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Interventions for treating iron deficiency anaemia in inflammatory bowel disease.
Gordon, M, Sinopoulou, V, Iheozor-Ejiofor, Z, Iqbal, T, Allen, P, Hoque, S, Engineer, J, Akobeng, AK
The Cochrane database of systematic reviews. 2021;(1):CD013529
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Abstract
BACKGROUND Inflammatory bowel disease affects approximately seven million people globally. Iron deficiency anaemia can occur as a common systemic manifestation, with a prevalence of up to 90%, which can significantly affect quality of life, both during periods of active disease or in remission. It is important that iron deficiency anaemia is treated effectively and not be assumed to be a normal finding of inflammatory bowel disease. The various routes of iron administration, doses and preparations present varying advantages and disadvantages, and a significant proportion of people experience adverse effects with current therapies. Currently, no consensus has been reached amongst physicians as to which treatment path is most beneficial. OBJECTIVES The primary objective was to evaluate the efficacy and safety of the interventions for the treatment of iron deficiency anaemia in people with inflammatory bowel disease. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, and two other databases on 21st November 2019. We also contacted experts in the field and searched references of trials for any additional trials. SELECTION CRITERIA Randomised controlled trials investigating the effectiveness and safety of iron administration interventions compared to other iron administration interventions or placebo in the treatment of iron deficiency anaemia in inflammatory bowel disease. We considered both adults and children, with studies reporting outcomes of clinical, endoscopic, histologic or surgical remission as defined by study authors. DATA COLLECTION AND ANALYSIS Two review authors independently conducted data extraction and 'Risk of bias' assessment of included studies. We expressed dichotomous and continuous outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using the GRADE methodology. MAIN RESULTS We included 11 studies (1670 randomised participants) that met the inclusion criteria. The studies compared intravenous iron sucrose vs oral iron sulphate (2 studies); oral iron sulphate vs oral iron hydroxide polymaltose complex (1 study); oral iron fumarate vs intravenous iron sucrose (1 study); intravenous ferric carboxymaltose vs intravenous iron sucrose (1 study); erythropoietin injection + intravenous iron sucrose vs intravenous iron sucrose + injection placebo (1 study); oral ferric maltol vs oral placebo (1 study); oral ferric maltol vs intravenous ferric carboxymaltose (1 study); intravenous ferric carboxymaltose vs oral iron sulphate (1 study); intravenous iron isomaltoside vs oral iron sulphate (1 study); erythropoietin injection vs oral placebo (1 study). All studies compared participants with CD and UC together, as well as considering a range of disease activity states. The primary outcome of number of responders, when defined, was stated to be an increase in haemoglobin of 20 g/L in all but two studies in which an increase in 10g/L was used. In one study comparing intravenous ferric carboxymaltose and intravenous iron sucrose, moderate-certainty evidence was found that intravenous ferric carboxymaltose was probably superior to intravenous iron sucrose, although there were responders in both groups (150/244 versus 118/239, RR 1.25, 95% CI 1.06 to 1.46, number needed to treat for an additional beneficial outcome (NNTB) = 9). In one study comparing oral ferric maltol to placebo, there was low-certainty evidence of superiority of the iron (36/64 versus 0/64, RR 73.00, 95% CI 4.58 to 1164.36). There were no other direct comparisons that found any difference in the primary outcomes, although certainty was low and very low for all outcomes, due to imprecision from sparse data and risk of bias varying between moderate and high risk. The reporting of secondary outcomes was inconsistent. The most common was the occurrence of serious adverse events or those requiring withdrawal of therapy. In no comparisons was there a difference seen between any of the intervention agents being studied, although the certainty was very low for all comparisons made, due to risk of bias and significant imprecision due to the low numbers of events. Time to remission, histological and biochemical outcomes were sparsely reported in the studies. None of the other secondary outcomes were reported in any of the studies. An analysis of all intravenous iron preparations to all oral iron preparations showed that intravenous administration may lead to more responders (368/554 versus 205/373, RR 1.17, 95% CI 1.05 to 1.31, NNTB = 11, low-certainty due to risk of bias and inconsistency). Withdrawals due to adverse events may be greater in oral iron preparations vs intravenous (15/554 versus 31/373, RR 0.39, 95% CI 0.20 to 0.74, low-certainty due to risk of bias, inconsistency and imprecision). AUTHORS' CONCLUSIONS Intravenous ferric carboxymaltose probably leads to more people having resolution of IDA (iron deficiency anaemia) than intravenous iron sucrose. Oral ferric maltol may lead to more people having resolution of IDA than placebo. We are unable to draw conclusions on which of the other treatments is most effective in IDA with IBD (inflammatory bowel disease) due to low numbers of studies in each comparison area and clinical heterogeneity within the studies. Therefore, there are no other conclusions regarding the treatments that can be made and certainty of all findings are low or very low. Overall, intravenous iron delivery probably leads to greater response in patients compared with oral iron, with a NNTB (number needed to treat) of 11. Whilst no serious adverse events were specifically elicited with any of the treatments studied, the numbers of reported events were low and the certainty of these findings very low for all comparisons, so no conclusions can be drawn. There may be more withdrawals due to such events when oral is compared with intravenous iron delivery. Other outcomes were poorly reported and once again no conclusions can be made as to the impact of IDA on any of these outcomes. Given the widespread use of many of these treatments in practice and the only guideline that exists recommending the use of intravenous iron in favour of oral iron, research to investigate this key issue is clearly needed. Considering the current ongoing trials identified in this review, these are more focussed on the impact in specific patient groups (young people) or on other symptoms (such as fatigue). Therefore, there is a need for studies to be performed to fill this evidence gap.
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Assessment of Vedolizumab Disease-Drug-Drug Interaction Potential in Patients With Inflammatory Bowel Diseases.
Sun, W, Lirio, RA, Schneider, J, Aubrecht, J, Kadali, H, Baratta, M, Gulati, P, Suri, A, Lin, T, Vasudevan, R, et al
Clinical pharmacology in drug development. 2021;(7):734-747
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Abstract
Disease-drug-drug interactions (DDDIs) have been identified in some inflammatory diseases in which elevated proinflammatory cytokines can downregulate the expression of cytochrome P450 (CYP) enzymes, potentially increasing systemic exposure to drugs metabolized by CYPs. Following anti-inflammatory treatments, CYP expression may return to normal, resulting in reduced drug exposure and diminished clinical efficacy. Vedolizumab has a well-established positive benefit-risk profile in patients with ulcerative colitis (UC) or Crohn's disease (CD) and has no known systemic immunosuppressive activity. A stepwise assessment was conducted to evaluate the DDDI potential of vedolizumab to impact exposure to drugs metabolized by CYP3A through cytokine modulation. First, a review of published data revealed that patients with UC or CD have elevated cytokine concentrations relative to healthy subjects; however, these concentrations remained below those reported to impact CYP expression. Exposure to drugs metabolized via CYP3A also appeared comparable between patients and healthy subjects. Second, serum samples from patients with UC or CD who received vedolizumab for 52 weeks were analyzed and compared with healthy subjects. Cytokine concentrations and the 4β-hydroxycholesterol-to-cholesterol ratio, an endogenous CYP3A4 biomarker, were comparable between healthy subjects and patients both before and during vedolizumab treatment. Finally, a medical review of postmarketing DDDI cases related to vedolizumab from the past 6 years was conducted and did not show evidence of any true DDDIs. Our study demonstrated the lack of clinically meaningful effects of disease or vedolizumab treatment on the exposure to drugs metabolized via CYP3A through cytokine modulation in patients with UC or CD.
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Effects of fiber intake on intestinal pH, transit, and predicted oral mesalamine delivery in patients with ulcerative colitis.
Yao, CK, Burgell, RE, Taylor, KM, Ward, MG, Friedman, AB, Barrett, JS, Muir, JG, Gibson, PR
Journal of gastroenterology and hepatology. 2021;(6):1580-1589
Abstract
BACKGROUND AND AIM Limited data are available on the effects of fermentable fiber in altering intestinal pH and transit to predict efficacy-based delivery profiles of pH-dependent mesalamine coatings in ulcerative colitis (UC). This study aimed to examine regional pH and transit after acute changes in fermentable fiber intake in quiescent UC patients and their effects on drug release systems. METHODS In a randomized, double-blind study, 18 patients with quiescent UC and 10 healthy controls were supplied meals high (13 g) or low (≤ 2 g) in fermentable fiber and subsequently ingested a wireless pH-motility capsule. After a ≥ 3-day washout, they crossed over to the other diet. Measurements of intestinal pH and transit were used to predict drug release for the various pH-dependent coatings. RESULTS Increasing fermentable fiber intake lowered overall (median 6.2 [6.1-6.7] vs low: 6.9 [range or interquartile range: 6.4-7.4]; P = 0.01) and distal pH (7.8 [7.3-8.1] vs 8.2 [8.0-8.5]; P = 0.04) in controls. In UC patients, only cecal pH was decreased (high: 5.1 [4.8-5.5] vs low: 5.5 [5.3-5.7]; P < 0.01). Colonic transit in the UC cohort varied widely after a low-fiber intake but tended to normalize after the high fermentable fiber intake. Hypothetical coating dissolution profiles were heterogeneous in UC patients, with a multi-matrix delayed release system having the highest likelihood of patients (20-40%) with incomplete dissolution, and predominant small intestinal dissolution predicted for Eudragit L (94% patients) and S (44-69%). CONCLUSIONS Patients with quiescent UC have abnormalities in intestinal pH and transit in response to acute changes in fermentable fiber intake. These have potentially detrimental effects on predicted luminal release patterns of pH-dependent 5-aminosalicylic acid release systems.
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Breaking the therapeutic ceiling in drug development in ulcerative colitis.
Alsoud, D, Verstockt, B, Fiocchi, C, Vermeire, S
The lancet. Gastroenterology & hepatology. 2021;(7):589-595
Abstract
Increased knowledge of the intricate pathogenesis of ulcerative colitis has triggered an advance in drug development during the past two decades, resulting in the advent of several biological agents and small-molecule therapies. Although the increase in therapeutic options is positive, remission rates of patients with ulcerative colitis given new therapeutic agents in induction trials remain at a modest 20-30%, seemingly facing a so-called therapeutic ceiling. This therapeutic ceiling requires a critical appraisal and highlights the need for alternative strategies for drug development. In this Review, we objectively itemise the boundaries of therapeutic efficacy in ulcerative colitis, provide possible explanations for the shortcomings of current strategies, and propose solutions to achieve better therapeutic outcomes in ulcerative colitis.
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Effects of saffron supplementation on oxidative/antioxidant status and severity of disease in ulcerative colitis patients: A randomized, double-blind, placebo-controlled study.
Tahvilian, N, Masoodi, M, Faghihi Kashani, A, Vafa, M, Aryaeian, N, Heydarian, A, Hosseini, A, Moradi, N, Farsi, F
Phytotherapy research : PTR. 2021;(2):946-953
Abstract
Supplementation with saffron helps improve antioxidant status. Oxidative stress plays an important role in ulcerative colitis (UC). The present study aimed to investigate the effect of saffron supplementation on disease severity and Oxidative/Antioxidant factors in patients with UC. This randomized double-blinded study was conducted on 80 mild to moderate UC patients. Participants were randomly divided into intervention (100 mg saffron/daily) and placebo (100 mg maltodextrin/daily) groups. Of all the participants, 75 completed the study. After 8 weeks, there were significantly increased in the mean score of simple clinical colitis activity index questionnaire (3.83 ± 1.78 to 3 ± 1.60, p = .004), the serum levels of total antioxidant capacity (2.68 ± 0.90 to 2.79 ± 0.87, p = .016), superoxide dismutase (60.69 ± 9.59 to 66.30 ± 10.79, p = .009) and glutathione peroxidase (22.05 ± 14.27 to 29.67 ± 17.97, p = .011) in patients received saffron compared to the placebo group. Whereas, there was no significant difference in serum levels of malondialdehyde between the two groups. Finally, dietary saffron as an alternative therapy may effective in improving antioxidant factors and reducing the severity of disease in UC patients.
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Characterization of Creatine Kinase Levels in Tofacitinib-Treated Patients with Ulcerative Colitis: Results from Clinical Trials.
Panaccione, R, Isaacs, JD, Chen, LA, Wang, W, Marren, A, Kwok, K, Wang, L, Chan, G, Su, C
Digestive diseases and sciences. 2021;(8):2732-2743
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Abstract
BACKGROUND Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Creatine kinase (CK) levels and CK-related adverse events (AEs) in tofacitinib-treated patients with UC were evaluated. METHODS Data were analyzed for three UC cohorts: Induction (phase 2 and 3 induction studies); Maintenance (phase 3 maintenance study); Overall [patients who received tofacitinib 5 or 10 mg twice daily (b.d.) in phase 2, phase 3, or open-label, long-term extension studies; data at November 2017]. Clinical trial data for tofacitinib-treated patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis are presented for contextualization. RESULTS Week 8 mean change from baseline CK with tofacitinib 10 mg b.d. induction therapy was 91.1 U/L (95% CI, 48.1-134.1) versus 19.2 U/L (8.5-29.9) with placebo. Among patients completing induction with 10 mg b.d. and re-randomized to 52 weeks of maintenance therapy, mean increases from induction baseline to the end of maintenance were 35.9 (8.1-63.7), 90.3 (51.9-128.7), and 115.6 U/L (91.6-139.7), with placebo, 5 and 10 mg b.d., respectively. The incidence rate (unique patients with events per 100 patient-years) for AEs of CK elevation in the tofacitinib-treated UC Overall cohort was 6.6 versus 2.2, 6.5, and 3.7 for tofacitinib-treated patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis, respectively. No serious AEs of CK elevation or AEs of myopathy occurred in UC studies. CONCLUSIONS In patients with UC, CK elevations with tofacitinib appeared reversible and not associated with clinically significant AEs. UC findings were consistent with tofacitinib use in other inflammatory diseases. TRIAL REGISTRATION NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612; NCT01262118; NCT01484561; NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01059864; NCT01164579; NCT00976599; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT00413699; NCT00661661; NCT01710046; NCT00678210; NCT01276639; NCT01309737; NCT01241591; NCT01186744; NCT01163253; NCT01877668; NCT01882439; NCT01976364.
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Oral Sucrosomial Iron Is as Effective as Intravenous Ferric Carboxy-Maltose in Treating Anemia in Patients with Ulcerative Colitis.
Bertani, L, Tricò, D, Zanzi, F, Baiano Svizzero, G, Coppini, F, de Bortoli, N, Bellini, M, Antonioli, L, Blandizzi, C, Marchi, S
Nutrients. 2021;(2)
Abstract
Anemia is a frequent complication of ulcerative colitis, and is frequently caused by iron deficiency. Oral iron supplementation displays high rates of gastrointestinal adverse effects. However, the formulation of sucrosomial iron (SI) has shown higher tolerability. We performed a prospective study to compare the effectiveness and tolerability of oral SI and intravenous ferric carboxy-maltose (FCM) in patients with ulcerative colitis in remission and mild-to-moderate anemia. Patients were randomized 1:1 to receive 60 mg/day for 8 weeks and then 30 mg/day for 4 weeks of oral SI or intravenous 1000 mg of FCM at baseline. Hemoglobin and serum levels of iron and ferritin were assessed after 4, 8, and 12 weeks from baseline. Hemoglobin and serum iron increased in both groups after 4 weeks of therapy, and remained stable during follow up, without significant treatment or treatment-by-time interactions (p = 0.25 and p = 0.46 for hemoglobin, respectively; p = 0.25 and p = 0.26 for iron, respectively). Serum ferritin did not increase over time during SI supplementation, while it increased in patients treated with FCM (treatment effect, p = 0.0004; treatment-by-time interaction effect, p = 0.0002). Overall, this study showed that SI and FCM displayed similar effectiveness and tolerability for treatment of mild-to-moderate anemia in patients with ulcerative colitis under remission.
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Two-year effectiveness and safety of golimumab in ulcerative colitis: An IG-IBD study.
Pugliese, D, Privitera, G, Rogai, F, Variola, A, Viola, A, Laterza, L, Privitera, AC, Allocca, M, Bossa, F, Cappello, M, et al
United European gastroenterology journal. 2021;(1):102-109
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Abstract
BACKGROUND Few data exist regarding the long-term effectiveness of golimumab in ulcerative colitis. No data have been reported on real-world continuous clinical response. OBJECTIVE This study aimed to describe the long-term outcomes in a large cohort of patients on golimumab who had ulcerative colitis. METHODS Consecutive patients with active ulcerative colitis, started on golimumab, were enrolled and prospectively followed up. The primary end point was to evaluate the long-term persistence on golimumab therapy. RESULTS A total of 173 patients with ulcerative colitis were studied. Of these, 79.2% were steroid dependent, and 46.3% were naïve to anti-tumour necrosis factor alpha agents. The median duration of golimumab therapy was 52 weeks (range: 4-142 weeks). The cumulative probability of maintaining golimumab treatment was 47.3% and 22.5% at 54 and 108 weeks, respectively. Biological-naïve status (odds ratio [OR] = 3.02, 95% confidence interval [CI]: 1.44-6.29; p = 0.003) and being able to discontinue steroids at Week 8 (OR = 3.32, 95% CI: 1.34-8.30; p = 0.010) and Week 14 (OR = 2.94, 95% CI: 1.08-8.02; p = 0.036) were associated with longer persistence on therapy. At Week 54, 65/124 (52.4%) postinduction responders were in continuous clinical response. A continuous clinical response was associated with a lower likelihood of golimumab discontinuation throughout the subsequent year of therapy (p < 0.01). Overall, 40 (23.1%) patients were in clinical remission at the last follow-up visit. Twenty-six adverse events were recorded, leading to golimumab withdrawal in 9.2% of patients. CONCLUSIONS Biological-naïve status and not requiring steroids at Weeks 8 and 14 seem to be associated with a longer persistence on golimumab therapy in ulcerative colitis.
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Population Pharmacokinetics of Tofacitinib in Patients With Moderate to Severe Ulcerative Colitis.
Vong, C, Martin, SW, Deng, C, Xie, R, Ito, K, Su, C, Sandborn, WJ, Mukherjee, A
Clinical pharmacology in drug development. 2021;(3):229-240
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Abstract
Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We characterized tofacitinib pharmacokinetics in patients with moderate to severe UC, and the effects of covariates on variability in pharmacokinetic parameter estimates. Data were pooled from 1 8-week phase 2 and 2 8-week phase 3 induction studies, and a 52-week phase 3 maintenance study (N = 1096). Population pharmacokinetic analysis was conducted using nonlinear mixed-effects modeling. Potential predictors of apparent oral clearance (CL/F) and volume of distribution (V/F) were evaluated. The PK was described by a 1-compartment model parameterized in terms of CL/F (26.3 L/hour [h]) and V/F (115.8 L), with first-order absorption (Ka ; 9.85 h-1 ) and lag time (0.236 h). The derived elimination half-life was approximately 3.05 h. In the final model, baseline creatinine clearance, sex, and race (Asian vs non-Asian) were significant covariates for CL/F; significant covariates for V/F were age, sex, and body weight; baseline albumin and baseline Mayo score were not significant covariates. CL/F between-patient variability was estimated at 22%. Tofacitinib exposure did not change significantly over the duration of induction/maintenance treatment in patients with UC. Although statistically significant covariate effects on CL/F and V/F were observed, the magnitude of the effects are not clinically significant. Therefore, dose adjustment/restrictions for age, body weight, sex, race, or baseline disease severity are not required during tofacitinib treatment. ClinicalTrials.gov numbers: NCT00787202, NCT01465763, NCT01458951, NCT01458574.
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Chyle leak following total colectomy for ulcerative colitis: a case report and review of the literature.
Brewer, CF, Al-Abed, Y
Annals of the Royal College of Surgeons of England. 2021;(7):e231-e233
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Abstract
Chyle leak is a rare complication in colorectal surgery. It occurs due to disruption of the lymphatic drainage network in the abdomen or retroperitoneum. We describe the first reported case of chyle leak following total colectomy for inflammatory bowel disease. Our patient underwent total colectomy for severe ulcerative colitis not responsive to medical treatment. Four days postoperatively, a milky fluid was noted in the drainage bag. Analysis of the fluid confirmed chyle. The patient remained well and was successfully managed conservatively with a fat-free elemental diet and was discharged from hospital on day 12 postoperatively. A review of the literature suggests that conservative management with dietary modification is a common and effective management strategy; however, medical and surgical options exist for refractory cases.