This literature review aims to provide a comprehensive current summary of the pathogenesis, clinical features, disease course, host immune responses, and current investigational antiviral and immunomodulatory pharmacotherapies to facilitate the development of future therapies and measures for prevention and control.
Polyarticular juvenile idiopathic arthritis (pJIA) is a pediatric chronic inflammatory arthritis, much like rheumatoid arthritis (RA) in adults. Drug development for pJIA can potentially be expedited by using extrapolation of efficacy from adult RA; however, the lack of understanding of the response and exposure relationship between pJIA and RA to therapeutic interventions has been a major roadblock. To address this, the objective of our analysis was to conduct a systematic response and exposure comparison between pJIA and RA trials for biologic products. Data from registration RA and pJIA clinical trials (parallel or withdrawal design) for infliximab, tocilizumab, golimumab, and adalimumab were utilized. First, exposure was compared between the pJIA trials and RA pivotal trials. Subsequently, the pJIA vs. RA response similarity was assessed by comparing similar individual subcomponents of the American College of Rheumatology (ACR) scores between the two populations. The exposure comparison demonstrated that at the pJIA trial dose, exposure in pediatric patients was similar to or higher than adults for all biologics evaluated except infliximab, where lower exposure was observed in pJIA patients ≤ 35 kg. Response comparison for individual subcomponents indicated that in a majority of the cases, pJIA response was similar or higher as compared with response from RA trials. Overall, this analysis suggests response similarity between pJIA and RA across the biologic products when exposures are matched between the two populations. These analyses provide support for the use of pharmacokinetic exposure‐matching for extrapolation of efficacy from adult RA to pediatric pJIA for the products with established mechanism(s) of action.
Objectives To better understand the strengths and weaknesses, and to propose policy recommendations, regarding conducting high-quality clinical research in Shenzhen, China. Design A qualitative study conducted from August to November 2016 using a semistructured interview format involving both focus group interviews and individual interviews. Setting Shenzhen, China. Participants Stratified purposive and convenience sampling were used. Thirty individuals experienced in conducting and managing clinical research were selected from key stakeholder groups, comprising 11 from local hospitals, 14 from pharmaceutical/medical device companies and 5 from government agencies. Methods A semistructured interview guide was developed by the study group and used by experienced interviewers in focus group discussions and individual interviews. The interviewees were encouraged to share their opinions freely and discuss their own topics of interest during the interviews. Thematic analysis was used for analysis and all data were coded and extracted using NVivo V.11.0 software. Results Favourable driving factors for clinical research in Shenzhen identified by all stakeholders included the recent trend of increased governmental funding for clinical research, supportive governmental policies, wide recognition of the value of clinical research and high demands from local industry. The major challenges include a lack of technical infrastructure, weak human research subject protection and a lack of capable research resources. Conclusions Despite the established strengths, Shenzhen still needs to develop suitable technical platforms, human resources training programmes and strong human research subject protection programmes pertaining to clinical research. This would facilitate the establishment of a functional system that can be expected to lead to increased medical research innovation in Shenzhen.
To investigate the anxiety and pregnancy-associated stress of pregnant women with chronic hepatitis B virus (HBV) infection in the People's Republic of China and analyze the relationship between anxiety and pregnancy-associated stress in the hope of finding ways to reduce the stress or improve the coping skills for these mothers-to-be during pregnancy.A cross-sectional study was conducted. One hundred and sixty chronic HBV-infected pregnant women (HBV group) and 160 healthy pregnant women (control group) selected from three Peking University-affiliated hospitals participated in the study, and completed the State-Trait Anxiety Inventory (STAI) and Pregnancy Stress Rating Scale (PSRS) survey.The mean scores of STAI and PSRS for the HBV group were higher than for the control group. Factor 2 of PSRS (stress caused by worrying about mother and child's health and safety) was the highest, and was significantly higher in the HBV group than in the control group. Correlation analysis showed STAI scores were significantly correlated with economic status and diagnosis, as well as the total score, factor 1 (stress about identifying with the role of mother), and factor 2 of PSRS, but not significantly correlated with factor 3 of PSRS (stress caused by the changes of body shape and physical activity).Pregnant women with chronic HBV infection experienced higher levels of anxiety and stress than healthy pregnant women. Their major stress came from concerns for the health and safety of the mother and the child.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and chronic inflammation. The etiology and pathogenesis of SLE are complicated in which dysfunction of CD4+ T cells is largely engaged. In this study, we investigated the manners of CD4+ T cells in antibody production in a lupus-like mouse model through peritoneal injection of pristane reagent. With the increase in total IgG/IgM and autoantibody production after 6 months, CD4+ T cells exhibited activated phenotypes with the elevated CD44, ICOS, OX40, and PD-1 expression. Pristane injection induced the increase in IgM levels in both wild-type and T cell-deficient TCRα-/- mice whereas IgG, IgG1, and IgG2a production was impaired. When adoptively transferring CD4+ T cells into T cell-deficient mice or coculturing CD4+ T cells and B cells in vitro, it was found that CD4+ T cells derived from pristane-treated mice could help the production of total IgG as well as IgG1/IgG2a in a more efficient manner both in vivo and in vitro. While MHC was dispensable for IgG production, ICAM-1 likely functioned as an attenuating factor for IgG production. Our study thus reveals that CD4+ T cells in pristane-treated mice play important roles in IgG production, which implies the critical roles in the induction of pathological autoantibodies in MHC-independent and ICAM-1-dependent manners.
Mycobacterial lipoproteins are considered to be involved in both virulence and immunoregulatory processes during Mycobacterium tuberculosis (M.tb) infection. In our previous investigations on the immunoreactivity of more than 30 M.tb proteins in active TB patients, we identified mycobacterial lipoprotein Z (LppZ) as one of the most immune dominant antigens. How LppZ triggers immune responses is still unclear. In this study, we analyzed LppZ-mediated innate and adaptive immunity using a murine air pouch model and an M.tb infection model, respectively. We found that LppZ could not only recruit inflammatory cells but also induce the production of proinflammatory cytokines inside the pouches. LppZ could also induce strong Th1 responses following immunization and confer protection against challenge with M.tb virulent strain H37Rv at a similar level to BCG vaccination but with less pathological damage in the lungs. Furthermore, we revealed the presence of LppZ-specific functional CD4+ T cells in the lungs of the challenged mice that were capable of secreting double or triple cytokines, including IFN-γ, IL-2 and TNF-α. Our study thus demonstrates that LppZ is of strong immunogenicity during M.tb infection in both humans and mice and has the ability to trigger effective innate and cellular immunity. Considering the limitations of candidate antigens in the pipeline of TB vaccine development, LppZ-mediated immune protection against M.tb challenge in the mouse model implies its potential application in vaccine development.
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