Demographic and clinical characteristics associated with advanced stage colorectal cancer: a registry-based cohort study in Saudi Arabia.

BACKGROUND: In Saudi Arabia, approximately one-third of colorectal cancer (CRC) patients are diagnosed at an advanced stage. Late diagnosis is often associated with a worse prognosis. Understanding the risk factors for late-stage presentation of CRC is crucial for developing targeted interventions enabling earlier detection and improved patient outcomes. METHODS: We conducted a retrospective cohort study on 17,541 CRC patients from the Saudi Cancer Registry (1997-2017). We defined distant CRCs as late-stage and localized and regional CRCs as early-stage. To assess risk factors for late-stage CRC, we first used multivariable logistic regression, then developed a decision tree to segment regions by late-stage CRC risk, and finally used stratified logistic regression models to examine geographical and sex variations in risk factors. RESULTS: Of all cases, 29% had a late-stage diagnosis, and 71% had early-stage CRC. Young (< 50 years) and unmarried women had an increased risk of late-stage CRC, overall and in some regions. Regional risk variations by sex were observed. Sex-related differences in late-stage rectosigmoid cancer risk were observed in specific regions but not in the overall population. Patients diagnosed after 2001 had increased risks of late-stage presentation. CONCLUSION: Our study identified risk factors for late-stage CRC that can guide targeted early detection efforts. Further research is warranted to fully understand these relationships and develop and evaluate effective prevention strategies.

Incidence, morbidity, mortality and disparities in dementia: A population linked electronic health records study of 4.3 million individuals.

INTRODUCTION: We report dementia incidence, comorbidities, reasons for health-care visits, mortality, causes of death, and examined dementia patterns by relative deprivation in the UK. METHOD: 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. RESULTS: 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. DISCUSSION: There is a considerable disparity of dementia that informs priorities of prevention and provision of patient care.

Statistical methods for measuring trends in colorectal cancer incidence in registries: A systematic review.

Background: Monitoring cancer trends in a population is essential for tracking the disease's burden, allocating resources, and informing public health policies. This review describes variations in commonly employed methods to estimate colorectal cancer (CRC) incidence trends. Methods: We performed a systematic literature search in four databases to identify population-based studies reporting CRC incidence trends, published between January 2010 and May 2020. We extracted and described data on methods to estimate trends and assess model validity, and the software used. Results: This review included 145 articles based on studies conducted in five continents. The majority (93%) presented visual summaries of trends combined with absolute, relative, or annual change estimates. Fourteen (10%) articles exclusively calculated the relative change in incidence over a given time interval, presented as the percentage of change in rates. Joinpoint regression analysis was the most commonly used method for assessing incidence trends (n= 65, 45%), providing estimates of the annual percentage change (APC) in rates. Nineteen (13%) studies performed Poisson regression and 18 (12%) linear regression analysis. Age-period-cohort modeling- a type of generalized linear models- was conducted in 18 (12%) studies. Thirty-nine (37%) of the studies modeling incidence trends (n=104, 72%) indicated the method used to evaluate model fitness. The joinpoint program (52%) was the statistical software most commonly used. Conclusion: This review identified variation in the calculation of CRC incidence trends and inadequate reporting of model fit statistics. Our findings highlight the need for increasing clarity and transparency in reporting methods to facilitate interpretation, reproduction, and comparison with findings from previous studies.

Correction: Incidence of Lyme disease in the United Kingdom and association with fatigue: A population-based, historical cohort study.

[This corrects the article DOI: 10.1371/journal.pone.0265765.].

Interplay between demographic, clinical and polygenic risk factors for severe COVID-19.

BACKGROUND: We aimed to identify clinical, socio-demographic and genetic risk factors for severe COVID-19 (hospitalization, critical care admission or death) in the general population. METHODS: In this observational study, we identified 9560 UK Biobank participants diagnosed with COVID-19 during 2020. A polygenic risk score (PRS) for severe COVID-19 was derived and optimized using publicly available European and trans-ethnic COVID-19 genome-wide summary statistics. We estimated the risk of hospital or critical care admission within 28 days or death within 100 days following COVID-19 diagnosis, and assessed associations with socio-demographic factors, immunosuppressant use and morbidities reported at UK Biobank enrolment (2006-2010) and the PRS. To improve biological understanding, pathway analysis was performed using genetic variants comprising the PRS. RESULTS: We included 9560 patients followed for a median of 61 (interquartile range = 34-88) days since COVID-19 diagnosis. The risk of severe COVID-19 increased with age and obesity, and was higher in men, current smokers, those living in socio-economically deprived areas, those with historic immunosuppressant use and individuals with morbidities and higher co-morbidity count. An optimized PRS, enriched for single-nucleotide polymorphisms in multiple immune-related pathways, including the 'oligoadenylate synthetase antiviral response' and 'interleukin-10 signalling' pathways, was associated with severe COVID-19 (adjusted odds ratio 1.32, 95% CI 1.11-1.58 for the highest compared with the lowest PRS quintile). CONCLUSION: This study conducted in the pre-SARS-CoV-2-vaccination era, emphasizes the novel insights to be gained from using genetic data alongside commonly considered clinical and socio-demographic factors to develop greater biological understanding of severe COVID-19 outcomes.

Systemic Inflammation Is Associated With Future Risk of Fatal Infection: An Observational Cohort Study.

BACKGROUND: Many diseases are associated with chronic inflammation, resulting in widening application of anti-inflammatory therapies. Although they are effective as disease-modifying agents, these anti-inflammatory therapies increase the risk of serious infection; however, it remains unknown whether chronic systemic inflammation per se is also associated with fatal infection. METHODS: Using serum C-reactive protein (CRP) data from 461 052 UK Biobank participants, we defined incidence rate ratios (IRRs) for death from infection, cardiovascular disease, or other causes and adjusted for comorbidities and the use of anti-inflammatory therapies. RESULTS: Systemic inflammation, defined as CRP ≥2 mg/L, was common in all comorbidities considered. After adjusting for confounding factors, systemic inflammation was associated with a higher IRR point estimate for infection death (1.70; 95% confidence interval [CI], 1.51-1.92) than cardiovascular (1.48; CI, 1.40-1.57) or other death (1.41; CI, 1.37-1.45), although CIs overlapped. C-reactive protein thresholds of ≥5 and ≥10 mg/L yielded similar findings, as did analyses in people with ≥2, but not <2, comorbidities. CONCLUSIONS: Systemic inflammation per se identifies people at increased risk of infection death, potentially contributing to the observed risks of anti-inflammatory therapies in clinical trials. In future clinical trials of anti-inflammatory therapies, researchers should carefully consider risks and benefits in target populations, guided by research into mechanisms of infection risk.

A systematic review of methods to estimate colorectal cancer incidence using population-based cancer registries.

BACKGROUND: Epidemiological studies of incidence play an essential role in quantifying disease burden, resource planning, and informing public health policies. A variety of measures for estimating cancer incidence have been used. Appropriate reporting of incidence calculations is essential to enable clear interpretation. This review uses colorectal cancer (CRC) as an exemplar to summarize and describe variation in commonly employed incidence measures and evaluate the quality of reporting incidence methods. METHODS: We searched four databases for CRC incidence studies published between January 2010 and May 2020. Two independent reviewers screened all titles and abstracts. Eligible studies were population-based cancer registry studies evaluating CRC incidence. We extracted data on study characteristics and author-defined criteria for assessing the quality of reporting incidence. We used descriptive statistics to summarize the information. RESULTS: This review retrieved 165 relevant articles. The age-standardized incidence rate (ASR) (80%) was the most commonly reported incidence measure, and the 2000 U.S. standard population the most commonly used reference population (39%). Slightly more than half (54%) of the studies reported CRC incidence stratified by anatomical site. The quality of reporting incidence methods was suboptimal. Of all included studies: 45 (27%) failed to report the classification system used to define CRC; 63 (38%) did not report CRC codes; and only 20 (12%) documented excluding certain CRC cases from the numerator. Concerning the denominator estimation: 61% of studies failed to state the source of population data; 24 (15%) indicated census years; 10 (6%) reported the method used to estimate yearly population counts; and only 5 (3%) explicitly explained the population size estimation procedure to calculate the overall average incidence rate. Thirty-three (20%) studies reported the confidence interval for incidence, and only 7 (4%) documented methods for dealing with missing data. CONCLUSION: This review identified variations in incidence calculation and inadequate reporting of methods. We outlined recommendations to optimize incidence estimation and reporting practices. There is a need to establish clear guidelines for incidence reporting to facilitate assessment of the validity and interpretation of reported incidence.

The Effect of Endogenous Cushing Syndrome on All-cause and Cause-specific Mortality.

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 < .001), CD (P < .001), and ACS (P = .01). The causes of death were atherosclerotic diseases and thromboembolism (43.4%), infection (12.7%), malignancy (10.6%), active disease (3.5%), adrenal insufficiency (3.0%), and suicide (2.2%). Despite improved outcomes in recent years, increased mortality from CS persists. The causes of death highlight the need to prevent and manage comorbidities in addition to treating hypercortisolism.

Cardiovascular outcomes associated with treatment of type 2 diabetes in patients with ischaemic heart failure.

AIM: The optimal strategy for diabetes control in patients with heart failure (HF) following myocardial infarction (MI) remains unknown. Metformin, a guideline-recommended therapy for patients with chronic HF and type 2 diabetes mellitus (T2DM), is associated with reduced mortality and HF hospitalizations. However, worse outcomes have been reported when used at the time of MI. We compared outcomes of patients with T2DM and HF of ischaemic aetiology according to antidiabetic treatment. METHODS AND RESULTS: This study used linked data from primary care, hospital admissions, and death registries for 4.7 million inhabitants in England, as part of the CALIBER resource. The primary endpoint was a composite of cardiovascular mortality and HF hospitalization. The secondary endpoints were the individual components of the primary endpoint and all-cause mortality. To evaluate the effect of temporal changes in diabetes treatment, antidiabetic medication was included as time-dependent covariates in survival analyses. The study included 1172 patients with T2DM and prior MI and incident HF between 3 January 1998 and 26 February 2010. Five hundred and ninety-six patients had the primary outcome over median follow-up of 2.53 (IQR: 0.98-4.92) years. Adjusted analyses showed a reduced hazard of the composite endpoint for exposure to all antidiabetic medication with hazard ratios (HRs) of 0.50 [95% confidence interval (CI): 0.42-0.59], 0.66 (95% CI: 0.55-0.80), and 0.53 (95% CI: 0.43-0.65), respectively. A similar effect was seen for all-cause mortality [HRs of 0.43 (95% CI: 0.35-0.52), 0.57 (95% CI: 0.46-0.70), and 0.34 (95% CI: 0.27-0.43), respectively]. CONCLUSIONS: When considering changes in antidiabetic treatment over time, all drug classes were associated with reduced risk of cardiovascular mortality and HF hospitalization.

Incidence of Lyme disease in the United Kingdom and association with fatigue: A population-based, historical cohort study.

BACKGROUND: Estimations of Lyme disease incidence rates in the United Kingdom vary. There is evidence that this disease is associated with fatigue in its early stage but reports are contradictory as far as long-term fatigue is concerned. METHODS AND FINDINGS: A population-based historical cohort study was conducted on patients treated in general practices contributing to IQVIA Medical Research Data: 2,130 patients with a first diagnosis of Lyme disease between 2000 and 2018 and 8,510 randomly-sampled patients matched by age, sex, and general practice, followed-up for a median time of 3 years and 8 months. Main outcome measure was time to consultation for (1) any fatigue-related symptoms or diagnosis; or (2) myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Adjusted hazard ratios (HRs) were estimated from Cox models. Average incidence rate for Lyme disease across the UK was 5.18 per 100,000 person-years, increasing from 2.55 in 2000 to 9.33 in 2018. In total, 929 events of any types of fatigue were observed, leading to an incidence rate of 307.90 per 10,000 person-years 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: adjusted HRs were the highest in autumn and winter with 3.14 (95%CI: 1.92-5.13) and 2.23 (1.21-4.11), respectively. For ME/CFS, 17 events were observed in total. Incidence rates were 11.76 per 10,000 person-years in Lyme patients (12 events) and 1.20 in comparators (5 events), corresponding to an adjusted HR of 16.95 (5.17-55.60). Effects were attenuated 6 months after diagnosis but still clearly visible. CONCLUSIONS: UK primary care records provided strong evidence that Lyme disease was associated with subsequent fatigue and ME/CFS. Albeit weaker on the long-term, these effects persisted beyond 6 months, suggesting patients and healthcare providers should remain alert to fatigue symptoms months to years following Lyme disease diagnosis.

Both incidence and prevalence of ischaemic heart disease are declining in parallel: a national data-linkage study in New Zealand (ANZACS-QI 52).

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.

Changes in ankylosing spondylitis incidence, prevalence and time to diagnosis over two decades.

OBJECTIVES: To assess changes in ankylosing spondylitis (AS) incidence, prevalence and time to diagnosis, between 1998 and 2017. METHODS: Using UK GP data from the Clinical Practice Research Datalink, we identified patients diagnosed with AS between 1998 and 2017. We estimated the annual AS incidence, prevalence and length of time from first recorded symptom of back pain to rheumatology referral and diagnosis. RESULTS: We identified 12 333 patients with AS. The incidence declined from 0.72 (±0.14) per 10 000 patient-years in 1998 to 0.39 (±0.06) in 2007, with this decline significant only in men, then incidence rose to 0.57 (±0.11) in 2017. By contrast, prevalence increased between 1998 and 2017 (from 0.13%±0.006 to 0.18%±0.006), rising steeply among women (from 0.06%±0.05 to 0.10%±0.06) and patients aged ≥60 (from 0.14%±0.01 to 0.26%±0.01). The overall median time from first symptom to rheumatology referral was 4.87 years (IQR=1.42-10.23). The median time from first symptom to diagnosis rose between 1998 and 2017 (from 3.62 years (IQR=1.14-7.07) to 8.31 (IQR=3.77-15.89)) and was longer in women (6.71 (IQR=2.30-12.36)) than men (5.65 (IQR=1.66-11.20)). CONCLUSION: AS incidence declined significantly between 1998 and 2007, with an increase between 2007 and 2017 that may be explained by an improvement in the recognition of AS or confidence in diagnosing AS over time, stemming from increased awareness of inflammatory back pain and the importance of early treatment. The rising AS prevalence may indicate improved patient survival. The persisting delay in rheumatology referral and diagnosis remains of concern, particularly in women.

Causes of Death in People With Cardiovascular Disease: A UK Biobank Cohort Study.

Background Therapeutic advances have reduced cardiovascular death rates in people with cardiovascular diseases (CVD). We aimed to define the rates of cardiovascular and noncardiovascular death in people with specified CVDs or accruing cardiovascular multimorbidity. Methods and Results We studied 493 280 UK residents enrolled in the UK Biobank cohort study. The proportion of deaths attributed to cardiovascular, cancer, infection, or other causes were calculated in groups defined by 9 distinct self-reported CVDs at baseline, or by the number of these CVDs at baseline. Poisson regression analyses were then used to define adjusted incidence rate ratios for these causes of death, accounting for sociodemographic factors and comorbidity. Of 27 729 deaths, 20.4% were primarily attributed to CVD, 53.6% to cancer, 5.0% to infection, and 21.0% to other causes. As cardiovascular multimorbidity increased, the proportion of cardiovascular and infection-related deaths was greater, contrasting with cancer and other deaths. Compared with people without CVD, those with 3 or more CVDs experienced adjusted incidence rate ratios of 7.0 (6.2-7.8) for cardiovascular death, 4.4 (3.4-5.6) for infection death, 1.5 (1.4-1.7) for cancer death, and 2.0 (1.7-2.4) for other causes of death. There was substantial heterogeneity in causes of death, both in terms of crude proportions and adjusted incidence rate ratios, among the 9 studied baseline CVDs. Conclusions Noncardiovascular death is common in people with CVD, although its contribution varies widely between people with different CVDs. Holistic and personalized care are likely to be important tools for continuing to improve outcomes in people with CVD.

Non-communicable disease, sociodemographic factors, and risk of death from infection: a UK Biobank observational cohort study.

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.

Changes in the pharmacological management of rheumatoid arthritis over two decades.

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.

Dose-dependent oral glucocorticoid cardiovascular risks in people with immune-mediated inflammatory diseases: A population-based cohort study.

BACKGROUND: Glucocorticoids are widely used to reduce disease activity and inflammation in patients with a range of immune-mediated inflammatory diseases. It is uncertain whether or not low to moderate glucocorticoid dose increases cardiovascular risk. We aimed to quantify glucocorticoid dose-dependent cardiovascular risk in people with 6 immune-mediated inflammatory diseases. METHODS AND FINDINGS: We conducted a population-based cohort analysis of medical records from 389 primary care practices contributing data to the United Kingdom Clinical Practice Research Datalink (CPRD), linked to hospital admissions and deaths in 1998-2017. We estimated time-variant daily and cumulative glucocorticoid prednisolone-equivalent dose-related risks and hazard ratios (HRs) of first all-cause and type-specific cardiovascular diseases (CVDs). 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 = 3,951), and/or vasculitis (n = 5,199), and no prior CVD. Mean age was 56 years and 34.1% were men. The median follow-up time was 5.0 years, and the proportions of person-years spent at each level of glucocorticoid daily exposure were 80% for non-use, 6.0% for <5 mg, 11.2% for 5.0-14.9 mg, 1.6% for 15.0-24.9 mg, and 1.2% for ≥25.0 mg. Incident CVD occurred in 13,426 (15.3%) people, including 6,013 atrial fibrillation, 7,727 heart failure, and 2,809 acute myocardial infarction events. One-year cumulative risks of all-cause CVD increased from 1.4% in periods of non-use to 8.9% for a daily prednisolone-equivalent dose of ≥25.0 mg. Five-year cumulative risks increased from 7.1% to 28.0%, respectively. Compared to periods of non-glucocorticoid use, those with <5.0 mg daily prednisolone-equivalent dose had increased all-cause CVD risk (HR = 1.74; 95% confidence interval [CI] 1.64-1.84; range 1.52 for polymyalgia rheumatica and/or giant cell arteritis to 2.82 for systemic lupus erythematosus). Increased dose-dependent risk ratios were found regardless of disease activity level and for all type-specific CVDs. HRs for type-specific CVDs and <5.0-mg daily dose use were: 1.69 (95% CI 1.54-1.85) for atrial fibrillation, 1.75 (95% CI 1.56-1.97) for heart failure, 1.76 (95% CI 1.51-2.05) for acute myocardial infarction, 1.78 (95% CI 1.53-2.07) for peripheral arterial disease, 1.32 (95% CI 1.15-1.50) for cerebrovascular disease, and 1.93 (95% CI 1.47-2.53) for abdominal aortic aneurysm. The lack of hospital medication records and drug adherence data might have led to underestimation of the dose prescribed when specialists provided care and overestimation of the dose taken during periods of low disease activity. The resulting dose misclassification in some patients is likely to have reduced the size of dose-response estimates. CONCLUSIONS: In this study, we observed an increased risk of CVDs associated with glucocorticoid dose intake even at lower doses (<5 mg) in 6 immune-mediated diseases. These results highlight the importance of prompt and regular monitoring of cardiovascular risk and use of primary prevention treatment at all glucocorticoid doses.

Glucocorticoid dose-dependent risk of type 2 diabetes in six immune-mediated inflammatory diseases: a population-based cohort analysis.

INTRODUCTION: In immune-mediated inflammatory diseases, there is a lack of -estimates of glucocorticoid dose-response diabetes risk that consider changes in prescribed dose over time and disease activity. RESEARCH DESIGN AND METHODS: Population-based longitudinal analysis of electronic health records from the UK Clinical Practice Research Datalink, linked to hospital admissions and the mortality registry (1998-2017). We included 100 722 adult patients without diabetes history, diagnosed with giant cell arteritis or polymyalgia rheumatica (n=32 593), inflammatory bowel disease (n=29 272), rheumatoid arthritis (n=28 365), vasculitis (n=6082), or systemic lupus erythematosus (n=4410). We estimated risks and HRs of type 2 diabetes associated with time-variant daily and total cumulative prednisolone-equivalent glucocorticoid dose using Cox regression methods. RESULTS: Average patient age was 58.6 years, 65 469 (65.0%) were women and 8858 (22.6%) had a body mass index (BMI) ≥30 kg/m2. Overall, 8137 (8.1%) people developed type 2 diabetes after a median follow-up of 4.9 years. At 1 year, the cumulative risk of diabetes increased from 0.9% during periods of non-use to 5.0% when the daily prednisolone-equivalent dose was ≥25.0 mg. We found strong dose-dependent associations for all immune-mediated diseases, BMI levels and underlying disease duration, even after controlling for periods of active systemic inflammation. Adjusted HR for a <5.0 mg daily dose versus non-use was 1.90, 95% CI 1.44 to 2.50; range 1.70 for rheumatoid arthritis to 2.93 for inflammatory bowel disease. CONCLUSIONS: We report dose-dependent risks of type 2 diabetes associated with glucocorticoid use for six common immune-mediated inflammatory diseases. These results underline the need for regular diabetic risk assessment and testing during glucocorticoid therapy in these patients.

Oral glucocorticoids and incidence of hypertension in people with chronic inflammatory diseases: a population-based cohort study.

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.

Feasibility and Face Validity of Outcome Measures for Use in Future Studies of Polymyalgia Rheumatica: An OMERACT Study.

OBJECTIVE: To survey participants with polymyalgia rheumatica (PMR) to evaluate the face validity, acceptability, and domain match of proposed candidate outcome measures. METHODS: A structured, online, anonymous survey was disseminated by patient support groups through their networks and online forums. The candidate outcome measures comprised (1) visual analog scale (VAS) and numerical rating score (NRS) to assess pain; (2) VAS, NRS, and duration to assess stiffness; (3) the modified Health Assessment Questionnaire and Health Assessment Questionnaire Disability Index to assess physical function; and (4) C-reactive protein and erythrocyte sedimentation rate to assess inflammation. Free-text answers were analyzed using descriptive thematic analysis to determine respondents' views of the candidate instruments. RESULTS: Seventy-eight people with PMR from 6 countries (UK, France, USA, Canada, Australia, and New Zealand) participated in the survey. Most respondents agreed candidate instruments were acceptable or "good to go." Free-text analysis identified 5 themes that participants considered inadequately covered by the proposed instruments. These related to (1) the variability, context, and location of pain; (2) the variability of stiffness; (3) fatigue; (4) disability; and (5) the correlation of inflammatory marker levels and severity of symptoms, sometimes reflecting disease activity and other times not. CONCLUSION: Participants reported additional aspects of their experience that are not covered by the proposed instruments, particularly for the experience of stiffness and effect of fatigue. New patient-reported outcome measures are required to increase the relevance of results from clinical trials to patients with PMR.