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Multiple Sclerosis and Related Disorders Sep 2016Randomised studies have demonstrated efficacy of disease-modifying therapies in relapsing remitting multiple sclerosis (RRMS). However it is unclear how the magnitude of... (Comparative Study)
Comparative Study Meta-Analysis Review
INTRODUCTION
Randomised studies have demonstrated efficacy of disease-modifying therapies in relapsing remitting multiple sclerosis (RRMS). However it is unclear how the magnitude of treatment efficacy varies across all currently available therapies.
OBJECTIVE
To perform a systematic review and network meta-analysis to evaluate the comparative efficacy of available therapies in reducing relapses and disability progression in RRMS.
METHODS
A systematic review identified 28 randomised, placebo-controlled and direct comparative trials. A network meta-analysis was conducted within a Bayesian framework to estimate comparative annualised relapse rates (ARR) and risks of disability progression (defined by both a 3-month, and 6-month confirmation interval). Potential sources of treatment-effect modification from study-level covariates and baseline risk were evaluated through meta-regression methods. The Surface Under the Cumulative RAnking curve (SUCRA) method was used to provide a ranking of treatments for each outcome.
RESULTS
The magnitude of ARR reduction varied between 15-36% for all interferon-beta products, glatiramer acetate and teriflunomide, and from 50 to 69% for alemtuzumab, dimethyl fumarate, fingolimod and natalizumab. The risk of disability progression (3-month) was reduced by 19-28% with interferon-beta products, glatiramer acetate, fingolimod and teriflunomide, by 38-45% for pegylated interferon-beta, dimethyl fumarate and natalizumab and by 68% with alemtuzumab. Broadly similar estimates for the risk of disability progression (6-month), with the exception of interferon-beta-1b 250mcg which was much more efficacious based on this definition. Alemtuzumab and natalizumab had the highest SUCRA scores (97% and 95% respectively) for ARR, while ranking for disability progression varied depending on the definition of the outcome. Interferon-beta-1b 250mcg ranked among the most efficacious treatments for disability progression confirmed after six months (92%) and among the least efficacious when the outcome was confirmed after three months (30%). No significant modification of relative treatment effects was identified from study-level covariates or baseline risk.
CONCLUSION
Compared with placebo, clear reductions in ARR with disease-modifying therapies were accompanied by more uncertain changes in disability progression. The magnitude of the reduction and the uncertainty associated with treatment effects varied between DMTs. While natalizumab and alemtuzumab demonstrated consistently high ranking across outcomes, with older interferon-beta and glatiramer acetate products ranking lowest, variation in disability progression definitions lead to variation in the relative ranking of treatments. Rigorously conducted comparative studies are required to fully evaluate the comparative treatment effects of disease modifying therapies for RRMS.
Topics: Humans; Multiple Sclerosis, Relapsing-Remitting; Randomized Controlled Trials as Topic
PubMed: 27645339
DOI: 10.1016/j.msard.2016.06.001 -
Medicine Jul 2017Alemtuzumab (ALEM) is widely used as an induction therapy for organ transplantation, and numerous randomized controlled trials (RCTs) have been published to evaluate its... (Comparative Study)
Comparative Study Meta-Analysis Review
Alemtuzumab (ALEM) is widely used as an induction therapy for organ transplantation, and numerous randomized controlled trials (RCTs) have been published to evaluate its efficacy and safety in kidney transplantation as compared with antithymocyte globulin (ATG). The purpose of this study was to compare the benefits and safety of ALEM with those of ATG for induction therapy.A systematic literature search in three electronic databases, including PubMed, EmBase, and Cochrane Library, since inception through October 2016, was conducted to identify potential RCTs for inclusion. Trials that investigated the risk of biopsy-proven acute rejection (BPAR), mortality, graft failure, delayed graft function (DGF), chronic allograft nephropathy (CAN), infections, cytomegalovirus (CMV) infections, new-onset diabetes mellitus after transplant (NODAT), and granulocyte colony stimulation factor (GCSF) use in kidney transplant recipients who received ALEM or ATG as an induction therapy were included. Relative risk (RR) and 95% confidence intervals (CIs) were calculated using a random-effects model.Six RCTs involving 446 kidney transplantation patients were included in this meta-analysis. The effects of ALEM therapy were not significantly different from those of ATG therapy, including the incidence of BPAR (RR: 0.77; 95% CI: 0.51-1.18; P = .229), mortality (RR: 0.64; 95% CI: 0.30-1.39; P = .263), graft failure (RR: 0.81; 95% CI: 0.49-1.33; P = .411), DGF (RR: 1.00; 95% CI: 0.60-1.67; P = .999), CAN (RR: 1.42; 95% CI: 0.44-4.57; P = .556), infections (RR: 1.00; 95% CI: 0.74-1.35; P = .989), CMV infections (RR: 0.70; 95% CI: 0.38-1.30; P = .263), NODAT (RR: 0.50; 95% CI: 0.18-1.36; P = .174), and GCSF use (RR: 1.16; 95% CI: 0.81-1.66; P = .413). Sensitivity analyses were consistent with the overall analysis for all effects except CAN, suggesting that the risk of CAN might be higher with ALEM therapy than ATG therapy (RR: 2.45; 95% CI: 1.02-5.94; P = .046).The findings of this study suggest that the beneficial effects of ALEM therapy are greater than those of ATG therapy in kidney transplantation patients; however, the effects were not statistically significant because of the limited number of trials. Further large-scale RCTs are needed to verify the treatment effects of ALEM.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Transplantation; Randomized Controlled Trials as Topic
PubMed: 28700465
DOI: 10.1097/MD.0000000000007151 -
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 -
The Cochrane Database of Systematic... Nov 2014Most people who receive a kidney transplant die from either cardiovascular disease or cancer before their transplant fails. The most common reason for someone with a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Most people who receive a kidney transplant die from either cardiovascular disease or cancer before their transplant fails. The most common reason for someone with a kidney transplant to lose the function of their transplanted kidney necessitating return to dialysis is chronic kidney transplant scarring. Immunosuppressant drugs have side effects that increase risks of cardiovascular disease, cancer and chronic kidney transplant scarring. Belatacept may provide sufficient immunosuppression while avoiding unwanted side effects of other immunosuppressant drugs. However, high rates of post-transplant lymphoproliferative disease (PTLD) have been reported when belatacept is used in particular kidney transplant recipients at high dosage.
OBJECTIVES
1) Compare the relative efficacy of belatacept versus any other primary immunosuppression regimen for preventing acute rejection, maintaining kidney transplant function, and preventing death. 2) Compare the incidence of several adverse events: PTLD; other malignancies; chronic transplant kidney scarring (IF/TA); infections; change in blood pressure, lipid and blood sugar control. 3) Assess any variation in effects by study, intervention and recipient characteristics, including: differences in pre-transplant Epstein Barr virus serostatus; belatacept dosage; and donor-category (living, standard criteria deceased, or extended criteria deceased).
SEARCH METHODS
We searched the Cochrane Renal Group's Specialised Register to 1 September 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.
SELECTION CRITERIA
Randomised controlled trials (RCT) that compared belatacept versus any other immunosuppression regimen in kidney transplant recipients were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data for study quality and transplant outcomes and synthesized results using random effects meta-analysis, expressed as risk ratios (RR) and mean differences (MD), both with 95% confidence intervals (CI). Subgroup analyses and univariate meta-regression were used to investigate potential heterogeneity.
MAIN RESULTS
We included five studies that compared belatacept and calcineurin inhibitors (CNI) that reported data from a total of 1535 kidney transplant recipients. Of the five studies, three (478 participants) compared belatacept and cyclosporin and two (43 recipients) compared belatacept and tacrolimus. Co-interventions included basiliximab (4 studies, 1434 recipients); anti-thymocyte globulin (1 study, 89 recipients); alemtuzumab (1 study, 12 recipients); mycophenolate mofetil (MMF, 5 studies, 1509 recipients); sirolimus (1 study, 26 recipients) and prednisone (5 studies, 1535 recipients).Up to three years following transplant, belatacept and CNI-treated recipients were at similar risk of dying (4 studies, 1516 recipients: RR 0.75, 95% CI 0.39 to 1.44), losing their kidney transplant and returning to dialysis (4 studies, 1516 recipients: RR 0.91, 95% CI 0.61 to 1.38), and having an episode of acute rejection (4 studies, 1516 recipients: RR 1.56, 95% CI 0.85 to 2.86). Belatacept-treated kidney transplant recipients were 28% less likely to have chronic kidney scarring (3 studies, 1360 recipients: RR 0.72, 95% CI 0.55 to 0.94) and also had better graft function (measured glomerular filtration rate (GFR) (3 studies 1083 recipients): 10.89 mL/min/1.73 m², 95% CI 4.01 to 17.77; estimated GFR (4 studies, 1083 recipients): MD 9.96 mL/min/1.73 m², 95% CI 3.28 to 16.64) than CNI-treated recipients. Blood pressure was lower (systolic (2 studies, 658 recipients): MD -7.51 mm Hg, 95% CI -10.57 to -4.46; diastolic (2 studies, 658 recipients): MD -3.07 mm Hg, 95% CI -4.83 to -1.31, lipid profile was better (non-HDL (3 studies 1101 recipients): MD -12.25 mg/dL, 95% CI -17.93 to -6.57; triglycerides (3 studies 1101 recipients): MD -24.09 mg/dL, 95% CI -44.55 to -3.64), and incidence of new-onset diabetes after transplant was reduced by 39% (4 studies (1049 recipients): RR 0.61, 95% CI 0.40 to 0.93) among belatacept-treated versus CNI-treated recipients.Risk of PTLD was similar in belatacept and CNI-treated recipients (4 studies, 1516 recipients: RR 2.79, 95% CI 0.61 to 12.66) and was no different among recipients who received different belatacept dosages (high versus low dosage: ratio of risk ratios (RRR) 1.06, 95% CI 0.11 to 9.80, test of difference = 0.96) or among those who were Epstein Barr virus seronegative compared with those who were seropositive before their kidney transplant (seronegative versus seropositive; RRR 1.49, 95% CI 0.15 to 14.76, test for difference = 0.73).The belatacept dose used (high versus low), type of donor kidney the recipient received (extended versus standard criteria) and whether the kidney transplant recipient received tacrolimus or cyclosporin made no difference to kidney transplant survival, incidence of acute rejection or estimated GFR. Selective outcome reporting meant that data for some key subgroup comparisons were sparse and that estimates of the effect of treatment in these groups of recipients remain imprecise.
AUTHORS' CONCLUSIONS
There is no evidence of any difference in the effectiveness of belatacept and CNI in preventing acute rejection, graft loss and death, but treatment with belatacept is associated with less chronic kidney scarring and better kidney transplant function. Treatment with belatacept is also associated with better blood pressure and lipid profile and a lower incidence of diabetes versus treatment with a CNI. Important side effects (particularly PTLD) remain poorly reported and so the relative benefits and harms of using belatacept remain unclear. Whether short-term advantages of treatment with belatacept are maintained over the medium- to long-term or translate into better cardiovascular outcomes or longer kidney transplant survival with function remains unclear. Longer-term, fully reported and published studies comparing belatacept versus tacrolimus are needed to help clinicians decide which patients might benefit most from using belatacept.
Topics: Abatacept; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Basiliximab; Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunoconjugates; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Mycophenolic Acid; Prednisone; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Sirolimus; Tacrolimus
PubMed: 25416857
DOI: 10.1002/14651858.CD010699.pub2 -
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 -
Farmacia Hospitalaria : Organo Oficial... Mar 2020To identify and describe cost-effectiveness studies that evaluate disease modifying therapies in the context of relapsing- remitting multiple sclerosis. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To identify and describe cost-effectiveness studies that evaluate disease modifying therapies in the context of relapsing- remitting multiple sclerosis.
METHOD
A systematic review of the literature was carried out by searching MEDLINE, Embase, the Cochrane Library, LILACS, the Tufts Medical Center Cost-Effectiveness Analysis Registry, the National Health Service Economic Evaluation Database and Open Grey. The search was performed in January 2018 and covered articles published between January 2010 and December 2017. The studies reviewed were payer- perspective cost-effectiveness analyses for interferon beta-1a, interferon beta-1b, glatiramer acetate, teriflunomide, fingolimod, dimethyl fumarate, natalizumab, alemtuzumab and rituximab. The Quality of Health Economic Studies instrument was used to determine the quality of the studies reviewed. Risk of bias was assessed without a standardized tool. An analysis was made of direct costs, quality- adjusted life-years and the incremental cost-effectiveness ratio. Data extraction and evaluation of information were conducted separately by each author.
RESULTS
Four hundred one references were found; nine studies were included. A great degree of variability was identified for several methodological aspects. Two studies that applied the incremental cost- effectiveness ratio (cost) showed no first-line therapy to be cost- effective. A third study demonstrated dominance of interferon beta-1b over placebo (USD -315,109.45) and a fourth paper showed dominance of teriflunomide over interferons and glatiramer acetate (USD - 121,840.37). As regards second-line therapies, dimethyl fumarate was cost-effective in a study that compared it to glatiramer acetate and interferon beta-1a and it was dominant in another study that compared it with glatiramer acetate (USD -158,897.93) and fingolimod (USD - 92,988.97). In the third line of treatment, one study showed natalizumab to be cost-effective as compared with fingolimod, and another study showed alemtuzumab to be dominant over fingolimod (USD -49,221). A third trial demonstrated alemtuzumab to be dominant over natalizumab (USD -1,656,266.07). Many of the trials have sponsorship bias. Eight of the trials received a high QHES score.
CONCLUSIONS
The present paper shows that cost-effectiveness studies have high levels of methodological variability, some of them reaching contradictory results. As a result, it is not possible to determine which disease- modifying therapy is really cost-effective in the context of relapsingremitting multiple sclerosis.
Topics: Antibodies, Monoclonal; Antirheumatic Agents; Cost-Benefit Analysis; Humans; Immunosuppressive Agents; Multiple Sclerosis, Chronic Progressive; Quality-Adjusted Life Years
PubMed: 32452318
DOI: 10.7399/fh.11385 -
The Cochrane Database of Systematic... Jan 2017Prolonging kidney transplant survival is an important clinical priority. Induction immunosuppression with antibody therapy is recommended at transplantation and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Prolonging kidney transplant survival is an important clinical priority. Induction immunosuppression with antibody therapy is recommended at transplantation and non-depleting interleukin-2 receptor monoclonal antibodies (IL2Ra) are considered first line. It is suggested that recipients at high risk of rejection should receive lymphocyte-depleting antibodies but the relative benefits and harms of the available agents are uncertain.
OBJECTIVES
We aimed to: evaluate the relative and absolute effects of different antibody preparations (except IL2Ra) when used as induction therapy in kidney transplant recipients; determine how the benefits and adverse events vary for each antibody preparation; determine how the benefits and harms vary for different formulations of antibody preparation; and determine whether the benefits and harms vary in specific subgroups of recipients (e.g. children and sensitised recipients).
SEARCH METHODS
Randomised controlled trials (RCTs) comparing monoclonal or polyclonal antibodies with placebo, no treatment, or other antibody therapy in adults and children who had received a kidney transplant.
SELECTION CRITERIA
Randomised controlled trials (RCTs) comparing monoclonal or polyclonal antibodies with placebo, no treatment, or other antibody therapy in adults and children who had received a kidney transplant.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data and assessed risk of bias. Dichotomous outcomes are reported as relative risk (RR) and continuous outcomes as mean difference (MD) together with their 95% confidence intervals (CI).
MAIN RESULTS
We included 99 studies (269 records; 8956 participants; 33 with contemporary agents). Methodology was incompletely reported in most studies leading to lower confidence in the treatment estimates.Antithymocyte globulin (ATG) prevented acute graft rejection (17 studies: RR 0.63, 95% CI 0.51 to 0.78). The benefits of ATG on graft rejection were similar when used with (12 studies: RR 0.61, 0.49 to 0.76) or without (5 studies: RR 0.65, 0.43 to 0.98) calcineurin inhibitor (CNI) treatment. ATG (with CNI therapy) had uncertain effects on death (3 to 6 months, 3 studies: RR 0.41, 0.13 to 1.22; 1 to 2 years, 5 studies: RR 0.75, 0.27 to 2.06; 5 years, 2 studies: RR 0.94, 0.11 to 7.81) and graft loss (3 to 6 months, 4 studies: RR 0.60, 0.34 to 1.05; 1 to 2 years, 3 studies: RR 0.65, 0.36 to 1.19). The effect of ATG on death-censored graft loss was uncertain at 1 to 2 years and 5 years. In non-CNI studies, ATG had uncertain effects on death but reduced death-censored graft loss (6 studies: RR 0.55, 0.38 to 0.78). When CNI and older non-CNI studies were combined, a benefit was seen with ATG at 1 to 2 years for both all-cause graft loss (7 studies: RR 0.71, 0.53 to 0.95) and death-censored graft loss (8 studies: RR 0.55, 0.39 to 0.77) but not sustained longer term. ATG increased cytomegalovirus (CMV) infection (6 studies: RR 1.55, 1.24 to 1.95), leucopenia (4 studies: RR 3.86, 2.79 to 5.34) and thrombocytopenia (4 studies: RR 2.41, 1.61 to 3.61) but had uncertain effects on delayed graft function, malignancy, post-transplant lymphoproliferative disorder (PTLD), and new onset diabetes after transplantation (NODAT).Alemtuzumab was compared to ATG in six studies (446 patients) with early steroid withdrawal (ESW) or steroid minimisation. Alemtuzumab plus steroid minimisation reduced acute rejection compared to ATG at one year (4 studies: RR 0.57, 0.35 to 0.93). In the two studies with ESW only in the alemtuzumab arm, the effect of alemtuzumab on acute rejection at 1 year was uncertain compared to ATG (RR 1.27, 0.50 to 3.19). Alemtuzumab had uncertain effects on death (1 year, 2 studies: RR 0.39, 0.06 to 2.42; 2 to 3 years, 3 studies: RR 0.67, 95% CI 0.15 to 2.95), graft loss (1 year, 2 studies: RR 0.39, 0.13 to 1.30; 2 to 3 years, 3 studies: RR 0.98, 95% CI 0.47 to 2.06), and death-censored graft loss (1 year, 2 studies: RR 0.38, 0.08 to 1.81; 2 to 3 years, 3 studies: RR 2.45, 95% CI 0.67 to 8.97) compared to ATG. Creatinine clearance was lower with alemtuzumab plus ESW at 6 months (2 studies: MD -13.35 mL/min, -23.91 to -2.80) and 2 years (2 studies: MD -12.86 mL/min, -23.73 to -2.00) compared to ATG plus triple maintenance. Across all 6 studies, the effect of alemtuzumab versus ATG was uncertain on all-cause infection, CMV infection, BK virus infection, malignancy, and PTLD. The effect of alemtuzumab with steroid minimisation on NODAT was uncertain, compared to ATG with steroid maintenance.Alemtuzumab plus ESW compared with triple maintenance without induction therapy had uncertain effects on death and all-cause graft loss at 1 year, acute rejection at 6 months and 1 year. CMV infection was increased (2 studies: RR 2.28, 1.18 to 4.40). Treatment effects were uncertain for NODAT, thrombocytopenia, and malignancy or PTLD.Rituximab had uncertain effects on death, graft loss, acute rejection and all other adverse outcomes compared to placebo.
AUTHORS' CONCLUSIONS
ATG reduces acute rejection but has uncertain effects on death, graft survival, malignancy and NODAT, and increases CMV infection, thrombocytopenia and leucopenia. Given a 45% acute rejection risk without ATG induction, seven patients would need treatment to prevent one having rejection, while incurring an additional patient experiencing CMV disease for every 12 treated. Excluding non-CNI studies, the risk of rejection was 37% without induction with six patients needing treatment to prevent one having rejection.In the context of steroid minimisation, alemtuzumab prevents acute rejection at 1 year compared to ATG. Eleven patients would require treatment with alemtuzumab to prevent 1 having rejection, assuming a 21% rejection risk with ATG.Triple maintenance without induction therapy compared to alemtuzumab combined with ESW had similar rates of acute rejection but adverse effects including NODAT were poorly documented. Alemtuzumab plus steroid withdrawal would cause one additional patient experiencing CMV disease for every six patients treated compared to no induction and triple maintenance, in the absence of any clinical benefit. Overall, ATG and alemtuzumab decrease acute rejection at a cost of increased CMV disease while patient-centred outcomes (reduced death or lower toxicity) do not appear to be improved.
Topics: Acute Disease; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Calcineurin Inhibitors; Cytomegalovirus Infections; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Muromonab-CD3; Randomized Controlled Trials as Topic; Receptors, Interleukin-2; Steroids
PubMed: 28073178
DOI: 10.1002/14651858.CD004759.pub2 -
Systematic Reviews Oct 2021The aim of this study was to review the scientific evidence and describe the ocular treatment-emergent adverse events (TEAEs) related to pharmacological treatment in... (Review)
Review
PURPOSE
The aim of this study was to review the scientific evidence and describe the ocular treatment-emergent adverse events (TEAEs) related to pharmacological treatment in patients with multiple sclerosis.
METHODS
A systematic review of literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines in the MEDLINE, LILACS, EMBASE, and COCHRANE databases. Articles were filtered based on title and abstract considering the selection criteria and subsequently filtered by full-text reading. The resulting articles were evaluated using the Joanna Briggs Institute Quality Tools. Study characteristics and results were extracted and presented in structured tables to conduct a narrative synthesis.
RESULTS
A total of 2852 published articles were extracted using our strategy. After removing duplicates, 2841 articles were screened based on title and abstract, 102 articles were evaluated using quality tools, and 69 articles were filtered by full-text reading. Through this search strategy, 60 articles met all the inclusion criteria and seven articles, through a search update conducted in the same manner, were included. This resulted in 67 articles meeting the inclusion criteria, of which 11 were experimental and 56 were observational. The therapies related to ocular TEAEs were alemtuzumab, amantadine, fingolimod, steroids, CTLA-4 Ig, estriol, interferon β, natalizumab, hyperbaric oxygen, rituximab, siponimod, teriflunomide, and tovaxin. Fingolimod and siponimod were commonly associated with macular edema, interferon β was associated with retinopathy, alemtuzumab was associated with thyroid eye disease, amantadine was associated with corneal edema, and steroids were associated with acute retinal necrosis. Opportunistic infections were also found, and there was one life-threatening case.
CONCLUSIONS
Our search revealed different methodological assessments of the topic. However, longitudinal studies regarding ocular TEAEs related to multiple sclerosis therapy are necessary to provide evidence-based recommendations, especially in understudied regions such as Latin America and Africa. Physicians should monitor ocular symptoms in patients being treated for multiple sclerosis and consider an interdisciplinary approach.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO ID CRD42020106886.
Topics: Africa; Humans; Multiple Sclerosis
PubMed: 34711264
DOI: 10.1186/s13643-021-01782-7 -
Blood Mar 2015We analyzed cost-effectiveness studies related to hematologic malignancies from the Tufts Medical Center Cost-Effectiveness Analysis Registry (www.cearegistry.org),... (Review)
Review
We analyzed cost-effectiveness studies related to hematologic malignancies from the Tufts Medical Center Cost-Effectiveness Analysis Registry (www.cearegistry.org), focusing on studies of innovative therapies. Studies that met inclusion criteria were categorized by 4 cancer types (chronic myeloid leukemia, chronic lymphocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma) and 9 treatment agents (interferon-α, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide). We examined study characteristics and stratified cost-effectiveness ratios by type of cancer, treatment, funder, and year of study publication. Twenty-nine studies published in the years 1996-2012 (including 44 cost-effectiveness ratios) met inclusion criteria, 22 (76%) of which were industry funded. Most ratios fell below $50,000 per quality-adjusted life-years (QALY) (73%) and $100,000/QALY (86%). Industry-funded studies (n = 22) reported a lower median ratio ($26,000/QALY) than others (n = 7; $33,000/QALY), although the difference was not statistically significant. Published data suggest that innovative treatments for hematologic malignancies may provide reasonable value for money.
Topics: Antineoplastic Agents; Cost-Benefit Analysis; Decision Making; Diffusion of Innovation; Economics, Medical; Hematologic Neoplasms; Humans; Models, Economic; Quality of Life; Quality-Adjusted Life Years; Registries; Treatment Outcome
PubMed: 25655601
DOI: 10.1182/blood-2014-07-592832 -
Frontiers in Neurology 2024The purpose of this study was to evaluate the risk of secondary immune thrombocytopenia in multiple sclerosis patients treated with alemtuzumab through a meta-analysis.
OBJECT
The purpose of this study was to evaluate the risk of secondary immune thrombocytopenia in multiple sclerosis patients treated with alemtuzumab through a meta-analysis.
METHODS
We searched databases including PubMed, Web of Science, OVID and EMBASE for studies reporting changes in platelet levels in MS patients treated with alemtuzumab from their inception until May 2023 and performed a meta-analysis. Information and data were screened and extracted by two researchers. The inclusion and exclusion criteria were established according to the PICOS principle. The obtained data were analyzed using the R software meta package and the quality assessment was conducted using Newcastle-Ottawa Scale (NOS). The causes of heterogeneity were analyzed using subgroup analysis and sensitivity analysis. Publication bias was evaluated using funnel plots and Egger test.
RESULTS
A total of 15 studies were included, encompassing 1,729 multiple sclerosis patients. Meta-analysis of overall secondary ITP in the included studies yielded a pooled rate of 0.0243. The overall incidence of secondary autoimmune events was 0.2589. In addition, subgroup analysis was applied using study regions and study types. The results showed that the incidence rate of secondary ITP in Europe was about 0.0207, while the incidence of autoimmune events (AEs) was 0.2158. The incidence rate of secondary ITP and AEs in North America was significantly higher than in Europe, being 0.0352 and 0.2622. And the analysis showed that the incidence rates of secondary ITP and AEs in prospective studies were 0.0391 and 0.1771. Retrospective studies had an incidence rate of secondary ITP at 2.16, and an incidence rate of AEs at 0.2743.
CONCLUSION
This study found that there was a certain incidence of Immune thrombocytopenia in multiple sclerosis patients after treatment with alemtuzumab. Alemtuzumab may have some interference with platelet levels, and the mechanism may be associated with Treg cells. But due to the absence of a control group in the included literature, we cannot determine the specific impact of Alemtuzumab on platelet levels in patients with MS. Therefore, clinical physicians should perform a comprehensive assessment of the patient's benefit-to-risk ratio before initiating alemtuzumab.
SYSTEMATIC REVIEW REGISTRATION
Inplasy website, DOI number is 10.37766/inplasy2024.3.0007.
PubMed: 38660089
DOI: 10.3389/fneur.2024.1375615