Search

Objectives: Pulmonary manifestations in RA are common comorbidities, but the underlying mechanisms are largely unknown. The added value of a multiplex of ACPA and genetic risk markers was evaluated for the development of pulmonary fibrosis (PF) in an inception cohort., Methods: A total of 1184 patients with early RA were consecutively included and followed prospectively from the index date until death or 31 December 2016. The presence of 21 ACPA fine specificities was analysed using a custom-made microarray chip (Thermo Fisher Scientific, Uppsala, Sweden). Three SNPs, previously found related to PF were evaluated, rs2609255 (FAM13A), rs111521887 (TOLLIP) and rs35705950 (MUC5B). ACPA and genetic data were available for 841 RA patients, of whom 50 developed radiologically defined PF., Results: In unadjusted analyses, 11 ACPA specificities were associated with PF development. In multiple variable analyses, six ACPA specificities were associated with increased risk of PF: vimentin (Vim)60-75, fibrinogen (Fib)β62-78 (72), Fibα621-635, Bla26, collagen (C)II359-369 and F4-CIT-R (P < 0.01 to P < 0.05). The number of ACPA specificities was also related to PF development (P < 0.05 crude and adjusted models). In multiple variable models respectively adjusted for each of the SNPs, the number of ACPA specificities (P < 0.05 in all models), anti-Vim60-75 (P < 0.05, in all models), anti-Fibβ62-78 (72) (P < 0.001 to P < 0.05), anti-CII359-369 (P < 0.05 in all models) and anti-F4-CIT-R AQ4 (P < 0.01 to P < 0.05), anti-Fibα621-635 (P < 0.05 in one) and anti-Bla26 (P < 0.05 in two) were significantly associated with PF development., Conclusion: The development of PF in an inception cohort of RA patients was associated with both presence of certain ACPA and the number of ACPA specificities and risk genes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Pulmonary manifestations in RA are common comorbidities. Interstitial lung disease (ILD), both idiopathic and in RA, has been associated with several genetic variants. We assessed pulmonary fibrosis (PF) in an inception cohort of RA patients in relation to genetic variants and disease-related factors., Methods: A total of 1466 early RA patients were consecutively included and followed prospectively from the index date until death or 31 December 2016. Clinical and laboratory data and treatment were continuously registered according to the Swedish Rheumatology Quality Register. DNA was available from 1184 patients and 571 151 genome-wide single-nucleotide polymorphisms (SNPs) were analysed. Thirteen identified genetic variants were extracted. At follow-up, the patients answered a questionnaire regarding disease progression and lung involvement that was validated by reviewing medical records and analysing radiological examinations., Results: The prevalence of PF was 5.6% and the annualized incidence rate was 5.0/1000 (95% CI 3.80, 6.54). Four SNPs were associated with PF in RA: rs35705950 [MUC5B; OR 2.5 (95% CI 1.5, 4.0), adjusted P-value = 0.00016, q-value = 0.0021]; rs111521887 [TOLLIP; OR 1.9 (95% CI 1.3, 2.8), adjusted P-value = 0.0014, q-value = 0.0092]; rs2609255 [FAM13A; OR 1.7 (95% CI 1.1, 2.5), adjusted P-value = 0.013, q-value = 0.055] and rs2736100 [TERT; OR 1.5 (95% CI 1.0, 2.2), adjusted P-value = 0.046, q-value = 0.15]. Older age and RF positivity were associated with increased risk, while MTX treatment was associated with a lower risk of PF., Conclusions: Development of PF in an inception cohort of RA patients was associated with 4 of 12 ILD risk genes. RA-related factors except for age at diagnosis and RF positivity were of limited importance in PF development., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: The value of family history of coronary artery disease (CAD) in diagnosing acute coronary syndrome (ACS) in chest pain patients is uncertain, especially in relation to high-sensitivity assays for cardiac troponin T (hs-cTnT), which have improved ACS diagnostics. Our objective was to investigate the association between verified family history of CAD and ACS in chest pain patients, overall and in different strata of initial hs-cTnT., Methods: Data on chest pain patients visiting four emergency departments in Sweden during 2013-2016 were cross-referenced with national registers of kinship, diseases and prescriptions. Family history of early CAD was defined as the occurrence of myocardial infarction or coronary revascularization before the age of 55 years in male and 65 years in female first-degree relatives. The outcome was combined including ACS and cardiovascular death within 30 days of presentation., Results: Of 28,188 patients, 4.7% of patients had ACS. In total, 8.2% and 32.4% had a family history of early and ever-occurring CAD, respectively. Family history of CAD was positively associated with the outcome, independently of age, gender, cardiovascular risk factors and electrocardiogram findings. The strongest association was observed for family history of early CAD (odds ratio 1.62, 95% confidence interval 1.35-1.94). Stronger associations were observed in young patients (e.g. <65 years) and in patients with non-elevated initial hs-cTnT levels ( p -value for interaction = 0.004 and 0.001, respectively)., Conclusions: Family history of CAD is associated with ACS in chest pain patients, especially in patients of young age or with non-elevated initial hs-cTnT levels.

Background: The introduction of high-sensitivity cardiac troponin (hs-cTn) assays has improved the early assessment of chest pain patients. A number of hs-cTn-based algorithms and accelerated diagnostic protocols (ADPs) have been developed and tested subsequently. In this review, we summarize the data on the performance and clinical utility of these strategies., Content: We reviewed studies investigating the diagnostic and prognostic performance of hs-cTn algorithms [level of detection (LoD) strategy, 0/1-h, 0/2-h, and 0/3-h algorithms) and of hs-cTn-based ADPs, together with the implications of these strategies when implemented as clinical routine. The LoD strategy, when combined with a nonischemic electrocardiogram, is best suited for safe rule-out of myocardial infarction and the identification of patients eligible for early discharge from the emergency department. The 0/1-h algorithms appear to identify most patients as being eligible for rule-out. The hs-cTn-based ADPs mainly focus on prognostic assessment, which is in contrast with the hs-cTn algorithms. They identify smaller proportions of rule-out patients, but there is increasing evidence from prospective studies on their successful clinical implementation. Such information is currently lacking for hs-cTn algorithms., Conclusions: There is a trade-off between safety and efficacy for different hs-cTn-based strategies. This trade-off should be considered for the intended strategy, along with its user-friendliness and evidence from clinical implementation studies. However, several gaps in knowledge remain. At present, we suggest the use of an ADP in conjunction with serial hs-cTn results to optimize the early assessment of chest pain patients., (© 2018 American Association for Clinical Chemistry.)

Background: The aim of this study was to examine the value of predischarge exercise electrocardiogram (ECG) testing of chest pain patients in whom acute myocardial infarction (MI) had been ruled out by means of high-sensitivity troponins, ECG and history., Methods: All patients hospitalised for chest pain who underwent exercise ECG testing before discharge from the Department of Cardiology, Södersjukhuset, Stockholm, Sweden from January 2011 to June 2012 were included. Endpoints were death, MI and post-discharge revascularisation within 90 and 365 days, respectively. The background one-year risk of death and MI for a corresponding age, gender and calendar time-matched Swedish population was also examined., Results: A total of 951 patients were included. In 585 patients (61.5%) the exercise ECG test was negative, in 94 (9.9%) positive and in 272 (28.6%) inconclusive. There were no significant differences regarding death or MI between patients with a positive or a negative test, neither at 90 ( n=1 (1.1%) vs. n=1 (0.2%)) nor at 365 days ( n=2 (2.1%) vs. n=4 (0.7%)) of follow-up. In total there were nine (0.9%) deaths and 10 (1.1%) MIs within 365 days. The one-year rates of death (1.3%) and MI (0.5%) in a matched Swedish population were comparable., Conclusions: Predischarge exercise ECG testing after rule out of MI did not predict subsequent death or MI in a population of patients hospitalised for chest pain. Furthermore, the risks of death and MI in this population were comparable to a matched Swedish population. These findings suggest that patients could be discharged without this test.

Aims: International guidelines advocate an implantable cardioverter and defibrillator (ICD) in patients with reduced left ventricular ejection fraction (LVEF) to prevent sudden death (SCD). Previous data suggest that the benefit of ICD therapy in real life may be lower than expected from the results of controlled studies and side-effects are not negligible. It is also unclear whether women benefit from treatment to the same extent as men. The aim of this study was to investigate the balance between benefits and complications of ICD therapy in a real-life population of patients with heart failure., Methods and Results: We studied 865 consecutive patients with reduced LVEF treated with ICDs for primary prevention of SCD in 2006-11 in four tertiary care hospitals in Sweden (age 64 ± 11 years, 82% men, 62% ischaemic). The patients' medical records were scrutinized as regards appropriate therapies, complications related to the defibrillator, all-cause mortality, and gender differences. Mean follow-up was 35 ± 18 months. During follow-up 155 patients (18%) received appropriate ICD therapy, 61 patients (7%) had inappropriate shocks, 110 patients (13%) had at least one complication that required reoperation and 213 patients (25%) died. Men were twice as likely to receive ICD treatment compared with women (20 vs. 9%, P < 0.01), but neither total mortality nor complication rates differed., Conclusions: Ventricular arrhythmias necessitating ICD therapy are common (6% annually). Women are less likely to have correct ICD treatment, but have the same degree of treatment complications, thus reducing the net benefit of their treatment., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: The purpose of this study is to investigate compliance to established guidelines regarding primary prevention with implantable cardioverter-defibrillator (ICD) in patients with left ventricular dysfunction after acute myocardial infarction (AMI) in a clinical setting., Methods and Results: A retrospective study of medical records from patients admitted to two hospitals in Stockholm during 2008-2009 with a diagnosis of AMI and who at discharge had a left ventricular ejection fraction ≤35%. An evaluation of follow-up and echocardiographic recordings was performed 1-3 months after AMI. A total of 2023 patients <80 years, with AMI discharged from hospital, were screened for left ventricular dysfunction defined as ejection fraction (EF) ≤35%. Altogether 187 patients were identified and an ICD was implanted in 25 (13%) patients. In 52 (28%) patients, there were contraindications for ICD therapy. An improved EF at follow-up, making ICD treatment redundant, was observed in 48 (41%) patients who underwent an ECHO at follow-up or later. Seventeen (9%) patients without an ICD died during follow-up and out of these five patients died from sudden cardiac death (SCD), they had no contraindication to ICD therapy. An inadequate follow-up according to guidelines was found in 59 (32%) patients., Conclusion: The follow-up of post-myocardial infarction patients with left ventricular dysfunction according to guidelines was insufficient in this population and may have increased the risk for SCD. A significant proportion of patients experienced improved left ventricular function during short-term follow-up making preventive ICD treatment redundant.

Chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) is a protein that binds and blocks the C5a receptor (C5aR) and formylated peptide receptor, thereby inhibiting the immune cell recruitment associated with inflammation. If CHIPS was less reactive with existing human antibodies, it would be a promising anti-inflammatory drug candidate. Therefore, we applied directed evolution and computational/rational design to the CHIPS gene in order to generate new CHIPS variants displaying lower interaction with human IgG, yet retaining biological function. The optimization was performed in four rounds: one round of random mutagenesis to add diversity into the CHIPS gene and three rounds of DNA recombination by Fragment INduced Diversity (FIND). Every round was screened by phage selection and/or ELISA for decreased interaction with human IgG and retained C5aR binding. The mean binding of human anti-CHIPS IgG decreased with every round of evolution. For further optimization, new amino acid substitutions were introduced by rational design, based on the mutations identified during directed evolution. Finally, seven CHIPS variants with low interaction with human IgG and retained C5aR blocking capacity could be identified.