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ESMO Open Apr 2023Programmed death-ligand 1[PD-(L)1], cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3) inhibitors are recent breakthroughs in... (Review)
Review
Programmed death-ligand 1[PD-(L)1], cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3) inhibitors are recent breakthroughs in cancer treatment, however not all patients benefit from it. Thus new therapies are under investigation, such as anti-TIGIT [anti-T-cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif domains] antibodies. TIGIT is an immune checkpoint inhibiting lymphocyte T cells by several mechanisms. In vitro models showed its inhibition could restore antitumor response. Furthermore, its association with anti-PD-(L)1 therapies could synergistically improve survival. We carried out a review of the clinical trial about TIGIT referenced in the PubMed database, finding three published clinical trials on anti-TIGIT therapies. Vibostolimab was evaluated in a phase I alone or in combination with pembrolizumab. The combination had an objective response rate of 26% in patients with a non-small-cell lung cancer (NSCLC) naïve of anti-programmed cell death protein 1 (anti-PD-1). Etigilimab was tested in a phase I alone or in combination with nivolumab, but the study was stopped due to business reasons. In the phase II CITYSCAPE trial, tiragolumab demonstrated higher objective response rate and progression-free survival in combination with atezolizumab than atezolizumab alone in advanced PD-L1-high NSCLC. The ClinicalTrials.gov database references 70 trials of anti-TIGIT in patients with cancer, 47 of them with ongoing recruitment. Only seven were phase III, including five about patients with NSCLC, mostly with combination therapy. Data from phase I-II trials highlighted that targeting TIGIT represents a safe therapeutic approach, with an acceptable toxicity profile maintained when adding anti-PD-(L)1 antibodies. Frequent adverse events were pruritus, rash, and fatigue. Grade 3-4 adverse events were reported in nearly one in three patients. Anti-TIGIT antibodies are under development as a novel immunotherapy approach. A promising research area includes the combination with anti-PD-1 therapies in advanced NSCLCs.
Topics: Humans; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Nivolumab
PubMed: 36933320
DOI: 10.1016/j.esmoop.2023.101184 -
JAMA Network Open Feb 2023Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infection in children younger than 5 years; effective prevention strategies are... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infection in children younger than 5 years; effective prevention strategies are urgently needed.
OBJECTIVE
To compare the efficacy and safety of monoclonal antibodies for the prevention of RSV infection in infants and children.
DATA SOURCES
In this systematic review and network meta-analysis, PubMed, Embase, CENTRAL, and ClinicalTrials.gov were searched from database inception to March 2022.
STUDY SELECTION
Randomized clinical trials that enrolled infants at high risk of RSV infection to receive a monoclonal antibody or placebo were included. Keywords and extensive vocabulary related to monoclonal antibodies, RSV, and randomized clinical trials were searched.
DATA EXTRACTION AND SYNTHESIS
The Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline was used. Teams of 2 reviewers independently performed literature screening, data extraction, and risk of bias assessment. The Grading of Recommendations, Assessments, Developments, and Evaluation approach was used to rate the certainty of evidence. A random-effects model network meta-analysis was conducted using a consistency model under the frequentist framework.
MAIN OUTCOMES AND MEASURES
The main outcomes were all-cause mortality, RSV-related hospitalization, RSV-related infection, drug-related adverse events, intensive care unit admission, supplemental oxygen use, and mechanical ventilation use.
RESULTS
Fifteen randomized clinical trials involving 18 395 participants were eligible; 14 were synthesized, with 18 042 total participants (median age at study entry, 3.99 months [IQR, 3.25-6.58 months]; median proportion of males, 52.37% [IQR, 50.49%-53.85%]). Compared with placebo, with moderate- to high-certainty evidence, nirsevimab, palivizumab, and motavizumab were associated with significantly reduced RSV-related infections per 1000 participants (nirsevimab: -123 [95% CI, -138 to -100]; palivizumab: -108 [95% CI, -127 to -82]; motavizumab: -136 [95% CI, -146 to -125]) and RSV-related hospitalizations per 1000 participants (nirsevimab: -54 [95% CI, -64 to -38; palivizumab: -39 [95% CI, -48 to -28]; motavizumab: -48 [95% CI, -58 to -33]). With moderate-certainty evidence, both motavizumab and palivizumab were associated with significant reductions in intensive care unit admissions per 1000 participants (-8 [95% CI, -9 to -4] and -5 [95% CI, -7 to 0], respectively) and supplemental oxygen use per 1000 participants (-59 [95% CI, -63 to -54] and -55 [95% CI, -61 to -41], respectively), and nirsevimab was associated with significantly reduced supplemental oxygen use per 1000 participants (-59 [95% CI, -65 to -40]). No significant differences were found in all-cause mortality and drug-related adverse events. Suptavumab did not show any significant benefits for the outcomes of interest.
CONCLUSIONS AND RELEVANCE
In this study, motavizumab, nirsevimab, and palivizumab were associated with substantial benefits in the prevention of RSV infection, without a significant increase in adverse events compared with placebo. However, more research is needed to confirm the present conclusions, especially for safety and cost-effectiveness.
Topics: Male; Infant; Child; Humans; Antibodies, Monoclonal; Palivizumab; Respiratory Syncytial Viruses; Network Meta-Analysis; Respiratory Syncytial Virus Infections; Respiratory Tract Infections; Oxygen; Randomized Controlled Trials as Topic
PubMed: 36800182
DOI: 10.1001/jamanetworkopen.2023.0023 -
Frontiers in Immunology 2022Chronic kidney disease (CKD) is a major public-health problem that increases the risk of end-stage kidney disease (ESKD), cardiovascular diseases, and other... (Review)
Review
INTRODUCTION
Chronic kidney disease (CKD) is a major public-health problem that increases the risk of end-stage kidney disease (ESKD), cardiovascular diseases, and other complications. Kidney transplantation is a renal-replacement therapy that offers better survival compared to dialysis. Antibody-mediated rejection (ABMR) is a significant complication following kidney transplantation: it contributes to both short- and long-term injury. The standard-of-care (SOC) therapy combines plasmapheresis and Intravenous Immunoglobulins (IVIg) with or without steroids, with or without rituximab: however, despite this combined treatment, ABMR remains the main cause of graft loss. IL-6 is a key cytokine: it regulates inflammation, and the development, maturation, and activation of T cells, B cells, and plasma cells. Tocilizumab (TCZ) is the main humanized monoclonal aimed at IL-6R and appears to be a safe and possible strategy to manage ABMR in sensitized recipients. We conducted a literature review to assess the place of the anti-IL-6R monoclonal antibody TCZ within ABMR protocols.
MATERIALS AND METHODS
We systematically reviewed the PubMed literature and reviewed six studies that included 117 patients and collected data on the utilization of TCZ to treat ABMR.
RESULTS
Most studies report a significant reduction in levels of Donor Specific Antibodies (DSAs) and reduced inflammation and microvascular lesions (as found in biopsies). Stabilization of the renal function was observed. Adverse events were light to moderate, and mortality was not linked with TCZ treatment. The main side effect noted was infection, but infections did not occur more frequently in patients receiving TCZ as compared to those receiving SOC therapy.
CONCLUSION
TCZ may be an alternative to SOC for ABMR kidney-transplant patients, either as a first-line treatment or after failure of SOC. Further randomized and controlled studies are needed to support these results.
Topics: Antibodies, Monoclonal, Humanized; Female; Graft Rejection; Graft Survival; HLA Antigens; Humans; Inflammation; Isoantibodies; Kidney Transplantation; Male
PubMed: 35493469
DOI: 10.3389/fimmu.2022.839380 -
Dermatologic Therapy Sep 2022Hidradenitis suppurativa (HS) is a chronic inflammatory often recalcitrant to treatment. There is a lack of an updated systematic data review for infliximab use in HS.... (Meta-Analysis)
Meta-Analysis Review
Hidradenitis suppurativa (HS) is a chronic inflammatory often recalcitrant to treatment. There is a lack of an updated systematic data review for infliximab use in HS. We conducted a systematic review and meta-analysis of literature on infliximab in HS. This study was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was pre-registered on PROSPERO (CRD42021283596). In 9/2021, MEDLINE and EMBASE were systematically searched for articles on infliximab in HS. Non-English, duplicate, and studies with <5 HS patients were excluded. Study quality was assessed utilizing Cochrane Risk of Bias for prospective trials and Newcastle-Ottawa Scale for cohort studies. Random effects meta-analytical model, Cochran's Q statistic, and I squared index were performed. Nineteen articles (314 patients) met inclusion criteria (six prospective, 13 retrospective studies). All patients with HS severity data available (n = 299) had moderate-to-severe disease. Outcome measures used for meta-analysis of the pooled response rate were largely based on clinician reported outcomes (16 studies). One utilized both clinician and patient assessment. Two utilized patient-reported response alone. The pooled response rate of HS patients to infliximab was 83% (95% CI, 0.71-0.91). The most common adverse events (AEs) included non-serious infections (13.2%) and infusion reaction (2.9%). The rate of serious AEs was 2.9%. Study limitations include the small number of prospective studies and heterogeneity between studies. Overall, infliximab is an effective treatment for moderate-to-severe HS. Efficacy of infliximab in HS should be compared to other biologics in larger, randomized controlled trials.
Topics: Antibodies, Monoclonal; Hidradenitis Suppurativa; Humans; Infliximab; Prospective Studies; Retrospective Studies
PubMed: 35790062
DOI: 10.1111/dth.15691 -
The Cochrane Database of Systematic... Mar 2022Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome are rare, severe cutaneous adverse reactions usually triggered by... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome are rare, severe cutaneous adverse reactions usually triggered by medications. In addition to tertiary-level supportive care, various systemic therapies have been used including glucocorticoids, intravenous immunoglobulins (IVIGs), cyclosporin, N-acetylcysteine, thalidomide, infliximab, etanercept, and plasmapheresis. There is an unmet need to understand the efficacy of these interventions.
OBJECTIVES
To assess the effects of systemic therapies (medicines delivered orally, intramuscularly, or intravenously) for the treatment of SJS, TEN, and SJS/TEN overlap syndrome.
SEARCH METHODS
We searched the following databases up to March 2021: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched five clinical trial registers, the reference lists of all included studies and of key review articles, and a number of drug manufacturer websites. We searched for errata or retractions of included studies.
SELECTION CRITERIA
We included only randomised controlled trials (RCTs) and prospective observational comparative studies of participants of any age with a clinical diagnosis of SJS, TEN, or SJS/TEN overlap syndrome. We included all systemic therapies studied to date and permitted comparisons between each therapy, as well as between therapy and placebo.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures as specified by Cochrane. Our primary outcomes were SJS/TEN-specific mortality and adverse effects leading to discontinuation of SJS/TEN therapy. Secondary outcomes included time to complete re-epithelialisation, intensive care unit length of stay, total hospital length of stay, illness sequelae, and other adverse effects attributed to systemic therapy. We rated the certainty of the evidence for each outcome using GRADE.
MAIN RESULTS
We included nine studies with a total of 308 participants (131 males and 155 females) from seven countries. We included two studies in the quantitative meta-analysis. We included three RCTs and six prospective, controlled observational studies. Sample sizes ranged from 10 to 91. Most studies did not report study duration or time to follow-up. Two studies reported a mean SCORe of Toxic Epidermal Necrosis (SCORTEN) of 3 and 1.9. Seven studies did not report SCORTEN, although four of these studies reported average or ranges of body surface area (BSA) (means ranging from 44% to 51%). Two studies were set in burns units, two in dermatology wards, one in an intensive care unit, one in a paediatric ward, and three in unspecified inpatient units. Seven studies reported a mean age, which ranged from 29 to 56 years. Two studies included paediatric participants (23 children). We assessed the results from one of three RCTs as low risk of bias in all domains, one as high, and one as some concerns. We judged the results from all six prospective observational comparative studies to be at a high risk of bias. We downgraded the certainty of the evidence because of serious risk of bias concerns and for imprecision due to small numbers of participants. The interventions assessed included systemic corticosteroids, tumour necrosis factor-alpha (TNF-alpha) inhibitors, cyclosporin, thalidomide, N-acetylcysteine, IVIG, and supportive care. No data were available for the main comparisons of interest as specified in the review protocol: etanercept versus cyclosporin, etanercept versus IVIG, IVIG versus supportive care, IVIG versus cyclosporin, and cyclosporin versus corticosteroids. Corticosteroids versus no corticosteroids It is uncertain if there is any difference between corticosteroids (methylprednisolone 4 mg/kg/day for two more days after fever had subsided and no new lesions had developed) and no corticosteroids on disease-specific mortality (risk ratio (RR) 2.55, 95% confidence interval (CI) 0.72 to 9.03; 2 studies; 56 participants; very low-certainty evidence). Time to complete re-epithelialisation, length of hospital stay, and adverse effects leading to discontinuation of therapy were not reported. IVIG versus no IVIG It is uncertain if there is any difference between IVIG (0.2 to 0.5 g/kg cumulative dose over three days) and no IVIG in risk of disease-specific mortality (RR 0.33, 95% CI 0.04 to 2.91); time to complete re-epithelialisation (mean difference (MD) -2.93 days, 95% CI -4.4 to -1.46); or length of hospital stay (MD -2.00 days, 95% CI -5.81 to 1.81). All results in this comparison were based on one study with 36 participants, and very low-certainty evidence. Adverse effects leading to discontinuation of therapy were not reported. Etanercept (TNF-alpha inhibitor) versus corticosteroids Etanercept (25 mg (50 mg if weight > 65 kg) twice weekly "until skin lesions healed") may reduce disease-specific mortality compared to corticosteroids (intravenous prednisolone 1 to 1.5 mg/kg/day "until skin lesions healed") (RR 0.51, 95% CI 0.16 to 1.63; 1 study; 91 participants; low-certainty evidence); however, the CIs were consistent with possible benefit and possible harm. Serious adverse events, such as sepsis and respiratory failure, were reported in 5 of 48 participants with etanercept and 9 of 43 participants with corticosteroids, but it was not clear if they led to discontinuation of therapy. Time to complete re-epithelialisation and length of hospital stay were not reported. Cyclosporin versus IVIG It is uncertain if there is any difference between cyclosporin (3 mg/kg/day or intravenous 1 mg/kg/day until complete re-epithelialisation, then tapered off (10 mg/day reduction every 48 hours)) and IVIG (continuous infusion 0.75 g/kg/day for 4 days (total dose 3 g/kg) in participants with normal renal function) in risk of disease-specific mortality (RR 0.13, 95% CI 0.02 to 0.98, 1 study; 22 participants; very low-certainty evidence). Time to complete re-epithelialisation, length of hospital stay, and adverse effects leading to discontinuation of therapy were not reported. No studies measured intensive care unit length of stay.
AUTHORS' CONCLUSIONS
When compared to corticosteroids, etanercept may result in mortality reduction. For the following comparisons, the certainty of the evidence for disease-specific mortality is very low: corticosteroids versus no corticosteroids, IVIG versus no IVIG and cyclosporin versus IVIG. There is a need for more multicentric studies, focused on the most important clinical comparisons, to provide reliable answers about the best treatments for SJS/TEN.
Topics: Acetylcysteine; Adrenal Cortex Hormones; Adult; Autoimmune Diseases; Child; Cyclosporine; Etanercept; Female; Humans; Immunoglobulins, Intravenous; Male; Middle Aged; Observational Studies as Topic; Stevens-Johnson Syndrome; Thalidomide; Tumor Necrosis Factor-alpha
PubMed: 35274741
DOI: 10.1002/14651858.CD013130.pub2 -
Clinical Gastroenterology and... Dec 2022Patients with Crohn's disease (CD) treated with ustekinumab who experience inadequate response, or loss of response after standard induction and/or maintenance dosing... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND & AIMS
Patients with Crohn's disease (CD) treated with ustekinumab who experience inadequate response, or loss of response after standard induction and/or maintenance dosing may benefit from dose escalation. We conducted a systematic review and meta-analysis examining the effectiveness of reinduction and/or dose interval shortening of ustekinumab in patients with active CD despite standard induction and maintenance.
METHODS
Through a systematic literature search through March 31, 2021, we identified 15 cohort studies in 925 adults with CD with inadequate response or loss of response to standard dose ustekinumab, underwent dose escalation (reinduction and/or dose interval shortening to <8 weeks), and reported rates of achieving clinical response, corticosteroid-free clinical remission, endoscopic response, and/or remission. We calculated pooled rates (with 95% confidence intervals) using random effects meta-analysis and examined factors associated with response to dose escalation through qualitative synthesis of individual studies.
RESULTS
On meta-analysis, 55% of patients (95% confidence interval, 52%-58%) with inadequate response or loss of response who underwent ustekinumab dose escalation achieved clinical response, with moderate heterogeneity (I = 57%). Approximately 61% of patients were able to achieve endoscopic response, including 29% who achieved endoscopic remission. Dose interval shortening alone recaptured response in 57% patients. No consistent factors associated with response to dose escalation were identified on qualitative synthesis.
CONCLUSION
In real word settings, ustekinumab dose escalation was effective in achieving response in patients with CD with inadequate response, or loss of response to standard dose induction and/or maintenance therapy.
Topics: Adult; Humans; Ustekinumab; Crohn Disease; Remission Induction; Endoscopy; Treatment Outcome
PubMed: 34628078
DOI: 10.1016/j.cgh.2021.10.002 -
Cancer Control : Journal of the Moffitt... 2021Treatment options for advanced gastric esophageal cancer are quite limited. Chemotherapy is unavoidable at certain stages, and research on targeted therapies has mostly... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Treatment options for advanced gastric esophageal cancer are quite limited. Chemotherapy is unavoidable at certain stages, and research on targeted therapies has mostly failed. The advent of immunotherapy has brought hope for the treatment of advanced gastric esophageal cancer. The aim of the study was to analyze the safety of anti-PD-1/PD-L1 immunotherapy and the long-term survival of patients who were diagnosed as gastric esophageal cancer and received anti-PD-1/PD-L1 immunotherapy.
METHOD
Studies on anti-PD-1/PD-L1 immunotherapy of advanced gastric esophageal cancer published before February 1, 2020 were searched online. The survival (e.g. 6-month overall survival, 12-month overall survival (OS), progression-free survival (PFS), objective response rates (ORR)) and adverse effects of immunotherapy were compared to that of control therapy (physician's choice of therapy).
RESULTS
After screening 185 studies, 4 comparative cohort studies which reported the long-term survival of patients receiving immunotherapy were included. Compared to control group, the 12-month survival (OR = 1.67, 95% CI: 1.31 to 2.12, P < 0.0001) and 18-month survival (OR = 1.98, 95% CI: 1.39 to 2.81, P = 0.0001) were significantly longer in immunotherapy group. The 3-month survival rate (OR = 1.05, 95% CI: 0.36 to 3.06, P = 0.92) and 18-month survival rate (OR = 1.44, 95% CI: 0.98 to 2.12, P = 0.07) were not significantly different between immunotherapy group and control group. The ORR were not significantly different between immunotherapy group and control group (OR = 1.54, 95% CI: 0.65 to 3.66, P = 0.01). Meta-analysis pointed out that in the PD-L1 CPS ≥10 sub group population, the immunotherapy could obviously benefit the patients in tumor response rates (OR = 3.80, 95% CI: 1.89 to 7.61, P = 0.0002).
CONCLUSION
For the treatment of advanced gastric esophageal cancer, the therapeutic efficacy of anti-PD-1/PD-L1 immunotherapy was superior to that of chemotherapy or palliative care.
Topics: Antibodies, Monoclonal, Humanized; Esophageal Neoplasms; Humans; Immunotherapy; Stomach Neoplasms; Survival Analysis
PubMed: 33618535
DOI: 10.1177/1073274821997430 -
The Cochrane Database of Systematic... Feb 2021Belimumab, the first biologic approved for the treatment of systemic lupus erythematosus (SLE), has been shown to reduce autoantibody levels in people with SLE and help... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Belimumab, the first biologic approved for the treatment of systemic lupus erythematosus (SLE), has been shown to reduce autoantibody levels in people with SLE and help control disease activity.
OBJECTIVES
To assess the benefits and harms of belimumab (alone or in combination) in systematic lupus erythematosus.
SEARCH METHODS
An Information Specialist carried out the searches of CENTRAL, MEDLINE, Embase, CINAHL, Web of Science, the World Health Organization (WHO) International Clinical Trials Registry Platform, and clinicaltrials.gov from inception to 25 September 2019. There were no language or date restrictions.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) or controlled clinical trials (CCTs) of belimumab (alone or in combination) compared to placebo/control treatment (immunosuppressive drugs, such as azathioprine, cyclosporine, mycophenolate mofetil or another biologic), in adults with SLE.
DATA COLLECTION AND ANALYSIS
We used standard methodologic procedures expected by Cochrane.
MAIN RESULTS
Six RCTs (2917 participants) qualified for quantitative analyses. All included studies were multicenter, international or US-based. The age range of the included participants was 22 to 80 years; most were women; and study duration ranged from 84 days to 76 weeks. The risk of bias was generally low except for attrition bias, which was high in 67% of studies. Compared to placebo, more participants on belimumab 10 mg/kg (Food and Drug Administration (FDA)-approved dose) showed at least a 4-point improvement (reduction) in Safety of Estrogen in Lupus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, a validated SLE disease activity index: (risk ratio (RR) 1.33, 95% confidence interval (CI) 1.22 to 1.45; 829/1589 in belimumab group and 424/1077 in placebo; I= 0%; 4 RCTs; high-certainty evidence). Change in health-related quality of life (HRQOL), assessed by Short Form-36 Physical Component Summary score improvement (range 0 to 100), showed there was probably little or no difference between groups (mean difference 1.6 points, 95% CI 0.30 to 2.90; 401 in belimumab group and 400 in placebo; I= 0%; 2 RCTs; moderate-certainty evidence). The belimumab 10 mg/kg group showed greater improvement in glucocorticoid dose, with a higher proportion of participants reducing their dose by at least 50% compared to placebo (RR 1.59, 95% CI 1.17 to 2.15; 81/269 in belimumab group and 52/268 in placebo; I= 0%; 2 RCTs; high-certainty evidence). The proportion of participants experiencing harm may not differ meaningfully between the belimumab 10 mg/kg and placebo groups: one or more serious adverse event (RR 0.87, 95% CI: 0.68 to 1.11; 238/1700 in belimumab group and 199/1190 in placebo; I= 48%; 5 RCTs; low-certainty evidence; ); one or more serious infection (RR 1.01, 95% CI: 0.66 to 1.54; 44/1230 in belimumab group and 40/955 in placebo; I= 0%; 4 RCTs; moderate-certainty evidence); and withdrawals due to adverse events (RR 0.82, 95% CI: 0.63 to 1.07; 113/1700 in belimumab group and 94/1190 in placebo; I= 0%; 5 RCTs; moderate-certainty evidence). Mortality was rare, and may not differ between belimumab 10 mg/kg and placebo (Peto odds ratio 1.15, 95% CI 0.41 to 3.25; 9/1714 in belimumab group and 6/1203 in placebo; I= 4%; 6 RCTs; low-certainty evidence).
AUTHORS' CONCLUSIONS
The six studies that provided evidence for benefits and harms of belimumab were well-designed, high-quality RCTs. At the FDA-approved dose of 10 mg/kg, based on moderate to high-certainty data, belimumab was probably associated with a clinically meaningful efficacy benefit compared to placebo in participants with SLE at 52 weeks. Evidence related to harms is inconclusive and mostly of moderate to low-certainty evidence. More data are needed for the longer-term efficacy of belimumab.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Bias; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Male; Middle Aged; Placebos; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome; Young Adult
PubMed: 33631841
DOI: 10.1002/14651858.CD010668.pub2 -
The Cochrane Database of Systematic... Jul 2022This is the second update of previously published reviews in the Cochrane Library (2015, first update 2017). Interleukin-5 (IL-5) is the main cytokine involved in the... (Review)
Review
BACKGROUND
This is the second update of previously published reviews in the Cochrane Library (2015, first update 2017). Interleukin-5 (IL-5) is the main cytokine involved in the proliferation, maturation, activation and survival of eosinophils, which cause airway inflammation and are a classic feature of asthma. Studies of monoclonal antibodies targeting IL-5 or its receptor (IL-5R) suggest they reduce asthma exacerbations, improve health-related quality of life (HRQoL) and lung function in appropriately selected patients, justifying their inclusion in the latest guidelines.
OBJECTIVES
To compare the effects of therapies targeting IL-5 signalling (anti-IL-5 or anti-IL-5Rα) with placebo on exacerbations, health-related quality-of-life (HRQoL) measures and lung function in adults and children with chronic asthma, and specifically in those with eosinophilic asthma refractory to existing treatments.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, and two trials registers, manufacturers' websites, and reference lists of included studies. The most recent search was 7 February 2022.
SELECTION CRITERIA
We included randomised controlled trials comparing mepolizumab, reslizumab and benralizumab versus placebo in adults and children with asthma.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and analysed outcomes using a random-effects model. We used standard methods expected by Cochrane.
MAIN RESULTS
Seventeen studies on about 7600 participants met the inclusion criteria. Six used mepolizumab, five used reslizumab, and six used benralizumab. One study using benralizumab was terminated early due to sponsor decision and contributed no data. The studies were predominantly on people with severe eosinophilic asthma, which was similarly but variably defined. One was in children aged 6 to 17 years; nine others included children over 12 years but did not report results by age group separately. We deemed the overall risk of bias to be low, with all studies contributing data of robust methodology. We considered the certainty of the evidence for all comparisons to be high overall using the GRADE scheme, except for intravenous (IV) mepolizumab and subcutaneous (SC) reslizumab because these are not currently licensed delivery routes. The anti-IL-5 treatments assessed reduced rates of 'clinically significant' asthma exacerbation (defined by treatment with systemic corticosteroids for three days or more) by approximately half in participants with severe eosinophilic asthma on standard care (at least medium-dose inhaled corticosteroids (ICS)) with poorly controlled disease (either two or more exacerbations in the preceding year or Asthma Control Questionnaire (ACQ) score of 1.5 or more), except for reslizumab SC. The rate ratios for these effects were 0.45 (95% confidence interval (CI) 0.36 to 0.55; high-certainty evidence) for mepolizumab SC, 0.53 (95% CI 0.44 to 0.64; moderate-certainty evidence) for mepolizumab IV, 0.43 (95% CI 0.33 to 0.55; high-certainty evidence) for reslizumab IV, and 0.59 (95% CI 0.52 to 0.66; high-certainty evidence) for benralizumab SC. Non-eosinophilic participants treated with benralizumab also showed a significant reduction in exacerbation rates, an effect not seen with reslizumab IV, albeit in only one study. No data were available for non-eosinophilic participants treated with mepolizumab. There were improvements in validated HRQoL scores with all anti-IL-5 agents in severe eosinophilic asthma. This met the minimum clinically important difference (MCID) for the broader St. George's Respiratory Questionnaire (SGRQ; 4-point change) for benralizumab only, but the improvement in the ACQ and Asthma Quality of Life Questionnaire (AQLQ), which focus on asthma symptoms, fell short of the MCID (0.5 point change for both ACQ and AQLQ) for all of the interventions. The evidence for an improvement in HRQoL scores in non-eosinophilic participants treated with benralizumab and reslizumab was weak, but the tests for subgroup difference were negative. All anti-IL-5 treatments produced small improvements in mean pre-bronchodilator forced expiratory flow in one second (FEV) of between 0.08 L and 0.15 L in eosinophilic participants, which may not be sufficient to be detected by patients. There were no excess serious adverse events with any anti-IL-5 treatment; in fact, there was a reduction in such events with benralizumab, likely arising from fewer asthma-related hospital admissions. There was no difference compared to placebo in adverse events leading to discontinuation with mepolizumab or reslizumab, but significantly more discontinued benralizumab than placebo, although the absolute numbers were small (42/2026 (2.1%) benralizumab versus 11/1227 (0.9%) placebo). The implications for efficacy or adverse events are unclear.
AUTHORS' CONCLUSIONS
Overall this analysis supports the use of anti-IL-5 treatments as an adjunct to standard care in people with severe eosinophilic asthma and poor symptom control. These treatments roughly halve the rate of asthma exacerbations in this population. There is limited evidence for improved HRQoL scores and lung function, which may not meet clinically detectable levels. The studies did not report safety concerns for mepolizumab or reslizumab, or any excess serious adverse events with benralizumab, although there remains a question over adverse events significant enough to prompt discontinuation. Further research is needed on biomarkers for assessing treatment response, optimal duration and long-term effects of treatment, risk of relapse on withdrawal, non-eosinophilic patients, children (particularly under 12 years), comparing anti-IL-5 treatments to each other and, in patients meeting relevant eligibility criteria, to other biological (monoclonal antibody) therapies. For benralizumab, future studies should closely monitor rates of adverse events prompting discontinuation.
Topics: Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Asthma; Child; Chronic Disease; Disease Progression; Humans; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 35838542
DOI: 10.1002/14651858.CD010834.pub4 -
The Journal of Allergy and Clinical... Apr 2022Chronic rhinosinusitis with nasal polyposis (CRSwNP) is an inflammatory condition of the upper airways. Optimal management is unclear. (Meta-Analysis)
Meta-Analysis
Comparative efficacy and safety of monoclonal antibodies and aspirin desensitization for chronic rhinosinusitis with nasal polyposis: A systematic review and network meta-analysis.
BACKGROUND
Chronic rhinosinusitis with nasal polyposis (CRSwNP) is an inflammatory condition of the upper airways. Optimal management is unclear.
OBJECTIVE
We compared the effects of mAbs and aspirin desensitization (ASA-D) for treatment of CRSwNP.
METHODS
We searched the Medline, Embase, Cochrane Central Register of Controlled Trials, International Clinical Trials Registry Platform, US Food and Drug Administration, and the European Medicines Agency databases from inception to August 4, 2021, for randomized controlled trials comparing the effects of mAbs and ASA-D for CRSwNP. We conducted network meta-analysis of sinusitis symptoms, heath-related quality of life, rescue oral corticosteroids and surgery, endoscopic and radiologic scores, and adverse events. We used the Grades of Recommendation Assessment, Development and Evaluation (GRADE) approach to assess certainty of evidence. PROSPERO CRD42020177334.
RESULTS
Twenty-nine randomized controlled trials evaluating 8 treatments (n = 3461) were included in the network meta-analysis. Compared to placebo, moderate to high certainty evidence showed that health-related quality of life (SNOT-22) improved with dupilumab (mean difference [MD] -19.91 [95% confidence interval (CI) -22.50, -17.32]), omalizumab (MD -16.09 [95% CI -19.88, -12.30]), mepolizumab (MD -12.89 [95% CI -16.58, -9.19], ASA-D (MD -10.61 [95% CI -14.51, -6.71]), and benralizumab (MD -7.68 [95% CI -12.09, -3.27]). The risk of rescue nasal polyp surgery likely decreased with dupilumab (risk difference [RD] -16.35% [95% CI -18.13, -13.48]), omalizumab (RD -7.40% [95% CI -11.04, -2.43]), mepolizumab (RD -12.33% [95% CI -15.56, -7.22]), and ASA-D (RD -16.00% [95% CI -19.79, 0.21]; all moderate certainty). Comparisons among agents show with moderate to high certainty that dupilumab ranks among the most beneficial for 7 of 7 outcomes, omalizumab for 2 of 7, mepolizumab for 1 of 7, and ASA-D for 1 of 7.
CONCLUSIONS
Multiple biologics and ASA-D credibly improve patient-important outcomes, with clinically important differences in effects among agents; dupilumab uniquely ranks among the most beneficial for all outcomes studied.
Topics: Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Aspirin; Chronic Disease; Humans; Nasal Polyps; Network Meta-Analysis; Omalizumab; Quality of Life; Sinusitis
PubMed: 34543652
DOI: 10.1016/j.jaci.2021.09.009