Higher levels of anti-phosphorylcholine autoantibodies in early rheumatoid arthritis indicate lower risk of incident cardiovascular events

Abstract Background The increased risk of cardiovascular events (CVE) in rheumatoid arthritis (RA) is not fully explained by traditional risk factors. Immuno-inflammatory mechanisms and autoantibodies could be involved in the pathogenesis of atherosclerotic disease. It has been suggested that anti-phosphorylcholine antibodies (anti-PC) of the IgM subclass may have atheroprotective effects. Here, we aimed to investigate the association between levels of IgM anti-PC antibodies with CVE in patients with early RA. Methods The study population was derived from the BARFOT early RA cohort, recruited in 1994–1999. The outcome of incident CVE (AMI, angina pectoris, coronary intervention, ischemic stroke, TIA) was tracked through the Swedish Hospital Discharge and the National Cause of Death Registries. Sera collected at inclusion and the 2-year visit were analyzed with ELISA to determine levels of anti-PC IgM. The Kaplan-Meier estimates and Cox proportional hazards regression models were used to compare CV outcome in the groups categorized by baseline median level of IgM anti-PC. Results In all, 653 patients with early RA, 68% women, mean (SD) age 54.8 (14.7) years, DAS28 5.2 (1.3), 68% seropositive, and without prevalent CVD, were included. During the follow-up of mean 11.7 years, 141 incident CVE were recorded. Baseline IgM anti-PC above median was associated with a reduction in risk of incident CVE in patients aged below 55 years at inclusion, HR 0.360 (95% CI, 0.142–0.916); in males, HR 0.558 (0.325–0.958); in patients with BMI above 30 kg/m2, HR 0.235 (0.065–0.842); and in those who did not achieve DAS28 remission at 1 year, HR 0.592 (0.379–0.924). The pattern of associations was confirmed in the models with AUC IgM anti-PC over 2 years. Conclusion Protective effects of higher levels of innate IgM anti-PC autoantibodies on CVE were detected in younger patients with RA and those at high risk of CVE: males, presence of obesity, and non-remission at 1 year.

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Serum FGF21 Is Associated with Future Cardiovascular Events in Patients with Coronary Artery Disease

Cardiology ◽

10.1159/000486127 ◽

2018 ◽

Vol 139 (4) ◽

pp. 212-218 ◽

Cited By ~ 9

Author(s):

Yun Shen ◽

Xueli Zhang ◽

Yiting Xu ◽

Qin Xiong ◽

Zhigang Lu ◽

...

Keyword(s):

Coronary Artery Disease ◽

Regression Analysis ◽

Coronary Artery ◽

Cardiovascular Events ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Regression ◽

Proportional Hazards Regression ◽

Kaplan Meier ◽

Artery Disease

Objectives: To investigate whether serum fibroblast growth factor 21 (FGF21) levels can be used to predict the future development of major adverse cardiovascular events (MACEs). Methods: This study included 253 patients who received subsequent follow-up, and complete data were collected for 234 patients. Independent predictors of MACEs were identified by using the Cox proportional-hazards regression analysis. The prognostic value of FGF21 levels for MACEs was evaluated by Kaplan-Meier survival analysis. Results: Of 229 patients finally enrolled in the analysis, 27/60 without coronary artery disease (CAD) at baseline experienced a MACE, and 132/169 patients with CAD at baseline experienced a MACE. Among patients with CAD at baseline, serum FGF21 levels were significantly higher in patients with MACEs (p < 0.05) than in patients without MACEs. Kaplan-Meier survival analysis showed patients with a higher serum FGF21 had a significantly lower event-free survival (p = 0.001) than those with a lower level. Further Cox proportional-hazards regression analysis, including the traditional risk factors for cardiovascular disease, showed that serum FGF21 was an independent predictor of MACE occurrence. Conclusions: In patients with CAD at baseline, an elevated serum FGF21 level was associated with the development of a MACE in the future.

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Socioeconomically Disadvantaged Neighborhoods Face Increased Persistence of SARS-CoV-2 Clusters

Frontiers in Public Health ◽

10.3389/fpubh.2020.626090 ◽

2021 ◽

Vol 8 ◽

Cited By ~ 1

Author(s):

David De Ridder ◽

José Sandoval ◽

Nicolas Vuilleumier ◽

Andrew S. Azman ◽

Silvia Stringhini ◽

...

Keyword(s):

Proportional Hazards ◽

Detection Algorithm ◽

Spatial Cluster ◽

Cox Proportional Hazards ◽

Socioeconomic Deprivation ◽

Deprivation Index ◽

Socioeconomically Disadvantaged ◽

Disadvantaged Neighborhoods ◽

Kaplan Meier ◽

Increased Risk

Objective: To investigate the association between socioeconomic deprivation and the persistence of SARS-CoV-2 clusters.Methods: We analyzed 3,355 SARS-CoV-2 positive test results in the state of Geneva (Switzerland) from February 26 to April 30, 2020. We used a spatiotemporal cluster detection algorithm to monitor SARS-CoV-2 transmission dynamics and defined spatial cluster persistence as the time in days from emergence to disappearance. Using spatial cluster persistence measured outcome and a deprivation index based on neighborhood-level census socioeconomic data, stratified survival functions were estimated using the Kaplan-Meier estimator. Population density adjusted Cox proportional hazards (PH) regression models were then used to examine the association between neighborhood socioeconomic deprivation and persistence of SARS-CoV-2 clusters.Results: SARS-CoV-2 clusters persisted significantly longer in socioeconomically disadvantaged neighborhoods. In the Cox PH model, the standardized deprivation index was associated with an increased spatial cluster persistence (hazard ratio [HR], 1.43 [95% CI, 1.28–1.59]). The adjusted tercile-specific deprivation index HR was 1.82 [95% CI, 1.56–2.17].Conclusions: The increased risk of infection of disadvantaged individuals may also be due to the persistence of community transmission. These findings further highlight the need for interventions mitigating inequalities in the risk of SARS-CoV-2 infection and thus, of serious illness and mortality.

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Abstract P353: Survival after Acute Coronary Syndrome in the Community

Circulation ◽

10.1161/circ.127.suppl_12.ap353 ◽

2013 ◽

Vol 127 (suppl_12) ◽

Author(s):

Sheila M McNallan ◽

Yariv Gerber ◽

Susan A Weston ◽

Jill Killian ◽

Shannon M Dunlay ◽

...

Keyword(s):

Acute Coronary Syndrome ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Survival Estimate ◽

Risk Of Death ◽

Coronary Syndrome ◽

Kaplan Meier ◽

Increased Risk ◽

Over Time

Background: Contemporary data on survival after incident acute coronary syndrome (ACS), including both myocardial infarction (MI) and unstable angina (UA), are limited. Objective: To describe survival after incident ACS, to determine if it differs by ACS type (MI or UA) and to determine whether it has improved over time. Methods: Olmsted County, MN residents hospitalized between 1/1/2005-12/31/2010 were screened for incident ACS. ACS was defined as either MI validated by standard epidemiological criteria or UA validated by the Braunwald classification. Patients were followed for death from any cause. Cox proportional hazards regression was used to determine whether survival differed by ACS type, while adjusting for year of diagnosis, age, sex and comorbidities. Results: Among 1,160 incident ACS cases (mean±SD age 66.9±14.8, 60% male), 35% were UA and 65% were MI. After a mean (SD) follow up of 3.7 (2.1) years, 274 deaths occurred. The 3-year Kaplan-Meier survival estimate for MI was 79.6% (95% CI: 76.7%-82.6%) and for UA was 84.9% (95% CI: 81.3%-88.6%) (log-rank p=0.011). The association of ACS type with survival differed by age (p=0.056). After adjustment for year of diagnosis, sex and comorbidities, no difference in survival was observed between ACS types among those aged <60 (HR for MI vs. UA: 0.64, 95% 0.29-1.42). By contrast, among patients aged 60-79, those with an MI had 2 times the risk of death compared to those with UA (HR: 2.04, 95% CI: 1.24-3.37). Patients aged 80 or older who had an MI had a 40% increased risk of death compared to patients of the same age who had UA (HR: 1.42, 95% CI: 1.02-1.98). There was no difference in survival over time (HR for 2010 vs. 2005: 0.91, 95% CI: 0.61-1.36). Conclusions: Survival did not differ between UA and MI patients younger than 60, however among patients 60 or older, survival was worse among those with an MI. Survival after ACS did not change over the study period.

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Depression as a risk factor for the development of rheumatoid arthritis: a population-based cohort study

RMD Open ◽

10.1136/rmdopen-2018-000670 ◽

2018 ◽

Vol 4 (2) ◽

pp. e000670 ◽

Cited By ~ 12

Author(s):

Isabelle A Vallerand ◽

Ryan T Lewinson ◽

Alexandra D Frolkis ◽

Mark W Lowerison ◽

Gilaad G Kaplan ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Cohort Study ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Future Research ◽

Health Improvement ◽

Proportional Hazards Models ◽

Cox Proportional Hazards Models ◽

Increased Risk ◽

Antidepressant Use

ObjectivesMajor depressive disorder (MDD) is associated with increased levels of systemic proinflammatory cytokines, including tumour necrosis factor alpha. As these cytokines are pathogenic in autoimmune diseases such as rheumatoid arthritis (RA), our aim was to explore on a population-level whether MDD increases the risk of developing RA.MethodsA retrospective cohort study was conducted using The Health Improvement Network (THIN) database (from 1986 to 2012). Observation time was recorded for both the MDD and referent cohorts until patients developed RA or were censored. Cox proportional hazards models were used to determine the risk of developing RA among patients with MDD, accounting for age, sex, medical comorbidities, smoking, body mass index and antidepressant use.ResultsA cohort of 403 932 patients with MDD and a referent cohort of 5 339 399 patients without MDD were identified in THIN. Cox proportional hazards models revealed a 31% increased risk of developing RA among those with MDD in an unadjusted model (HR=1.31, 95% CI 1.25 to 1.36, p<0.0001). When adjusting for all covariates, the risk remained significantly increased among those with MDD (HR=1.38, 95% CI 1.31 to 1.46, p<0.0001). Antidepressant use demonstrated a confounding effect that was protective on the association between MDD and RA.ConclusionMDD increased the risk of developing RA by 38%, and antidepressants may decrease this risk in these patients. Future research is necessary to confirm the underlying mechanism of MDD on the pathogenesis of RA.

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Polypharmacy and Unplanned Hospitalizations in Patients with Rheumatoid Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.160818 ◽

2017 ◽

Vol 44 (12) ◽

pp. 1786-1793 ◽

Cited By ~ 10

Author(s):

Maria Filkova ◽

João Carvalho ◽

Sam Norton ◽

David Scott ◽

Tim Mant ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Proportional Hazards ◽

Hospital Admissions ◽

Epidemiologic Studies ◽

Cox Proportional Hazards ◽

Adjusted Risk ◽

Increased Risk ◽

Comorbidity Burden ◽

Multiple Drugs ◽

Unplanned Hospital Admissions

Objective.Polypharmacy (PP), the prescribing of multiple drugs for an individual, is rising in prevalence. PP associates with an increased risk of adverse drug reactions (ADR) and hospital admissions. We investigated the relationship between PP, characteristics of rheumatoid arthritis (RA), and the risk of unplanned hospital admissions.Methods.Patients from a hospital RA cohort were retrospectively analyzed. Information was collected from electronic medical records. Cox proportional hazards were used to compare hospitalization risk according to levels of PP. Admissions were adjudicated to determine whether an ADR was implicated.Results.The study included 1101 patients; the mean number of all medications was 5. PP correlated with increasing age, disease duration, disease activity, and disability. At least 1 unplanned admission occurred for 16% of patients. Patients taking ≥ 10 medications had an adjusted HR for hospitalization of 3.1 (95% CI 2.1–4.5), compared to those taking 0–5 medications. Corticosteroid use associated with a doubling in adjusted risk of admission of 1.7 (95% CI 1.2–2.4). The most common reason for hospitalization was infection (28%). While in half of all admissions an ADR was a possible contributing factor, only 2% of admissions were found to directly result from an ADR.Conclusion.PP is common in RA and is a prognostic marker associated with increased risk of acute hospitalizations. Our data suggest that PP may be an indicator of comorbidity burden rather than a contributing cause of a drug-related toxicity. PP should be monitored to minimize inappropriate combination of prescribed medications. PP may be a useful predictor of clinical outcomes in epidemiologic studies.

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Maternal Hypothyroidism during Pregnancy and the Risk for Infectious Morbidity of the Offspring

American Journal of Perinatology ◽

10.1055/s-0039-3400980 ◽

2019 ◽

Vol 37 (03) ◽

pp. 291-295 ◽

Cited By ~ 2

Author(s):

Ofer Beharier ◽

Asnat Walfisch ◽

Tamar Wainstock ◽

Irit Szaingurten-Solodkin ◽

Daniela Landau ◽

...

Keyword(s):

Animal Studies ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Infectious Morbidity ◽

Hazards Model ◽

Kaplan Meier ◽

Increased Risk

Abstract Objective Animal studies indicate a possible intrauterine immunological imprinting in pregnancies complicated by hypothyroidism. We aimed to evaluate whether exposure to maternal hypothyroidism during pregnancy increases the risk of long-term infectious morbidity of the offspring. Study Design A retrospective cohort study compared the long-term risk of hospitalization associated with infectious morbidity in children exposed and unexposed in utero to maternal hypothyroidism. Outcome measures included infectious diagnoses obtained during any hospitalization of the offspring (up to the age of 18 years). Results The study included 224,950 deliveries. Of them, 1.1% (n = 2,481) were diagnosed with maternal hypothyroidism. Children exposed to maternal hypothyroidism had a significantly higher rate of hospitalizations related to infectious morbidity (13.2 vs. 11.2% for control; odds ratio: 1.2; 95% confidence interval: 1.08–1.36; p = 0.002). Specifically, incidences of ear, nose, and throat; respiratory; and ophthalmic infections were significantly higher among the exposed group. The Kaplan–Meier curve indicated that children exposed to maternal hypothyroidism had higher cumulative rates of long-term infectious morbidity. In the Cox proportional hazards model, maternal hypothyroidism remained independently associated with an increased risk of infectious morbidity in the offspring while adjusting for confounders. Conclusion Maternal hypothyroidism during pregnancy is associated with significant pediatric infectious morbidity of the offspring.

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Severe varicose veins and the risk of mortality: a nationwide population-based cohort study

BMJ Open ◽

10.1136/bmjopen-2019-034245 ◽

2020 ◽

Vol 10 (6) ◽

pp. e034245

Author(s):

Nan-Chun Wu ◽

Zhih-Cherng Chen ◽

I-Jung Feng ◽

Chung-Han Ho ◽

Chun-Yen Chiang ◽

...

Keyword(s):

Cohort Study ◽

Cardiovascular Events ◽

Proportional Hazards ◽

Varicose Veins ◽

Systemic Disease ◽

Cox Proportional Hazards ◽

Major Adverse Cardiovascular Events ◽

Coronary Syndrome ◽

Risk Of Mortality ◽

Increased Risk

ObjectiveVaricose veins (VVs) are common and although considered benign may cause morbidity. However, the association between VV severity and cardiovascular and mortality risks remains unknown. The aim of this study was to investigate the factors associated with overall mortality in patients with VV.MethodsA total of 4644 patients with newly diagnosed VV between 1999 and 2013 were identified from Taiwan’s National Health Insurance Database. VV severity was classified from grade 1 to 3 according to the presentation of ulcers or inflammation. Moreover, 9497, 2541 and 5722 age-matched, sex-matched and chronic cardiovascular risk factor-matched controls, as assessed based on propensity score, were separately selected for three grading VV groups. Enrolled patients were analysed using conditional Cox proportional hazards regression analysis to estimate risk of mortality and major adverse cardiovascular events (MACEs) in the VV and control groups.ResultsMost patients with VV were free from systemic disease. However, compared with matched controls, patients with VV showed a 1.37 times increased risk of mortality (95% CI 1.19 to 1.57; p<0.0001). Compared with matched controls, older (age ≧65 years) (adjusted HR: 1.38; 95% CI 1.17 to 1.62; p=0.0001) and male patients with VV (adjusted HR 1.41; 95% CI 1.18 to 1.68; p=0.0001) showed increased risk of mortality. Furthermore, compared with controls, patients with VV showed 2.05 times greater risk of MACE. Compared with matched controls, population at grade 3 increased 1.83 times risk of mortality and 2.04 to 38.42 times risk of heart failure, acute coronary syndrome, ischaemic stroke and venous thromboembolism.ConclusionsThis nationwide cohort study demonstrated that patients with VV are at a risk of cardiovascular events and mortality. Our findings suggest that presence of VV warrants close attention in terms of prognosis and treatment.

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Racial Disparities in Delivery Gestational Age among Twin Pregnancies

American Journal of Perinatology ◽

10.1055/s-0037-1603764 ◽

2017 ◽

Vol 34 (11) ◽

pp. 1065-1071

Author(s):

Catherine Vladutiu ◽

Tracy Manuck ◽

Jacqueline Grant

Keyword(s):

Gestational Age ◽

Proportional Hazards ◽

Secondary Analysis ◽

Neonatal Morbidity ◽

Cox Proportional Hazards ◽

Kaplan Meier ◽

Cox Proportional Hazards Models ◽

Hazard Ratios ◽

Increased Risk ◽

Hydroxyprogesterone Caproate

Objective This study aims to estimate the association between maternal race and delivery gestational age among women with twin gestations. Study Design Secondary analysis of a prospective, randomized control trial of 17-α hydroxyprogesterone caproate versus placebo for preterm birth (PTB) prevention in twin gestations. Non-Hispanic (NH) black and whites were included. Demographic and antenatal characteristics were compared. The primary outcome was delivery gestational age. Secondary outcomes included a composite of major neonatal morbidity. Kaplan–Meier curves estimated survival probabilities for delivery gestational age by race. Cox proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI). Results A total of 535 women with twin gestations were included; 150 were NH black. NH blacks delivered earlier than NH whites (33.6 ± 4.8 weeks vs. 35.1 ± 3.5 weeks, p < 0.001). Differences in delivery gestational age between NH blacks and whites were consistent across gestation. In adjusted analyses, NH black race (HR: 1.24, 95% CI: 1.02–1.51), prior PTB (HR: 1.59, 95% CI: 1.15–2.19), and cerclage (HR: 3.90, 95% CI: 2.00–7.60) were associated with an increased risk of earlier delivery. Major neonatal morbidity was higher for NH blacks compared with NH whites (12.7 vs. 7.0%, p = 0.036). Conclusion NH blacks with twin gestations have an increased risk of early delivery and neonatal morbidity compared with NH whites.

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Reduced mortality in patients with extended duration of methadone maintenance treatment: a five-year retrospective nationwide study

Psychological Medicine ◽

10.1017/s0033291721002051 ◽

2021 ◽

pp. 1-9

Author(s):

Chieh-Liang Huang ◽

I-Ju Tsai ◽

Wen-Chi Lin ◽

Cheng-Li Lin ◽

Ing-Kang Ho ◽

...

Keyword(s):

Methadone Maintenance Treatment ◽

Maintenance Treatment ◽

Proportional Hazards ◽

Methadone Maintenance ◽

Cohort Analysis ◽

Cox Proportional Hazards ◽

Research Database ◽

Risk Of Death ◽

Kaplan Meier ◽

Increased Risk

Abstract Background The retention of patients under methadone maintenance treatment (MMT) is an indication for the effectiveness of the therapy. We aimed to explore the relation between mortality and the cumulative MMT duration. Methods A retrospective cohort analysis was performed using Taiwan Illicit Drug Issue Database (TIDID) and National Health Insurance Research Database (NHIRD) during 2012–2016. We included 9149 and 11 112 MMT patients as the short and long groups according to the length of their cumulative MMT duration, 1–364 and ⩾365 days, respectively. The risk of mortality was calculated by Cox proportional hazards regression model with time-dependent exposure to MMT, and the survival probability was plotted with the Kaplan-Meier curve. Results The mortality rates were 2.51 and 1.51 per 100 person-years in the short and long cumulative MMT duration groups, respectively. After adjusting for on or off MMT, age, sex, marital status, education level, maximum methadone dose, and comorbidities (human immunodeficiency virus, depression, hepatitis C virus, hepatitis B virus, alcoholic liver disease, and cardiovascular disease), the long group had a lower risk of death (hazard ratio = 0.67; 95% confidence interval 0.60–0.75) than the short group. Increased risk was observed in patients with advanced age, being male, unmarried, infected by HIV, HCV, and HBV, and diagnosed with depression, ALD, and CVD. Causes of death were frequently related to drug and injury. Conclusions Longer cumulative MMT duration is associated with lower all-cause and drug-related mortality rate.

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IL6 trans-signalling is associated with a higher risk of cardiovascular events in individuals with diabetes

European Heart Journal ◽

10.1093/eurheartj/ehab724.2510 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

L Ziegler ◽

B Gigante

Keyword(s):

Diabetes Mellitus ◽

Cardiovascular Events ◽

Ternary Complex ◽

Proportional Hazards ◽

Cox Regression ◽

Interaction Analysis ◽

Cox Proportional Hazards ◽

Public Institution ◽

Additive Interaction ◽

Increased Risk

Abstract Background Pro-inflammatory interleukin 6 (IL6) trans-signalling is associated with an increased risk of future cardiovascular events (CVE). Diabetes mellitus is a well-known risk factor for CVE but its relation to IL6 trans-signalling is not investigated. Purpose We aimed at analysing if the CVE risk associated with IL6 trans-signalling differed between individuals with/without diabetes. Method In a prospective cohort of 60-year-old men and women from our city (n=4232), 629 CVE (myocardial infarction, hospitalised angina pectoris and ischemic stroke) occurred during a 20-year follow-up. The risk of CVE associated with IL6 trans-signalling was assessed using the binary/ternary complex ratio (B/T ratio), a novel marker of IL6 trans-signalling derived from the serum molar concentrations of IL6 and the soluble IL6 receptors (sIL6R; sgp130). As a B/T ratio > median, mirroring active IL6 trans-signalling with a relative excess of the active binary IL6 complex in relation to the inactive ternary complex, previously was demonstrated to be associated with an increased CVE risk in this cohort we chose the same cut-off. The CVE risk was assessed by Cox proportional hazards models and described as hazard ratios (HR) with 95% confidence intervals (CI) in individuals with/without diabetes mellitus type 1 or 2 (n=114) defined as either self-reported, or fasting glucose >7.0 mmol/L in the baseline blood test. In the adjusted model, risk estimates were adjusted for the common cardiovascular risk factors. The additive interaction between IL6 trans-signalling and diabetes on the CVE risk was analysed using Cox regression and presented as Synergy index (S) with 95% CI where S > or <1 indicate presence of an interaction. Result There was a higher CVE risk associated with IL6 trans-signalling assessed by B/T ratio > median in individuals with diabetes (adjusted HR 3.42; 95% CI 1.60–7.29) compared to participants without (adjusted HR 1.36; 95% CI 1.15–1.60) and the interaction analysis suggested a presence of additive interaction between IL6 trans-signalling and diabetes on the CVE risk (adjusted S=5.23; 95% CI 0.93–29.26) as seen in Figure 1. Conclusion Individuals with diabetes mellitus have an increased risk of CVE associated with IL6 trans-signalling possibly in part due to an additive interaction between the two. FUNDunding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): The Stockholm County Council ALF projectStrategic research in Epidemiology at Karolinska Institutet Figure 1

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