RESUMO
Background: The treatment of rheumatoid arthritis (RA), a chronic systemic inflammatory autoimmune disease, is based on disease-modifying anti-rheumatic drugs (DMARDs). Typically, it starts with conventional synthetic DMARDs (csDMARDs), and depending on the patient's response to the treatment and the adverse events experienced, biological DMARDs (bDMARDs) are initiated. bDMARDs are more specific to inflammatory factors than csDMARDs and more efficient in inducing remission and low disease activity. Thus, this study aimed to assess the effectiveness of biological therapy in patients with rheumatoid arthritis in administrative health databases. Methods: PubMed, Embase, Lilacs, Ovid, Scopus, and Web of Science databases were searched from inception to 21 October 2021, to identify observational studies that evaluated the effectiveness of biological therapy in patients with rheumatoid arthritis using administrative databases and real-world data. The methodological quality was assessed by the methodological index for non-randomized studies (MINORS). A fixed or random-effects model estimated risk ratios with 95% confidence intervals. The analysis was divided into four groups: tumor necrosis factor inhibitors (TNFi) versus non-TNFi; TNFi versus TNFi (adalimumab, etanercept, and golimumab versus infliximab); bDMARDs versus Janus kinase inhibitors (JAKi); and bDMARDs monotherapy versus combination therapy (bDMARDs and MTX). Results: Twenty-one records were eligible for inclusion in this systematic review and meta-analysis; seven population-based cohorts, eight prospective, and six retrospective cohort studies. Overall, 182,098 rheumatoid arthritis patients were evaluated. In the meta-analysis, lower effectiveness was observed among TNFi users than in non-TNFi (RR: 0.88; 95% CI: 0.81-0.95; p < 0.01; I2 = 94.0%) and bDMARDs than in JAKi (RR: 0.86; 95% CI: 0.79-0.94; p < 0.01; I2 = 93.0%). Higher effectiveness among adalimumab, etanercept, and golimumab than in infliximab (RR: 1.19; 95% CI: 1.05-1.36; p < 0.01; I2 = 96.0%) was found. No significant differences in the effectiveness of bDMARD monotherapy compared to combination therapy (RR: 0.83; 95% CI: 0.68-1.00; p < 0.01; I2 = 81.0%) was observed. E-value analysis indicated that the estimates were not robust against unmeasured confounding. Conclusion: According to the available real-world data, our results suggest that biological therapy effectively treats patients with rheumatoid arthritis, indicating higher effectiveness with non-TNFi and JAKi than with TNFi. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID#CRD42020190838, identifier CRD42020190838.
RESUMO
Background: Rheumatoid arthritis (RA) is a systemic inflammatory disease that affects the synovial fluid of joints, tendons, and some extra-articular sites. Biologic agents have been highly effective and are comparable in reducing RA symptoms, slowing disease progression, and improving physical function; however, concerns have been raised about the risks of several potential adverse effects. Thus, this study aimed to assess the safety of biological therapy in patients with rheumatoid arthritis in observational studies using administrative health databases. Methods: PubMed, Embase, Lilacs, Ovid, Scopus, and Web of Science were searched from inception to 21 October 2021. The analysis was divided into five groups: tumor necrosis factor inhibitors (TNFi) versus non-TNFi; TNFi versus csDMARDs; bDMARDs versus csDMARDs; abatacept versus bDMARDs; and TNFi versus Janus kinase inhibitors (JAKi). The adverse events were cancer, cardiovascular events, infection, herpes zoster, tuberculosis, and death. The methodological quality of the studies was assessed by the Newcastle-Ottawa Scale. A random-effects model estimated risk ratios with 95% confidence intervals. Results: Thirty-one studies were eligible for inclusion in the present systematic review, published from 2014 to 2021. A total of 1,039,398 RA patients were assessed. The 31 studies evaluated eleven different biological drugs. No significant differences were found regarding safety between TNFi versus non-TNFi (RR 1.08; 95% CI 0.92-1.28; p < 0.01; I2 = 93.0%), TNFi versus csDMARDs (RR 0.91; 95% CI 0.75-1.10; p < 0.01; I2 = 87.0%), bDMARDs versus csDMARDs (RR 0.99; 95% CI 0.82-1.20; p < 0.01; I2 = 93.0%), abatacept versus bDMARDs (RR 0.80; 95% CI 0.54-1.18; p < 0.01; I2 = 90.0%), and TNFi versus JAKi (RR 3.54; 95% CI 0.30-42.09; p = 0.01; I2 = 81.0%). In the subgroup analysis, among studies comparing abatacept to TNFi, a lower risk of cardiovascular events was associated with abatacept (RR 0.37; 95% CI 0.24-0.55). Conclusion: Our results do not suggest an increased risk of adverse events associated with biological therapy in treating RA patients, indicating a lower risk of cardiovascular events with abatacept than TNFi. However, these findings must be interpreted with caution given the limitations of this study and the low/very low certainty of the evidence. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?, identifier [CRD42020190838].
RESUMO
RESUMO Trata-se de um ensaio sobre a construção das listas de produtos estratégicos para o Sistema Único de Saúde brasileiro elegíveis para a apresentação de propostas de projetos de Parcerias para o Desenvolvimento Produtivo (PDP). O objetivo deste estudo foi analisar, de modo crítico, o processo de construção dessas listas, revendo os critérios utilizados, a interação existente atualmente com a avaliação de tecnologias em saúde, a colaboração entre tomadores de decisão e pesquisadores ou instituições de referência e a influência da composição da lista no desfecho dos projetos e alcance dos objetivos da iniciativa. Verificou-se que o uso de evidências científicas e as ações de colaboração de pesquisadores são reduzidos na tomada de decisão, e que a composição da lista apresenta grande influência no desfecho das PDP, sendo a sua construção fator primordial para o sucesso dessa iniciativa e internalização das tecnologias. Apresenta-se, como sugestão para organização dos trabalhos de elaboração da lista, a definição regimental de uso de um programa de respostas rápidas independentes organizado entre o governo, academia e instituições envolvidas nas aprovações das PDP para que a melhor evidência científica esteja disponível para os tomadores de decisão em um curto prazo.
ABSTRACT This is an essay on the construction of strategic product lists for the Brazilian Unified Health System (SUS) eligible for the submission of proposals for Productive Development Partnerships (PDP). The objective of this study was to critically analyze the process of constructing these lists, reviewing the criteria used, the interaction currently existing with the evaluation of health technologies, the collaboration between decision makers and researchers or reference institutions, and the influence of the composition of the list on the outcome of the projects and reach of the objectives of the initiative. It was found that the use of scientific evidence and collaborative actions of researchers are reduced in decision making, and that the composition of the list has a great influence on the outcome of the PDP, and its construction is a key factor for the success of this initiative and the internalization of technologies. A suggestion for organizing the list-making work is the regimental definition of the use of an independent rapid response program organized between the government, the academy, and institutions involved in PDP approvals, so that the best scientific evidence is available to policy decision makers in the short term.
RESUMO
In the struggle for life, the capacity of microorganisms to synthesize and secrete toxic compounds (inhibiting competitors) plays an important role in successful survival of these species. This ability must come together with the capability of being unaffected by these same compounds. Several mechanisms are thought to avoid the toxic effects. One of them is toxin extrusion from the intracellular environment to the outside vicinity, using special transmembrane proteins, referred to as transporters. These proteins are also important for other reasons, since most of them are involved in nutrient uptake and cellular excretion. In cancer cells and in pathogens, and particularly in fungi, some of these proteins have been pointed out as responsible for an important phenotype known as multidrug resistance (MDR). In the present study, we tried to identify in the Paracoccidioides brasiliensis transcriptome, transporter-ortholog genes from the two major classes: ATP binding cassette and major facilitator superfamily transporter. We found 22 groups with good similarity with other fungal ATP binding cassette transporters, and four Paracoccidioides brasilienses assembled expressed sequence tags that probably code for major facilitator superfamily proteins. We also focused on fungicide resistance orthologs already characterized in other pathogenic fungi. We were able to find homologs to C. albicans CDR1, CDR2, and MDR1, Saccharomyces cerevisiae PDR5 and Aspergillus AtrF genes, all of them related to azole resistance. As current treatment for paracoccidioidomycosis mainly uses azole derivatives, the presence of these genes can be postulated to play a similar role in P. brasiliensis, warning us for the possibility of resistant isolate emergence.