Gout and incidence of 12 cardiovascular diseases: a case-control study including 152 663 individuals with gout and 709 981 matched controls.

BACKGROUND: Gout, a common crystal arthropathy, is associated with increased risk of cardiovascular disease. We aimed to identify how this risk varies by individual cardiovascular disease across a broad spectrum of conditions. METHODS: In this matched case-control study, we used linked primary and secondary electronic health records from the UK Clinical Practice Research Datalink to assemble a cohort of individuals with a first-time diagnosis of gout between Jan 1, 2000 and Dec 31, 2017, who were aged 80 years or younger at diagnosis, and free of cardiovascular diseases up to 12 months after diagnosis. The control cohort comprised up to five control individuals per patient with gout, matched on age, sex, socioeconomic status, geographical region, and calendar time, randomly selected among individuals free of gout at any time before and during the study period. The cohorts were followed up until June 30, 2019. We investigated the incidence of 12 cardiovascular diseases and used Cox proportional hazards models to examine differences in people with and without gout, overall and by subgroups of sex, age, socioeconomic status, and year of study inclusion. We further adjusted models for known cardiovascular risk factors (blood pressure, BMI, smoking status, cholesterol, type 2 diabetes, chronic kidney disease, and history of hypertension). FINDINGS: We identified 152 663 individuals with gout (mean age 56·2 years [SD 13·3]; 120 324 [78·8%] men and 32 339 [21·2%] women) and 709 981 matched controls (mean age 56·5 years [13·2]; 561 002 [79·0%] men and 148 979 [21·0%] women). Of these individuals, 31 479 (20·6%) with gout and 106 520 (15·0%) without gout developed cardiovascular disease during a median follow-up of 6·5 years (IQR 3·1-10·5). Patients with gout had higher risk of cardiovascular diseases than matched controls (hazard ratio [HR] 1·58 [95% CI 1·52-1·63]). Excess risk of cardiovascular disease in gout was greater in women than men (women: HR 1·88 [1·75-2·02]; men: HR 1·49 [1·43-1·56]), and, among all age groups, was highest in younger individuals (HR in people aged <45 years: 2·22 [1·92-2·57]). Excess risk was observed across all 12 cardiovascular diseases investigated. Patients with gout had higher BMI than matched controls (mean difference 2·90 kg/m2 [95% CI 2·87-2·93]) and higher prevalence of chronic kidney disease, dyslipidaemia, history of hypertension, obesity, and type 2 diabetes. Adjusting for known cardiovascular risk factors attenuated but did not eliminate the excess risk of cardiovascular disease related to gout (adjusted HR 1·31 [1·27-1·36]). INTERPRETATION: Patients with gout had an excess risk of developing a broad range of cardiovascular diseases that extend beyond atherosclerotic diseases and include heart failure, arrhythmias, valve disease, and thromboembolic diseases. Excess risk was highest in women and younger individuals. These findings suggest that strategies to reduce cardiovascular risk in patients with gout need to evolve and be implemented in clinical practice. FUNDING: Research Foundation Flanders.

Association of gamma-glutamyltransferase levels with total mortality, liver-related and cardiovascular outcomes: A prospective cohort study in the UK Biobank.

Background: Gamma-glutamyltransferase (GGT) levels in the blood can be a sensitive marker of liver injury but the extent to which they give insight into risk across multiple outcomes in a clinically useful way remains uncertain. Methods: Using data from 293,667 UK Biobank participants, the relationship of GGT concentrations to self-reported alcohol intake and adiposity markers were investigated. We next investigated whether GGT predicted liver-related, cardiovascular (CV) or all-cause mortality, and potentially improved CV risk prediction. Findings: Higher alcohol intake and greater waist circumference (WC) were associated with higher GGT; the association was stronger for alcohol with evidence of a synergistic effect of WC. Higher GGT concentrations were associated with multiple outcomes. Compared to a GGT of 14.5 U/L (lowest decile), values of 48 U/L for women and 60 U/L for men (common upper limits of 'normal') had hazard ratios (HRs) for liver-related mortality of 1.83 (95% CI 1.60-2.11) and 3.25 (95% CI 2.38-4.42) respectively, for CV mortality of 1.21 (95% CI 1.14-1.28) and 1.43 (95% CI 1.27-1.60) and for all-cause mortality of 1.15 (95% CI 1.12-1.18) and 1.31 (95% CI 1.24-1.38). Adding GGT to a risk algorithm for CV mortality reclassified an additional 1.24% (95% CI 0.14-2.34) of participants across a binary 5% 10-year risk threshold. Interpretation: Our study suggests that a modest elevation in GGT levels should trigger a discussion with the individual to review diet and lifestyle including alcohol intake and consideration of formal liver disease and CV risk assessment if not previously done. Funding: British Heart Foundation Centre of Research Excellence Grant (grant number RE/18/6/34217), NHS Research Scotland (grant number SCAF/15/02), the Medical Research Council (grant number MC_UU_00022/2); and the Scottish Government Chief Scientist Office (grant number SPHSU17).

Osteoporosis and Its Association With Cardiovascular Disease, Respiratory Disease, and Cancer: Findings From the UK Biobank Prospective Cohort Study.

OBJECTIVE: To investigate sex-specific associations of osteoporosis with incidence of and mortality from cardiovascular disease (CVD), respiratory disease, and cancer as well as with all-cause mortality. METHODS: In total, 305,072 participants (53% [161,383] women) of UK Biobank were included in this study (2007-2010). Self-reported diagnosis of osteoporosis at baseline was the exposure of interest. The outcomes were CVD, respiratory disease, chronic obstructive pulmonary disease (COPD), all cancer, and prostate and breast cancer incidence and mortality and all-cause mortality. Associations between osteoporosis and outcomes were investigated using Cox proportional hazards models. RESULTS: In men, osteoporosis was associated with a higher incident risk of all respiratory diseases (hazard ratio [HR], 1.26; 95% CI, 1.06 to 1.50) including COPD (HR, 1.82; 95% CI, 1.38 to 2.40). Men with osteoporosis also had a higher mortality risk from all causes (HR, 1.71; 95% CI, 1.38 to 2.11), CVD (HR, 1.68; 95% CI, 1.19 to 2.37), respiratory disease (HR, 2.35; 95% CI, 1.70 to 3.24), and COPD (HR, 3.64; 95% CI, 2.24 to 5.91). These associations persisted after adjustment for age, body mass index, and comorbidities. Women with osteoporosis had a higher risk of incident CVD (HR, 1.24; 95% CI, 1.97 to 1.44), respiratory disease (HR, 1.23; 95% CI, 1.13 to 1.33), and COPD (HR, 1.29; 95% CI, 1.10 to 1.52). Women with osteoporosis also had a higher mortality risk from respiratory disease (HR, 1.31; 95% CI, 1.00 to 1.72) and breast cancer (HR, 1.60; 95% CI, 1.14 to 2.26). CONCLUSION: Compared with women, men with osteoporosis had a higher risk of all-cause mortality, mortality from respiratory diseases including COPD, and cancer incidence. Osteoporosis was strongly associated with respiratory disease and COPD in both sexes, even after full adjustment for covariates, although men with osteoporosis experienced a higher risk of adverse outcomes.

Effect of the phosphodiesterase 4 inhibitor apremilast on cardiometabolic outcomes in psoriatic disease-results of the Immune Metabolic Associations in Psoriatic Arthritis study.

OBJECTIVES: Studies have suggested phosphodiesterase 4 (PDE4) inhibition may be associated with weight loss and other cardiometabolic benefits. We evaluated the effect of the PDE4 inhibitor apremilast on body weight and composition, glucose homeostasis, lipid profiles and vascular function in psoriatic disease and whether weight change correlated with therapeutic response. METHODS: We conducted a prospective, open-label study (Immune Metabolic Associations in Psoriatic Arthritis) of adults receiving apremilast 30 mg as part of routine care for PsA and/or psoriasis. Cardiometabolic, anthropometric and disease activity assessments were performed at baseline (pre-apremilast) and at months 1, 3 and 6 of apremilast treatment in 60 patients. A subgroup underwent further assessment of endothelial function, body composition and adipocyte morphology. RESULTS: In patients (median age 54.5 years, 63% women, median BMI 33.2 kg/m2), apremilast was associated with a mean weight loss of 2.2 kg (95% CI 1.4, 3.0; P < 0.001) and a mean BMI decrease of 0.8 kg/m2 (95% CI 0.5, 1.2; P < 0.001) after 6 months of treatment. Body composition analysis demonstrated a reduction in total abdominal fat [mean decrease 0.52 L (95% CI 0.08, 0.96), P = 0.022], principally subcutaneous adipose tissue [mean decrease 0.37 L (95% CI 0.05, 0.68), P = 0.022]. There was no change in adipocyte diameter, haemoglobin A1c, lipid, glucagon-like peptide-1 or vascular function. Psoriatic disease activity improved with apremilast, although this was not correlated with weight change. CONCLUSION: Following apremilast treatment, we observed weight loss, principally abdominal subcutaneous fat, and improvement in psoriatic disease activity. The latter was independent of weight change, suggesting apremilast likely acts through direct immunological mechanisms.

Association of sarcopenia with incident osteoporosis: a prospective study of 168,682 UK biobank participants.

BACKGROUND: Sarcopenia often co-occurs with osteoporosis in cross-sectional studies. However, this association has rarely been studied in prospective studies. This study aimed to investigate the association between sarcopenia categories-along with its individual components-and incident osteoporosis in both middle-aged and older men and women from the UK Biobank study. METHODS: A total of 168,682 participants (48.8% women, aged 37 to 70 years at baseline) were included in this prospective study. Categories of sarcopenia (pre-sarcopenia and sarcopenia), and its individual components, were defined according to the EWGSOP2 criteria (2019). Associations with incident osteoporosis by sex were investigated using Cox-proportional hazard models adjusted for socio-demographic, lifestyle and health-related factors, and morbidity count. Associations between categories of sarcopenia and incident osteoporosis were also investigated by age-groups and subtype of osteoporosis (with and without pathological fractures). RESULTS: After a median follow-up of 7.4 years, 6296 participants were diagnosed with osteoporosis. When the analyses were adjusted for a range of relevant confounding factors, pre-sarcopenia was associated with 1.3-times higher risk of osteoporosis in men (HR: 1.30 [95% CI: 1.03 to 1.63]) but not in women, and sarcopenia was associated with 1.66-times increased osteoporosis risk in women (HR: 1.66 [95% CI: 1.33 to 2.08]) but not in men compared with people without sarcopenia or pre-sarcopenia. A similar magnitude of associations was found in osteoporosis without pathological fractures but weaker for those with pathological fractures. Within the individual components, low muscle mass (HRwomen : 1.36 [95% CI: 1.22 to 1.51] and HRmen : 3.07 [95% CI: 1.68 to 5.59]), followed by slow gait speed (HRwomen : 1.30 [95% CI: 1.17 to 1.45] and HRmen : 1.70 [95% CI: 1.43 to 2.02]), were associated with a higher risk of incident osteoporosis in both sexes. Low grip strength was associated with a higher risk of incident osteoporosis in men (HR: 1.38 [95% CI: 1.15 to 1.65]), but not in women. No significant interaction between the exposures and incident osteoporosis by age groups were identified. CONCLUSIONS: Our findings demonstrated that pre-sarcopenic men and sarcopenic women had a higher risk of developing osteoporosis even after adjustment for a large range of potential confounders. Considering that sarcopenia could be prevented, health interventions to improve physical capability may delay or prevent the onset of osteoporosis.

Psoriatic arthritis is associated with adverse body composition predictive of greater coronary heart disease and type 2 diabetes propensity - a cross-sectional study.

OBJECTIVES: To compare body composition in PsA with metabolic disease free (MDF) controls and type 2 diabetes and assess body-composition predicted propensity for cardiometabolic disease. METHODS: Detailed MRI body composition profiles of 26 PsA participants from the IMAPA study were compared with 130 age, sex and BMI-matched MDF controls and 454 individuals with type 2 diabetes from UK Biobank. The body-composition predicted propensity for coronary heart disease (CHD) and type 2 diabetes was compared between PsA and matched MDF controls. RESULTS: PsA participants had a significantly greater visceral adipose tissue (VAT) volume [mean 5.89 l (s.d. 2.10 l)] compared with matched-MDF controls [mean 4.34 l (s.d. 1.83 l)] (P <0.001) and liver fat percentage [median 8.88% (interquartile range 4.42-13.18%)] compared with MDF controls [3.29% (1.98-7.25%)] (P <0.001). These differences remained significant after adjustment for age, sex and BMI. There were no statistically significant differences in VAT, liver fat or muscle fat infiltration (MFI) between PsA and type 2 diabetes. PsA participants had a lower thigh muscle volume than MDF controls and those with type 2 diabetes. Body composition-predicted propensity for CHD and type 2 diabetes was 1.27 and 1.83 times higher, respectively, for PsA compared with matched-MDF controls. CONCLUSION: Individuals with PsA have an adverse body composition phenotype with greater visceral and ectopic liver fat and lower thigh muscle volume than matched MDF controls. Body fat distribution in PsA is more in keeping with the pattern observed in type 2 diabetes and is associated with greater propensity to cardiometabolic disease. These data support the need for greater emphasis on weight loss in PsA management to lessen CHD and type 2 diabetes risk.

Modifiable and non-modifiable risk factors for COVID-19, and comparison to risk factors for influenza and pneumonia: results from a UK Biobank prospective cohort study.

OBJECTIVES: We aimed to investigate demographic, lifestyle, socioeconomic and clinical risk factors for COVID-19, and compared them to risk factors for pneumonia and influenza in UK Biobank. DESIGN: Cohort study. SETTING: UK Biobank. PARTICIPANTS: 49-83 year olds (in 2020) from a general population study. MAIN OUTCOME MEASURES: Confirmed COVID-19 infection (positive SARS-CoV-2 test). Incident influenza and pneumonia were obtained from primary care data. Poisson regression was used to study the association of exposure variables with outcomes. RESULTS: Among 235 928 participants, 397 had confirmed COVID-19. After multivariable adjustment, modifiable risk factors were higher body mass index and higher glycated haemoglobin (HbA1C) (RR 1.28 and RR 1.14 per SD increase, respectively), smoking (RR 1.39), slow walking pace as a proxy for physical fitness (RR 1.53), and use of blood pressure medications as a proxy for hypertension (RR 1.33). Higher forced expiratory volume in 1 s (FEV1) and high-density lipoprotein (HDL) cholesterol were both associated with lower risk (RR 0.84 and RR 0.83 per SD increase, respectively). Non-modifiable risk factors included male sex (RR 1.72), black ethnicity (RR 2.00), socioeconomic deprivation (RR 1.17 per SD increase in Townsend Index), and high cystatin C (RR 1.13 per SD increase). The risk factors overlapped with pneumonia somewhat, less so for influenza. The associations with modifiable risk factors were generally stronger for COVID-19, than pneumonia or influenza. CONCLUSION: These findings suggest that modification of lifestyle may help to reduce the risk of COVID-19 and could be a useful adjunct to other interventions, such as social distancing and shielding of high risk.

Cardiometabolic comorbidities in RA and PsA: lessons learned and future directions.

Cardiometabolic comorbidities present a considerable burden for patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA). Both RA and PsA are associated with an increased risk of cardiovascular disease (CVD). PsA more often exhibits an increased risk of metabolically linked comorbidities such as obesity, insulin resistance, type 2 diabetes mellitus and non-alcoholic fatty liver disease. Although both RA and PsA are characterized by a state of chronic inflammation, the mechanisms that contribute to CVD risk in these conditions might not be identical. In RA, systemic inflammation is thought to directly contribute to CVD risk, whereas in PsA, adiposity is thought to contribute to a notable metabolic phenotype that, in turn, contributes to CVD risk. Hence, appropriate management strategies that consider the increased risk of cardiometabolic comorbidities in patients with inflammatory arthropathy are important. In RA, such strategies should focus on the prediction of CVD risk and its management through targeting chronic inflammation and traditional CVD risk factors. In PsA, management strategies should additionally focus on targeting metabolic components, including weight management, which might not only help improve disease activity in the joints, entheses and skin, but also reduce the risk of metabolic comorbidities and improve the quality of life of patients.

Association of central adiposity with psoriasis, psoriatic arthritis and rheumatoid arthritis: a cross-sectional study of the UK Biobank.

OBJECTIVES: To determine the independent association of central adiposity, assessed by waist circumference, with odds of psoriasis, PsA and RA prevalence after controlling for general adiposity (BMI). METHODS: A cross-sectional study of UK Biobank participants aged 40-70 years was performed. Logistic regression was used to calculate the odds of psoriasis, PsA and RA occurrence compared with controls without these conditions by waist circumference, adjusting for covariates: age, sex, smoking status, socioeconomic deprivation and self-reported physical activity (Model 1), followed additionally by BMI (Model 2). RESULTS: A total of 502 417 participants were included; 5074 with psoriasis (1.02%), 905 with PsA (0.18%), 5532 with RA (1.11%) and 490 906 controls without these conditions. Adjusted odds ratios (ORs) (Model 1) for psoriasis, PsA and RA, per s.d. (13.5 cm) higher waist circumference were 1.20 (95% CI 1.16, 1.23), 1.30 (95% CI 1.21, 1.39) and 1.21 (95% CI 1.17, 1.24), respectively (all P < 0.001). These ORs remained significant after further adjustment for BMI (Model 2) in psoriasis [OR 1.19 (95% CI 1.12, 1.27), P < 0.001] and RA [OR 1.19 (95% CI 1.12, 1.26), P < 0.001], but not in PsA [OR 1.11 (95% CI 0.95, 1.29), P = 0.127]. CONCLUSION: Central adiposity as measured by waist circumference is associated with greater odds of psoriasis and RA prevalence after adjustment for confounders and for BMI. Our findings add support for central adiposity as a long-term clinically relevant component of these conditions.