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Alimentary Pharmacology & Therapeutics Apr 2015The benefit of the combination of infliximab (IFX) and immunosuppressant (IS) therapy is debated in ulcerative colitis (UC). (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The benefit of the combination of infliximab (IFX) and immunosuppressant (IS) therapy is debated in ulcerative colitis (UC).
AIMS
To determine whether the combination of IFX and IS therapy is more effective than infliximab alone for active UC regardless of prior IS use.
METHODS
We identified all controlled trials including patients with moderate-to-severe active UC, treated by either IFX or combined IFX-IS therapy. The main outcome was clinical remission at 4-6 months. Two statistical methods were used, Mantel-Haenszel and Der-Simonian and Laird. Inter-trial heterogeneity was taken into account and publication bias was assessed.
RESULTS
Four controlled trials were analysed and included in the meta-analysis. These four trials included 765 patients, 389 treated with IFX alone and 376 treated with IFX and IS. At 4-6 months' therapy, the clinical remission rate was significantly lower for the IFX monotherapy group OR 0.50, 95% CI [0.34-0.73], P < 0.01 (P-heterogeneity = 0.49). The Harbord test did not show evidence of publication bias (P = 0.29). Calculation of an adjusted OR using the Duval and Tweedie method did not significantly modify results [OR 0.63, 95% CI (0.47-0.85)]. According to Orwin's formula, four additional medium-sized nonsignificant studies would be necessary to reduce the effect size to a nonsignificant value. At 12 months of therapy, there was no significant difference between the two groups: OR 0.60, 95% CI [0.17-2.06], P = 0.41 (P-heterogeneity = 0.01).
CONCLUSION
Combination therapy with IFX-IS is more effective than IFX alone for achieving and maintaining clinical remission at 4-6 months for patients with moderate-to-severe ulcerative colitis, regardless of prior IS use.
Topics: Antibodies, Monoclonal; Clinical Trials as Topic; Colitis, Ulcerative; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Infliximab; Middle Aged; Time Factors
PubMed: 25678223
DOI: 10.1111/apt.13102 -
Scandinavian Journal of Gastroenterology Sep 2017Various investigational medicinal products have been developed for ulcerative colitis (UC). Our aim was to systematically evaluate novel pharmacological therapeutic... (Review)
Review
OBJECTIVES
Various investigational medicinal products have been developed for ulcerative colitis (UC). Our aim was to systematically evaluate novel pharmacological therapeutic agents for the treatment of UC.
MATERIAL AND METHODS
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were followed. A search of the medical literature was conducted in the MEDLINE database for original research papers published between 01 January 2010 and 31 October 2014.
RESULTS
Twenty one studies, including 11,524 adults were analyzed. Thirteen different novel therapeutic drug options were identified. Vedolizumab and golimumab were superior to placebo as induction and maintenance therapy. Tofacitinib showed dose related efficacy for induction therapy. Etrolizumab showed higher clinical remission rates compared to placebo. Phosphatidylcholine led to an improved clinical activity index. HMPL-004 may become a mesalamine alternative for mild to moderate UC. PF00547,659 was well tolerated. Statins were not beneficial for acute exacerbations of UC. Abatacept, rituximab and visilizumab did not lead to improved outcomes compared to placebo. Higher concentration of BMS 936557 was associated with improved efficacy compared to placebo. Basiliximab did not enhance corticosteroid efficacy.
CONCLUSIONS
Patients with UC might achieve clinical response or remission by utilizing some of these agents with a favorable side effect profile. Further studies are needed to evaluate their short- and long-term efficacy and safety.
Topics: Andrographis paniculata; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Colitis, Ulcerative; Gastrointestinal Agents; Humans; Induction Chemotherapy; Mesalamine; Piperidines; Plant Extracts; Pyrimidines; Pyrroles; Remission Induction
PubMed: 28503977
DOI: 10.1080/00365521.2017.1326163 -
International Immunopharmacology Aug 2015Standard therapeutic schemes for vasculitis are usually associated with numerous side effects and uneven clinical response. However, recent advances in understanding of... (Review)
Review
Standard therapeutic schemes for vasculitis are usually associated with numerous side effects and uneven clinical response. However, recent advances in understanding of the pathogenesis of these systemic diseases have resulted in the development of a group of biologic agents potentially useful in patients with vasculitis. Thus, anti-tumor necrosis factor-α drugs may be effective in patients with refractory Kawasaki disease but have failed to do so in giant cell arteritis, and their role in Takayasu arteritis is yet unclear. Preliminary reports on the use of the anti-IL6-receptor antibody, tocilizumab, in large-vessel vasculitis have been encouraging. Interferon alpha has showed positive results in hepatitis B virus-associated polyarteritis nodosa, and hepatitis C virus-induced cryoglobulinemia. Early experience with rituximab in several types of vasculitis has been quite promising, but must be confirmed in ongoing randomized clinical trials. The development of new biologic targeted therapies will probably open a hopeful future for patients with vasculitis.
Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Biological Therapy; Humans; Systemic Vasculitis
PubMed: 25828585
DOI: 10.1016/j.intimp.2015.03.020 -
BMJ (Clinical Research Ed.) Sep 2021To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19).
DESIGN
Living systematic review and network meta-analysis, with pairwise meta-analysis for outcomes with insufficient data.
DATA SOURCES
WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, and six Chinese databases (up to 21 July 2021).
STUDY SELECTION
Trials randomising people with suspected, probable, or confirmed covid-19 to antiviral antibody therapies, blood products, or standard care or placebo. Paired reviewers determined eligibility of trials independently and in duplicate.
METHODS
After duplicate data abstraction, we performed random effects bayesian meta-analysis, including network meta-analysis for outcomes with sufficient data. We assessed risk of bias using a modification of the Cochrane risk of bias 2.0 tool. The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We meta-analysed interventions with ≥100 patients randomised or ≥20 events per treatment arm.
RESULTS
As of 21 July 2021, we identified 47 trials evaluating convalescent plasma (21 trials), intravenous immunoglobulin (IVIg) (5 trials), umbilical cord mesenchymal stem cells (5 trials), bamlanivimab (4 trials), casirivimab-imdevimab (4 trials), bamlanivimab-etesevimab (2 trials), control plasma (2 trials), peripheral blood non-haematopoietic enriched stem cells (2 trials), sotrovimab (1 trial), anti-SARS-CoV-2 IVIg (1 trial), therapeutic plasma exchange (1 trial), XAV-19 polyclonal antibody (1 trial), CT-P59 monoclonal antibody (1 trial) and INM005 polyclonal antibody (1 trial) for the treatment of covid-19. Patients with non-severe disease randomised to antiviral monoclonal antibodies had lower risk of hospitalisation than those who received placebo: casirivimab-imdevimab (odds ratio (OR) 0.29 (95% CI 0.17 to 0.47); risk difference (RD) -4.2%; moderate certainty), bamlanivimab (OR 0.24 (0.06 to 0.86); RD -4.1%; low certainty), bamlanivimab-etesevimab (OR 0.31 (0.11 to 0.81); RD -3.8%; low certainty), and sotrovimab (OR 0.17 (0.04 to 0.57); RD -4.8%; low certainty). They did not have an important impact on any other outcome. There was no notable difference between monoclonal antibodies. No other intervention had any meaningful effect on any outcome in patients with non-severe covid-19. No intervention, including antiviral antibodies, had an important impact on any outcome in patients with severe or critical covid-19, except casirivimab-imdevimab, which may reduce mortality in patients who are seronegative.
CONCLUSION
In patients with non-severe covid-19, casirivimab-imdevimab probably reduces hospitalisation; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit.
SYSTEMATIC REVIEW REGISTRATION
This review was not registered. The protocol established a priori is included as a data supplement.
FUNDING
This study was supported by the Canadian Institutes of Health Research (grant CIHR- IRSC:0579001321).
READERS' NOTE
This article is a living systematic review that will be updated to reflect emerging evidence. Interim updates and additional study data will be posted on our website (www.covid19lnma.com).
Topics: Antibodies, Monoclonal; Antibodies, Viral; Antiviral Agents; Bayes Theorem; COVID-19; Cell- and Tissue-Based Therapy; Clinical Trials as Topic; Humans; Immunization, Passive; Network Meta-Analysis; SARS-CoV-2; Treatment Outcome; COVID-19 Serotherapy
PubMed: 34556486
DOI: 10.1136/bmj.n2231 -
Annals of Oncology : Official Journal... Dec 2017Targeted therapies (TT) and immune checkpoint inhibitors (ICI) are currently modifying the landscape of metastatic cancer management and are increasingly used over the... (Review)
Review
BACKGROUND
Targeted therapies (TT) and immune checkpoint inhibitors (ICI) are currently modifying the landscape of metastatic cancer management and are increasingly used over the course of many cancers treatment. They allow long-term survival with controlled extra-cerebral disease, contributing to the increasing incidence of brain metastases (BMs). Radiation therapy remains the cornerstone of BMs treatment (either whole brain irradiation or stereotactic radiosurgery), and investigating the safety profile of radiation therapy combined with TT or ICI is of high interest. Discontinuing an efficient systemic therapy, when BMs irradiation is considered, might allow systemic disease progression and, on the other hand, the mechanisms of action of these two therapeutic modalities might lead to unexpected toxicities and/or greater efficacy, when combined.
PATIENTS AND METHODS
We carried out a systematic literature review focusing on the safety profile and the efficacy of BMs radiation therapy combined with targeted agents or ICI, emphasizing on the role (if any) of the sequence of combination scheme (drug given before, during, and/or after radiation therapy).
RESULTS
Whereas no relevant toxicity has been noticed with most of these drugs, the concomitant use of some other drugs with brain irradiation requires caution.
CONCLUSION
Most of available studies appear to advocate for TT or ICI combination with radiation therapy, without altering the clinical safety profiles, allowing the maintenance of systemic treatments when stereotactic radiation therapy is considered. Cognitive functions, health-related quality of life and radiation necrosis risk remain to be assessed. The results of prospective studies are awaited in order to complete and validate the above discussed retrospective data.
Topics: Antibodies, Monoclonal; Brain Neoplasms; Combined Modality Therapy; Cranial Irradiation; Humans; Immunotherapy; Molecular Targeted Therapy; Radiosurgery
PubMed: 29045524
DOI: 10.1093/annonc/mdx408 -
Frontiers in Immunology 2022CD47-SIRPα interaction acts as a "don't eat me" signal and is exploited by cancer to downregulate innate and adaptive immune surveillance. There has been intense... (Meta-Analysis)
Meta-Analysis
CD47-SIRPα interaction acts as a "don't eat me" signal and is exploited by cancer to downregulate innate and adaptive immune surveillance. There has been intense interest to develop a mechanism of blockade, and we aimed to analyze the emerging data from early clinical trials. We performed a systematic review and meta-analysis of relevant databases and conference abstracts including clinical trials using CD47 and/or SIRPα inhibitors in cancer treatment. Nonlinear mixed models were applied for comparison of response and toxicity. We retrieved 317 articles, 24 of which were eligible. These included 771 response-evaluable patients with hematologic (47.1%) and solid tumors (52.9%). Of these, 6.4% experienced complete response, 10.4% partial response, and 26.1% stable disease for a 16.7% objective response rate (ORR), 42.8% disease control rate, and 4.8-month median duration of response. ORR was significantly higher for hematologic cancers (25.3%) than solid cancers (9.1%, p=0.042). Comparing by mechanism, seven CD47 monoclonal antibodies (mAbs) and six selective SIRPα blockers were given alone or combined with checkpoint inhibitors, targeted therapy, and/or chemotherapy. In solid cancers, selective SIRPα blockade showed a higher ORR (16.2%) than anti-CD47 mAbs (2.8%, p=0.079), which was significant for combination therapies (ORR 28.3% vs 3.0%, respectively, p=0.010). Responses were seen in head and neck, colorectal, endometrial, ovarian, hepatocellular, non-small cell lung, and HER2+gastroesophageal cancers. Dose-limiting toxicity (DLT) was seen in 3.3% of patients (5.4% anti-CD47 mAbs, 1.4% selective SIRPα blockers; p=0.01). The frequency of treatment-related adverse events (TRAEs) ≥grade 3 was 18.0%, similar between the two groups (p=0.082), and mostly laboratory abnormalities. For anti-CD47 mAbs, the most common toxicities included grade 1-2 fatigue (27.2%), headache (21.0%), and anemia (20.5%). For selective SIRPα blockers, these included grade 1-2 infusion reaction (23.1%) and fatigue (15.8%). Anti-CD47 mAbs were significantly more likely than selective SIRPα blockers to cause grade 1-2 fever, chills, nausea/vomiting, headache, and anemia. In conclusion, combination therapies using selective SIRPα blockade had higher response rates in solid tumors than anti-CD47 mAb combinations. Hematologic changes were the main TRAEs, and selective SIRPα blockers seemed to have a better grade 1-2 toxicity profile. Treatment was well-tolerated with minimal DLTs.
Topics: Humans; Protein Binding; Antibodies, Monoclonal; Fatigue; Headache; Neoplasms; CD47 Antigen
PubMed: 36439116
DOI: 10.3389/fimmu.2022.1027235 -
International Journal of Environmental... Aug 2021Tocilizumab is an anti-IL-6 therapy widely adopted in the management of the so-called "cytokine storm" related to SARS-CoV-2 virus infection, but its effectiveness, use... (Meta-Analysis)
Meta-Analysis Review
Systematic Review and Meta-Analysis of Tocilizumab Therapy versus Standard of Care in over 15,000 COVID-19 Pneumonia Patients during the First Eight Months of the Pandemic.
BACKGROUND
Tocilizumab is an anti-IL-6 therapy widely adopted in the management of the so-called "cytokine storm" related to SARS-CoV-2 virus infection, but its effectiveness, use in relation to concomitant corticosteroid therapy and safety were unproven despite widespread use in numerous studies, mostly open label at the start of the pandemic.
METHODS
We performed a systematic review and meta-analysis of case-control studies utilising tocilizumab in COVID-19 on different databases (PubMed/MEDLINE/Scopus) and preprint servers (medRxiv and SSRN) from inception until 20 July 2020 (PROSPERO CRD42020195690). Subgroup analyses and meta-regressions were performed. The impact of tocilizumab and concomitant corticosteroid therapy or tocilizumab alone versus standard of care (SOC) on the death rate, need for mechanical ventilation, ICU admission and bacterial infections were assessed.
RESULTS
Thirty-nine studies with 15,531 patients (3657 cases versus 11,874 controls) were identified. Unadjusted estimates ( = 28) failed to demonstrate a protective effect of tocilizumab on survival (OR 0.74 ([95%CI 0.55-1.01], = 0.057), mechanical ventilation prevention (OR 2.21 [95%CI 0.53-9.23], = 0.277) or prevention of ICU admission (OR 3.79 [95%CI 0.38-37.34], = 0.254). Considering studies with adjusted, estimated, tocilizumab use was associated with mortality rate reduction (HR 0.50 ([95%CI 0.38-0.64], < 0.001) and prevention of ICU admission (OR 0.16 ([95%CI 0.06-0.43], < 0.001). Tocilizumab with concomitant steroid use versus SOC was protective with an OR of 0.49 ([95%CI 0.36-0.65], < 0.05) as was tocilizumab alone versus SOC with an OR of 0.59 ([95%CI 0.34-1.00], < 0.001). Risk of infection increased (2.36 [95%CI 1.001-5.54], = 0.050; based on unadjusted estimates).
CONCLUSION
Despite the heterogeneity of included studies and large number of preprint articles, our findings from the first eight of the pandemic in over 15,000 COVID-19 cases suggested an incremental efficacy of tocilizumab in severe COVID-19 that were confirmed by subsequent meta-analyses of large randomized trials of tocilizumab. This suggests that analysis of case-control studies and pre-print server data in the early stages of a pandemic appeared robust for supporting incremental benefits and lack of major therapeutic toxicity of tocilizumab for severe COVID-19.
Topics: Antibodies, Monoclonal, Humanized; Humans; Pandemics; SARS-CoV-2; Standard of Care; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 34501738
DOI: 10.3390/ijerph18179149 -
Transplantation Oct 2014Rituximab is a B lymphocyte-depleting agent used to treat lymphoma and autoimmune diseases. Recently, it has been used for desensitization therapy in ABO-incompatible... (Review)
Review
BACKGROUND
Rituximab is a B lymphocyte-depleting agent used to treat lymphoma and autoimmune diseases. Recently, it has been used for desensitization therapy in ABO-incompatible and highly sensitized recipients undergoing renal transplantation.
METHODS
A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Four databases and three trial registries were searched for studies comparing rituximab with non-rituximab desensitization protocols. A lack of randomized evidence precluded meta-analysis, and thus a narrative review was conducted.
RESULTS
Forty-five records met the inclusion criteria, relating to 21 individual studies (two randomized controlled trials and 19 retrospective cohort studies). Ten studies investigated the use of rituximab in ABO-incompatible patients; most found no significant differences in patient and graft outcomes when compared most frequently to splenectomy-based protocols. Nine studies of limited quality focused on highly sensitized recipients (positive cross-match, donor-specific antibody, and elevated panel reactive antibody) and demonstrated some benefits in graft survival, acute and chronic rejection, and sensitization levels with rituximab. The remaining two studies combined ABO-incompatible and highly sensitized recipients and found no statistically significant increase in infectious complications with rituximab.
CONCLUSION
Evidence of limited quality was identified to support the use of rituximab desensitization in highly sensitized recipients. Among ABO-incompatible recipients, rituximab was found to be equivalent to splenectomy, indicating that this invasive surgical procedure is not necessary. Further randomized controlled trials are required to better define the efficacy, long-term safety, and optimal dosing regimen of rituximab in this setting.
Topics: ABO Blood-Group System; Antibodies, Monoclonal, Murine-Derived; Blood Group Incompatibility; Desensitization, Immunologic; Histocompatibility Testing; Humans; Isoantibodies; Kidney Transplantation; Randomized Controlled Trials as Topic; Rituximab; Tissue Donors
PubMed: 25321163
DOI: 10.1097/TP.0000000000000362 -
BioDrugs : Clinical Immunotherapeutics,... Nov 2021Immunogenicity with formation of anti-drug antibodies (ADA) to biologics is an important reason for treatment failure in inflammatory bowel disease (IBD). Our aim was to... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Immunogenicity with formation of anti-drug antibodies (ADA) to biologics is an important reason for treatment failure in inflammatory bowel disease (IBD). Our aim was to assess the rate of ADA, the effect of combination therapy with immunomodulators on ADA and the influence of ADA on efficacy and safety of biologics for IBD treatment.
METHODS
MEDLINE, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to April 2020 for trials of biologics that assessed immunogenicity. The overall certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). The primary outcome was rate of ADA. Secondary outcomes included efficacy and safety outcomes among patients with detectable versus undetectable ADA. For dichotomous outcomes, pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated.
RESULTS
Data from 68 studies were analyzed and 33 studies (5850 patients) were included in the meta-analysis. Pooled ADA rates for biologic monotherapy were 28.0% for infliximab, 7.5% for adalimumab, 3.8% for golimumab, 10.9% for certolizumab, 6.2% for ustekinumab and 16.0% for natalizumab. Pooled ADA rates were 8.4% for vedolizumab and 5.0% for etrolizumab for combo- and monotherapy combined. In all biologics, ADA rates were underestimated by use of drug-sensitive ADA assays and higher dose and/or frequency. ADA rate was significantly reduced in patients treated with combination therapy for infliximab (RR 0.52; 95% CI 0.44-0.62), adalimumab (RR 0.31; 95% CI 0.14-0.69), golimumab (RR 0.29; 95% CI 0.10-0.83), certolizumab pegol (RR 0.30; 95% CI 0.14-0.67) and natalizumab (RR 0.20; 95% CI 0.11-0. 39). ADA to infliximab were associated with lower clinical response rates (RR 0.75; 95% CI 0.61-0.91) and higher rates of infusion reactions (RR 2.36; 95% CI 1.85-3.01).
CONCLUSIONS
Differences in analytical methods to detect ADA hamper comparison of true ADA rates across biologics in IBD. Use of combination therapy with immunomodulators appeared to reduce ADA positivity for most biologics. For infliximab, ADA were associated with reduced drug efficacy and increased adverse events.
Topics: Adalimumab; Antibody Formation; Biological Factors; Humans; Inflammatory Bowel Diseases; Infliximab
PubMed: 34797516
DOI: 10.1007/s40259-021-00507-5 -
Journal of Reproductive Immunology Feb 2023This systematic review and meta-analysis were designed to identify possible correlations between isolated serum antinuclear antibody (ANA) and (i) infertility in the... (Meta-Analysis)
Meta-Analysis Review
This systematic review and meta-analysis were designed to identify possible correlations between isolated serum antinuclear antibody (ANA) and (i) infertility in the context of in-vitro fertilization (IVF), (ii) idiopathic recurrent pregnancy losses (RPL), and (iii) second/ third trimester pregnancy complications. We performed a systematic review and meta-analysis of the literature in PubMed Library database from inception to March 2022 following PRISMA guidelines. Our pooled results showed a lower pregnancy rate among ANA-positive women undergoing IVF/ICSI compared to ANA-negative women undergoing the same procedures (279/908 versus 1136/2347, random effect, odds ratio -OR- 0.50, 95% confidence interval -CI- 0.38-0.67, p 0.00001, I = 58%). We also reported a higher miscarriage rate among ANA-positive compared to ANA-negative women (48/223 versus 109/999, random effect, OR: 3.25 95% CI: 1.57-6.76, p = 0.002, I = 61%) and a lower implantation rate (320/1489 versus 1437/4205, random effect, OR: 0.51, 95% CI: 0.36-0.72, p = 0.0001, I = 78%). Regarding RPL, pooled results demonstrated a higher prevalence of ANA-positivity in RPL women compared to controls (698/2947 versus 240/3145, random effect, OR: 3.22, 95% CI: 2.12-4.88, p 0.00001, I 77%), either using > 2 or > 3 pregnancy losses threshold for defining RPL. Heterogeneity of reporting outcome did not allow a quantitative analysis and led to no clear demonstration of an effect of serum ANA on the incidence of stillbirth, preeclampsia and hypertensive disorders. In conclusion, the unfavorable effect of serum ANA was observed in women following IVF. Similarly, ANA were associated with the risk of RPL, while data were unconclusive in terms of late pregnancy complications.
Topics: Pregnancy; Female; Humans; Antibodies, Antinuclear; Embryo Implantation; Fertilization in Vitro; Pregnancy Rate; Abortion, Habitual; Infertility, Female
PubMed: 36621091
DOI: 10.1016/j.jri.2022.103794