The role of computer-assisted radiographer reporting in lung cancer screening programmes.

OBJECTIVES: Successful lung cancer screening delivery requires sensitive, timely reporting of low-dose computed tomography (LDCT) scans, placing a demand on radiology resources. Trained non-radiologist readers and computer-assisted detection (CADe) software may offer strategies to optimise the use of radiology resources without loss of sensitivity. This report examines the accuracy of trained reporting radiographers using CADe support to report LDCT scans performed as part of the Lung Screen Uptake Trial (LSUT). METHODS: In this observational cohort study, two radiographers independently read all LDCT performed within LSUT and reported on the presence of clinically significant nodules and common incidental findings (IFs), including recommendations for management. Reports were compared against a 'reference standard' (RS) derived from nodules identified by study radiologists without CADe, plus consensus radiologist review of any additional nodules identified by the radiographers. RESULTS: A total of 716 scans were included, 158 of which had one or more clinically significant pulmonary nodules as per our RS. Radiographer sensitivity against the RS was 68-73.7%, with specificity of 92.1-92.7%. Sensitivity for detection of proven cancers diagnosed from the baseline scan was 83.3-100%. The spectrum of IFs exceeded what could reasonably be covered in radiographer training. CONCLUSION: Our findings highlight the complexity of LDCT reporting requirements, including the limitations of CADe and the breadth of IFs. We are unable to recommend CADe-supported radiographers as a sole reader of LDCT scans, but propose potential avenues for further research including initial triage of abnormal LDCT or reporting of follow-up surveillance scans. KEY POINTS: • Successful roll-out of mass screening programmes for lung cancer depends on timely, accurate CT scan reporting, placing a demand on existing radiology resources. • This observational cohort study examines the accuracy of trained radiographers using computer-assisted detection (CADe) software to report lung cancer screening CT scans, as a potential means of supporting reporting workflows in LCS programmes. • CADe-supported radiographers were less sensitive than radiologists at identifying clinically significant pulmonary nodules, but had a low false-positive rate and good sensitivity for detection of confirmed cancers.

Lung Screen Uptake Trial: results from a single lung cancer screening round.

The Lung Screen Uptake Trial tested a novel invitation strategy to improve uptake and reduce socioeconomic and smoking-related inequalities in lung cancer screening (LCS) participation. It provides one of the first UK-based 'real-world' LCS cohorts. Of 2012 invited, 1058 (52.6%) attended a 'lung health check'. 768/996 (77.1%) in the present analysis underwent a low-dose CT scan. 92 (11.9%) and 33 (4.3%) participants had indeterminate pulmonary nodules requiring 3-month and 12-month surveillance, respectively; 36 lung cancers (4.7%) were diagnosed (median follow-up: 1044 days). 72.2% of lung cancers were stage I/II and 79.4% of non-small cell lung cancer had curative-intent treatment.

Evaluation of cardiovascular risk in a lung cancer screening cohort.

INTRODUCTION: Lung cancer screening (LCS) by low-dose computed tomography (LDCT) offers an opportunity to impact both lung cancer and coronary heart disease mortality through detection of coronary artery calcification (CAC). Here, we explore the value of CAC and cardiovascular disease (CVD) risk assessment in LCS participants in the Lung Screen Uptake Trial (LSUT). METHODS: In this cross-sectional study, current and ex-smokers aged 60-75 were invited to a 'lung health check'. Data collection included a CVD risk assessment enabling estimation of 10 year CVD risk using the QRISK2 score. Participants meeting the required lung cancer risk underwent an ungated, non-contrast LDCT. Descriptive data, bivariate associations and a multivariate analysis of predictors of statin use are presented. RESULTS: Of 1005 individuals enrolled, 680 were included in the final analysis. 421 (61.9%) had CAC present and in 49 (7.2%), this was heavy. 668 (98%) of participants had a QRISK2≥10% and QRISK2 was positively associated with increasing CAC grade (OR 4.29 (CI 0.93 to 19.88) for QRISK2=10%-20% and 12.29 (CI 2.68 to 56.1) for QRISK2≥20% respectively). Of those who qualified for statin primary prevention (QRISK2≥10%), 56.8% did not report a history of statin use. In the multivariate analysis statin use was associated with age, body mass index and history of hypertension and diabetes. CONCLUSIONS: LCS offers an important opportunity for instituting CVD risk assessment in all LCS participants irrespective of the presence of LDCT-detected CAC. Further studies are needed to determine whether CAC could enhance uptake and adherence to primary preventative strategies.

Sequential screening for lung cancer in a high-risk group: randomised controlled trial: LungSEARCH: a randomised controlled trial of Surveillance using sputum and imaging for the EARly detection of lung Cancer in a High-risk group.

BACKGROUND: Low-dose computed tomography (LDCT) screening detects early-stage lung cancer and reduces mortality. We proposed a sequential approach targeted to a high-risk group as a potentially efficient screening strategy. METHODS: LungSEARCH was a national multicentre randomised trial. Current/ex-smokers with mild/moderate chronic obstructive pulmonary disease (COPD) were allocated (1:1) to have 5 years surveillance or not. Screened participants provided annual sputum samples for cytology and cytometry, and if abnormal were offered annual LDCT and autofluorescence bronchoscopy (AFB). Those with normal sputum provided annual samples. The primary end-point was the percentage of lung cancers diagnosed at stage I/II (nonsmall cell) or limited disease (small cell). RESULTS: 1568 participants were randomised during 2007-2011 from 10 UK centres. 85.2% of those screened provided an adequate baseline sputum sample. There were 42 lung cancers among 785 screened individuals and 36 lung cancers among 783 controls. 54.8% (23 out of 42) of screened individuals versus 45.2% (14 out of 31) of controls with known staging were diagnosed with early-stage disease (one-sided p=0.24). Relative risk was 1.21 (95% CI 0.75-1.95) or 0.82 (95% CI 0.52-1.31) for early-stage or advanced cancers, respectively. Overall sensitivity for sputum (in those randomised to surveillance) was low (40.5%) with a cumulative false-positive rate (FPR) of 32.8%. 55% of cancers had normal sputum results throughout. Among sputum-positive individuals who had AFB, sensitivity was 45.5% and cumulative FPR was 39.5%; the corresponding measures for those who had LDCT were 100% and 16.1%, respectively. CONCLUSIONS: Our sequential strategy, using sputum cytology/cytometry to select high-risk individuals for AFB and LDCT, did not lead to a clear stage shift and did not improve the efficiency of lung cancer screening.

High prevalence of malignancy in HIV-positive patients with mediastinal lymphadenopathy: a study in the era of antiretroviral therapy.

BACKGROUND AND OBJECTIVE: Mediastinal lymphadenopathy (MLN) in human immunodeficiency virus (HIV) infection has a wide spectrum of aetiologies with different prognoses and treatments. The decision to pursue a histopathological diagnosis represents a clinical challenge as patients present with non-specific symptoms. This study aimed to determine the aetiology and predictive factors of MLN in a cohort of HIV-infected patients in the combination antiretroviral therapy (cART) era. METHODS: Single-centre retrospective cohort study of 217 consecutive HIV-infected patients who underwent computed tomography (CT) of the chest between January 2004 and December 2009. Fifty-two patients were identified to have MLN (>10 mm in short axis). CT images were re-reviewed by an independent radiologist blinded to the clinical information. Final diagnoses of MLN were obtained from clinical records. Multivariate analysis was performed to identify predictors of aetiology of MLN. RESULTS: Seventeen patients (33%) had a diagnosis of malignancy. Consolidation on CT was associated with a reduced likelihood of malignancy odds ratio (OR) 0.03 (95% confidence interval 0.002-0.422), and larger lymph nodes were associated with an increase in the odds of malignancy (OR 2.89; 95% confidence interval 1.24-6.71). CD4 count was found not to be a predictor of aetiology of MLN. CONCLUSIONS: In the era of combination cART, opportunistic infections and malignancy remain to be the frequent causes of MLN in HIV-positive patients, but the prevalence of non-HIV related malignancy has increased compared with previous studies. Although certain findings are predictors of non-malignant disease, pathological diagnosis of MLN in HIV-positive patients should be pursued whenever possible.

Endobronchial ultrasound-guided transbronchial needle aspiration prevents mediastinoscopies in the diagnosis of isolated mediastinal lymphadenopathy: a prospective trial.

RATIONALE: Patients with isolated mediastinal lymphadenopathy (IML) are a common presentation to physicians, and mediastinoscopy is traditionally considered the "gold standard" investigation when a pathological diagnosis is required. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is established as an alternative to mediastinoscopy in patients with lung cancer. OBJECTIVE: To determine the efficacy and health care costs of EBUS-TBNA as an alternative initial investigation to mediastinoscopy in patients with isolated IML. METHODS: Prospective multicenter single-arm clinical trial of 77 consecutive patients with IML from 5 centers between April 2009 and March 2011. All patients underwent EBUS-TBNA. If EBUS-TBNA did not provide a diagnosis, then participants underwent mediastinoscopy. MEASUREMENTS AND MAIN RESULTS: EBUS-TBNA prevented 87% of mediastinoscopies (95% confidence interval [CI], 77-94%; P < 0.001) but failed to provide a diagnosis in 10 patients (13%), all of whom underwent mediastinoscopy. The sensitivity and negative predictive value of EBUS-TBNA in patients with IML were 92% (95% CI, 83-95%) and 40% (95% CI, 12-74%), respectively. One patient developed a lower respiratory tract infection after EBUS-TBNA, requiring inpatient admission. The cost of the EBUS-TBNA procedure per patient was £1,382 ($2,190). The mean cost of the EBUS-TBNA strategy was £1,892 ($2,998) per patient, whereas a strategy of mediastinoscopy alone was significantly more costly at £3,228 ($5,115) per patient (P < 0.001). The EBUS-TBNA strategy is less costly than mediastinoscopy if the cost per EBUS-TBNA procedure is less than £2,718 ($4,307) per patient. CONCLUSIONS: EBUS-TBNA is a safe, highly sensitive, and cost-saving initial investigation in patients with IML. Clinical trial registered with ClinicalTrials.gov (NCT00932854).

Prevalence, Symptom Burden, and Underdiagnosis of Chronic Obstructive Pulmonary Disease in a Lung Cancer Screening Cohort.

Rationale: Individuals eligible for lung cancer screening (LCS) by low-dose computed tomography (LDCT) are also at risk of chronic obstructive pulmonary disease (COPD) due to age and smoking exposure. Whether the LCS episode is useful for early detection of COPD is not well established.Objectives: To explore associations between symptoms, comorbidities, spirometry, and emphysema in participants enrolled in the Lung Screen Uptake Trial.Methods: This cross-sectional study was a prespecified analysis nested within Lung Screen Uptake Trial, which was a randomized study testing the impact of differing invitation materials on attendance of 60- to 75-year-old smokers and ex-smokers to a "lung health check" between November 2015 and July 2017. Participants with a smoking history ≥30 pack-years and who quit ≤15 years ago, or meeting a lung cancer risk of ≥1.51% via the Prostate Lung Colorectal Ovarian model or ≥2.5% via the Liverpool Lung Project model, were offered LDCT. COPD was defined and classified according to the GOLD (Global Initiative for Obstructive Lung Disease) criteria using prebronchodilator spirometry. Analyses included the use of descriptive statistics, chi-square tests to examine group differences, and univariable and multivariable logistic regression to explore associations between symptom prevalence, airflow limitation, and visually graded emphysema.Results: A total of 560 of 986 individuals included in the analysis (57%) had prebronchodilator spirometry consistent with COPD; 67% did not have a prior history of COPD and were termed "undiagnosed." Emphysema prevalence in those with known and "undiagnosed" COPD was 73% and 68%, respectively. A total of 32% of those with "undiagnosed COPD" had no emphysema on LDCT. Inhaler use and symptoms were more common in the "known" than the "undiagnosed" COPD group (63% vs. 33% with persistent cough [P < 0.001]; 73% vs. 33% with dyspnea [P < 0.001]). Comorbidities were common in all groups. Adjusted odds ratio (aOR) of respiratory symptoms were more significant for airflow obstruction (aOR GOLD 1 and 2, 1.57; confidence interval [CI], 1.14-2.17; aOR GOLD 3 and 4, 4.6; CI, 2.17-9.77) than emphysema (aOR mild, 1.12; CI, 0.81-1.55; aOR moderate, 1.33; CI, 0.85-2.09; aOR severe, 4.00; CI, 1.57-10.2).Conclusions: There is high burden of "undiagnosed COPD" and emphysema in LCS participants. Adding spirometry findings to the LDCT enhances identification of individuals with COPD.Clinical trial registered with www.clinicaltrials.gov (NCT02558101).

C-reactive protein and coronary artery calcium in asymptomatic women with systemic lupus erythematosus or rheumatoid arthritis.

Patients with systemic lupus erythematosus (SLE) and those with rheumatoid arthritis (RA) have increased risk for atherosclerotic cardiovascular disease. The aims of this study were to compare the presence of coronary artery calcium (CAC) in age- and race-matched women with SLE, those with RA, and healthy controls without diabetes mellitus or history of myocardial infarction, angina pectoris, or stroke and to investigate its relation with traditional risk factors, inflammation, and endothelial activation. Study subjects completed cardiovascular risk factor assessment and electron-beam computed tomography that measured CAC. The 2 patient groups had similar prevalence and extent of CAC as well as significantly increased odds of having any CAC (odds ratio 1.87, 95% confidence interval 1.09 to 3.21) and more extensive CAC (odds ratio 4.04, 95% confidence interval 1.42 to 11.56 for CAC score >100) compared with healthy controls. After controlling for differences in cardiovascular risk factors, including insulin resistance and hypertension, the results remained statistically significant. After adjustment for differences in levels of C-reactive protein and/or soluble intercellular adhesion molecule-1, however, women with chronic inflammatory diseases no longer had significantly increased odds of having any CAC or more extensive CAC compared with controls. In conclusion, asymptomatic and nondiabetic women with chronic inflammatory diseases had significantly increased odds of having CAC and more extensive CAC compared with age- and race-matched healthy controls. The increased odds for CAC may in part result from higher levels of inflammation and endothelial activation in these patients.

Contact lenses and corrective flying spectacles in military aircrew--implications for flight safety.

BACKGROUND: Refractive devices used by aviators need to suit the aerospace environment or their failure can have serious implications. A relatively minor visual disability can result in loss of life and aircraft. We surveyed commonly occurring problems with the different types of refractive correction worn by Royal Air Force (RAF) aircrew over the previous 12 mo. We also asked if they had experienced any flight safety incidents (FSI) relating to their refractive correction. METHODS: A retrospective anonymous questionnaire survey was given to 700 active aircrew occupationally graded as requiring corrective flying spectacles (CFS) or contact lenses (CL) for flying. RESULTS: 63% (443) of the questionnaires were completed. CL were worn by 53% of aircrew; 71% of them used daily disposable CL. CFS were worn by the remaining 47% of aircrew, 14% of whom used multifocal lenses. Of CFS wearers, 83% reported problems including misting, moving, discomfort, and conflict with helmet-mounted devices (HMD). CL-related ocular symptoms were reported in 67% of wearers including cloudy vision, dry eye, photophobia, red eyes, excessive mucus formation, CL movement, itching, and grittiness. No CL-related FSI were reported over the previous 12 mo compared with 5% CFS-related FSI (p < 0.001). The graded performance of CL for vision, comfort, handling, convenience, and overall satisfaction was significantly higher than for CFS. CONCLUSION: CFS are associated with problems in terms of comfort and safety. CL are well tolerated by aircrew, and deliver improved visual performance.

Relation of carotid intima-media thickness and plaque with incident cardiovascular events in women with systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) are at increased risk for cardiovascular (CV) disease. The aim of this study was to investigate the association between subclinical CV disease as measured by carotid intima-media thickness (IMT) and plaque using B-mode carotid ultrasound and incident CV events in a combined cohort of female patients with SLE. This was a prospective, 2-center observational study of 392 adult women with SLE and no previous CV events with a mean 8 years of follow-up. Incident CV events confirmed by clinicians were defined as angina, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, fatal cardiac arrest, transient ischemic attack, and cerebrovascular accident. Incident hard CV events excluded angina and transient ischemic attack. The mean age was 43.5 years, and most patients were Caucasian (77.3%). During follow-up, 38 patients had incident CV events, and 17 had incident hard CV events. Patients with incident hard CV events had higher mean carotid IMT (0.80 vs 0.64 mm, p <0.01) and presence of carotid plaque (76.5% vs 30.4%, p <0.01) compared with those without incident hard CV events. Baseline carotid IMT and presence of plaque were predictive of any incident hard CV event (hazard ratio 1.35, 95% confidence interval 1.12 to 1.64, and hazard ratio 4.26, 95% confidence interval 1.23 to 14.83, respectively), independent of traditional CV risk factors and medication use. In conclusion, in women with SLE without previous CV events, carotid IMT and plaque are predictive of future CV events. This suggests that carotid ultrasound may provide an additional tool for CV risk stratification in patients with SLE.

Genetic variation in the paraoxonase-3 (PON3) gene is associated with serum PON1 activity.

Low serum paraoxonase1 (PON1) activity determined by paraoxon substrate is associated with coronary heart disease (CHD), diabetes and systemic lupus erythematosus (SLE) risk. In this investigation, we have examined the role of genetic variation in the PON3 gene in relation to PON1 activity and SLE risk in a biracial sample comprising 377 SLE patients and 482 controls from US whites and blacks. We genotyped six PON3 tagging single nucleotide polymorphisms (tagSNPs) and examined their associations with PON1 activity, SLE risk, antiphopholipid autoantibodies (APA), lupus nephritis, carotid vascular disease, and inflammation. With the exception of PON1 activity, no other significant associations were found with PON3 SNPs. Multiple regression analysis including all six PON3 tagSNPs and PON1/Q192R and L55M SNPs revealed significant association of PON1 activity with 4 SNPs: PON3/A10340C (p < 0.0001), PON3/A2115T (p = 0.002), PON1/L55M (p < 0.0001) and PON1/Q192R (p < 0.0001). These four SNPs explained 2%, 1%, 8% and 19% of the variation in PON1 activity, respectively. In summary, our new data indicate that genetic variation in the PON3 gene influences serum PON1 activity independently of the known effect of PON1 genetic variation. To our knowledge, this is the first study reporting the association of the PON3 gene variants with PON1 activity.

Genetic variation in C-reactive protein (CRP) gene may be associated with risk of systemic lupus erythematosus and CRP concentrations.

OBJECTIVE: The gene coding for C-reactive protein (CRP) is located on chromosome 1q23.2, which falls within a linkage region thought to harbor a systemic lupus erythematosus (SLE) susceptibility gene. Recently, 2 single-nucleotide polymorphisms (SNP) in the CRP gene (+838, +2043) have been shown to be associated with CRP concentrations and/or SLE risk in a British family-based cohort. Our study was done to confirm the reported association in an independent population-based case-control cohort, and also to investigate the influence of 3 additional CRP tagSNP (-861, -390, +90) on SLE risk and serum CRP concentrations. METHODS: DNA from 337 Caucasian women who met the American College of Rheumatology criteria for definite (n = 324) or probable (n = 13) SLE and 448 Caucasian healthy female controls was genotyped for 5 CRP tagSNP (-861, -390, +90, +838, +2043). Genotyping was performed using restriction fragment length polymorphism-polymerase chain reaction, pyrosequencing, or TaqMan assays. Serum CRP levels were measured using ELISA. Association studies were performed using the chi-squared distribution, Z-test, Fisher's exact test, and analysis of variance. Haplotype analysis was performed using EH software and the haplo.stats package in R 2.1.2. RESULTS: While none of the SNP were found to be associated with SLE risk individually, there was an association with the 5 SNP haplotypes (p < 0.001). Three SNP (-861, -390, +90) were found to significantly influence serum CRP level in SLE cases, both independently and as haplotypes. CONCLUSION: Our data suggest that unique haplotype combinations in the CRP gene may modify the risk of developing SLE and influence circulating CRP levels.

Guidelines for the use of imaging in the management of myeloma.

In 2001, reference to the use of imaging in the British Committee for Standards in Haematology guidelines for the diagnosis and management of myeloma was confined to the standard use of plain X-rays in the diagnostic skeletal survey and emergency use of computed tomography (CT) and magnetic resonance (MR) imaging in the setting of cord compression. Since then, there has been a steady rise in interest in the use of various imaging techniques in the management of myeloma. The purpose of imaging in the management of myeloma includes the assessment of the extent and severity of the disease at presentation, the identification and characterisation of complications, and the assessment of response to therapy. Plain radiography, CT, and MR imaging are generally established examination techniques in myeloma whilst positron emission tomography (PET) and (99)Technetium sestamibi (MIBI) imaging are promising newer scanning techniques under current evaluation. These stand-alone imaging guidelines discuss recommendations for the use of each modality of imaging at diagnosis and in the follow up of patients with myeloma.

Surveillance for the detection of early lung cancer in patients with bronchial dysplasia.

BACKGROUND: The natural history of bronchial preinvasive lesions and the risk of developing lung cancer in patients with these lesions are not clear. Previous studies have treated severe dysplasia and carcinoma in situ (CIS) on the assumption that most will progress to invasive carcinoma. AIMS: To define the natural history of preinvasive lesions and assess lung cancer risk in patients with these lesions. HYPOTHESIS: Most preinvasive lesions will not progress to invasive carcinoma but patients with these lesions will be at high risk. METHODS: A cohort of patients with preinvasive lesions underwent fluorescence bronchoscopy every 4-12 months and computed tomography of the chest annually. The main end point was the development of invasive carcinoma. RESULTS: 22 patients with 53 lesions were followed up for 12-85 months. 11 cancers were diagnosed in 9 patients. Of the 36 high-grade lesions (severe dysplasia and CIS), 6 progressed to invasive cancers. 5 separate cancers developed at remote sites in patients with high-grade lesions. All cancers were N0M0 and curative treatment was given to 8 of the 9 patients. The cumulative risk of developing lung cancer in a patient with a high-grade lesion was 33% and 54% at 1 and 2 years, respectively. Of the 17 low-grade lesions, none progressed to invasive carcinoma. CONCLUSIONS: Although the risk of malignant progression of individual preinvasive lesions is relatively small, patients with high-grade lesions are at high risk of lung cancer. Surveillance facilitated early detection and treatment with curative intent in most patients.

Association study of Toll-like receptor 5 (TLR5) and Toll-like receptor 9 (TLR9) polymorphisms in systemic lupus erythematosus.

OBJECTIVE: Toll-like receptors (TLR) play an important role in both adaptive and innate immunity. Variations in TLR genes have been shown to be associated with various infectious and inflammatory diseases. We investigated the association of TLR5 (Arg392Stop, rs5744168) and TLR9 (-1237T-->C, rs5743836) single nucleotide polymorphisms (SNP) with systemic lupus erythematosus (SLE) in Caucasian American subjects. METHODS: We performed a case-control association study and genotyped 409 Caucasian women with SLE and 509 Caucasian healthy female controls using TaqMan allelic discrimination (rs5744168) or polymerase chain reaction-restriction fragment length polymorphism analysis (rs5743836). RESULTS: None of the 2 TLR SNP showed a statistically significant association with SLE risk in our cohort. CONCLUSION: Our results do not indicate a major influence of these putative functional TLR SNP on the susceptibility to (or protection from) SLE.

Relationship of serum paraoxonase 1 activity and paraoxonase 1 genotype to risk of systemic lupus erythematosus.

OBJECTIVE: Low serum paraoxonase 1 (PON1) activity determined with paraoxon as substrate has been found to be associated with coronary artery disease. This study was undertaken to examine the relationship of PON1 activity and genotype to risk of systemic lupus erythematosus (SLE). METHODS: The impact of 7 PON1 single-nucleotide polymorphisms (SNPs) was analyzed in relation to PON1 activity, SLE risk, lupus nephritis, antiphospholipid antibody (aPL) positivity, and carotid vascular disease in 380 SLE patients (334 white, 46 black) and 497 controls (455 white, 42 black). RESULTS: Compared with findings in controls, PON1 activity with paraoxon substrate was reduced both in white lupus patients (mean +/- SEM 618.9 +/- 24.0 units/liter versus 719.6 +/- 24.6 units/liter; P = 0.007) and in black lupus patients (991.1 +/- 82.7 units/liter versus 1,164.3 +/- 101.4 units/liter; P = 0.2711). Low PON1 activity in SLE was not associated with the occurrence of aPL, carotid vascular disease, or the use of immunosuppressive drugs. In multiple regression analyses, the Q192R SNP was found to be independently associated with PON1 activity and explained 28% and 41% of the variation in PON1 activity in white patients and black patients, respectively. Stratification of the lupus sample by presence (n = 81) or absence (n = 247) of renal disease revealed significant associations with 3 promoter SNPs, with odds ratios of 3.82 (95% confidence interval [95% CI] 1.49-9.82, P = 0.005), 3.41 (95% CI 1.35-8.61, P = 0.009), and 2.17 (95% CI 1.01-4.68, P = 0.049). CONCLUSION: To our knowledge, this is the first study to assess the role of PON1 activity in SLE risk in a large biracial sample from the US. Our data indicate that low PON1 activity determined with paraoxon substrate is independently associated with SLE and that certain PON1 SNPs are associated with lupus nephritis.

Platelet C4d is highly specific for systemic lupus erythematosus.

OBJECTIVE: Complement-activation product C4d is deposited on normal erythrocytes, while abnormal levels have been observed on the surface of erythrocytes of patients with systemic lupus erythematosus (SLE). This study examines whether C4d also deposits on human platelet surfaces, and whether platelet-bound C4d may provide a biomarker for SLE. METHODS: We conducted a cross-sectional study of 105 patients with SLE, 115 patients with other diseases, and 100 healthy controls. Levels of C4d on the surface of platelets were examined by flow cytometry and scanning confocal microscopy. Statistical analyses were performed to determine the clinical variables associated with platelet C4d. RESULTS: Abnormal levels of platelet C4d were found to be highly specific for SLE. Platelet C4d was detected in 18% of patients with SLE, being 100% specific for a diagnosis of SLE compared with healthy controls and 98% specific for SLE compared with patients with other diseases (P < 0.0001). In addition, platelet C4d was significantly associated with positivity for lupus anticoagulant (P < 0.0001) and anticardiolipin antibodies of the IgG (P = 0.035) or the IgM (P = 0.016) isotype. Platelet C4d was also significantly associated with SLE disease activity according to the SLE Disease Activity Index (P = 0.039), low serum C4 (P = 0.046), an elevated erythrocyte sedimentation rate (P = 0.006), and abnormal levels of C4d on erythrocytes (P < 0.0001). CONCLUSION: This observation suggests that platelet-bound C4d may be a useful biomarker for SLE and may be a clue to the pathogenic mechanisms responsible for the myriad thrombotic and vascular complications of lupus associated with antiphospholipid antibodies.