Association of Tocilizumab Use and Adverse Health Outcomes in Rheumatoid Arthritis Patients: an Umbrella Review of Meta-analyses of Randomized Clinical Trials and Cohort Studies

Tocilizumab (TCZ), a humanized anti-IL-6 receptor monoclonal antibody was first granted regulatory approval in Japan for the treatment of moderate to severe rheumatoid arthritis, followed by approvals in Europe in 2009 and the United States in 2010. The substantial body of clinical evidence accumulated during the past decade, from both randomized clinical trials (RCTs) and real-world settings, has firmly established the efficacy of TCZ in the treatment of adult patients with rheumatoid arthritis. Several useful meta-analyses of RCTs and cohort studies have been published examining the safety of TCZ in the management of rheumatoid arthritis patients. However, there has been a limited comprehensive assessment and synthesis of the collective strength and quality of the available evidence on this topic from meta-analyses. The technique of umbrella reviews offers a comprehensive approach to synthesizing evidence from multiple meta-analyses on the same topic. It enables the grading of evidence according to sample size, number of cases, precision, strength of the association, together with assessments of potential biases. This umbrella review aimed to systematically identify relevant meta-analyses of RCTs and cohort studies of TCZ in rheumatoid arthritis patients and then summarize their findings on adverse health outcomes. It also assessed the certainty of evidence for the identified associations

Chemoprevention of Gastrointestinal Cancers: An Umbrella Review of Meta‐Analyses of Randomized Controlled Trials and Cohort Studies

ABSTRACT Several meta‐analyses have investigated the association between chemopreventive agents (CPAs) and the risk of gastrointestinal cancers, but syntheses of the quality of evidence in aggregate are lacking. This umbrella review aimed to assess the quality of evidence from meta‐analyses of randomized controlled trials (RCTs) and cohort studies that examine inverse associations between CPAs and the risk of gastrointestinal cancers or any premalignant conditions. Summary effect sizes from random‐effects models, between‐study heterogeneity, 95% prediction interval, small‐study effect, excess significance, and credibility ceilings were devised to classify the credibility of evidence from meta‐analyses of cohort studies, whereas the GRADE approach was used for meta‐analyses of RCTs. From 20,296 publications, 577 full‐text articles were evaluated for eligibility, and 69 articles that provided 194 unique meta‐analyses were included. Among meta‐analyses of RCTs (N = 93), 26 reached statistical significance (p < 0.05). Seven inverse associations were graded as either high quality (celecoxib and colorectal adenomas, (N = 4)) or moderate (aspirin and colorectal adenomas, (N = 2) and H‐pylori eradication and gastric cancer (N = 1)). Among meta‐analyses of cohort studies (N = 101), 60 reached statistical significance. Four inverse associations were graded as either convincing (antivirals with hepatocellular carcinoma (HCC); N = 1) or highly suggestive (aspirin with HCC (N = 2) and colorectal cancer (N = 1)). This review suggests that the associations with the most consistent empirical evidence were confined to those targeting the well‐established risk factors of gastrointestinal cancer progression. Despite the limited established evidence, the inverse associations observed between metformin and colorectal, esophageal, and gastric cancers, as well as between statins and HCC and gastric cancer, merit further research

Efficacy of antidepressants in functional dyspepsia: Systematic review and meta-analysis with trial sequential analysis of randomized controlled trials

Introduction: The beneficial effects of using antidepressants in improving functional dyspepsia (FD) symptoms have been reported in previous meta-analyses; however, the results have not been conclusive. The aim was to perform an updated meta-analysis coupled with trial sequential analysis (TSA) to assess the efficacy of the use of any antidepressants in the treatment of FD in adults. Methods: Electronic databases were searched up to March 2024 for randomized controlled trials (RCTs) recruiting adults with FD. Data of overall symptoms improved between the antidepressants and placebo groups was pooled to obtain risk ratio (RR) employing the random-effects model. The effect of random errors was evaluated with TSA. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence. Analyses were performed using STATA version 16.0. Results: Nine RCTs with 924 patients met the eligible criteria. The RRs of FD symptoms improving with any antidepressants, tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors were (n = 9, RR = 1.30 [95% CI, 1.02-1.67]), (n = 5, RR = 1.41 [95% CI, 1.07-1.85]) and (n = 2, RR = 0.97 [95% CI, 0.72-1.29]), respectively. TSA demonstrated conclusive evidence for the beneficial effect of TCAs. The number needed to treat (NNT) with any depressants and TCAs were 11 (95% CI, 7-36) and 6 (95% CI, 4-15), respectively. The certainty of the evidence for an effect of TCAs was that of moderate GRADE quality. The benefit, however, was limited to the western population (n = 3, RR = 1.43 [95% CI, 1.04-1.96]) and did not extend to the Asian population (n = 2, RR = 1.32 [95% CI, 0.75-2.32]). Conversely, antidepressant-using patients experienced adverse events more frequently. However, no statistically significant association was found between TCAs and any adverse events (n = 3; RR = 1.36 [95% CI, 0.91-2.04]). Conclusion: Evidence was obtained suggesting TCAs can be an effective alternative in the treatment of FD, but more evidence from high-quality large trials is required to support their use, especially in the Asian population

The Comparative Efficacy of FDA-approved Medications for Alcohol Use Disorder: A Network Meta-Analysis of Randomized Clinical Trials

Alcohol Use Disorder (AUD) is a chronic relapsing condition that affects millions of individuals worldwide. This study aimed to evaluate the comparative efficacy of FDA-approved medications for the treatment of AUD. A systematic search of PubMed, Embase, and CENTRAL was conducted up to January 2025. Randomized controlled trials with at least 12 weeks of treatment duration that enrolled adults with AUD and evaluated an FDA-approved medication (acamprosate, disulfiram, or naltrexone) alone or in combination compared with placebo or another FDA-approved medication were eligible. A random-effects network meta-analysis (NMA) using a consistency model within a frequentist approach will be employed. The primary outcome chosen was relapse, which was defined as a return to any level of drinking, while the secondary outcome was a return to heavy drinking

Antidepressants for Non-specific Chronic Low Back Pain: A Network Meta-Analysis of Randomized Clinical Trials

Antidepressants have been evaluated in randomized clinical trials (RCTs) for the management of chronic non-specific low back pain (CNSLBP); however, their comparative safety and efficacy remain uncertain. This study aims to systematically review and conduct an NMA of eligible randomized controlled trials (RCTs) to evaluate the comparative safety and efficacy of various antidepressant classes in the treatment of CNSLBP

Cellular Immune Responses to Live Attenuated Japanese Encephalitis (JE) Vaccine SA14-14-2 in Adults in a JE/Dengue Co-Endemic Area

Background Japanese encephalitis (JE) virus (JEV) causes severe epidemic encephalitis across Asia, for which the live attenuated vaccine SA14-14-2 is being used increasingly. JEV is a flavivirus, and is closely related to dengue virus (DENV), which is co-endemic in many parts of Asia, with clinically relevant interactions. There is no information on the human T cell response to SA14-14-2, or whether responses to SA14-14-2 cross-react with DENV. We used live attenuated JE vaccine SA14-14-2 as a model for studying T cell responses to JEV infection in adults, and to determine whether these T cell responses are cross-reactive with DENV, and other flaviviruses. Methods We conducted a single arm, open label clinical trial (registration: clinicaltrials.gov NCT01656200) to study T cell responses to SA14-14-2 in adults in South India, an area endemic for JE and dengue. Results Ten out of 16 (62.5%) participants seroconverted to JEV SA14-14-2, and geometric mean neutralising antibody (NAb) titre was 18.5. Proliferation responses were commonly present before vaccination in the absence of NAb, indicating a likely high degree of previous flavivirus exposure. Thirteen of 15 (87%) participants made T cell interferon-gamma (IFN gamma) responses against JEV proteins. In four subjects tested, at least some T cell epitopes mapped cross-reacted with DENV and other flaviviruses. Conclusions JEV SA14-14-2 was more immunogenic for T cell IFN gamma than for NAb in adults in this JE/DENV co-endemic area. The proliferation positive, NAb negative combination may represent a new marker of long term immunity/exposure to JE. T cell responses can cross-react between JE vaccine and DENV in a co-endemic area, illustrating a need for greater knowledge on such responses to inform the development of next-generation vaccines effective against both diseases

A sub-optimal cross-reactive CD8⁺ T cell response dominated by MIP-1β single positive cells.

(A) Flow cytometry data from the same experiment as Fig 6E. Data are log10 fluorescence units, gated on live, CD3+, CD8+ cells. (B) SPICE analysis of 16-week post vaccine TCL responses from the same experiment as in Fig 6E, stimulated with JEV wild type (left), JEV vaccine (centre) and DENV2/4 (right) peptides. Cells were stained for IFNγ, TNFα and MIP-1β; pie slices correspond to the relative proportion of the response made up of triple cytokine+ cells (black), double cytokine+ cells and single cytokine+ cells, which were exclusively MIP-1β+ in this experiment.</p

Summary of cross reactive T cell responses identified after vaccination with JEV SA14-14-2.

<p>Summary of cross reactive T cell responses identified after vaccination with JEV SA14-14-2.</p

Cross-reactivity of anti-JEV IFNγ responses.

<p>(A) cross-reactive T cell responses to variant peptides from dengue virus (DENV) in participant VA012/3. Data are percent IFNγ⁺ CD8⁺ T cells from a short-term T cell line expanded with JE vaccine NS3 peptide TAVLAPTRVVAAEMAEVL in an ICS assay to the peptides indicated. Two earlier experiments expanding TCL to wild type and vaccine library peptides, which differ only in a Val/Ala substitution at position 17, outside the region of epitope conservation (dotted lines), gave the same result. Inset: Reciprocal PRNT₅₀ for all four DENV serotypes and JEV; HLA type. (B) cross-reactive T cell responses to variant peptides from West Nile virus and DENV in participant VA020/1. Data are percent IFNγ⁺ CD8⁺ T cells from a short-term T cell line expanded with JE vaccine E peptide GATWVDLVLEGDSCLTIM in an ICS assay to the peptides indicated. The dotted lines indicate the region of epitope conservation subsequently shown in another experiment (<a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005263#pntd.0005263.s004" target="_blank">S4 Fig</a> panel A). Inset: Reciprocal PRNT₅₀ for all four DENV serotypes and JEV; HLA type.</p