Outcomes and adverse events in children and young adults undergoing tacrolimus therapy for steroid-refractory colitis

Watson, Sheree L.; Pensabene, Licia; Mitchell, Paul D.; Bousvaros, Athos

doi:10.1002/ibd.21418

Cited by 61 publications

(41 citation statements)

References 42 publications

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“…Thus far, several uncontrolled (9,14,15,17,19) and two placebo-controlled studies (13,18) have demonstrated that tacrolimus can induce remission in both adults (9, 13-15, 17, 18) and children (19). Another calcineurin inhibitor, CsA, is also highly active (60% to 80%) in patients with UC whose disease fails to respond to intravenous corticosteroid therapy (20).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, CsA is known to be associated with many adverse effects, such as infections, renal dysfunction, hypertension and neurological toxicity (6). Although similar adverse events, including tremors, hyperglycemia, nephrotoxicity and infection, are observed in association with tacrolimus therapy, these effects are generally mild and reversible (19)(20)(21); thus, tacrolimus can be safely administered on a long-term basis. Yamamoto et al investigated the efficacy of tacrolimus as maintenance therapy for patients with refractory UC and suggested that the administration of tacrolimus with low trough levels (5 to 10 ng/mL) as maintenance therapy may represent an alternative therapy for UC patients (22).…”

Section: Discussionmentioning

confidence: 99%

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The Efficacy of Oral Tacrolimus in Patients with Moderate/Severe Ulcerative Colitis not Receiving Concomitant Corticosteroid Therapy

et al. 2013

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Objective The calcineurin inhibitor tacrolimus has been shown to be safe and effective as salvage therapy for steroid-refractory ulcerative colitis (UC). Since differences in the onset of action between various agents are thought to influence the achievement and maintenance of disease remission, top-down or accelerated stepup therapy with tacrolimus may be useful. However, the efficacy of tacrolimus in moderate to severe UC patients not receiving concomitant steroids remains unknown. Methods Ten patients (11 attacks) with active, moderate to severe UC were treated with oral tacrolimus at a dose of 0.1 mg/kg body weight daily. The dosages were adapted to maintain trough whole-blood levels of 10 to 15 ng/mL to induce remission and 5 to 10 ng/mL to maintain remission. Lichtiger scores, the incidence of adverse effects (serum creatinine and glucose) and long-term outcomes were assessed. Results At four weeks after the initiation of tacrolimus therapy, clinical remissions were observed for eight attacks (72.7%) and clinical responses were demonstrated for three attacks. At 12 weeks after the initiation of tacrolimus treatment, clinical remissions were achieved for nine attacks (90%). After a mean follow-up of 10.4 months, clinical remissions were maintained for eight of 11 attacks. During the tacrolimus treatment, the serum creatinine and glucose levels were not significantly elevated. Conclusion Oral tacrolimus is a safe and effective therapy for the treatment of moderate to severe UC in patients not receiving concomitant treatment with systemic steroids. Although further studies are required to establish the efficacy and safety of oral tacrolimus therapy in patients with UC, oral tacrolimus may represent a top-down or accelerated step-up treatment option for patients with moderate to severe UC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Efficacy of Oral Tacrolimus in Patients with Moderate/Severe Ulcerative Colitis not Receiving Concomitant Corticosteroid Therapy

et al. 2013

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“…Effectiveness data were drawn from a number of sources including RCTs and non-randomised studies. 49,[87][88][89][90][91][92][93][94][95][96][97][98][99] The effectiveness of IFX in inducing and maintaining response and remission was based on the results of the ACT1 and ACT2 studies. 49 The rate of developing colorectal cancer was derived from an observational study.…”

Section: Assessment Of Cost-effectivenessmentioning

confidence: 99%

Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy (including a review of TA140 and TA262): clinical effectiveness systematic review and economic model

Archer

Tappenden

Ren

et al. 2016

Health Technol Assess

143

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BackgroundUlcerative colitis (UC) is the most common form of inflammatory bowel disease in the UK. UC can have a considerable impact on patients’ quality of life. The burden for the NHS is substantial.ObjectivesTo evaluate the clinical effectiveness and safety of interventions, to evaluate the incremental cost-effectiveness of all interventions and comparators (including medical and surgical options), to estimate the expected net budget impact of each intervention, and to identify key research priorities.Data sourcesPeer-reviewed publications, European Public Assessment Reports and manufacturers’ submissions. The following databases were searched from inception to December 2013 for clinical effectiveness searches and from inception to January 2014 for cost-effectiveness searches for published and unpublished research evidence: MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, The Cochrane Library including the Cochrane Systematic Reviews Database, Cochrane Controlled Trials Register, Database of Abstracts of Reviews of Effects, the Health Technology Assessment database and NHS Economic Evaluation Database; ISI Web of Science, including Science Citation Index, and the Conference Proceedings Citation Index-Science and Bioscience Information Service Previews. The US Food and Drug Administration website and the European Medicines Agency website were also searched, as were research registers, conference proceedings and key journals.Review methodsA systematic review [including network meta-analysis (NMA)] was conducted to evaluate the clinical effectiveness and safety of named interventions. The health economic analysis included a review of published economic evaluations and the development of a de novo model.ResultsTen randomised controlled trials were included in the systematic review. The trials suggest that adult patients receiving infliximab (IFX) [Remicade®, Merck Sharp & Dohme Ltd (MSD)], adalimumab (ADA) (Humira®, AbbVie) or golimumab (GOL) (Simponi®, MSD) were more likely to achieve clinical response and remission than those receiving placebo (PBO). Hospitalisation data were limited, but suggested more favourable outcomes for ADA- and IFX-treated patients. Data on the use of surgical intervention were sparse, with a potential benefit for intervention-treated patients. Data were available from one trial to support the use of IFX in paediatric patients. Safety issues identified included serious infections, malignancies and administration site reactions. Based on the NMA, in the induction phase, all biological treatments were associated with statistically significant beneficial effects relative to PBO, with the greatest effect associated with IFX. For patients in response following induction, all treatments except ADA and GOL 100 mg at 32–52 weeks were associated with beneficial effects when compared with PBO, although these were not significant. The greatest effects at 8–32 and 32–52 weeks were associated with 100 mg of GOL and 5 mg/kg of IFX, respectively. For patients in remission following induction, all treatments except ADA at 8–32 weeks and GOL 50 mg at 32–52 weeks were associated with beneficial effects when compared with PBO, although only the effect of ADA at 32–52 weeks was significant. The greatest effects were associated with GOL (at 8–32 weeks) and ADA (at 32–52 weeks). The economic analysis suggests that colectomy is expected to dominate drug therapies, but for some patients, colectomy may not be considered acceptable. In circumstances in which only drug options are considered, IFX and GOL are expected to be ruled out because of dominance, while the incremental cost-effectiveness ratio for ADA versus conventional treatment is approximately £50,300 per QALY gained.LimitationsThe health economic model is subject to several limitations: uncertainty associated with extrapolating trial data over a lifetime horizon, the model does not consider explicit sequential pathways of non-biological treatments, and evidence relating to complications of colectomy was identified through consideration of approaches used within previous models rather than a full systematic review.ConclusionsAdult patients receiving IFX, ADA or GOL were more likely to achieve clinical response and remission than those receiving PBO. Further data are required to conclusively demonstrate the effect of interventions on hospitalisation and surgical outcomes. The economic analysis indicates that colectomy is expected to dominate medical treatments for moderate to severe UC.Study registrationThis study is registered as PROSPERO CRD42013006883.FundingThe National Institute for Health Research Health Technology Assessment programme.

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“…Ninety-three percent of patients were discharged without undergoing surgery and the probability of avoiding colectomy after starting tacrolimus was 40% at 26 months. 42 We report the published experience from our group of 6 pediatric steroidrefractory patients with moderate/ severe UC who were treated with tacrolimus (0.1 mg/kg/dose twice daily) achieving blood levels between 7 and 10 ng/mL. Response was evaluated by using PUCAI scores, and all patients responded within 1 to 2 weeks.…”

Section: Tacrolimusmentioning

confidence: 99%

Management of Acute Severe Colitis in Children With Ulcerative Colitis in the Biologics Era

et al. 2016

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BACKGROUND AND OBJECTIVE: Approximately one-third of children with ulcerative colitis will experience at least 1 attack of acute severe colitis (ASC) before 15 years of age. Severe disease can be defined in children when Pediatric Ulcerative Colitis Activity Index is >65 and/or ≥6 bloody stools per day, and/or 1 of the following: tachycardia, fever, anemia, and elevated erythrocyte sedimentation rate with or without systemic toxicity. Our aim was to provide practical suggestions on the management of ASC in children. The goal of medical therapy is to avoid colectomy while preventing complications of disease, side effects of medications, and mortality. METHODS: A systematic search was carried out through Medline via PubMed to identify all articles published in English to date, based on the following keywords “ulcerative colitis,” “pediatric ulcerative colitis,” “biological therapy,” and “acute severe colitis.” Multidisciplinary clinical evaluation is recommended to identify early nonresponders to conventional treatment with intravenous corticosteroids, and to start, if indicated, second-line therapy or “rescue therapy,” such as calcineurin inhibitors (cyclosporine, tacrolimus) and anti–tumor necrosis factor molecules (infliximab). RESULTS: Pediatric Ulcerative Colitis Activity Index is a valid predictive tool that can guide clinicians in evaluating response to therapy. Surgery should be considered in the case of complications or rapid clinical deterioration during medical treatment. CONCLUSIONS: Several pitfalls may be present in the management of ASC, and a correct clinical and therapeutic approach is recommended to reduce surgical risk.

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Outcomes and adverse events in children and young adults undergoing tacrolimus therapy for steroid-refractory colitis

Cited by 61 publications

References 42 publications

The Efficacy of Oral Tacrolimus in Patients with Moderate/Severe Ulcerative Colitis not Receiving Concomitant Corticosteroid Therapy

The Efficacy of Oral Tacrolimus in Patients with Moderate/Severe Ulcerative Colitis not Receiving Concomitant Corticosteroid Therapy

Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy (including a review of TA140 and TA262): clinical effectiveness systematic review and economic model

Management of Acute Severe Colitis in Children With Ulcerative Colitis in the Biologics Era

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