ABSTRACT
BACKGROUND: Our knowledge of immune-mediated inflammatory disease (IMID) aetiology and pathogenesis has improved greatly over recent years, however, very little is known of the factors that trigger disease relapses (flares), converting diseases from inactive to active states. Focussing on rheumatoid arthritis (RA), the challenge that we will address is why IMIDs remit and relapse. Extrapolating from pathogenetic factors involved in disease initiation, new episodes of inflammation could be triggered by recurrent systemic immune dysregulation or locally by factors within the joint, either of which could be endorsed by overarching epigenetic factors or changes in systemic or localised metabolism. METHODS: The BIO-FLARE study is a non-randomised longitudinal cohort study that aims to enrol 150 patients with RA in remission on a stable dose of non-biologic disease-modifying anti-rheumatic drugs (DMARDs), who consent to discontinue treatment. Participants stop their DMARDs at time 0 and are offered an optional ultrasound-guided synovial biopsy. They are studied intensively, with blood sampling and clinical evaluation at weeks 0, 2, 5, 8, 12 and 24. It is anticipated that 50% of participants will have a disease flare, whilst 50% remain in drug-free remission for the study duration (24 weeks). Flaring participants undergo an ultrasound-guided synovial biopsy before reinstatement of previous treatment. Blood samples will be used to investigate immune cell subsets, their activation status and their cytokine profile, autoantibody profiles and epigenetic profiles. Synovial biopsies will be examined to profile cell lineages and subtypes present at flare. Blood, urine and synovium will be examined to determine metabolic profiles. Taking into account all generated data, multivariate statistical techniques will be employed to develop a model to predict impending flare in RA, highlighting therapeutic pathways and informative biomarkers. Despite initial recruitment to time and target, the SARS-CoV-2 pandemic has impacted significantly, and a decision was taken to close recruitment at 118 participants with complete data. DISCUSSION: This study aims to investigate the pathogenesis of flare in rheumatoid arthritis, which is a significant knowledge gap in our understanding, addressing a major unmet patient need. TRIAL REGISTRATION: The study was retrospectively registered on 27/06/2019 in the ISRCTN registry 16371380 .
ABSTRACT
AIM: To assess the association of country-level obesity prevalence with COVID-19 case and mortality rates, to evaluate the impact of obesity prevalence on worldwide variation. METHODS: Data on COVID-19 prevalence and mortality, country-specific governmental actions, socioeconomic, demographic, and healthcare capacity factors were extracted from publicly available sources. Multivariable negative binomial regression was used to assess the independent association of obesity with COVID-19 case and mortality rates. RESULTS: Across 168 countries for which data were available, higher obesity prevalence was associated with increased COVID-19 mortality and prevalence rates. For every 1% increase in obesity prevalence, the mortality rate was increased by 8.3% (incidence rate ratio [IRR] 1.083, 95% confidence interval [CI] 1.048-1.119; P < 0.001) and the case rate was higher by 6.6% (IRR 1.066, 95% CI 1.035-1.099; P < 0.001). Additionally, higher median population age, greater female ratio, higher Human Development Index (HDI), lower population density, and lower hospital bed availability were all significantly associated with higher COVID-19 mortality rate. In addition, stricter governmental actions, higher HDI and lower mean annual temperature were significantly associated with higher COVID-19 case rate. CONCLUSION: These findings demonstrate that obesity prevalence is a significant and potentially modifiable risk factor of increased COVID-19 national caseload and mortality. Future research to study whether weight loss improves COVID-19 outcomes is urgently required.