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1.
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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Efficacy and safety of pharmacological cachexia interventions: systematic review and network meta-analysis.
Saeteaw, M, Sanguanboonyaphong, P, Yoodee, J, Craft, K, Sawangjit, R, Ngamphaiboon, N, Shantavasinkul, PC, Subongkot, S, Chaiyakunapruk, N
BMJ supportive & palliative care. 2021;(1):75-85
Abstract
AIMS: Randomised controlled trials (RCTs) demonstrated benefits of pharmacological interventions for cachexia in improving weight and appetite. However, comparative efficacy and safety are not available. We conducted a systematic review and network meta-analysis (NMA) to evaluate the relative efficacy and safety of pharmacological interventions for cachexia. METHODS PubMed, EmBase, Cochrane, and ClinicalTrials.gov were searched for RCTs until October 2019. Key outcomes were total body weight (TBW) improvement, appetite (APP) score and serious adverse events. Two reviewers independently extracted data and assessed risk of bias. NMA was performed to estimate weight gain and APP score increase at 8 weeks, presented as mean difference (MD) or standardised MD with 95% CI. RESULTS 80 RCTs (10 579 patients) with 12 treatments were included. Majority is patients with cancer (7220). Compared with placebo, corticosteroids, high-dose megestrol acetate combination (Megace_H_Com) (≥400 mg/day), medroxyprogesterone, high-dose megestrol acetate (Megace_H) (≥400 mg/day), ghrelin mimetic and androgen analogues (Androgen) were significantly associated with MD of TBW of 6.45 (95% CI 2.45 to 10.45), 4.29 (95% CI 2.23 to 6.35), 3.18 (95% CI 0.94 to 5.41), 2.66 (95% CI 1.47 to 3.85), 1.73 (95% CI 0.27 to 3.20) and 1.50 (95% CI 0.56 to 2.44) kg. For appetite improvement, Megace_H_Com, Megace_H and Androgen significantly improved standardised APP score, compared with placebo. There is no significant difference in serious adverse events from all interventions compared with placebo. CONCLUSIONS Our findings suggest that several pharmacological interventions have potential to offer benefits in treatment of cachexia especially Megace_H and short-term use corticosteroids. Nonetheless, high-quality comparative studies to compare safety and efficacy are warranted for better management of cachexia.
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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 fragility of randomized placebo-controlled trials for irritable bowel syndrome.
Williams, MO, Sedarous, M, Dennis, B, Dlamini, V, Nwaiwu, O, Nguyen, L, Okafor, PN
Neurogastroenterology and motility. 2021;(8):e14166
Abstract
BACKGROUND The fragility index (FI) represents the number of participants whose status in a trial would have to change from a non-event (not experiencing the primary endpoint) to an event (experiencing the primary endpoint) in order to turn a statistically significant result into a non-significant result. We sought to evaluate the fragility indices of irritable bowel syndrome [IBS-mixed (IBS-M), IBS-constipation (IBS-C), & IBS-diarrhea (IBS-D)] trials. METHODS Irritable bowel syndrome trials published in high-impact journals were identified from Medline. Trials had to be in adults, randomized, parallel-armed, with at least one statistically significant binary outcome, and an achieved primary endpoint of therapeutic efficacy. FI and correlation coefficients were calculated, and regression modeling used to identify predictors of a high FI. KEY RESULTS Twelve trials were analyzed with a median FI of 6 (range: 0-38). Median sample size in all trials was 366 (range: 44-856). Trial publication year (p = 0.71), journal impact factor (p = 0.52), duration of study (p = 0.12), and number need to treat [NNT] (p = 0.29) were not predictive of a high FI. While a lower p-value correlated with a higher FI (p = 0.039), no correlation was noted between FI and impact factor (R = -0.20, p = 0.52), trial publication year (R = 0.12, p = 0.71), duration of trial (R = -0.46, p = 0.13), NNT (R = -0.34, p = 0.29), and sample size (R = 0.23, p = 0.5). The highest FI was in a Ramosetron trial (FI = 30) for IBS-D. CONCLUSION & INFERENCES A median of six participants is needed to nullify results in the included IBS trials suggesting how easily statistical significance based on a threshold p-value may be overturned.
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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.
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Ventricular voltage-gated ion channels: Detection, characteristics, mechanisms, and drug safety evaluation.
Chen, L, He, Y, Wang, X, Ge, J, Li, H
Clinical and translational medicine. 2021;(10):e530
Abstract
Cardiac voltage-gated ion channels (VGICs) play critical roles in mediating cardiac electrophysiological signals, such as action potentials, to maintain normal heart excitability and contraction. Inherited or acquired alterations in the structure, expression, or function of VGICs, as well as VGIC-related side effects of pharmaceutical drug delivery can result in abnormal cellular electrophysiological processes that induce life-threatening cardiac arrhythmias or even sudden cardiac death. Hence, to reduce possible heart-related risks, VGICs must be acknowledged as important targets in drug discovery and safety studies related to cardiac disease. In this review, we first summarize the development and application of electrophysiological techniques that are employed in cardiac VGIC studies alone or in combination with other techniques such as cryoelectron microscopy, optical imaging and optogenetics. Subsequently, we describe the characteristics, structure, mechanisms, and functions of various well-studied VGICs in ventricular myocytes and analyze their roles in and contributions to both physiological cardiac excitability and inherited cardiac diseases. Finally, we address the implications of the structure and function of ventricular VGICs for drug safety evaluation. In summary, multidisciplinary studies on VGICs help researchers discover potential targets of VGICs and novel VGICs in heart, enrich their knowledge of the properties and functions, determine the operation mechanisms of pathological VGICs, and introduce groundbreaking trends in drug therapy strategies, and drug safety evaluation.
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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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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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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.