Cardiovascular risk in rheumatoid arthritis patients treated with targeted synthetic and biological disease-modifying antirheumatic drugs: A multi-centre cohort study.

BACKGROUND: This study aimed to compare the cardiovascular safety of interleukin-6 inhibitors (IL-6i) and Janus Kinase inhibitors (JAKi) to tumour necrosis factor inhibitors (TNFi). METHODS: We conducted a retrospective cohort study using population-based electronic databases from Hong Kong, Taiwan and Korea. We identified newly diagnosed patients with rheumatoid arthritis (RA) who received b/tsDMARDs first time. We followed patients from b/tsDMARD initiation to the earliest outcome (acute coronary heart disease, stroke, heart failure, venous thromboembolism and systemic embolism) or censoring events (death, transformation of b/tsDMARDs on different targets, discontinuation and study end). Using TNFi as reference, we applied generalized linear regression for the incidence rate ratio estimation adjusted by age, sex, disease duration and comorbidities. Random effects meta-analysis was used for pooled analysis. RESULTS: We identified 8689 participants for this study. Median (interquartile range) follow-up years were 1.45 (2.77) in Hong Kong, 1.72 (2.39) in Taiwan and 1.45 (2.46) in Korea. Compared to TNFi, the adjusted incidence rate ratios (aIRRs) (95% confidence interval [CI]) of IL-6i in Hong Kong, Taiwan and Korea are 0.99 (0.25, 3.95), 1.06 (0.57, 1.98) and 1.05 (0.59, 1.86) and corresponding aIRR of JAKi are 1.50 (0.42, 5.41), 0.60 (0.26, 1.41), and 0.81 (0.38, 1.74), respectively. Pooled aIRRs showed no significant risk of cardiovascular events (CVEs) associated with IL-6i (1.05 [0.70, 1.57]) nor JAKi (0.80 [0.48, 1.35]) compared to TNFi. CONCLUSION: There was no difference in the risk of CVE among RA patients initiated with IL-6i, or JAKi compared to TNFi. The finding is consistent in Hong Kong, Taiwan and Korea.

Carditis After COVID-19 Vaccination With a Messenger RNA Vaccine and an Inactivated Virus Vaccine : A Case-Control Study.

BACKGROUND: Case reports of carditis after BNT162b2 vaccination are accruing worldwide. OBJECTIVE: To examine the association of BNT162b2 and CoronaVac (Sinovac) vaccination with carditis. DESIGN: Case-control study with hospital control participants. SETTING: Territory-wide, public health care database with linkage to population-based vaccination records in Hong Kong. PATIENTS: Inpatients aged 12 years or older first diagnosed with carditis were selected as case patients. All other hospitalized patients without carditis were treated as control participants. Ten control participants were randomly matched with each case patient by age, sex, and admission date. INTERVENTION: Vaccination with BNT162b2 or CoronaVac. MEASUREMENTS: Incident diagnosis of carditis based on the International Classification of Diseases, Ninth Revision, and elevated troponin levels. RESULTS: A total of 160 case patients and 1533 control participants were included. Incidence of carditis per 100 000 doses of CoronaVac and BNT162b2 administered was estimated to be 0.31 (95% CI, 0.13 to 0.66) and 0.57 (CI, 0.36 to 0.90), respectively. Multivariable analyses showed that recipients of the BNT162b2 vaccine had higher odds of carditis (adjusted odds ratio [OR], 3.57 [CI, 1.93 to 6.60]) than unvaccinated persons. Stratified by sex, the OR was 4.68 (CI, 2.25 to 9.71) for males and 2.22 (CI, 0.57 to 8.69) for females receiving the BNT162b2 vaccine. The ORs for adults and adolescents receiving the BNT162b2 vaccine were 2.41 (CI, 1.18 to 4.90) and 13.79 (CI, 2.86 to 110.38), respectively. Subanalysis showed an OR of 9.29 (CI, 3.94 to 21.91) for myocarditis and 1.06 (CI, 0.35 to 3.22) for pericarditis associated with BNT162b2. The risk was mainly seen after the second dose of BNT162b2 rather than the first. No association between CoronaVac and carditis with a magnitude similar to that for BNT162b2 was seen. LIMITATION: Limited sample size, absence of electrocardiography and other clinical investigative data, and unrecorded overseas vaccination exposure. CONCLUSION: Despite a low absolute risk, there is an increased risk for carditis associated with BNT162b2 vaccination. This elevated risk should be weighed against the benefits of vaccination. PRIMARY FUNDING SOURCE: Health and Medical Research Fund.

Two-dose COVID-19 vaccination and possible arthritis flare among patients with rheumatoid arthritis in Hong Kong.

OBJECTIVES: To investigate the relationship between COVID-19 full vaccination (two completed doses) and possible arthritis flare. METHODS: Patients with rheumatoid arthritis (RA) were identified from population-based electronic medical records with vaccination linkage and categorised into BNT162b2 (mRNA vaccine), CoronaVac (inactive virus vaccine) and non-vaccinated groups. The risk of possible arthritis flare after vaccination was compared using a propensity-weighted cohort study design. We defined possible arthritis flare as hospitalisation and outpatient consultation related to RA or reactive arthritis, based on diagnosis records during the episode. Weekly prescriptions of rheumatic drugs since the launch of COVID-19 vaccination programme were compared to complement the findings from a diagnosis-based analysis. RESULTS: Among 5493 patients with RA (BNT162b2: 653; CoronaVac: 671; non-vaccinated: 4169), propensity-scored weighted Poisson regression showed no significant association between arthritis flare and COVID-19 vaccination ((BNT162b2: adjusted incidence rate ratio 0.86, 95% Confidence Interval 0.73 to 1.01); CoronaVac: 0.87 (0.74 to 1.02)). The distribution of weekly rheumatic drug prescriptions showed no significant differences among the three groups since the launch of the mass vaccination programme (all p values >0.1 from Kruskal-Wallis test). CONCLUSIONS: Current evidence does not support that full vaccination of mRNA or inactivated virus COVID-19 vaccines is associated with possible arthritis flare.

Autoimmune conditions following mRNA (BNT162b2) and inactivated (CoronaVac) COVID-19 vaccination: A descriptive cohort study among 1.1 million vaccinated people in Hong Kong.

BACKGROUND: Concerns regarding the autoimmune safety of COVID-19 vaccines may negatively impact vaccine uptake. We aimed to describe the incidence of autoimmune conditions following BNT162b2 and CoronaVac vaccination and compare these with age-standardized incidence rates in non-vaccinated individuals. METHODS: This is a descriptive cohort study conducted in public healthcare service settings. Territory-wide longitudinal electronic medical records of Hong Kong Hospital Authority users (≥16 years) were linked with COVID-19 vaccination records between February 23, 2021 and June 30, 2021. We classified participants into first/second dose BNT162b2 groups, first/second dose CoronaVac groups and non-vaccinated individuals for incidence comparison. The study outcomes include hospitalized autoimmune diseases (16 types of immune-mediated diseases across six body systems) within 28 days after first and second dose of vaccination. Age-standardized incidence rate ratios (IRRs) with exact 95% confidence intervals (CIs) were estimated using Poisson distribution. RESULTS: This study included around 3.9 million Hong Kong residents, of which 1,122,793 received at least one dose of vaccine (BNT162b2: 579,998; CoronaVac: 542,795), and 721,588 completed two doses (BNT162b2: 388,881; CoronaVac: 332,707). Within 28 days following vaccination, cumulative incidences for all autoimmune conditions were below 9 per 100,000 persons, for both vaccines and both doses. None of the age-standardized incidence rates were significantly higher than the non-vaccinated individuals, except for an observed increased incidence of hypersomnia following the first dose of BNT162b2 (standardized IRR: 1.47; 95% CI: 1.10-1.94). CONCLUSIONS: Autoimmune conditions requiring hospital care are rare following mRNA and inactivated COVID-19 vaccination with similar incidence to non-vaccinated individuals. The association between first dose BNT162b2 vaccination and immune-related sleeping disorders requires further research. Population-based robust safety surveillance is essential to detect rare and unexpected vaccine safety events.

Associations between residential environments and late-onset schizophrenia in UK Biobank: Interaction with genetic risk factor.

BACKGROUND: Environment and genes both contribute to schizophrenia. However, the impact of different natural environments surrounding residential addresses on schizophrenia in urban settings remains unknown. This study aimed to investigate the association of urbanisation, measured by residential environments, with late-onset schizophrenia and explore whether genetic risk for schizophrenia modified the associations. METHODS: We examined the associations between residential environments and late-onset schizophrenia and its interaction with genetic risk factors in UK Biobank, followed from 2006 to 2010 (baseline) to Dec 2021. Residential environments, including greenspace, domestic garden, blue space, and total natural environment, were evaluated using land use coverage percentage. The polygenic risk score (PRS) of schizophrenia was derived using a Bayesian approach and adjusted it against ancestry. Cox proportional hazard regression model was used to assess the associations between per interquartile (IQR) increase of each type of residential environments and late-onset schizophrenia. Interactive effects of PRS and residential environments on late-onset schizophrenia were assessed on both additive and multiplicative scales. RESULTS: A total of 393,680 participants were included in the analysis, with 844 cases of late-onset schizophrenia being observed after 12.8 years of follow-up. Within 300 m buffer surrounding the residential addresses, per interquartile increase in greenspace (31.5 %) and total natural environment (34.4 %) were both associated with an 11 % (HR = 0.89, 95 % CI 0.80, 0.99) lower risk of late-onset schizophrenia. Domestic garden and blue space did not show significant protective effects on late-onset schizophrenia. A strong dose-response relationship between schizophrenia PRS and schizophrenia was found, while no additive or multiplicative interaction effects were present between residential environments and PRS on late-onset schizophrenia. CONCLUSION: Residential greenspace and total natural environment may protect against late-onset schizophrenia in older people regardless of genetic risk. These findings shed light on the prevention of schizophrenia and urban planning to optimise ecosystem benefits linked to schizophrenia.

Green space, genetic susceptibility, and risk of osteoporosis:a cohort study from the UK Biobank.

OBJECTIVE: This study aimed to investigate the effect of residential exposure to green space on the incident osteoporosis and further explore the modification effect of genetic susceptibility. METHODS: Participants from the UK Biobank were followed from 2006 to 2010 (baseline) to December 31st, 2022. Using land use coverage, we evaluated exposure to residential surrounding green space, natural environment, and domestic gardens. We used the Cox regression to examine the association between the residential environment and incident osteoporosis. The interactive effects between polygenic risk score (PRS) of osteoporosis and residential environments on incident osteoporosis were investigated. RESULTS: This study included 292,662 participants. Over a median follow-up period of 13.65 years, we documented 9177 incidents of osteoporosis. Per interquartile (IQR) increase in greenness and natural environment at a 300 m buffer was associated with a 4% lower risk of incident osteoporosis [HR = 0.96 (95% CI: 0.93, 0.99)] and [HR = 0.96 (95% CI: 0.93, 0.98)], respectively. We did not identify any interactive effects between genetic risk and residential environment on incident osteoporosis. CONCLUSIONS: This study found that public greenness and natural environments could reduce the risk of incident osteoporosis regardless of genetic predisposition. Developing sustainable and publicly accessible natural environments might benefit populations' bone health.

Effects of sequential vs single pneumococcal vaccination on cardiovascular diseases among older adults: a population-based cohort study.

BACKGROUND: Recommendations around the use of 23-valent pneumococcal polysaccharide vaccine (PPSV23) and 13-valent pneumococcal conjugate vaccine (PCV13) seldom focus on potential benefits of vaccine on comorbidities. We aimed to investigate whether sequential vaccination with PCV13 and PPSV23 among older adults would provide protection against cardiovascular diseases (CVD) compared with using a single pneumococcal vaccine. METHODS: We conducted a Hong Kong-wide retrospective cohort study between 2012 and 2020. Adults aged ≥65 years were identified as receiving either a single or sequential dual vaccination and followed up until the earliest CVD occurrence, death or study end. To minimize confounding, we matched each person receiving a single vaccination to a person receiving sequential vaccination according to their propensity scores. We estimated the hazard ratio (HR) of CVD risk using Cox regression and applied structural equation modelling to test whether the effect of sequential dual vaccination on CVD was mediated via the reduction in pneumonia. RESULTS: After matching, 69 390 people remained in each group and the median (interquartile range) follow-up time was 1.89 (1.55) years. Compared with those receiving a single vaccine, those receiving sequential dual vaccination had a lower risk of CVD [HR (95% CI): 0.75 (0.71, 0.80), P < 0.001]. Post-hoc mediation analysis showed strong evidence that the decreased CVD risk was mediated by the reduction in all-cause pneumonia. CONCLUSIONS: Sequential dual pneumococcal vaccination was associated with lower risk of CVD compared with single-dose PCV13 or PPSV23 in older adults. Such additional CVD benefits should be considered when making decisions about pneumococcal vaccination.

Treatment-resistant depression and risk of autoimmune diseases: evidence from a population-based cohort and nested case-control study.

Recent literature indicates that patients with depression had increased immune activation. We hypothesised that treatment-resistant depression (TRD), an indicator of non-responsive depression with long-term dysregulated inflammation, could be an independent risk factor for subsequent autoimmune diseases. We performed a cohort study and a nested case-control study to examine the association between TRD and risk of autoimmune diseases, and to explore potential sex-specific difference. Using electronic medical records in Hong Kong, we identified 24,576 patients with incident depression between 2014 and 2016 without autoimmune history and followed up from diagnosis to death or December 2020 to identify TRD status and autoimmune incidence. TRD was defined as having at least two antidepressant regimens and the third regimen to confirm previous treatment failures. Based on age, sex and year of depression, we matched TRD patients 1:4 to the non-TRD in the cohort analysis using nearest-neighbour matching, and matched cases and controls 1:10 using incidence density sampling in the nested case-control analysis. We conducted survival analyses and conditional logistic regression respectively for risk estimation, adjusting for medical history. Across the study period, 4349 patients without autoimmune history (17.7%) developed TRD. With 71,163 person-years of follow-up, the cumulative incidence of 22 types of autoimmune diseases among the TRD patients was generally higher than the non-TRD (21.5 vs. 14.4 per 10,000 person-years). Cox model suggested a non-significant association (HR:1.48, 95% CI: 0.99-2.24, p = 0.059), whereas conditional logistic model showed a significant association (OR: 1.67, 95% CI: 1.10-2.53, p = 0.017) between TRD status and autoimmune diseases. Subgroup analysis showed that the association was significant in organ-specific diseases but not in systemic diseases. Risk magnitudes were generally higher among men compared to women. In conclusion, our findings provide evidence for an increased risk of autoimmune diseases in patients with TRD. Controlling chronic inflammation in hard-to-treat depression might play a role in preventing subsequent autoimmunity.

Impact of Introducing Infliximab Biosimilars on Total Infliximab Consumption and Originator Infliximab Prices in Eight Regions: An Interrupted Time-Series Analysis.

OBJECTIVE: We aimed to assess whether the introduction of the first infliximab biosimilar was associated with changes in overall infliximab consumption (originator and biosimilars) and price changes to the originator infliximab. METHODS: An interrupted time series analysis using infliximab sales data from 2010 to 2020 from the IQVIA Multinational Integrated Data Analysis System for eight selected regions: Australia, Canada, Hong Kong, Korea, India, Japan, the UK, and the USA. Quarterly measures of infliximab consumption and list prices were respectively defined as the number of standard units (SU)/1000 inhabitants and as 2020 USA dollars (USD)/SU. RESULTS: Following the introduction of infliximab biosimilars, overall infliximab consumption increased in Australia [immediate change: 0.145 SU/1000 inhabitants (P = 0.014); long-term change: 0.022 SU/1000 inhabitants per quarter (P < 0.001)], Canada [immediate change 0.415 (P = 0.008)], the UK [long-term change 0.024 (P < 0.001)], and Hong Kong [immediate change: 0.042 (P < 0.001)]. The list price of originator infliximab also decreased following biosimilar introduction in Australia [immediate change: - 187.84 USD/SU (P < 0.001); long-term change - 6.46 USD/SU per quarter (P = 0.043)], Canada [immediate change: - 145.58 (P < 0.001)], the UK [immediate change: - 34.95 (P = 0.010); long-term change: - 4.77 (P < 0.001)], and Hong Kong [long-term change: - 4.065 (P = 0.046)]. Consumption and price changes were inconsistent in India, Japan, Korea, and the USA. CONCLUSIONS: Introduction of the first infliximab biosimilar was not consistently associated with increased consumption across regions. Additional policy and healthcare system interventions to support biosimilar infliximab adoption are needed.

Postmarketing safety of orphan drugs: a longitudinal analysis of the US Food and Drug Administration database between 1999 and 2018.

BACKGROUND: Information about the specific regulatory environment of orphan drugs is scarce and inconsistent. Uncertainties surrounding the postmarketing long-term safety of orphan drugs remain. This study aimed to evaluate the labelling changes of orphan drugs and to identify postmarketing safety-associated approval factors. METHODS: This retrospective cohort study includes all drugs with orphan drug designation approved by the Center for Drug Evaluation and Research of the US Food and Drug Administration between 1999 and 2018. Main outcomes are safety-related labelling changes up to 31 December 2019. We defined any safety-related labelling changes as postmarketing safety events (PMSE). Safety-related withdrawals, suspensions, and boxed warnings were further categorised as severe postmarketing safety events (SPSE). Outcome measurements include frequencies of PMSE, SPSE, and association between approval factors and the occurrence of safety events. RESULTS: Amongst the 214 drugs identified with orphan drug designation (25.7% biologics), 83.6% were approved through at least one expedited programme, and 29.4% were approved with boxed warnings. During a median follow-up of 6.74 years since approval, 69.2% and 14.5% of the analysed orphan drugs had PMSE and SPSE, respectively. Safety-related withdrawal (0%, 0/214), suspended marketing (0.46%, 1/214) and new boxed warnings are uncommon (3.7%, 8/214). The safety-related labelling changes were more frequent in the drugs approved with boxed warnings [Incidence rate ratio (IRR): 1.95 (1.02-3.73)] and approved for long-term use [IRR: 2.76 (1.52-5.00)]. CONCLUSIONS AND RELEVANCE: In this long-term postmarketing analysis, approximately 70% of FDA-approved orphan drugs had safety-related labelling changes although severe safety events were rare. While maintaining early access to orphan drugs, the drug regulatory body has taken timely regulatory action with postmarketing surveillance to ensure patient safety.

Monoclonal antibodies and Fc-fusion protein biologic medicines: A multinational cross-sectional investigation of accessibility and affordability in Asia Pacific regions between 2010 and 2020.

Background: Monoclonal antibody (mAb) and Fc-fusion protein (FcP) are highly effective therapeutic biologics. We aimed to analyse consumption and expenditure trends in 14 Asia-Pacific countries/regions (APAC) and three benchmark countries (the UK, Canada, and the US). Methods: We analysed 440 mAb and FcP biological products using the IQVIA-MIDAS global sales database. For each year between 2010 and 2020 inclusive, we used standard units (SU) sold per 1000 population and manufacture level price (standardised in 2019 US dollars) to evaluate consumption (accessibility) and expenditure (affordability). Changes of consumption and expenditure were estimated using compound annual growth rate (CAGR). Correlations between consumption, country's economic and health performance indicators were measured using Spearman correlation coefficient. Findings: Between 2010 and 2020, CAGRs of consumption in each region ranged from 7% to 34% and the CAGRs of expenditure ranged from 9% to 31%. The median consumption of biologics was extremely low in lower-middle-income economies (0·29 SU/1000 population) compared with upper-middle-income economies (1·20), high-income economies (40·94) and benchmark countries (109·55), although the median CAGRs of biologics consumption in lower-middle-income economies (31%) was greater than upper-middle-income (14%), high-income economies (13%) and benchmark countries (9%). Consumption was correlated with GDP per capita [Spearman's rank correlation coefficient (r) = 0·75, p < 0·001], health expenditure as a percentage of total (r = 0·83, p < 0·001) and medical doctors' density (r = 0·85, p < 0·001). Interpretation: There have been significant increases in mAb and FcP biologics consumption and expenditure, however accessibility of biological medicines remains unequal and is largely correlated with country's income level. Funding: This research was funded by NHMRC Project Grant GNT1157506 and GNT1196900; Enhanced Start-up Fund for new academic staff and Internal Research Fund, Department of Medicine, LKS Faculty of Medicine, University of Hong Kong.

COVID-19 vaccine preferences among university students in Hong Kong: a discrete choice experiment.

OBJECTIVE: To promote public health and resume university activities, COVID-19 vaccination has been mandated from an increasing number of universities worldwide. The objective of the study is to understand the factors that impact preference and willingness to take the vaccine among university students in Hong Kong universities utilizing an online questionnaire. The findings will be imperative for health education and the success of the vaccination program. RESULTS: We conducted a discrete choice experiment survey among university students in Hong Kong and applied conditional logit regression to estimate their vaccine preference and the weight of each attribute. Regression results showed adverse reactions, efficacy, origin of the vaccine, required number of doses and out-of-pocket price are significant determinants for the choice of vaccine, ranked from the most to least important. Similar preference weighting results were observed after adjusting age, sex, monthly household income, studying medical-related subjects and recent influenza vaccination. Safety, efficacy and origin of the vaccine are key drivers for vaccination decisions among young adults in Hong Kong. Health education and communication focused on these factors are urgently needed to overcome vaccine hesitancy and improve the vaccine uptake.

A practical framework for predicting residential indoor PM2.5 concentration using land-use regression and machine learning methods.

People typically spend most of their time indoors. It is of importance to establish prediction models to estimate PM2.5 concentration in indoor environments (e.g., residential households) to allow accurate assessments of exposure in epidemiological studies. This study aimed to develop models to predict PM2.5 concentration in residential households. PM2.5 concentration and related parameters (e.g., basic information about the households and ventilation settings) were collected in 116 households during the winter and summer seasons in Hong Kong. Outdoor PM2.5 concentration at households was estimated using a land-use regression model. The random forest machine learning algorithm was then applied to develop indoor PM2.5 prediction models. The results show that the random forest model achieved a promising predictive accuracy, with R2 and cross-validation R2 values of 0.93 and 0.65, respectively. Outdoor PM2.5 concentration was the most important predictor variable, followed in descending order by the household marked number, outdoor temperature, outdoor relative humidity, average household area and air conditioning. The external validation result using an independent dataset confirmed the potential application of the random forest model, with an R2 value of 0.47. Overall, this study shows the value of a combined land-use regression and machine learning approach in establishing indoor PM2.5 prediction models that provide a relatively accurate assessment of exposure for use in epidemiological studies.

Prediction model for air particulate matter levels in the households of elderly individuals in Hong Kong.

Air pollution has shown to cause adverse health effects on mankind. Aging causes functional decline and leaves elderly people more susceptible to health threats associated with air pollution exposure. Elderly spend approximately 80% of their lifetime at home every day. To understand air pollution exposure, indoor air pollutants are the targets for consideration especially for the elderly population. However, indoor air monitoring for epidemiological studies requires a large population, is labor intensive and time consuming. As a result, a prediction model is necessary. For 3 consecutive days in summer and winter, 24-h average of mass concentrations of fine particulate matter (aerodynamic diameter <2.5 µm: PM2.5) were measured in indoors for 116 households. A PM2.5 prediction model for elderly households in Hong Kong has been developed by combining ambient PM2.5 concentrations obtained from land use regression model and questionnaire-elicited information related to the indoor PM2.5 sources. The fitted linear mixed-effects model is moderately predictive for the observed indoor PM2.5, with R2 = 0.67 (or R2 = 0.61 by cross-validation). The model shows indoor PM2.5 was positively influenced by outdoor PM2.5 levels. Meteorological factors (e.g. temperature and relative humidity) were related to the indoor PM2.5 in a relatively complex manner. Congested living areas, opening windows for extended periods for ventilation and use of liquefied petroleum gas for cooking were the factors determining the ultimate indoor air quality. This study aims to provide information about controlling household air quality and can be used for future epidemiological studies associated with indoor air pollution in large population.