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The British Journal of Ophthalmology Aug 2020Biologics are increasingly used in management of Behçet's Disease (BD) including ocular BD, but the evidence base is limited, mostly from studies of uveitis and BD...
BACKGROUND
Biologics are increasingly used in management of Behçet's Disease (BD) including ocular BD, but the evidence base is limited, mostly from studies of uveitis and BD manifestations.
OBJECTIVE
To review the evidence base for biologics in the treatment of ocular BD.
METHODS
Systematic literature search was made using exploded key words-Behçet's, ocular, biologics in MEDLINE, Cochrane library, Database of Abstracts Reviews and Effects, Clinical Trials.gov, Science Direct and Google Scholar. There was no limitation on region, language or date (Search updated 16th October 2018). Literature retrieval was restricted to randomised controlled trials (RCTs) of biologics.
RESULTS
Of 237 papers retrieved, eight met the inclusion criteria. RCTs on interferon alpha 2a (INF-α 2a), adalimumab, secukinumab, gevokizumab, rituximab and daclizumab were retrieved (two for adalimumab and gevokizumab). The outcome measures were not met for secukinumab, daclizumab and gevokizumab. Rituximab and INF-α 2a showed promising preliminary results but sufficiently powered RCTs are needed to provide adequate evidence of efficacy. The RCTs on adalimumab did not evaluate efficacy for BD uveitis specifically, hence are of limited value for this review.
CONCLUSION
Some biologics show promise in treating BD uveitis, but more RCTs are needed for firm conclusions about efficacy. A phase IV study or, registry of adalimumab could provide data on its efficacy in BD uveitis compared to other forms.
Topics: Adalimumab; Antibodies, Monoclonal, Humanized; Behcet Syndrome; Biological Factors; Biological Therapy; Daclizumab; Humans; Interferon-alpha; Rituximab; Uveitis
PubMed: 31676596
DOI: 10.1136/bjophthalmol-2019-314154 -
Rheumatology International Jan 2019The aim of this study is to compare the efficacy and safety of biological therapy with cyclosporin A (CsA), azathioprine (AZA), or placebo in uveitis flares and other... (Comparative Study)
Comparative Study
Efficacy and safety of biological therapy compared to synthetic immunomodulatory drugs or placebo in the treatment of Behçet's disease associated uveitis: a systematic review.
The aim of this study is to compare the efficacy and safety of biological therapy with cyclosporin A (CsA), azathioprine (AZA), or placebo in uveitis flares and other ocular outcomes in patients with Behçet disease. A comprehensive and sensitive search in MEDLINE, EMBASE, and the Cochrane Library was performed. We selected articles including: (1) adult patients with Behçet's and uveitis; (2) on biological therapies; (3) placebo or active control with CsA or AZA; (4) analyzing efficacy (number of uveitis flares, macular edema, etc.) and/or safety outcomes. Meta-analyses, systematic reviews, clinical trials, and observational studies with > 10 patients were included. The selection, data collection and quality assessment (Oxford scale) was carried out by 2 reviewers independently. Nine articles of moderate quality were included (6 randomized clinical trials and 3 retrospective studies) involving 378 patients. Most of them, apart from the study drugs received systemic corticosteroids and other immunosuppressant drugs. Infliximab was more effective than CsA in reducing short-term uveitis flares and severe complications of retinal vasculitis in the long term. Rituximab was similar to a combination of cytotoxic drugs in improving inflammatory activity. In patients with active uveitis adalimumab was associated with a lower risk of uveitic flare or visual impairment, and in patients with inactive uveitis to a significantly lowered the risk of flare upon corticosteroid withdrawal. Secukinumab and daclizumab were not superior to placebo in reducing uveitis flares, like interferonα compared to other drugs. Our results highlight the need for better designed comparative studies on Behçet's uveitis.
Topics: Behcet Syndrome; Biological Products; Humans; Immunosuppressive Agents; Synthetic Drugs; Treatment Outcome; Uveitis
PubMed: 30421105
DOI: 10.1007/s00296-018-4193-z -
Current Medical Research and Opinion Aug 2018To assess the comparative efficacy and safety of cladribine tablets versus alternative disease modifying treatments (DMTs) in patients with active relapsing-remitting... (Comparative Study)
Comparative Study
OBJECTIVE
To assess the comparative efficacy and safety of cladribine tablets versus alternative disease modifying treatments (DMTs) in patients with active relapsing-remitting multiple sclerosis (RRMS), and in a subgroup with high disease activity (HRA + DAT), using systematic literature review (SLR) and network meta-analysis (NMA).
METHODS
MEDLINE, Embase, MEDLINE In-Process and CENTRAL databases were systematically searched to identify English-language publications of relevant studies of approved DMTs for RRMS. Searches were conducted from database inception to January 2017. Conference websites and trial registries were also searched. NMA considered the effects of DMTs on annualized relapse rate (ARR), confirmed disease progression (CDP), no evidence of disease activity (NEDA) and safety.
RESULTS
Of 10,825 articles retrieved and screened, 44 studies assessing 12 DMTs contributed to the NMA. In patients with active RRMS, cladribine tablets were associated with a significant 58% reduction in ARR versus placebo (p < .05); cladribine tablets were similar or significantly better than other DMT regimens and ranked fourth among DMTs, behind alemtuzumab, natalizumab and ocrelizumab. For CDP for 6 months and NEDA, improvements with cladribine tablets were significantly greater than those of placebo (p < .05), with no comparator DMT demonstrating significantly better results. Similar findings were reported in the HRA + DAT population. Overall adverse event risk for cladribine tablets did not differ significantly from that of placebo and most alternative DMTs.
CONCLUSION
In this first NMA to consider cladribine tablets, ocrelizumab and daclizumab for treatment of RRMS, cladribine tablets are a comparatively effective and safe alternative to other DMTs in both active RRMS and HRA + DAT populations.
Topics: Alemtuzumab; Cladribine; Humans; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Network Meta-Analysis; Tablets
PubMed: 29149804
DOI: 10.1080/03007995.2017.1407303 -
The Cochrane Database of Systematic... Apr 2017The treatment of multiple sclerosis has changed over the last 20 years. The advent of disease-modifying drugs in the mid-1990s heralded a period of rapid progress in the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The treatment of multiple sclerosis has changed over the last 20 years. The advent of disease-modifying drugs in the mid-1990s heralded a period of rapid progress in the understanding and management of multiple sclerosis. With the support of magnetic resonance imaging early diagnosis is possible, enabling treatment initiation at the time of the first clinical attack. As most of the disease-modifying drugs are associated with adverse events, patients and clinicians need to weigh the benefit and safety of the various early treatment options before taking informed decisions.
OBJECTIVES
1. to estimate the benefit and safety of disease-modifying drugs that have been evaluated in all studies (randomised or non-randomised) for the treatment of a first clinical attack suggestive of MS compared either with placebo or no treatment;2. to assess the relative efficacy and safety of disease-modifying drugs according to their benefit and safety;3. to estimate the benefit and safety of disease-modifying drugs that have been evaluated in all studies (randomised or non-randomised) for treatment started after a first attack ('early treatment') compared with treatment started after a second attack or at another later time point ('delayed treatment').
SEARCH METHODS
We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register, MEDLINE, Embase, CINAHL, LILACS, clinicaltrials.gov, the WHO trials registry, and US Food and Drug Administration (FDA) reports, and searched for unpublished studies (until December 2016).
SELECTION CRITERIA
We included randomised and observational studies that evaluated one or more drugs as monotherapy in adult participants with a first clinical attack suggestive of MS. We considered evidence on alemtuzumab, azathioprine, cladribine, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, immunoglobulins, interferon beta-1b, interferon beta-1a (Rebif®, Avonex®), laquinimod, mitoxantrone, natalizumab, ocrelizumab, pegylated interferon beta-1a, rituximab and teriflunomide.
DATA COLLECTION AND ANALYSIS
Two teams of three authors each independently selected studies and extracted data. The primary outcomes were disability-worsening, relapses, occurrence of at least one serious adverse event (AE) and withdrawing from the study or discontinuing the drug because of AEs. Time to conversion to clinically definite MS (CDMS) defined by Poser diagnostic criteria, and probability to discontinue the treatment or dropout for any reason were recorded as secondary outcomes. We synthesized study data using random-effects meta-analyses and performed indirect comparisons between drugs. We calculated odds ratios (OR) and hazard ratios (HR) along with relative 95% confidence intervals (CI) for all outcomes. We estimated the absolute effects only for primary outcomes. We evaluated the credibility of the evidence using the GRADE system.
MAIN RESULTS
We included 10 randomised trials, eight open-label extension studies (OLEs) and four cohort studies published between 2010 and 2016. The overall risk of bias was high and the reporting of AEs was scarce. The quality of the evidence associated with the results ranges from low to very low. Early treatment versus placebo during the first 24 months' follow-upThere was a small, non-significant advantage of early treatment compared with placebo in disability-worsening (6.4% fewer (13.9 fewer to 3 more) participants with disability-worsening with interferon beta-1a (Rebif®) or teriflunomide) and in relapses (10% fewer (20.3 fewer to 2.8 more) participants with relapses with teriflunomide). Early treatment was associated with 1.6% fewer participants with at least one serious AE (3 fewer to 0.2 more). Participants on early treatment were on average 4.6% times (0.3 fewer to 15.4 more) more likely to withdraw from the study due to AEs. This result was mostly driven by studies on interferon beta 1-b, glatiramer acetate and cladribine that were associated with significantly more withdrawals for AEs. Early treatment decreased the hazard of conversion to CDMS (HR 0.53, 95% CI 0.47 to 0.60). Comparing active interventions during the first 24 months' follow-upIndirect comparison of interferon beta-1a (Rebif®) with teriflunomide did not show any difference on reducing disability-worsening (OR 0.84, 95% CI 0.43 to 1.66). We found no differences between the included drugs with respect to the hazard of conversion to CDMS. Interferon beta-1a (Rebif®) and teriflunomide were associated with fewer dropouts because of AEs compared with interferon beta-1b, cladribine and glatiramer acetate (ORs range between 0.03 and 0.29, with substantial uncertainty). Early versus delayed treatmentWe did not find evidence of differences between early and delayed treatments for disability-worsening at a maximum of five years' follow-up (3% fewer participants with early treatment (15 fewer to 11.1 more)). There was important variability across interventions; early treatment with interferon beta-1b considerably reduced the odds of participants with disability-worsening during three and five years' follow-up (OR 0.52, 95% CI 0.32 to 0.84 and OR 0.57, 95% CI 0.36 to 0.89). The early treatment group had 19.6% fewer participants with relapses (26.7 fewer to 12.7 fewer) compared to late treatment at a maximum of five years' follow-up and early treatment decreased the hazard of conversion to CDMS at any follow-up up to 10 years (i.e. over five years' follow-up HR 0.62, 95% CI 0.53 to 0.73). We did not draw any conclusions on long-term serious AEs or discontinuation due to AEs because of inadequacies in the available data both in the included OLEs and cohort studies.
AUTHORS' CONCLUSIONS
Very low-quality evidence suggests a small and uncertain benefit with early treatment compared with placebo in reducing disability-worsening and relapses. The advantage of early treatment compared with delayed on disability-worsening was heterogeneous depending on the actual drug used and based on very low-quality evidence. Low-quality evidence suggests that the chances of relapse are less with early treatment compared with delayed. Early treatment reduced the hazard of conversion to CDMS compared either with placebo, no treatment or delayed treatment, both in short- and long-term follow-up. Low-quality evidence suggests that early treatment is associated with fewer participants with at least one serious AE compared with placebo. Very low-quality evidence suggests that, compared with placebo, early treatment leads to more withdrawals or treatment discontinuation due to AEs. Difference between drugs on short-term benefit and safety was uncertain because few studies and only indirect comparisons were available. Long-term safety of early treatment is uncertain because of inadequately reported or unavailable data.
Topics: Adjuvants, Immunologic; Cladribine; Cohort Studies; Crotonates; Disease Progression; Glatiramer Acetate; Humans; Hydroxybutyrates; Immunosuppressive Agents; Interferon beta-1a; Multiple Sclerosis; Nitriles; Publication Bias; Randomized Controlled Trials as Topic; Recurrence; Time Factors; Toluidines
PubMed: 28440858
DOI: 10.1002/14651858.CD012200.pub2 -
Current Medical Research and Opinion Mar 2017The introduction of disease-modifying therapies (DMTs) - with varying degrees of efficacy for reducing annual relapse rate and disability progression - has considerably... (Review)
Review
OBJECTIVE
The introduction of disease-modifying therapies (DMTs) - with varying degrees of efficacy for reducing annual relapse rate and disability progression - has considerably transformed the therapeutic landscape of relapsing-remitting multiple sclerosis (RRMS). We aim to develop rational evidence-based treatment recommendations and algorithms for the management of clinically isolated syndrome (CIS) and RRMS that conform to the healthcare system in a fast-developing economic country such as Qatar.
RESEARCH DESIGN AND METHODS
We conducted a systematic review using a comprehensive search of MEDLINE, PubMed, and Cochrane Database of Systematic Reviews (1 January 1990 through 30 September 2016). Additional searches of the American Academy of Neurology and European Committee for Treatment and Research in Multiple Sclerosis abstracts from 2012 through 2016 were performed, in addition to searches of the Food and Drug Administration and European Medicines Agency websites to obtain relevant safety information on these DMTs.
RESULTS
For each of the DMTs, the mode of action, efficacy, safety and tolerability are briefly discussed. To facilitate the interpretation, the efficacy data of the pivotal phase III trials are expressed by their most clinically useful measure of therapeutic efficacy, the number needed to treat (NNT). In addition, an overview of head-to-head trials in RRMS is provided as well as a summary of the several different RRMS management strategies (lateral switching, escalation, induction, maintenance and combination therapy) and the potential role of each DMT. Finally, algorithms were developed for CIS, active and highly active or rapidly evolving RRMS and subsequent breakthrough disease or suboptimal treatment response while on DMTs. The benefit-to-risk profiles of the DMTs, taking into account patient preference, allowed the provision of rational and safe patient-tailored treatment algorithms.
CONCLUSIONS
Recommendations and algorithms for the management of CIS and RRMS have been developed relevant to the healthcare system of this fast-developing economic country.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Daclizumab; Dimethyl Fumarate; Fingolimod Hydrochloride; Humans; Immunoglobulin G; Interferons; Multiple Sclerosis, Relapsing-Remitting; Qatar
PubMed: 27892723
DOI: 10.1080/03007995.2016.1261818 -
Annals of Medicine Aug 2017Antibody induction therapy aims at preventing acute cellular rejection by reducing T-cell proliferation and activation. We evaluated the efficacy and side effects of two... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Antibody induction therapy aims at preventing acute cellular rejection by reducing T-cell proliferation and activation. We evaluated the efficacy and side effects of two anti-interleukin-2 receptor antibodies (IL2RAs), basiliximab and daclizumab, for prevention of liver transplant rejection in adult patients.
METHODS
Randomized controlled trials (RCTs) on basiliximab or daclizumab were identified by searching multiple databases and reference lists published up to July, 2015. Endpoints included acute rejection events and mortality rates. Risk ratio (RR) and 95% confidence interval (CI) were calculated and pooled for a meta-analysis.
RESULTS
Patients treated with IL2RA-based therapy were less likely to suffer acute rejection compared to control group (steroid or steroid-free). Patients in all groups had similar mortality rate. In the subgroup analysis, basiliximab and daclizumab-based therapies did not reduced acute rejection rate. No significant difference was found in mortality rate between both types of IL-2RA treatment groups and control groups. In the subgroup analysis regarding experimental design, no significant difference in the acute rejection and mortality rates were found between "steroid plus IL2RA versus steroid" and "IL2RA versus steroid" groups.
CONCLUSION
IL2RA-based induction therapy reduces rate of acute rejection events but does not reduce mortality. However, optimal regimen relating to IL2RA-based induction therapy remains undetermined. KEY MESSAGES IL2RA-based induction therapy was effective in reduction of acute rejection events but it did not reduce mortality rate. Basiliximab-based induction therapy might be more effective than daclizumab-based induction therapy in reduction of acute rejection. No significant difference in acute rejection and mortality rate was found between types of IL2RAs or IL2RA-steroid combined therapy.
Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Basiliximab; Daclizumab; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Interleukin-2; Liver Transplantation; Male; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Treatment Outcome
PubMed: 27813419
DOI: 10.1080/07853890.2016.1257862 -
Biology of Blood and Marrow... Jun 2016Despite extensive research in the last few decades, progress in treatment of acute graft-versus-host disease (aGVHD), a common complication of allogeneic hematopoietic... (Meta-Analysis)
Meta-Analysis Review
Despite extensive research in the last few decades, progress in treatment of acute graft-versus-host disease (aGVHD), a common complication of allogeneic hematopoietic cell transplantation (HCT), has been limited and steroids continue to be the standard frontline treatment. Randomized clinical trials (RCTs) have failed to find a beneficial effect of escalating immunosuppression using additional agents. Considering the small number of RCTs, limited sample sizes, and frequent early termination because of anticipated futility, we conducted a systematic review and an aggregate data meta-analysis to explore whether a true efficacy signal has been missed because of the limitations of individual RCTs. Seven reports met our inclusion criteria. The control arm in all studies was 2 mg/kg/day prednisone (or equivalent). The additional agent(s) used in the experimental arm(s) were higher-dose steroids, antithymocyte globulin, infliximab, anti-interleukin-2 receptor antibody (daclizumab and BT563), CD5-specific immunotoxin, and mycophenolate mofetil. Random effects meta-analysis revealed no efficacy signal in pooled response rates at various times points. Overall survival at 100 days was significantly worse in the experimental arm (relative risk [RR], .83; 95% confidence interval [CI], .74 to .94; P = .004, data from 3 studies) and showed a similar trend (albeit not statistically significantly) at 1 year as well (RR, .86; 95% CI, .68 to 1.09; P = .21, data from 5 studies). In conclusion, these results argue against the value of augmented generic immunosuppression beyond steroids for frontline treatment of aGVHD and emphasize the importance of developing alternative strategies. Novel forms of immunomodulation and targeted therapies against non-immune-related pathways may enhance the efficacy of steroids in this setting, and early predictive and prognostic biomarkers can help identify the subgroup of patients who would likely need treatments other than (or in addition to) generic immunosuppression.
Topics: Acute Disease; Drug Therapy, Combination; Graft vs Host Disease; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Randomized Controlled Trials as Topic; Steroids
PubMed: 26970383
DOI: 10.1016/j.bbmt.2016.02.021 -
The Cochrane Database of Systematic... Sep 2015Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biologics. Although there is consensus that these therapies reduce the frequency of relapses, their relative benefit in delaying new relapses or disability worsening remains unclear due to the limited number of direct comparison trials.
OBJECTIVES
To compare the benefit and acceptability of interferon beta-1b, interferon beta-1a (Avonex, Rebif), glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine and immunoglobulins for the treatment of people with RRMS and to provide a ranking of these treatments according to their benefit and acceptability, defined as the proportion of participants who withdrew due to any adverse event.
SEARCH METHODS
We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register, which contains trials from CENTRAL (2014, Issue 9), MEDLINE (1966 to 2014), EMBASE (1974 to 2014), CINAHL (1981 to 2014), LILACS (1982 to 2014), clinicaltrials.gov and the WHO trials registry, and US Food and Drug Administration (FDA) reports. We ran the most recent search in September 2014.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that studied one or more of the 15 treatments as monotherapy, compared to placebo or to another active agent, for use in adults with RRMS.
DATA COLLECTION AND ANALYSIS
Two authors independently identified studies from the search results and performed data extraction. We performed data synthesis by pairwise meta-analysis and network meta-analysis. We assessed the quality of the body of evidence for outcomes within the network meta-analysis according to GRADE, as very low, low, moderate or high.
MAIN RESULTS
We included 39 studies in this review, in which 25,113 participants were randomised. The majority of the included trials were short-term studies, with a median duration of 24 months. Twenty-four (60%) were placebo-controlled and 15 (40%) were head-to-head studies.Network meta-analysis showed that, in terms of a protective effect against the recurrence of relapses in RRMS during the first 24 months of treatment, alemtuzumab, mitoxantrone, natalizumab, and fingolimod outperformed other drugs. The most effective drug was alemtuzumab (risk ratio (RR) versus placebo 0.46, 95% confidence interval (CI) 0.38 to 0.55; surface under the cumulative ranking curve (SUCRA) 96%; moderate quality evidence), followed by mitoxantrone (RR 0.47, 95% CI 0.27 to 0.81; SUCRA 92%; very low quality evidence), natalizumab (RR 0.56, 95% CI 0.47 to 0.66; SUCRA 88%; high quality evidence), and fingolimod (RR 0.72, 95% CI 0.64 to 0.81; SUCRA 71%; moderate quality evidence).Disability worsening was based on a surrogate marker, defined as irreversible worsening confirmed at three-month follow-up, measured during the first 24 months in the majority of included studies. Both direct and indirect comparisons revealed that the most effective treatments were mitoxantrone (RR versus placebo 0.20, 95% CI 0.05 to 0.84; SUCRA 96%; low quality evidence), alemtuzumab (RR 0.35, 95% CI 0.26 to 0.48; SUCRA 94%; low quality evidence), and natalizumab (RR 0.64, 95% CI 0.49 to 0.85; SUCRA 74%; moderate quality evidence).Almost all of the agents included in this review were associated with a higher proportion of participants who withdrew due to any adverse event compared to placebo. Based on the network meta-analysis methodology, the corresponding RR estimates versus placebo over the first 24 months of follow-up were: mitoxantrone 9.92 (95% CI 0.54 to 168.84), fingolimod 1.69 (95% CI 1.32 to 2.17), natalizumab 1.53 (95% CI 0.93 to 2.53), and alemtuzumab 0.72 (95% CI 0.32 to 1.61).Information on serious adverse events (SAEs) was scanty, characterised by heterogeneous results and based on a very low number of events observed during the short-term duration of the trials included in this review.
AUTHORS' CONCLUSIONS
Conservative interpretation of these results is warranted, since most of the included treatments have been evaluated in few trials. The GRADE approach recommends providing implications for practice based on moderate to high quality evidence. Our review shows that alemtuzumab, natalizumab, and fingolimod are the best choices for preventing clinical relapses in people with RRMS, but this evidence is limited to the first 24 months of follow-up. For the prevention of disability worsening in the short term (24 months), only natalizumab shows a beneficial effect on the basis of moderate quality evidence (all of the other estimates were based on low to very low quality evidence). Currently, therefore, insufficient evidence is available to evaluate treatments for the prevention of irreversible disability worsening.There are two additional major concerns that have to be considered. First, the benefit of all of these treatments beyond two years is uncertain and this is a relevant issue for a disease with a duration of 30 to 40 years. Second, short-term trials provide scanty and poorly reported safety data and do not provide useful evidence in order to obtain a reliable risk profile of treatments. In order to provide long-term information on the safety of the treatments included in this review, it will be necessary also to evaluate non-randomised studies and post-marketing reports released from the regulatory agencies. Finally, more than 70% of the studies included in this review were sponsored by pharmaceutical companies and this may have influenced the results.There are three needs that the research agenda should address. First, randomised trials of direct comparisons between active agents would be useful, avoiding further placebo-controlled studies. Second, follow-up of the original trial cohorts should be mandatory. Third, more studies are needed to assess the medium and long-term benefit and safety of immunotherapies and the comparative safety of different agents.
Topics: Adult; Humans; Immunologic Factors; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Randomized Controlled Trials as Topic
PubMed: 26384035
DOI: 10.1002/14651858.CD011381.pub2 -
Pediatric Transplantation Dec 2014IL-2RA are frequently used as induction therapy in liver transplant recipients to decrease the risk of AR while allowing the reduction of concomitant immunosuppression.... (Meta-Analysis)
Meta-Analysis Review
IL-2RA are frequently used as induction therapy in liver transplant recipients to decrease the risk of AR while allowing the reduction of concomitant immunosuppression. The exact association with the use of IL-2RA, however, is uncertain. We performed a systematic literature search for relevant studies. Random effects models were used to assess the incidence of AR, steroid-resistant rejection, graft loss, patient death, and adverse drug reaction, with or without IL-2RA. Six studies (two randomized and four non-randomized) met the eligibility criteria. Acute rejection at six months or later favored the use of IL-2RA significantly (RR 0.38; 95% CI 0.22-0.66, p = 0.0005). Although not statistically significant, IL-2RA showed a substantial reduction of the risk of steroid-resistant rejection (RR 0.32; CI 0.19-1.03, p = 0.0594). Graft loss and patient death showed a reductive tendency through the use of IL-2RA. The use of IL-2RA is safe and is associated with a statistically significantly lower incidence of AR after transplantation and substantial reduction of steroid-resistant rejection, graft loss, and patient death.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Basiliximab; Child; Controlled Clinical Trials as Topic; Daclizumab; Graft Rejection; Graft Survival; Humans; Immunoglobulin G; Immunosuppressive Agents; Liver Transplantation; Models, Statistical; Receptors, Interleukin-2; Recombinant Fusion Proteins; Treatment Outcome
PubMed: 25283839
DOI: 10.1111/petr.12362 -
The Cochrane Database of Systematic... Jun 2014Liver transplantation is an established treatment option for end-stage liver failure. To date, no consensus has been reached on the use of immunosuppressive T-cell... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Liver transplantation is an established treatment option for end-stage liver failure. To date, no consensus has been reached on the use of immunosuppressive T-cell antibody induction for preventing rejection after liver transplantation.
OBJECTIVES
To assess the benefits and harms of immunosuppressive T-cell specific antibody induction compared with placebo, no induction, or another type of T-cell specific antibody induction for prevention of acute rejection in liver transplant recipients.
SEARCH METHODS
We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) until September 2013.
SELECTION CRITERIA
Randomised clinical trials assessing immunosuppression with T-cell specific antibody induction compared with placebo, no induction, or another type of antibody induction in liver transplant recipients. Our inclusion criteria stated that participants within each included trial should have received the same maintenance immunosuppressive therapy. We planned to include trials with all of the different types of T-cell specific antibodies that are or have been used for induction (ie., polyclonal antibodies (rabbit of horse antithymocyte globulin (ATG), or antilymphocyte globulin (ALG)), monoclonal antibodies (muromonab-CD3, anti-CD2, or alemtuzumab), and interleukin-2 receptor antagonists (daclizumab, basiliximab, BT563, or Lo-Tact-1)).
DATA COLLECTION AND ANALYSIS
We used RevMan analysis for statistical analysis of dichotomous data with risk ratio (RR) and of continuous data with mean difference (MD), both with 95% confidence intervals (CIs). We assessed the risk of systematic errors (bias) using bias risk domains with definitions. We used trial sequential analysis to control for random errors (play of chance). We presented outcome results in a summary of findings table.
MAIN RESULTS
We included 19 randomised clinical trials with a total of 2067 liver transplant recipients. All 19 trials were with high risk of bias. Of the 19 trials, 16 trials were two-arm trials, and three trials were three-arm trials. Hence, we found 25 trial comparisons with antibody induction agents: interleukin-2 receptor antagonist (IL-2 RA) versus no induction (10 trials with 1454 participants); monoclonal antibody versus no induction (five trials with 398 participants); polyclonal antibody versus no induction (three trials with 145 participants); IL-2 RA versus monoclonal antibody (one trial with 87 participants); and IL-2 RA versus polyclonal antibody (two trials with 112 participants). Thus, we were able to compare T-cell specific antibody induction versus no induction (17 trials with a total of 1955 participants). Overall, no difference in mortality (RR 0.91; 95% CI 0.64 to 1.28; low-quality of evidence), graft loss including death (RR 0.92; 95% CI 0.71 to 1.19; low-quality of evidence), and adverse events ((RR 0.97; 95% CI 0.93 to 1.02; low-quality evidence) outcomes was observed between any kind of T-cell specific antibody induction compared with no induction when the T-cell specific antibody induction agents were analysed together or separately. Acute rejection seemed to be reduced when any kind of T-cell specific antibody induction was compared with no induction (RR 0.85, 95% CI 0.75 to 0.96; moderate-quality evidence), and when trial sequential analysis was applied, the trial sequential monitoring boundary for benefit was crossed before the required information size was obtained. Furthermore, serum creatinine was statistically significantly higher when T-cell specific antibody induction was compared with no induction (MD 3.77 μmol/L, 95% CI 0.33 to 7.21; low-quality evidence), as well as when polyclonal T-cell specific antibody induction was compared with no induction, but this small difference was not clinically significant. We found no statistically significant differences for any of the remaining predefined outcomes - infection, cytomegalovirus infection, hepatitis C recurrence, malignancy, post-transplant lymphoproliferative disease, renal failure requiring dialysis, hyperlipidaemia, diabetes mellitus, and hypertension - when the T-cell specific antibody induction agents were analysed together or separately. Limited data were available for meta-analysis on drug-specific adverse events such as haematological adverse events for antithymocyte globulin. No data were found on quality of life.When T-cell specific antibody induction agents were compared with another type of antibody induction, no statistically significant differences were found for mortality, graft loss, and acute rejection for the separate analyses. When interleukin-2 receptor antagonists were compared with polyclonal T-cell specific antibody induction, drug-related adverse events were less common among participants treated with interleukin-2 receptor antagonists (RR 0.23, 95% CI 0.09 to 0.63; low-quality evidence), but this was caused by the results from one trial, and trial sequential analysis could not exclude random errors. We found no statistically significant differences for any of the remaining predefined outcomes: infection, cytomegalovirus infection, hepatitis C recurrence, malignancy, post-transplant lymphoproliferative disease, renal failure requiring dialysis, hyperlipidaemia, diabetes mellitus, and hypertension. No data were found on quality of life.
AUTHORS' CONCLUSIONS
The effects of T-cell antibody induction remain uncertain because of the high risk of bias of the randomised clinical trials, the small number of randomised clinical trials reported, and the limited numbers of participants and outcomes in the trials. T-cell specific antibody induction seems to reduce acute rejection when compared with no induction. No other clear benefits or harms were associated with the use of any kind of T-cell specific antibody induction compared with no induction, or when compared with another type of T-cell specific antibody. Hence, more randomised clinical trials are needed to assess the benefits and harms of T-cell specific antibody induction compared with placebo, and compared with another type of antibody, for prevention of rejection in liver transplant recipients. Such trials ought to be conducted with low risks of systematic error (bias) and low risk of random error (play of chance).
Topics: Acute Disease; Antibodies, Monoclonal; Antibody Formation; Graft Rejection; Humans; Immunity, Cellular; Immunosuppression Therapy; Liver Transplantation; Randomized Controlled Trials as Topic; T-Lymphocytes
PubMed: 24901467
DOI: 10.1002/14651858.CD010253.pub2