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We report dementia incidence, comorbidities, reasons for health-care visits, mortality, causes of death, and examined dementia patterns by relative deprivation in the UK.A longitudinal cohort analysis of linked electronic health records from 4.3 million people in the UK was conducted to investigate dementia incidence and mortality. Reasons for hospitalization and causes of death were compared in individuals with and without dementia.From 1998 to 2016 we observed 145,319 (3.1%) individuals with incident dementia. Repeated hospitalizations among senior adults for infection, unknown morbidity, and multiple primary care visits for chronic pain were observed prior to dementia diagnosis. Multiple long-term conditions are present in half of the individuals at the time of diagnosis. Individuals living in high deprivation areas had higher dementia incidence and high fatality.There is a considerable disparity of dementia that informs priorities of prevention and provision of patient care.

BACKGROUND: Non-communicable diseases (NCDs) have been highlighted as important risk factors for COVID-19 mortality. However, insufficient data exist on the wider context of infectious diseases in people with NCDs. We aimed to investigate the association between NCDs and the risk of death from any infection before the COVID-19 pandemic (up to Dec 31, 2019). METHODS: For this observational study, we used data from the UK Biobank observational cohort study to explore factors associated with infection death. We excluded participants if data were missing for comorbidities, body-mass index, smoking status, ethnicity, and socioeconomic deprivation, and if they were lost to follow-up or withdrew consent. Deaths were censored up to Dec 31, 2019. We used Poisson regression models including NCDs present at recruitment to the UK Biobank (obesity [defined by use of body-mass index] and self-reported hypertension, chronic heart disease, chronic respiratory disease, diabetes, cancer, chronic liver disease, chronic kidney disease, previous stroke or transient ischaemic attack, other neurological disease, psychiatric disorder, and chronic inflammatory and autoimmune rheumatological disease), age, sex, ethnicity, smoking status, and socioeconomic deprivation. Separate models were constructed with individual NCDs replaced by the total number of prevalent NCDs to define associations with multimorbidity. All analyses were repeated with non-infection-related death as an alternate outcome measure to establish differential associations of infection death and non-infection death. Associations are reported as incidence rate ratios (IRR) accompanied by 95% CIs. FINDINGS: After exclusion of 9210 (1·8%) of the 502 505 participants in the UK Biobank cohort, our study sample comprised 493 295 individuals. During 5 273 731 person-years of follow-up (median 10·9 years [IQR 10·1-11·6] per participant), 27 729 deaths occurred, of which 1385 (5%) were related to infection. Advancing age, male sex, smoking, socioeconomic deprivation, and all studied NCDs were independently associated with the rate of both infection death and non-infection death. Compared with White ethnicity, a pooled Black, Asian, and minority ethnicity group was associated with a reduced risk of infection death (IRR 0·64, 95% CI 0·46-0·87) and non-infection death (0·80, 0·75-0·86). Stronger associations with infection death than with non-infection death were observed for advancing age (age 65 years vs 45 years: 7·59, 95% CI 5·92-9·73, for infection death vs 5·21, 4·97-5·48, for non-infection death), current smoking (vs never smoking: 3·69, 3·19-4·26, vs 2·52, 2·44-2·61), socioeconomic deprivation (most vs least deprived quintile: 2·13, 1·78-2·56, vs 1·38, 1·33-1·43), class 3 obesity (vs non-obese: 2·21, 1·74-2·82, vs 1·55, 1·44-1·66), hypertension (1·36, 1·22-1·53, vs 1·15, 1·12-1·18), respiratory disease (2·21, 1·96-2·50, vs 1·28, 1·24-1·32), chronic kidney disease (5·04, 4·28-7·31, vs 2·50, 2·20-2·84), psychiatric disease (1·56, 1·30-1·86, vs 1·23, 1·18-1·29), and chronic inflammatory and autoimmune rheumatological disease (2·45, 1·99-3·02, vs 1·41, 1·32-1·51). Accrual of multimorbidity was also more strongly associated with risk of infection death (five or more comorbidities vs none: 9·53, 6·97-13·03) than of non-infection death (5·26, 4·84-5·72). INTERPRETATION: Several NCDs are associated with an increased risk of infection death, suggesting that some of the reported associations with COVID-19 mortality might be non-specific. Only a subset of NCDs, together with the accrual of multimorbidity, advancing age, smoking, and socioeconomic deprivation, were associated with a greater IRR for infection death than for other causes of death. Further research is needed to define why these risk factors are more strongly associated with infection death, so that more effective preventive strategies can be targeted to high-risk groups. FUNDING: British Heart Foundation.

Objective We aimed to perform a systematic review and meta-analysis of all-cause and cause-specific mortality of patients with benign endogenous Cushing syndrome (CS). Methods The protocol was registered in PROSPERO (CRD42017067530). PubMed, EMBASE, CINHAL, Web of Science, and Cochrane Central searches were undertaken from inception to January 2021. Outcomes were the standardized mortality ratio (SMR), proportion, and cause of deaths. The I2 test, subgroup analysis, and meta-regression were used to assess heterogeneity across studies. Results SMR was reported in 14 articles including 3691 patients (13 Cushing disease [CD] and 7 adrenal CS [ACS] cohorts). Overall SMR was 3.0 (95% CI, 2.3-3.9; I2 = 80.5%) for all CS, 2.8 (95% CI, 2.1-3.7; I2 = 81.2%) for CD and 3.3 (95% CI, 0.5-6.6; I2 = 77.9%) for ACS. Proportion of deaths, reported in 87 articles including 19 181 CS patients (53 CD, 24 ACS, and 20 combined CS cohorts), was 0.05 (95% CI, 0.03-0.06) for all CS subtypes with meta-regression analysis revealing no differences between CS subtypes (P = .052). The proportion of deaths was 0.1 (10%) in articles published before 2000 and 0.03 (3%) in 2000 until the last search for CS (P

The journal of infectious diseases 226(3), 554-562 (2022). doi:10.1093/infdis/jiac186, Published by Oxford Univ. Press, Oxford [u.a.]

Aims To examine trends in ischaemic heart disease (IHD) incidence and prevalence in New Zealand from 2005 to 2016, using comprehensive linked national hospitalization and mortality data as proxy measures of all significant events. Methods and results Incident and prevalent cases of IHD in people aged ≥25 years were identified using individual patient-linkage of routinely collected ICD-10-coded hospitalization and mortality data. Incidence rates and prevalence proportions were calculated by sex and age group and then age-standardized to the 2016 New Zealand population. Ischaemic heart disease incidence and prevalence declined in men and women in all age groups. The average annual rate of decline in age-standardized IHD incidence was 3.3% for women and 2.7% for men, and the rate of decline in age-standardized IHD prevalence was 3.2% for women and 2.2% for men. Despite a 17% increase in the New Zealand population aged 25 years and over during the study period, the total number of people living with IHD also decreased, particularly in those aged 65 years and older. Conclusion In contrast to observations from other countries, where IHD incidence but not IHD prevalence has been falling, declining IHD incidence in New Zealand in recent decades is now mirrored by declining IHD prevalence.

Journal of the American Heart Association : JAHA 10(22), e023188 (2021). doi:10.1161/JAHA.121.023188, Published by Association, New York, NY

BackgroundMany diseases are associated with chronic inflammation, resulting in widening indications for anti-inflammatory therapies. Whilst effective as disease modifying agents, these increase the risk of serious infection.ObjectiveTo determine if low-grade inflammation is associated with fatal infection, irrespective of associated comorbidity or anti-inflammatory therapy.DesignObservational cohort studySettingUK Biobank studyParticipants461,052 peopleInterventionsNoneMeasurementsIncidence rate ratio (IRR) of death from infection, cardiovascular disease, or other causes, adjusted for comorbidities and use of anti-inflammatory therapies, for serum C-reactive protein (CRP) at recruitment.ResultsLow grade inflammation was common in all morbidities considered and was more prevalent as multimorbidity accrued (CRP ≥2mg/L in 23.3% of people without disease and 58.7% with 3+ comorbidities; pLimitationsOur observational study design precludes assessment of causality. We lacked data on the use of anti-inflammatory therapies after study recruitment.ConclusionLow grade inflammation, irrespective of associated comorbidity, identifies people at particularly increased risk of infection death. Decisions to use anti-inflammatory therapies guided by low grade inflammation require careful consideration of the associated risks and benefits.

Aims To compare ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) mortality between Sweden and the UK, adjusting for background population rates of expected death, case mix, and treatments. Methods and results National data were collected from hospitals in Sweden [n = 73 hospitals, 180 368 patients, Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART)] and the UK [n = 247, 662 529 patients, Myocardial Ischaemia National Audit Project (MINAP)] between 2003 and 2013. There were lower rates of revascularization [STEMI (43.8% vs. 74.9%); NSTEMI (27.5% vs. 43.6%)] and pharmacotherapies at time of hospital discharge including [aspirin (82.9% vs. 90.2%) and (79.9% vs. 88.0%), β-blockers (73.4% vs. 86.4%) and (65.3% vs. 85.1%)] in the UK compared with Sweden, respectively. Standardized net probability of death (NPD) between admission and 1 month was higher in the UK for STEMI [8.0 (95% confidence interval 7.4–8.5) vs. 6.7 (6.5–6.9)] and NSTEMI [6.8 (6.4–7.2) vs. 4.9 (4.7–5.0)]. Between 6 months and 1 year and more than 1 year, NPD remained higher in the UK for NSTEMI [2.9 (2.5–3.3) vs. 2.3 (2.2–2.5)] and [21.4 (20.0–22.8) vs. 18.3 (17.6–19.0)], but was similar for STEMI [0.7 (0.4–1.0) vs. 0.9 (0.7–1.0)] and [8.4 (6.7–10.1) vs. 8.3 (7.5–9.1)]. Conclusion Short-term mortality following STEMI and NSTEMI was higher in the UK compared with Sweden. Mid- and longer-term mortality remained higher in the UK for NSTEMI but was similar for STEMI. Differences in mortality may be due to differential use of guideline-indicated treatments.

ObjectivesTo evaluate incidence rates of Lyme disease in the UK and to investigate a possible association with subsequent fatigueDesignPopulation-based historical cohort study with a comparator cohort matched by age, sex, and general practiceSettingPatients treated in UK general practices contributing to IQVIA Medical Research DataParticipants2,130 patients with a first diagnosis of Lyme disease between 2000 and 2018, and 8,510 randomly-sampled matched comparators, followed-up for a median time of 3 years and 8 months.Main outcome measuresTime from Lyme disease diagnosis to consultation for any fatigue-related symptoms or diagnosis and for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Adjusted hazard ratios (HRs) were estimated from Cox models.ResultsAverage incidence rate for Lyme disease across the UK was 5.18 per 100,000 py between 2000 and 2018, increasing from 2.55 in 2000 to 9.33 in 2018. In total 929 events of any types of fatigue were observed, i.e. an incidence rate of 307.90 per 10,000 py in the Lyme cohort (282 events) and 165.60 in the comparator cohort (647 events). Effect of Lyme disease on any subsequent fatigue varied by index season with highest adjusted HRs in autumn [3.14 (95%CI: 1.92 to 5.13)] and winter [2.23 (1.21 to 4.11)]. Incidence rates of ME/CFS were 11.16 per 10,000 py in Lyme patients (12 events) and 1.20 in comparators (5 events), corresponding to an adjusted HR of 16.95 (5.17 to 55.60). Effect on any types of fatigue and ME/CFS was attenuated 6 months after diagnosis but still clearly visible.ConclusionsUK primary care records provided strong evidence that Lyme disease was associated with acute and chronic fatigue. Albeit weaker, these effects persisted beyond 6 months, suggesting that patients and healthcare providers should remain alert to fatigue symptoms months to years following Lyme disease diagnosis.Key messages boxWhat is already known on this topicIncidence rates of Lyme disease in the UK are increasing but estimations vary according to data sources used.Reports investigating the association between Lyme disease and long-term fatigue are contradictory.What this study addsAverage incidence rate for Lyme disease across the UK was estimated at 5.18 per 100,000 py between 2000 and 2018, and followed an increasing trend.In patients with Lyme disease, a 2- and 3-fold increase in any subsequent fatigue was observed in winter and autumn, respectively, and a 16-fold increase in ME/CFS (all seasons combined), compared to a non-Lyme cohort matched by sex, age, and general practice.

Cardiovascular disease (CVD) mortality has substantially improved over recent decades. Some evidence indicates this has been paralleled by an increasing proportion of non-cardiovascular mortality in people with CVD. However, the contemporary causes of death across a broad spectrum of CVDs, either alone or in combination, remains unclear.We analysed cardiovascular, infection, cancer and other causes of death prior to the COVID-19 pandemic in 493,280 participants in the prospective UK Biobank study. Studied CVDs included baseline: abdominal aortic aneurysm, atrial fibrillation, coronary artery disease, heart failure, hypertension, peripheral vascular disease, stroke, valvular heart disease and venous thromboembolic disease; we separately considered cardiovascular multimorbidity defined as the total number of these baseline CVDs. Crude mortality rates and Poisson regression analysis were used to quantify the absolute and relative risk of cause-specific death. Associations are reported as incidence rate ratios (IRR) with 95% CIs.During a median follow-up of 10.9 [IQR 10.1-11.6] years per participant, there were 27,729 deaths (20.4% primarily attributed to CVD, 53.6% to cancer, 5.0% to infection and 21.0% to other causes). As the number of co-morbid CVDs increased, the proportion of cardiovascular and infection-related deaths increased, whereas cancer and other deaths decreased. Accrual of multiple CVDs was associated with marked increases in relative risk of infection and cardiovascular death; versus those without CVD, people with three or more CVDs, the relative risk of cardiovascular death increased most (IRR 3.89; 95%CI 3.59-4.21), followed by infection (4.41; 3.44-5.64), with other (2.01; 1.72-2.35) and cancer (1.52; 1.35-1.72) being substantially less increased. All studied CVDs except atrial fibrillation were independently associated with increased risk of infection death, with heart failure (2.73; 1.60-4.66) and valvular heart disease (3.09; 2.38-4.00) posing the greatest risk.In conclusion, causes of death vary substantially between differing baseline CVDs, and according to the number of baseline CVDs, with non-cardiovascular deaths due to cancer and infection making an important contribution. Holistic and personalized care are likely to be important tools for continuing to improve outcomes in people with CVD.

Objective The efficacy of the novel interleukin (IL)-23p19 inhibitor guselkumab for psoriatic arthritis (PsA) has recently been demonstrated in two phase 3 trials (DISCOVER-1 & -2) but has not been evaluated vs other targeted therapies for PsA. The objective was to compare guselkumab to targeted therapies for PsA for safety and joint and skin efficacy through network meta-analysis (NMA). Methods A systematic literature review was conducted in January 2020 to identify randomized controlled trials. Bayesian NMAs were performed to compare treatments on American College of Rheumatology (ACR) 20/50/70 response, mean change from baseline in van der Heijde-Sharp (vdH-S) score, Psoriasis Area Severity Index (PASI) 75/90/100 response, adverse events (AEs) and serious adverse events (SAEs). Results Twenty-six phase 3 studies evaluating 13 targeted therapies for PsA were included. For ACR 20 response, guselkumab 100 mg every 8 weeks (Q8W) was comparable to IL-17A inhibitors and subcutaneous tumor necrosis factor (TNF) inhibitors. Similar findings were observed for ACR 50 and 70. For vdH-S score, guselkumab Q8W was comparable to other agents except intravenous TNF therapies. Results for PASI 75 and PASI 90 response suggested guselkumab Q8W was better than most other agents. For PASI 100, guselkumab Q8W was comparable to other active agents. For AEs and SAEs, guselkumab Q8W ranked highly but comparative conclusions were uncertain. Similar results were observed for all outcomes for guselkumab 100 mg every four weeks. Conclusions In this NMA, guselkumab demonstrated favorable arthritis efficacy comparable to IL-17A and subcutaneous TNF inhibitors while offering better PASI response relative to many other treatments.

Objectives To assess whether modern management of RA has reduced the prescription of oral corticosteroids and NSAIDs and to evaluate use of pharmacological prophylaxis strategies. Methods Using the Clinical Practice Research Datalink, we explored long-term (≥3/12 months; ≥6/12 in sub-analyses) DMARD, corticosteroid and NSAID prescribing (annually, in the year post-diagnosis and across the patient’s life course to 15 years post-diagnosis), annual proportion with co-prescribing for prophylaxis of associated bone (corticosteroids, women only) and gastrointestinal (NSAIDs) comorbidity. Results Reported incidence of RA was 5.98 (0.37) per 10 000 person-years and prevalence was 0.91% (0.014) in 2017. In 71 411 RA patients, long-term DMARD prescribing initially rose post-diagnosis from 41.6% in 1998 to 67.9% in 2009. Corticosteroid prescribing changed little, overall [22.2% in 1998, 19.1% in 2016; incident risk ratio (IRR) 0.92, 95% CI: 0.82, 1.03] and across the life course from the first to fifteenth year (22.2% to 16.9%). NSAID prescribing declined from 57.7% in 1998, and significantly so from 2008, to 27.1% in 2016 (IRR 0.50, 95% CI: 0.44, 0.56). This continued across the life course (41.2% to 28.4%). Bone prophylaxis increased to 68.1% in 2008 before declining to 56.4% in 2017; gastrointestinal prophylaxis increased from 11.5% in 1998 to 62.6% in 2017. Sub-analyses showed consistent patterns. Conclusion Despite modern treatment strategies, corticosteroid prescribing in RA patients remains substantial and persists beyond 6 months once initiated. Rheumatologists need to determine causes and develop strategies to reduce corticosteroid use to minimize adverse event occurrence.

ObjectivesNon-communicable diseases (NCDs) have recently been highlighted as important risk factors for COVID-19 fatality. We set out to investigate the association between NCDs and the risk of death from any infection in the pre-COVID-19 era.DesignProspective population-based studySettingUK BiobankParticipants493,295 participantsMain outcome measuresInfection death prior to December 31st2019.ResultsDuring 5,277,344 participant-years of follow-up, 1,385 infection deaths occurred, accounting for 5% of all deaths. Competing risks regression revealed that advancing age, male sex, smoking, socio-economic deprivation and all studied NCDs were independently associated with both the risk of infection death and non-infection death; ethnicity was associated with neither. Only smoking, socio-economic deprivation, hypertension, respiratory disease, chronic kidney disease, psychiatric disease and rheumatological disease were associated with greater hazard ratios for infection than non-infection death. Accrual of multimorbidity was also associated with a greater increases in the risk of infection death (HR 9.03 [95% confidence interval 6.61 to 12.34] for 5+ comorbidities versus none; pConclusionsDiverse NCDs are associated with increased risk of infection death, suggesting that recently reported associations with COVID-19 death may be non-specific. Moreover, only a subset of NCDs, together with the accrual of multimorbidity, smoking and socio-economic deprivation, are associated with greater relative risks of infection death than other causes of death. Further research is needed to define why these risk factors are biased toward infection death so that more effective preventative strategies can be targeted to high-risk groups.What is already known on this topicInfection contributes to approximately one in five deaths globally and this often occurs in people with non-communicable diseases (NCDs).Many NCDs have recently been highlighted as risk factors for fatal COVID-19 infection.What this study addsWhilst diverse NCDs are associated with greater risk of infection death, only some pose greater hazards of infection than non-infection death.The association of many NCDs with fatal COVID-19 infection is unlikely to be specific to this pathogen.

Background Over 20 years, rheumatoid arthritis (RA) management has evolved to immediate initiation and more effective escalation of disease-modifying anti-rheumatic drugs (DMARDs) to suppress inflammation. We aimed to establish whether this has facilitated reduced long-term use of potentially toxic glucocorticosteroids (GCs) and nonsteroidal anti-inflammatory drugs (NSAIDs). Methods We investigated changes in DMARD, oral GC and NSAID prescribing over 1998-2017 in a UK primary care electronic health records database. We defined RA by coded diagnosis, sensitivity analyses requiring (a) two diagnoses ≥6 months apart; (b) ≥1 DMARD prescriptions. We calculated annual RA incidence and prevalence, annual prescribing and prescribing in the first to fifteenth year from diagnosis. Long-term prescribing was defined as ≥ 3 months (≥6 in a sensitivity analyses) and compared with a non-RA cohort (5:1 matched on age, sex and GP practice). Results We included 71,411 RA patients (44,426 with 2 diagnoses, 45,438 with DMARD). Incidence declined from 5.01 (±0.36) per 10,000 person-years in 1998 to 4.77 (±0.23) in 2011, before increasing following changes in Quality Outcomes Framework indicators. Prevalence rose from 0.70% (±0.013) in 1998 to 0.91% (±0.014) in 2017 and was highest among patients aged ≥70 (2.21%, ±0.05). Long-term DMARD prescribing rose from 30.97% in 1998 to 49.28% in 2017. Long-term NSAID prescribing fell (45.94% to 25.08%) particularly amongst incident RA patients, with only modest change in GCs (20.98% to 15.53%) (Table 1). By comparison, long-term GC prescribing in the matched non-RA population rose (0.90% to 2.01%) and NSAID prescribing changed little (6.37% to 8.41%). The proportion with long-term prescribing declined slightly from the first to the third year following diagnosis for GCs (22.18% to 17.87%) and NSAIDs (41.19% to 34.30%). Sensitivity analyses showed similar results. Conclusion Long-term GC prescribing among newly diagnosed RA patients has not appreciably reduced despite modern treatment paradigms and the expected observed increase in DMARD prescribing. Long-term NSAID prescribing did decrease in primary care for RA (especially from mid-2000 and among newly diagnosed patients), but interestingly, not for non-RA patients. Given the scope for further reduction in GC and NSAID prescribing, the reasons for persistent prescribing, including prescribing behaviours, require further investigation. Disclosures S.S.R. Crossfield: Grants/research support; Medical Research Council (MRC) Leeds Medical Bioinformatics Centre [MR/L01629X]. M.H. Buch: None. P. Baxter: None. S.R. Kingsbury: Grants/research support; National Institute for Health Research (NIHR) Leeds Biomedical Research Centre and the Versus Arthritis Experimental Osteoarthritis Treatment Centre [20083]. M. Pujades-Rodriguez: None. P.G. Conaghan: Grants/research support; National Institute for Health Research (NIHR) Leeds Biomedical Research Centre and the Versus Arthritis Experimental Osteoarthritis Treatment Centre [20083].

Chronic oral glucocorticoid (GC) exposure from therapeutic anti-inflammatory or immunosuppressive use is the most common cause of Cushing’s syndrome (CS). Previous studies of glucocorticoid therapy and mortality have produced inconsistent results and systematic reviews have only focused on endogenous CS. This is the first study that aimed to investigate all-cause and cause-specific mortality in association with exogenous CS from chronic oral GC therapy. The protocol was designed according to the principles of the PRISMA statement and registered in PROSPERO reference CRD42017067530. A literature review was performed in PubMed/MEDLINE (1966 to 31 Mar 2019), EMBASE (1974 to 31 Mar 2019), web of science (1900 to 31 Mar 2019), CINAHL (1981 to 31 Mar 2019) and reference lists within selected articles. Of 104,064 studies, 127 met the inclusion criteria, encompassing 51,380 patients. The Risk Of Bias In Non-randomized Studies of Interventions (ROBIN-I) tool was chosen and modified for evaluation of quality. The weighted percentage mortality by 5 groups of diseases including vasculitis, connective tissue diseases, inflammatory diseases, haematologic diseases and respiratory tract diseases, was 18.1, 12.7, 16.1, 28.2 and 5.7, respectively. The leading causes of death were cardiovascular disease (25.6%), malignancy (15.6 %), infection (13.4) and respiratory failure (10.8%). Although these studies showed high mortality in patients exposed to GC, estimates were not adjusted for known confounders and available data do not allow disentangling the relative contribution of CS vs. the underlying disease or non-GC immunosuppressive therapies. More extensive, high quality, prospective studies are needed to evaluate these associations and to identify modifiable risk factors.

Background Giant cell arteritis (GCA) is treated with high dose glucocorticoids and progressively reduced over months to years. We undertook an audit to evaluate self-reported adherence to the original recommended glucocorticoid course and explored reasons for any variation. Methods We recruited patients attending a single rheumatology department over 18 months. Respondents were given two self-administered questionnaires to record information regarding their use of glucocorticoids during the last 7 days and during the last 6 months. We retrieved 132 questionnaires (of whom 6 were discarded as incomplete). All data was analysed using SPSS Statistics v22. Results Of the 126 patients (mean age 74.9 ± 7.7 years), 59% were female. The mean duration of disease was 22.5 ± 19.1 months in patients with GCA and 32.9 ± 29.9 months in those with GCA and polymyalgia rheumatica (PMR). The mean daily number of medications taken was 9.2 ± 5.2 (range: 1 - 30); the mean number of types of daily tablets taken was 5.0 ± 2.1 (range: 1 - 10). The mean daily number of glucocorticoid tablets taken was 3.2 ± 2.6 (range: 0 - 12), with a mean daily dose of 11.1 ± 10.3 mg (range: 0 - 60 mg). Overall, in the last 7 days, 22% and in last 6 months, 40% of patients were not following their original recommended steroid regimens (Table 1). The total mean glucocorticoid dose in the last 7 days group (n = 81) was 77.8 ± 70.1 mg/week (11.1 ± 10.1 mg/day) whilst the total mean glucocorticoid dose in the last 6 months group (n = 45) was 1782.0 ± 1543.3 mg/6 month (9.9 ± 8.6 mg/day). Most respondents stated their glucocorticoid non-adherence was due to medical advice; other reasons included forgetting, fear of side effects, or confusion about different preparations of prescribed glucocorticoids. The presence of PMR did not influence glucocorticoid adherence. Conclusion There is significant variation in the use of glucocorticoids compared to the original starting regimen in patients with GCA, with or without PMR. However, the amount of the discrepancy is small. The commonest reason for non-adherence was medical advice received from either primary or secondary care. Disclosures H. Ariff: None. A. Awisat: None. J. Arnold: None. H. Al ani: None. L. O' neill: None. M. Rodriguez: None. R. Luqmani: None.

BackgroundEvidence for the association between glucocorticoid dose and cardiovascular risk is weak for moderate and low doses. To quantify glucocorticoid dose-dependent cardiovascular risk in people with six immune-mediated inflammatory diseases.Methods and FindingsPopulation-based cohort analysis of medical records from 389 primary care practices contributing data to the UK Clinical Practice Research Datalink, linked to hospital admissions and deaths in 1998-2017. There were 87,794 patients with giant cell arteritis and/or polymyalgia rheumatica (n=25,581), inflammatory bowel disease (n=27,739), rheumatoid arthritis (n=25,324), systemic lupus erythematosus (n=3951), and/or vasculitis (n=5199); and no prior cardiovascular disease (CVD). Mean age was 56 years and 34.1% were men. Median follow-up time was 5.0 years. Time-variant daily and cumulative glucocorticoid prednisolone-equivalent dose-related risks and hazard ratios of first all-cause and type-specific CVD.We found 13,426 (15.3%) people with incident CVD, including 6,013 atrial fibrillation, 7,727 heart failure and 2,809 acute myocardial infarction events. At 1 and 5 years, the cumulative risks of all-cause CVD increased from 1.5% in periods of non-use to 9.1% for a daily prednisolone-equivalent dose of ≥25.0mg, and from 7.6% to 29.9%, respectively. We found strong dose-dependent estimates for all immune-mediated diseases (hazard ratio [HR] for ConclusionsWe estimated glucocorticoid dose-dependent cardiovascular risk in six immune-mediated diseases. Results highlight the importance of prompt and regular monitoring of cardiovascular risk and use of primary prevention treatment at all glucocorticoid doses.

Background In healthy population cohorts, resting heart rate above 90 bpm is associated with mortality from coronary heart disease, but it is not clear whether associations are present at lower heart rates or whether these associations differ between women. Methods The CALIBER resource of linked electronic health records from primary care, hospitalisations, myocardial infarction registry and cause-specific mortality in the UK was used to assess associations between resting heart rate and 12 fatal and non-fatal coronary, cardiac, cerebral and peripheral vascular cardiovascular diseases and death using Cox proportional hazard models. Results Among 233,970 patients, 29,690 fatal and non-fatal events occurred. Fully adjusted models showed that resting heart rate was not associated in men or women with cerebrovascular events. In men a resting heart rate of 70–79 bpm (29.1% of all men) versus less than 60 bpm was associated with an increased risk of heart failure (hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.26–2.16), unheralded coronary death (HR 1.65, 95% CI 1.13–2.41), total cardiovascular events (HR 1.22, 95% CI 1.15–1.28) and all-cause mortality (HR 1.39, 95% CI 1.22–1.58). Women with a higher resting heart rate level of 80–89 bpm versus 60 bpm had a higher risk of total cardiovascular disease events (HR 1.17, 95% CI 1.07–1.24) and all-cause mortality (HR 1.21, 95% CI 1.07–1.35) compared to a resting heart rate less than 60 bpm. The risk was also present at higher heart rates (>90 bpm) for heart failure and sudden cardiac death. Conclusions A resting heart rate that clinicians currently consider as ‘normal’ in the general population is specifically associated with the incidence of certain major cardiovascular diseases and death, with the risk starting at lower resting heart rate levels in men compared to women. Further research is required to evaluate whether interventions to lower resting heart rate are warranted to prevent disease. The study is registered at: clinicaltrials.gov (ID: NCT01947361).

BACKGROUND: Only a few population-based studies have examined the association between glucocorticoids and hypertension, with inconsistent results. We aimed to investigate the effect of oral glucocorticoids on incidence of hypertension in adults with chronic inflammatory diseases. METHODS: We analyzed electronic health records from 389 practices in England during 1998–2017 of adults diagnosed with any of 6 chronic inflammatory diseases but with no previous diagnosis of hypertension. We used glucocorticoid prescription data to construct time-variant daily and cumulative variables of prednisolone-equivalent dose (cumulated from 1 year before the start of follow-up) and estimated incidence rates and adjusted hazard ratios (HRs) for hypertension using Cox regression analysis. RESULTS: Among 71 642 patients in the cohort, 24 896 (34.8%) developed hypertension during a median follow-up of 6.6 years. The incidence rate of hypertension was 46.7 (95% confidence interval [CI] 46.0–47.3) per 1000 person-years. Incidence rates increased with higher cumulative glucocorticoid prednisolone-equivalent dose, from 44.4 per 1000 person-years in periods of nonuse to 45.3 per 1000 person-years for periods with between > 0.0 and 959.9 mg (HR 1.14, 95% CI 1.09–1.19), to 49.3 per 1000 person-years for periods with 960–3054.9 mg (HR 1.20, 95% CI 1.14–1.27), and to 55.6 per 1000 person-years for periods with ≥ 3055 mg (HR 1.30, 95% CI 1.25–1.35). Cumulative effects were seen for the 6 diseases studied, but dose–response effects were not found for daily dose. INTERPRETATION: Cumulative dose of oral glucocorticoids was associated with increased incidence of hypertension, suggesting that blood pressure should be monitored closely in patients routinely treated with these drugs. Given that glucocorticoids are widely prescribed, the associated health burden could be high. Trial registration: ClinicalTrials. gov, no. NCT03760562.

Background The use of metformin after acute myocardial infarction (AMI) has been associated with reduced mortality in people with type 2 diabetes mellitus (T2DM). However, it is not known if it is acutely cardioprotective in patients taking metformin at the time of AMI. We compared patient outcomes according to metformin status at the time of admission for fatal and non-fatal AMI in a large cohort of patients in England. Methods This study used linked data from primary care, hospital admissions and death registry from 4.7 million inhabitants in England, as part of the CALIBER resource. The primary endpoint was a composite of acute myocardial infarction requiring hospitalisation, stroke and cardiovascular death. The secondary endpoints were heart failure (HF) hospitalisation and all-cause mortality. Results 4,030 patients with T2DM and incident AMI recorded between January 1998 and October 2010 were included. At AMI admission, 63.9% of patients were receiving metformin and 36.1% another oral hypoglycaemic drug. Median follow-up was 343 (IQR: 1–1436) days. Adjusted analyses showed an increased hazard of the composite endpoint in metformin users compared to non-users (HR 1.09 [1.01–1.19]), but not of the secondary endpoints. The higher risk of the composite endpoint in metformin users was only observed in people taking metformin at AMI admission, whereas metformin use post-AMI was associated with a reduction in risk of all-cause mortality (0.76 [0.62–0.93], P = 0.009). Conclusions Our study suggests that metformin use at the time of first AMI is associated with increased risk of cardiovascular disease and death in patients with T2DM, while its use post-AMI might be beneficial. Further investigation in well-designed randomised controlled trials is indicated, especially in view of emerging evidence of cardioprotection from sodium-glucose co-transporter-2 (SGLT2) inhibitors.

Context Adrenal insufficiency and Cushing syndrome are known adverse events of glucocorticoids. However, no population estimates of dose-related risks are available. Objective To investigate dose-related risks of adrenal dysfunction and death in adults with six chronic inflammatory diseases treated with oral glucocorticoids. Design and setting Retrospective, record-linkage, open-cohort study spanning primary and hospital care in England. Patients A total of 70,638 oral glucocorticoid users and 41,166 nonusers aged ≥18 years registered in 389 practices in 1998 to 2017. Main outcome measures Incidence rates and hazard ratios (HRs) of diagnosed adrenal dysfunction and death. Results During a median follow-up of 5.5 years, 183 patients had glucocorticoid-induced adrenal insufficiency and 248 had glucocorticoid-induced Cushing syndrome. A total of 22,317 (31.6%) and 7544 (18.3%) deaths occurred among glucocorticoid users and nonusers, respectively. The incidence of all outcomes increased with higher current daily and cumulative doses. For adrenal insufficiency, the increases in HRs were 1.07 (95% CI: 1.04 to 1.09) for every increase of 5 mg per day and 2.25 (95% CI: 2.15 to 2.35) per 1000 mg of cumulative prednisolone-equivalent dose over the past year. The respective increases in HRs for Cushing syndrome were 1.09 (95% CI: 1.08 to 1.11) and 2.31 (95% CI: 2.23 to 2.40) and for mortality 1.26 (95% CI: 2.24 to 1.28) and 2.05 (95% CI: 2.04 to 2.06). Conclusion We report a high glucocorticoid dose-dependent increased risk of adrenal adverse events and death. The low observed absolute risk of adrenal insufficiency highlights a potential lack of awareness and a need for increased physician and patient education about the risks of adrenal dysfunction induced by glucocorticoids., In this cohort study, we found high glucocorticoid dose-dependent increased risks of adrenal dysfunction and death but low absolute risks, indicating potential underdiagnosis in clinical practice.

BACKGROUND: Most patients with polymyalgia rheumatica or giant cell arteritis are treated with glucocorticoid therapy in primary care. We estimated dose–response risks of infection for this population in England. METHODS: We conducted a retrospective record-linkage study involving a cohort of people with polymyalgia rheumatica or giant cell arteritis registered in family practices across England (1998–2017). Estimates of first occurring infection per level of time-variant current and cumulative dose were obtained using Kaplan–Meier methods and multilevel proportional-hazards Cox models. RESULTS: Of 39 938 patients attending 389 family practices, 22 234 (55.7%) had at least 1 infection over a median follow-up period of 4.8 years, with 5937 (26.7%) requiring hospital admission and 1616 (7.3%) dying within 7 days of diagnosis. Cumulative risks of all-cause infection were 18.3% (95% confidence interval [CI] 17.9%–18.7%) at 1 year, 54.7% (95% CI 54.1%–55.2%) at 5 years and 76.9% (95% CI 76.2%–77.5%) at 10 years. Lower respiratory tract infections, conjunctivitis and herpes zoster were the most commonly diagnosed infections. The increases in adjusted hazard ratios (HRs) for all-cause infection per 5 mg prednisolone-equivalent daily dose increase and per 1000 mg cumulative dose increase in the last year from the patient’s end date of follow-up were 1.13 (95% CI 1.12–1.14) and 1.50 (95% CI 1.49–1.52), respectively. Adjusted HRs associated with periods of current glucocorticoid versus no glucocorticoid use ranged from 1.48 (95% CI 1.39–1.57) for fungal to 1.70 (95% CI 1.60–1.80) for bacterial infection. Stepwise dose-related associations were found for bacterial, viral, parasitic and fungal infections, irrespective of patient age, duration of underlying chronic disease and baseline vaccination status. INTERPRETATION: We quantified the excess risk of all-cause, bacterial, viral, parasitic and fungal infection conferred by oral glucocorticoids in people with polymyalgia rheumatica or giant cell arteritis and found strong dose responses for all types, even at daily doses of less than 5 mg prednisolone.

Summary: Background: Urinary tract infections (UTIs) are major drivers of antibiotic prescribing in primary care. Inappropriate antibiotic prescribing for UTIs likely drives antibiotic resistance. We aimed to describe current investigation and antibiotic treatment to examine opportunities for improved antimicrobial stewardship. Methods: We identified a cohort of all patients with lower UTI diagnosis between 2011 and 2015 in the 390 primary care practices contributing data to ResearchOne in England. We examined investigation, antibiotic treatment and antibiotic re-prescription within 28 days according to guideline-defined patient groups. We assessed risk factors for re-prescription using mixed-effect logistic regression. Findings: In total, 494,675 UTIs were diagnosed in 300,354 patients. Median age was 54 years, and 83.3% were women. Same-day antibiotic was prescribed for 85.7% of UTIs; 56.8% were treated with trimethoprim, and urine sampling was undertaken in 25.0%. The antibiotic re-prescription rate was low (17,430, 4.1%) and increased slightly over time in men (from 5.2% in 2011 to 6.2% in 2015). Overall, 21.1% of pre-prescription were for the same antibiotic. The percentage of adults with recurrent UTIs ranged from 1.0% in 18–64 year-old men to 2.6% in women ≥65 years. The risk of antibiotic re-prescription increased with age, calendar year, recent antibiotic prescribing and treatment with antibiotic other than trimethoprim or nitrofurantoin. Interpretation: Most patients diagnosed with lower UTI in primary care receive same-day empirical antibiotics with little diversity in choice of agent. The antibiotic re-prescription rate is low. Microbiological investigation and re-prescription of the same antibiotic given for the initial episode happened in one quarter of UTIs. Funding: UK National Health Service Improvement. Keywords: Antibiotics, Risk factors, Treatment failure, Diversity

Background Age of onset of multimorbidity and its prevalence are well documented. However, its contribution to inequalities in life expectancy has yet to be quantified. Methods A cohort of 1.1 million English people aged 45 and older were followed up from 2001 to 2010. Multimorbidity was defined as having 2 or more of 30 major chronic diseases. Multi-state models were used to estimate years spent healthy and with multimorbidity, stratified by sex, smoking status and quintiles of small-area deprivation. Results Unequal rates of multimorbidity onset and subsequent survival contributed to higher life expectancy at age 65 for the least (Q1) compared with most (Q5) deprived: there was a 2-year gap in healthy life expectancy for men [Q1: 7.7 years (95% confidence interval: 6.4–8.5) vs Q5: 5.4 (4.4–6.0)] and a 3-year gap for women [Q1: 8.6 (7.5–9.4) vs Q5: 5.9 (4.8–6.4)]; a 1-year gap in life expectancy with multimorbidity for men [Q1: 10.4 (9.9–11.2) vs Q5: 9.1 (8.7–9.6)] but none for women [Q1: 11.6 (11.1–12.4) vs Q5: 11.5 (11.1–12.2)]. Inequalities were attenuated but not fully attributable to socio-economic differences in smoking prevalence: multimorbidity onset was latest for never smokers and subsequent survival was longer for never and ex smokers. Conclusions The association between social disadvantage and multimorbidity is complex. By quantifying socio-demographic and smoking-related contributions to multimorbidity onset and subsequent survival, we provide evidence for more equitable allocation of prevention and health-care resources to meet local needs.