause of chronic watery diarrhea with a great impact on patient quality of life. Microscopic colitis includes two histological subtypes: collagenous colitis and lymphocytic colitis. Due to the increasing incidence and awareness of this disease over the last decades, several international guidelines have been recently published. However, there is still significant heterogeneity in the management of these patients, and treatments without solid scientific evidence support are often used in clinical practice. This article reviews the therapeutic role of budesonide in microscopic colitis and summarizes the current evidence regarding other treatments available for this disease, especially for the management of refractory patients. Finally, an updated treatment algorithm is proposed.
Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Antidiarrheals; Antimetabolites; Azathioprine; Biological Products; Budesonide; Colitis, Collagenous; Colitis, Lymphocytic; Colitis, Microscopic; Diarrhea; Humans; Loperamide; Malabsorption Syndromes; Mesalamine; Methotrexate; Prednisolone; Quality of Life; Randomized Controlled Trials as Topic; Recurrence; Remission Induction; Time Factors
PubMed: 31880163
DOI: 10.17235/reed.2019.6655/2019 -
Frontiers in Immunology 2022Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD). Its etiology is unclear. Much evidence suggests that the death of abnormal intestinal epithelial...
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD). Its etiology is unclear. Much evidence suggests that the death of abnormal intestinal epithelial cells (IECs) leads to intestinal barrier disruption, and the subsequent inflammatory response plays a vital role in UC. Pyroptosis is a form of programmed inflammatory cell death, and the role of pyroptosis in UC etiology remains to be explored. This study identified 10 hub genes in pyroptosis by gene expression profiles obtained from the GSE87466 dataset. Meanwhile, the biomarkers were screened based on gene significance (GS) and module membership (MM) through the Weighted Gene Co-Expression Network Analysis (WGCNA). The following analysis indicated that hub genes were closely associated with the UC progression and therapeutic drug response. The single-cell RNA (scRNA) sequencing data from UC patients within the GSE162335 dataset indicated that macrophages were most related to pyroptosis. Finally, the expression of hub genes and response to the therapeutic drug [5-aminosalicylic acid (5-ASA)] were verified in dextran sulfate sodium (DSS)-induced colitis mice. Our study identified as the critical pyroptosis-related biomarker in UC. The crosstalk between macrophage pyroptosis and IEC pyroptosis may play an essential role in UC, deserving further exploration.
Topics: Animals; Mice; Biomarkers, Pharmacological; Colitis; Colitis, Ulcerative; Dextran Sulfate; Mesalamine; Pyroptosis
PubMed: 36311726
DOI: 10.3389/fimmu.2022.998470