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Treatment of pouchitis, Crohn's disease, cuffitis, and other inflammatory disorders of the pouch: consensus guidelines from the International Ileal Pouch Consortium.
Shen, B, Kochhar, GS, Rubin, DT, Kane, SV, Navaneethan, U, Bernstein, CN, Cross, RK, Sugita, A, Schairer, J, Kiran, RP, et al
The lancet. Gastroenterology & hepatology. 2022;(1):69-95
Abstract
Pouchitis, Crohn's disease of the pouch, cuffitis, polyps, and extraintestinal manifestations of inflammatory bowel disease are common inflammatory disorders of the ileal pouch. Acute pouchitis is treated with oral antibiotics and chronic pouchitis often requires anti-inflammatory therapy, including the use of biologics. Aetiological factors for secondary pouchitis should be evaluated and managed accordingly. Crohn's disease of the pouch is usually treated with biologics and its stricturing and fistulising complications can be treated with endoscopy or surgery. The underlying cause of cuffitis determines treatment strategies. Endoscopic polypectomy is recommended for large, symptomatic inflammatory polyps and polyps in the cuff. The management principles of extraintestinal manifestations of inflammatory bowel disease in patients with pouches are similar to those in patients without pouches.
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First-line treatment with infliximab versus conventional treatment in children with newly diagnosed moderate-to-severe Crohn's disease: an open-label multicentre randomised controlled trial.
Jongsma, MME, Aardoom, MA, Cozijnsen, MA, van Pieterson, M, de Meij, T, Groeneweg, M, Norbruis, OF, Wolters, VM, van Wering, HM, Hojsak, I, et al
Gut. 2022;(1):34-42
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Abstract
OBJECTIVE In newly diagnosed paediatric patients with moderate-to-severe Crohn's disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid and immunomodulator therapies have failed. We aimed to investigate whether starting first-line IFX (FL-IFX) is more effective to achieve and maintain remission than conventional treatment. DESIGN In this multicentre open-label randomised controlled trial, untreated patients with a new diagnosis of CD (3-17 years old, weighted Paediatric CD Activity Index score (wPCDAI) >40) were assigned to groups that received five infusions of 5 mg/kg IFX at weeks 0, 2, 6, 14 and 22 (FL-IFX), or EEN or oral prednisolone (1 mg/kg, maximum 40 mg) (conventional). The primary outcome was clinical remission on azathioprine, defined as a wPCDAI <12.5 at week 52, without need for treatment escalation, using intention-to-treat analysis. RESULTS 100 patients were included, 50 in the FL-IFX group and 50 in the conventional group. Four patients did not receive treatment as per protocol. At week 10, a higher proportion of patients in the FL-IFX group than in the conventional group achieved clinical (59% vs 34%, respectively, p=0.021) and endoscopic remission (59% vs 17%, respectively, p=0.001). At week 52, the proportion of patients in clinical remission was not significantly different (p=0.421). However, 19/46 (41%) patients in the FL-IFX group were in clinical remission on azathioprine monotherapy without need for treatment escalation vs 7/48 (15%) in the conventional group (p=0.004). CONCLUSIONS FL-IFX was superior to conventional treatment in achieving short-term clinical and endoscopic remission, and had greater likelihood of maintaining clinical remission at week 52 on azathioprine monotherapy. TRIAL REGISTRATION NUMBER ClinicalTrials.gov Registry (NCT02517684).
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Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease.
Schreiber, S, Ben-Horin, S, Leszczyszyn, J, Dudkowiak, R, Lahat, A, Gawdis-Wojnarska, B, Pukitis, A, Horynski, M, Farkas, K, Kierkus, J, et al
Gastroenterology. 2021;(7):2340-2353
Abstract
BACKGROUND & AIMS This study compared pharmacokinetics, symptomatic and endoscopic efficacy, safety, and immunogenicity of a subcutaneous formulation of the infliximab biosimilar CT-P13 (CT-P13 SC) vs intravenous CT-P13 (CT-P13 IV) in patients with inflammatory bowel disease (IBD). METHODS This randomized, multicenter, open-label, parallel-group, phase 1 study enrolled tumor necrosis factor inhibitor-naïve patients with active ulcerative colitis (total Mayo score 6-12 points with endoscopic subscore ≥2) or Crohn's disease (Crohn's Disease Activity Index 220-450 points) at 50 centers. After CT-P13 IV induction at Week (W) 0/W2, patients were randomized (1:1) to receive CT-P13 SC every 2 weeks (q2w) from W6 to W54 or CT-P13 IV every 8 weeks from W6 to W22. At W30, all patients receiving CT-P13 IV switched to CT-P13 SC q2w until W54. The primary endpoint was noninferiority of CT-P13 SC to CT-P13 IV for observed predose CT-P13 concentration at W22 (Ctrough,W22), concluded if the lower bound of the 2-sided 90% confidence interval (CI) for the ratio of geometric least-squares means exceeded 80%. RESULTS Overall, 66 and 65 patients were randomized to CT-P13 SC and CT-P13 IV, respectively. The primary endpoint of noninferiority was met with a geometric least-squares means ratio for Ctrough,W22 of 1154.17% (90% CI 786.37-1694.00; n = 59 [CT-P13 SC]; n = 57 [CT-P13 IV]). W30/W54 clinical remission rates were comparable between arms. Other efficacy, safety, and immunogenicity assessments were also broadly comparable between arms, including after switching. CONCLUSIONS The pharmacokinetic noninferiority of CT-P13 SC to CT-P13 IV, and the comparable efficacy, safety, and immunogenicity profiles, support the potential suitability of CT-P13 SC treatment in IBD. ClinicalTrials.gov ID: NCT02883452.
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Irritable Bowel Syndrome in Pregnancy.
Moosavi, S, Pimentel, M, Wong, MS, Rezaie, A
The American journal of gastroenterology. 2021;(3):480-490
Abstract
Irritable bowel syndrome (IBS) affects a significant percentage of the general population and is more common in women. A large proportion of women affected with IBS are of childbearing age; however, there is a paucity of studies and guidelines to specifically address the epidemiology, course, maternal/fetal prognosis, or management of IBS in pregnancy. This scarcity of literature on IBS and pregnancy poses significant challenges to healthcare providers in counseling and managing patients. In this comprehensive review, we summarize the current literature and knowledge gaps regarding the effects of pregnancy on IBS and vice versa, along with the efficacy and safety profiles of commonly used IBS diets and medications in pregnancy. The management of pregnant women with IBS should be multidisciplinary, with emphasis on education and judicious use of dietary modifications and pharmacologic options that are deemed relatively safe during pregnancy.
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The Role of TNF-α and Anti-TNF-α Agents during Preconception, Pregnancy, and Breastfeeding.
Romanowska-Próchnicka, K, Felis-Giemza, A, Olesińska, M, Wojdasiewicz, P, Paradowska-Gorycka, A, Szukiewicz, D
International journal of molecular sciences. 2021;(6)
Abstract
Tumor necrosis factor-alpha (TNF-α) is a multifunctional Th1 cytokine and one of the most important inflammatory cytokines. In pregnancy, TNF-α influences hormone synthesis, placental architecture, and embryonic development. It was also shown that increased levels of TNF-α are associated with pregnancy loss and preeclampsia. Increased TNF-α levels in complicated pregnancy draw attention to trophoblast biology, especially migratory activity, syncytialisation, and endocrine function. Additionally, elevated TNF-α levels may affect the maternal-fetal relationship by altering the secretory profile of placental immunomodulatory factors, which in turn affects maternal immune cells. There is growing evidence that metabolic/pro-inflammatory cytokines can program early placental functions and growth in the first trimester of pregnancy. Furthermore, early pregnancy placenta has a direct impact on fetal development and maternal immune system diseases that release inflammatory (e.g., TNF-α) and immunomodulatory factors, such as chronic inflammatory rheumatic, gastroenterological, or dermatological diseases, and may result in an abnormal release of cytokines and chemokines in syncytiotrophoblasts. Pregnancy poses a challenge in the treatment of chronic disease in patients who plan to have children. The activity of the disease, the impact of pregnancy on the course of the disease, and the safety of pharmacotherapy, including anti-rheumatic agents, in pregnancy should be considered.
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The effect of 6-day subcutaneous glucose-dependent insulinotropic polypeptide infusion on time in glycaemic range in patients with type 1 diabetes: a randomised, double-blind, placebo-controlled crossover trial.
Heimbürger, SMN, Hoe, B, Nielsen, CN, Bergmann, NC, Hartmann, B, Holst, JJ, Vilsbøll, T, Dejgaard, TF, Christensen, MB, Knop, FK
Diabetologia. 2021;(11):2425-2431
Abstract
AIMS/HYPOTHESIS Type 1 diabetes is characterised by reduced glucagon response to hypoglycaemia, increasing the risk of insulin treatment-associated hypoglycaemia known to hamper glycaemic control. We previously reported a glucagonotropic effect of exogenous glucose-dependent insulinotropic polypeptide (GIP) during insulin-induced hypoglycaemia in individuals with type 1 diabetes. Here we investigate the effect of a 6-day s.c. GIP infusion on time in glycaemic range as assessed by continuous glucose monitoring (CGM) in individuals with type 1 diabetes. METHODS In a randomised, placebo-controlled, double-blind crossover study, time in glycaemic range (assessed by double-blinded CGM) was evaluated in 20 men with type 1 diabetes (18-75 years, stable insulin treatment ≥3 months, diabetes duration 2-15 years, fasting plasma C-peptide below 200 pmol/l, BMI 20-27 kg/m2, HbA1c <69 mmol/mol [8.5%]) during two × 6 days of continuous s.c. GIP (6 pmol kg-1 min-1) and placebo (saline [154 mmol/l NaCl]) infusion, respectively, with an interposed 7-day washout period. The primary outcome was glycaemic time below range, time in range and time above range. RESULTS There were no significant differences in time below range (<3.9 mmol/l, p = 0.53) or above range (>10 mmol/l, p = 0.32) during night-time or daytime, in mean glucose, or in hypoglycaemic events as assessed by CGM. GIP altered neither self-reported hypoglycaemia nor safety measures. Compared with placebo, GIP significantly increased time in tight range (3.9-7.8 mmol/l) during daytime (06:00-23:59 hours) by [mean ± SEM] 11.2 ± 5.1% [95% CI 0.41, 21.9] (p = 0.02). CONCLUSIONS/INTERPRETATION Six-day s.c. GIP infusion in men with type 1 diabetes did not procure convincing effect on overall time in range, but increased time in tight glycaemic range during daytime by ~2 h per day. TRIAL REGISTRATION ClinicalTrials.gov NCT03734718. FUNDING The study was funded by grants from The Leona M. and Harry B. Helmsley Charitable Trust and Aase og Ejnar Danielsens Fond.
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Nutritional and pharmacological strategy in children with short bowel syndrome.
Höllwarth, ME, Solari, V
Pediatric surgery international. 2021;(1):1-15
Abstract
Short bowel syndrome in neonates is a severe and life-threatening disease after a major loss of small bowel with or without large bowel. Intestinal adaptation, by which the organism tries to restore digestive and absorptive capacities, is entirely dependent on stimulation of the active enterocytes by enteral nutrition. This review summarizes recent knowledge about the pathophysiologic consequences after the loss of different intestinal parts and outlines the options for enteral nutrition and pharmacological therapies to support the adaptation process.
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Timely Monitoring of Inflammation by Fecal Lactoferrin Rapidly Predicts Therapeutic Response in Inflammatory Bowel Disease.
Sorrentino, D, Gray, JM
Inflammatory bowel diseases. 2021;(8):1237-1247
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Abstract
BACKGROUND Fecal lactoferrin (FL) levels may mirror drug-induced changes in inflammation in ulcerative colitis and Crohn disease in a timely way and could be used to assess loss of response (LOR) to biologics. METHODS This study is a retrospective outcome review in 61 patients on adalimumab, infliximab, or vedolizumab managed in our center and followed for 6 to 24 months. Patients were 1) in clinical remission or 2) were experiencing possible LOR. RESULTS For group 1, in 71% of 31 patients, FL slowly increased during the therapeutic interval (R2 = 0.769; P < 0.001), thus reflecting increasing inflammation as drug concentrations decreased. In the remaining patients, FL was undetectable throughout the therapeutic interval because of a stronger suppression of inflammation. For group 2, in 30 patients negative for infections, FL levels measured 1 to 3 days after infusion/injection compared to preadministration values either increased (nonresponders)-in these patients the medication was switched to another class; partially decreased (partial responders)-the therapeutic interval was shortened; or were normal throughout (responders)-causes for symptoms unrelated to disease activity were found for all. After FL-based management, 3-month standardized clinical scores were normalized in both partial responders (0.58 ± 0.21 vs 0.13 ± 0.09; P < 0.001) and nonresponders (0.81 ± 0.17 vs 0.12 ± 0.08; P < 0.001), and FL levels dropped by up to 99%. CONCLUSIONS Levels of FL reflect drug-induced changes in mucosal inflammation in a timely way, thus enabling rapid assessment of therapeutic response in patients with ulcerative colitis and with Crohn disease. In patients with suspected LOR, FL levels before and after infusion/injection accurately separated responders, partial responders, and nonresponders. The strategy proposed here is simple, accurate, and easily applicable to clinical practice.
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Efficacy and Safety of Over-the-Counter Therapies for Chronic Constipation: An Updated Systematic Review.
Rao, SSC, Brenner, DM
The American journal of gastroenterology. 2021;(6):1156-1181
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Abstract
INTRODUCTION Constipation is commonly treated with over-the-counter (OTC) products whose efficacy and safety remain unclear. We performed a systematic review of OTC therapies for chronic constipation and provide evidence-based recommendations. METHODS We searched PubMed and Embase for randomized controlled trials of ≥4-week duration that evaluated OTC preparations between 2004 and 2020. Studies were scored using the US Preventive Services Task Force criteria (0-5 scale) including randomization, blinding, and withdrawals. The strengths of evidence were adjudicated within each therapeutic category, and recommendations were graded (A, B, C, D, and I) based on the level of evidence (level I, good; II, fair; or III, poor). RESULTS Of 1,297 studies identified, 41 met the inclusion criteria. There was good evidence (grade A recommendation) for the use of the osmotic laxative polyethylene glycol (PEG) and the stimulant senna; moderate evidence (grade B) for psyllium, SupraFiber, magnesium salts, stimulants (bisacodyl and sodium picosulfate), fruit-based laxatives (kiwi, mango, prunes, and ficus), and yogurt with galacto-oligosaccharide/prunes/linseed oil; and insufficient evidence (grade I) for polydextrose, inulin, and fructo-oligosaccharide. Diarrhea, nausea, bloating, and abdominal pain were common adverse events, but no serious adverse events were reported. DISCUSSION The spectrum of OTC products has increased and quality of evidence has improved, but methodological issues including variability in study design, primary outcome measures, trial duration, and small sample sizes remain. We found good evidence to recommend polyethylene glycol or senna as first-line laxatives and moderate evidence supporting fiber supplements, fruits, stimulant laxatives, and magnesium-based products. For others, further validation with more rigorously designed studies is warranted.
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Candidacy of adult patients with short bowel syndrome for treatment with glucagon-like peptide-2 analogues: A systematic analysis of a single centre cohort.
Pironi, L, Sasdelli, AS, Venerito, FM, Musio, A, Pazzeschi, C, Guidetti, M
Clinical nutrition (Edinburgh, Scotland). 2021;(6):4065-4074
Abstract
BACKGROUND AND AIMS The glucagon-like peptide-2 (GLP-2) analogue, teduglutide, allows to reduce the intravenous supplementation (IVS) dependency of patients with short bowel syndrome and intestinal failure (SBS-IF). The rate of candidacy of SBS-IF patients for the treatment is unknown. The candidacy for teduglutide treatment of our patient cohort was investigated by a systematic analysis. METHODS The indications, contraindications, special warnings and precautions for use of teduglutide, listed in the drug monographs and in the phase-III trial protocol were adopted to categorize the patients as non-candidates (NC), potential candidates (PC) or straight candidates (SC) for the treatment. All the SBS-IF adult patients who were cured at our centre were assessed according to their clinical status on January 1st, 2020. RESULTS Seventy-nine patients were evaluated: 34.2% were NC due to risk of digestive malignancy, recent history of any other cancer, or listing for intestinal transplantation; 30.4% were PC, because of other premalignant conditions, risk of intestinal obstruction, entero-cutaneous fistulas, or severe co-morbidities; 35.4% were SC. The SC group showed the lowest requirement of IVS: the lowest number of days of infusion per week (p = 0.0054), the lowest amount of energy (p = 0.0110) and volume (p = 0.0136). CONCLUSIONS This systematic analysis allowed a pragmatic categorization of the candidacy of patients with SBS-IF for GLP-2 analogue treatment. The SC group appeared to have the highest probability of a successful response to the treatment. A systematic analysis of SBS-IF patient candidate for GLP-2 analogue therapy would allow a homogeneous patient selection and facilitate the worldwide comparison of the results of clinical practice and research.