The association between benzodiazepines and asthma exacerbation, influenza-like illness related pneumonia and mortality: population-based studies using the United Kingdom Primary care data.

Background: Influenza-like illness (ILI) and asthma are common diagnoses in the general practice and exert considerable morbidity and mortality worldwide. One potentially important strategy to reduce this is to determine whether commonly prescribed drugs modify the occurrence and outcomes of respiratory diseases including mortality. The benzodiazepines, a class of psychoactive drugs generally used in the treatment of anxiety and sleep disorders, have recently been suggested as having detrimental effects on immune response to infection, predisposing its users to increased risk of infection and mortality. These drugs have also been implicated in the pathogenesis of asthma. This thesis therefore aimed to investigate whether benzodiazepines modify the occurrence of asthma exacerbation and subsequent mortality in patients with asthma as well as ILI-related pneumonia and ILI-related mortality in patients with ILI. Methods: The Clinical Practice Research Datalink (CPRD) was used as the data source. CPRD contains the medical records of over 13 million patients prospectively collected from over 600 general practices across the United Kingdom and has linkages to the Hospital Episode Statistics database [HES] and national death registry data (the Office of National Statistics [ONS]) which were utilised in this study. CPRD-HES linked data was used to validate diagnoses of asthma exacerbation whereas ONS mortality data validated deaths identified from CPRD. Case-control and cohort study designs were used to investigate associations between benzodiazepines and the occurrence of asthma exacerbation, ILI-related pneumonia and mortality. Results: After adjusting for a wide range of potential confounders including physical and psychiatric comorbidities, and concurrent use of other drugs, exposure to benzodiazepines was associated with statistically significant increased occurrence of asthma exacerbation, ILI-related pneumonia and mortality. These associations were observed with both short term and chronic benzodiazepines use. However, the effect of individual benzodiazepines varied across the outcomes of interest with some of the associations lacking statistical significance. For instance, current use of diazepam and temazepam but not lorazepam showed statistically significant associations with increased occurrence of asthma exacerbation. Conclusion: Overall, findings of this research signal an adverse benzodiazepine effect and hence suggest that a precautionary approach should be exercised when prescribing benzodiazepines in the interim before conclusive evidence is yielded by further research, especially in patients who may already be at increased risk of asthma exacerbation or pneumonia and mortality

Implication of nurse intervention on engagement with urate-lowering drugs: a qualitative study of participants in a RCT of nurse led care

Objectives To explore patient perception of the role of a nurse-led complex package of care in facilitating engagement with urate-lowering therapies (ULTs) in the management of gout.Methods Thirty people who had participated in a randomised controlled trial investigating the effect of a nurse-led complex package of care for gout, were purposively sampled and interviewed between 18–26 months after the end of the trial. Interviews were recorded, transcribed and analysed using a modified grounded-theory approach. Data were managed using Nvivo. STATA v15 was used to describe summary statistics.Results Participants described their views and experiences of engaging with a nurse-led intervention designed to provide holistic assessment, individualised patient education, and involvement in shared decision-making for the long-term management of gout. The analysis revealed key themes in how nurse-led intervention facilitated engagement with ULT, namely by proving improved knowledge and understanding of gout and its treatment, involvement of patients in decision-making about treatment, and increased confidence about benefits from treatment. However, some treatment uncertainty and concern remained and one participant free of gout flares discontinued ULT, while another halved the dose after the end of the trial.Conclusions This study reports data on patient experience of engaging with ULT to manage gout after receiving nurse-led care. It demonstrates that shared decision-making and the joint efforts of fully informed practitioners and patients persuades patients to engage with ULTs, and that experiencing the benefits of curative treatment motivates them to maintain adherence

Association between benzodiazepine use and exacerbations and mortality in patients with asthma: a matched case-control and survival analysis using the United Kingdom Clinical Practice Research Datalink

Purpose: To investigate the association between the GABAergic drugs, benzodiazepines or zopiclone, and the occurrence of asthma exacerbations and subsequent mortality in a cohort of asthma patients. Methods: 105,747 patients without asthma exacerbation and 25,895 patients with exacerbated asthma were included. A nested case-control study probed the association between benzodiazepines or zopiclone and occurrence of asthma exacerbation (primary outcome) using conditional logistic regression. Cox regression was used to determine the association between the drugs and all-cause mortality in patients with recorded asthma exacerbation. Adjusted matched odds ratios (adj mOR), and adjusted hazard ratios (adj HR) with 95% confidence intervals (CI) are presented. Results: Current benzodiazepine use was associated with increased occurrence of asthma exacerbation (adj mOR 1.49; 1.15-1.93; P=0.001) as was current zopiclone use (adj mOR 1.59; 95% CI 1.37-1.85; P<0.001). In patients with an asthma exacerbation, current benzodiazepine use was associated with increased all-cause mortality during a median follow-up of 2 years (adj HR 2.78; 95% CI 1.26-6.12; P=0.011), and the association between zopiclone use and all-cause mortality showed borderline statistical significance (adj HR 1.58; 95% CI 0.98-2.54; P=0.058). Conclusion: Benzodiazepines and zopiclone may increase the likelihood of asthma exacerbation and benzodiazepines may also increase the likelihood of mortality following exacerbation. These data suggest that caution should be exercised when prescribing benzodiazepines to patients with asthma

Rheumatoid arthritis and excess mortality: down but not out: a primary care cohort study using data from Clinical Practice Research Datalink

Objectives: To examine temporal trends in all-cause and cause-specific mortality in RA. Methods: Data from the Clinical Practice Research Datalink (CPRD) were used. Incident RA cases and four age, sex and general practice matched controls were identified from at-risk cohorts for each calendar year and followed-up for up to five years. Mortality rates and 95% confidence intervals (95% CIs) were computed. Cox-proportional hazard ratios (HRs) were calculated to estimate associations and adjusted for covariates. Temporal trend in mortality was examined using the Joinpoints Regression Program. Data management and analysis were performed using Stata v.14. Results: 21,622 cases with incident RA and 86,488 controls were included. The mortality rate (95%CI) of RA cases and controls was 26.90 (25.87-27.97) and 18.92 (18.48-19.36)/1000 person-years respectively. The mortality rate in RA cases did not change significantly between 1990 and 2004, but reduced by 7.7%/year between 2005 and 2009. However, the mortality rate in controls improved steadily by 2.2%/year between 1990 and 2009. RA associated with 32% excess risk of mortality in the entire cohort (aHR (95%CI) 1.32(1.26-1.38), but this was only 15% in cases incident after 2006 (aHR (95%CI) 1.15(1.03-1.29)). Similarly, the HR of death due to cardiovascular diseases reduced in cases incident in recent years. Conclusion: The mortality rate in RA cases incident after the year 2006 has declined significantly, with a trend towards decline in death from cardiovascular diseases. This could be due to improved management of RA. However, even in cohorts from recent years, RA still associates with higher mortality rates

Association between serum urate, gout and comorbidities: a case–control study using data from the UK Biobank

Objectives To examine the association between comorbidities and serum urate (SU), gout and comorbidities, and to determine whether the association between gout and comorbidities is independent of SU. Methods We performed a case-control study using UK Biobank data. Two separate analyses were conducted: one excluding participants with gout to investigate the association between comorbidities and SU and the other with participants with gout as the index condition to examine the association between gout and comorbidities. SU was measured at the baseline visit. Self-reported physician-diagnosed illnesses were used to define gout and comorbidities, except for chronic kidney disease (CKD), which was defined using an estimated glomerular filtration rate cut-off. Participants prescribed urate-lowering treatment were also classified as gout. Logistic regression was used to examine associations. Odds ratios (ORs) and 95% CIs were calculated and adjusted for covariates including comorbidities and SU. Results Data for 458 781 UK Biobank participants were used to examine the association between comorbidities and SU. There was an association between hypertension, ischaemic heart disease (IHD), congestive cardiac failure (CCF), hyperlipidaemia, CKD and SU with and adjusted OR (aOR) of 1.10-3.14 for each 1 mg/dl SU increase. A total of 10 265 gout cases and 458 781 controls were included in the analysis of association between gout and comorbidities. Gout associated independently with hypertension, IHD, CCF, hyperlipidaemia and diabetes, with aORs of 1.21-4.15 after adjusting for covariates including SU. Conclusion Comorbidities associate with increasing SU. The association between gout and cardiometabolic comorbidities was independent of SU, suggesting separate SU-independent mechanisms such as inflammation driven by crystal deposition, pro-inflammatory genotype or non-purine dietary factors

Effectiveness of inactivated influenza vaccine in autoimmune rheumatic diseases treated with disease-modifying anti-rheumatic drugs

ObjectivesThe effectiveness of inactivated influenza vaccine in people with autoimmune rheumatic disease (AIRDs) is not known. We investigated whether the influenza vaccine is effective in preventing respiratory morbidity, mortality and all-cause mortality in AIRD patients.MethodsAdults with AIRDs treated with DMARDs prior to 1 September of each year between 2006 and 2009, and 2010 and 2015 were identified from the Clinical Practice Research Datalink. Exposure and outcome data were extracted. Data from multiple seasons were pooled. Propensity score (PS) for vaccination was calculated. Cox-proportional hazard ratios (HRs) and 95% CIs were calculated, and were (i) adjusted, (ii) matched for PS for vaccination.ResultsData for 30 788 AIRD patients (65.7% female, 75.5% with RA, 61.1% prescribed MTX) contributing 125 034 influenza cycles were included. Vaccination reduced risk of influenza-like illness [adjusted HR (aHR) 0.70], hospitalization for pneumonia (aHR 0.61) and chronic obstructive pulmonary disease exacerbations (aHR 0.67), and death due to pneumonia (aHR 0.56) on PS-adjusted analysis in the influenza active periods (IAPs). The associations were of similar magnitude and remained statistically significant on PS-matched analysis except for protection from influenza-like illness, which became non-significant. Sub-analysis restricted to pre-IAP, IAP and post-IAP did not yield evidence of residual confounding on influenza-like illness and death due to pneumonia. Vaccination reduced risk of all-cause mortality, although IAP-restricted analysis demonstrated residual confounding for this outcome.ConclusionInfluenza vaccine associates with reduced risk of respiratory morbidity and mortality in people with AIRDs. These findings call for active promotion of seasonal influenza vaccination in immunosuppressed people with AIRDs by healthcare professionals

Uptake and safety of pneumococcal vaccination in adults with immune mediated inflammatory diseases: a UK wide observational study

Objective The uptake and safety of pneumococcal vaccination in people with immune mediated inflammatory diseases (IMIDs) is poorly understood. We investigated the UK wide pneumococcal vaccine uptake in adults with IMIDs and explored the association between vaccination and IMID flare. Methods Adults with IMIDs diagnosed on or before 01/09/2018, prescribed steroid-sparing drugs within the last 12 months and contributing data to the Clinical Practice Research Datalink Gold were included. Vaccine uptake was assessed using a cross-sectional study design. Self-controlled case series (SCCS) analysis investigated the association between pneumococcal vaccination and IMID flare. The SCCS observation period was up-to six-month before and after pneumococcal vaccination. This was partitioned into a 14-day pre-vaccination induction, 90-days post-vaccination exposed, and the remaining unexposed periods. Results We included 32 277 patients, 14 151 with RA, 13 631 with IBD, 3,804 with axial spondyloarthritis and 691 with SLE. Overall, 57% were vaccinated against pneumococcus. Vaccine uptake was lower in those younger than 45 years (32%), with IBD (42%), and without additional indication(s) for vaccination (46%). In the vaccine-safety study, data for 1,067, 935, and 451vaccinated patients with primary-care consultations for joint pain, AIRD flare and IBD flare respectively were included. Vaccination against pneumococcal pneumonia was not associated with primary-care consultations for joint pain, AIRD flare and IBD flare in the exposed period with incidence rate ratios (95% Confidence Interval) 0.95 (0.83–1.09), 1.05 (0.92–1.19), and 0.83 (0.65–1.06) respectively. Conclusion Uptake of pneumococcal vaccination in UK patients with IMIDs was suboptimal. Vaccination against pneumococcal disease was not associated with IMID flare

Uptake and safety of pneumococcal vaccination in adults with immune mediated inflammatory diseases: a UK wide observational study

Objective The uptake and safety of pneumococcal vaccination in people with immune mediated inflammatory diseases (IMIDs) is poorly understood. We investigated the UK wide pneumococcal vaccine uptake in adults with IMIDs and explored the association between vaccination and IMID flare. Methods Adults with IMIDs diagnosed on or before 01/09/2018, prescribed steroid-sparing drugs within the last 12 months and contributing data to the Clinical Practice Research Datalink Gold were included. Vaccine uptake was assessed using a cross-sectional study design. Self-controlled case series (SCCS) analysis investigated the association between pneumococcal vaccination and IMID flare. The SCCS observation period was up-to six-month before and after pneumococcal vaccination. This was partitioned into a 14-day pre-vaccination induction, 90-days post-vaccination exposed, and the remaining unexposed periods. Results We included 32 277 patients, 14 151 with RA, 13 631 with IBD, 3,804 with axial spondyloarthritis and 691 with SLE. Overall, 57% were vaccinated against pneumococcus. Vaccine uptake was lower in those younger than 45 years (32%), with IBD (42%), and without additional indication(s) for vaccination (46%). In the vaccine-safety study, data for 1,067, 935, and 451vaccinated patients with primary-care consultations for joint pain, AIRD flare and IBD flare respectively were included. Vaccination against pneumococcal pneumonia was not associated with primary-care consultations for joint pain, AIRD flare and IBD flare in the exposed period with incidence rate ratios (95% Confidence Interval) 0.95 (0.83–1.09), 1.05 (0.92–1.19), and 0.83 (0.65–1.06) respectively. Conclusion Uptake of pneumococcal vaccination in UK patients with IMIDs was suboptimal. Vaccination against pneumococcal disease was not associated with IMID flare

The development and validation of prognostic model for leflunomide discontinuation with abnormal blood-tests during long-term treatment: a cohort study using data from Clinical Practice Research Datalink Gold and Aurum

Objective: To develop and validate a prognostic model for leflunomide discontinuation with abnormal blood-test results. Methods: Data from CPRD Gold and Aurum were used for model development and external validation respectively. Participants prescribed leflunomide between 01/01/2007 and 31/12/2019 were followed-up from six-months after first GP prescription to the earliest of date of outcome, death, 5-year follow-up or 31/12/2019. Candidate prognostic factors were ascertained using theory and data driven approaches. Penalised Cox regression was performed to develop the risk equation, followed by internal validation using 500-bootstraps to correct for optimism. Multiple imputation was applied to handle missing data. Model performance was assessed in terms of calibration and discrimination. Results: Data for 1,487 and 2,329 participants contributing 3,140 and 5,246 person years follow-up were included in the development and validation cohorts respectively. Thirteen candidate predictors were included in the model. Epilepsy, and either cytopenia or elevated liver enzymes during first six months of shared-care leflunomide prescription were strong predictors of drug discontinuation with hazard ratio (95%CI) 4.39 (1.74 -11.06) and 3.06 (2.15 - 4.35) respectively. The unadjusted and optimism adjusted calibration slope in development data was 1.00 (95% CI 0.75-1.25) and 0.72 (95% CI 0.47-0.97) respectively. The calibration slope in validation data was 0.91 (95% CI 0.74-1.07). The model showed prognostic separation with optimism adjusted Royston D statistic of 0.73 (95% CI 0.44-1.02). 3 Conclusion: We have developed and externally validated an easy-to-use prognostic model that may be used to risk-stratify monitoring for leflunomide toxicity and to make informed choices about risks when choosing treatment