Citations

ObjectiveTo study left ventricular (LV) geometry in patients with rheumatoid arthritis (RA) and no history of heart failure compared with that in subjects with neither RA nor a history of heart failure, and to determine the impact of RA on LV remodeling.MethodsA cross‐sectional, community‐based study was conducted among adult (age ≥50 years) patients with RA and age‐ and sex‐matched subjects with neither RA nor a history of heart failure. All participants underwent standard 2‐dimensional Doppler echocardiography. LV geometry was classified into the following 4 categories based on relative wall thickness and sex‐specific cutoffs for the LV mass index: concentric remodeling, concentric hypertrophy, eccentric hypertrophy, or normal geometry.ResultsAmong 200 patients with RA and 600 age‐ and sex‐matched subjects without RA, the mean age was 65 years, and 74% of the individuals in both cohorts were female. Compared with subjects without RA, patients with RA were significantly more likely to have abnormal LV geometry (odds ratio [OR] 1.44, 95% confidence interval [95% CI] 1.03–2.00), even after adjusting for cardiovascular risk factors and comorbidities. Among subjects with abnormal LV geometry, the odds of concentric LV remodeling were significantly increased in patients with RA (OR 4.73, 95% CI 2.85–7.83). In linear regression analyses, the LV mass index appeared to be lower in patients with RA who were currently receiving corticosteroids (β ± SE −0.082 ± 0.027, P = 0.002), even after adjusting for cardiovascular risk factors and comorbidities.ConclusionRA was strongly associated with abnormal LV remodeling (particularly concentric LV remodeling) among RA patients without heart failure. This association remained significant after adjustment for cardiovascular risk factors and comorbidities. RA disease–related factors may promote changes in LV geometry. The biologic mechanisms underlying LV remodeling warrant further investigation.

Granulomatosis with polyangiitis (Wegener's) is a rare autoimmune neutrophil-mediated vasculitis that can cause renal disease and mucosal manifestations. Antineutrophil cytoplasmic antibodies (ANCA) are present in many patients, vary in level over time, and induce neutrophil activation through engagement with Fc receptors (FcRs). Given roles for FcRs in ANCA-mediated neutrophil activation and IgA antibodies in mucosal immunity, we hypothesized that FcR genetics and previously unappreciated IgA ANCA affect clinical presentation. We assembled a total of 673 patients and 413 controls from two multicenter cohorts, performed ELISA and immunofluorescence assays to determine IgA and IgG ANCA positivity, and used Illumina, TaqMan, or Pyrosequencing to genotype eight haplotype-tagging SNPs in the IgA FcR ( FCAR ) and to determine NA1/NA2 genotype of FCGR3B, the most prevalent neutrophil IgG FcR. We evaluated neutrophil activation by measuring degranulation marker CD11b with flow cytometry or neutrophil extracellcular trap formation with confocal microscopy. Functional polymorphisms in FCGR3B and FCAR differed between patient groups stratified by renal involvement. IgA ANCA were found in ∼30% of patients and were less common in patients with severe renal disease. Neutrophil stimulation by IgA or IgG ANCA led to degranulation and neutrophil extracellcular trap formation in a FcR allele-specific manner (IgA:FCAR P = 0.008; IgG:FCGR3B P = 0.003). When stimulated with IgA and IgG ANCA together, IgG ANCA induced neutrophil activation was reduced ( P = 0.0001). FcR genotypes, IgA ANCA, and IgG ANCA are potential prognostic and therapeutic targets for understanding the pathogenesis and presentation of granulomatosis with polyangiitis (Wegener's).

Abstract The advent of improved biomarkers promises to enhance the clinical care for patients with rheumatoid arthritis (RA) and other immune-mediated disorders. We have developed an innovative approach to broadly assess the cytokine responsiveness of human PBMCs using a multistimulant panel and multiplexed immunoassays. The objective of this study was to demonstrate this concept by determining whether cytokine profiles could discriminate RA patients according to disease stage (early versus late) or severity. A 10-cytokine profile, consisting of IL-12, CCL4, TNF-α, IL-4, and IL-10 release in response to stimulation with anti-CD3/anti-CD28, CXCL8 and IL-6 in response to CMV and EBV lysate, and IL-17A, GM-CSF, and CCL2 in response to human heat shock protein 60, easily discriminated the early RA group from controls. These data were used to create an immune response score, which performed well in distinguishing the early RA patients from controls and also correlated with several markers of disease severity among the patients with late RA. In contrast, the same 10-cytokine profile assessed in serum was far less effective in discriminating the groups. Thus, our approach lays the foundation for the development of immunologic “signatures” that could be useful in predicting disease course and monitoring the outcomes of therapy among patients with immune-mediated diseases.

Abstract Further analyses from the Women's Health Initiative estrogen trial shows that CEE reduced fracture risk. The fracture reduction at the hip did not differ appreciably among risk strata. These data do not support overall benefit over risk, even in women at highest risk for fracture. Introduction: The Women's Health Initiative provided evidence that conjugated equine estrogen (CEE) can significantly reduce fracture risk in postmenopausal women. Additional analysis of the effects of CEE on BMD and fracture are presented. Materials and Methods: Postmenopausal women 50–79 years of age with hysterectomy were randomized to CEE 0.625 mg daily (n = 5310) or placebo (n = 5429) and followed for an average 7.1 years. Fracture incidence was assessed by semiannual questionnaire and verified by adjudication of radiology reports. BMD was measured in a subset of women (N = 938) at baseline and years 1, 3, and 6. A global index was used to examine whether the balance of risks and benefits differed by baseline fracture risk. Results: CEE reduced the risk of hip (hazard ratio [HR], 0.65; 95% CI, 0.45–0.94), clinical vertebral (HR, 0.64; 95% CI, 0.44–0.93), wrist/lower arm (HR, 0.58; 95% CI, 0.47–0.72), and total fracture (HR, 0.71; 95% CI, 0.64–0.80). This effect did not differ among strata according to age, oophorectomy status, past hormone use, race/ethnicity, fall frequency, physical activity, or fracture history. Total fracture reduction was less in women at the lowest predicted fracture risk in both absolute and relative terms (HR, 0.86; 95% CI, 0.68–1.08). CEE also provided modest but consistent positive effects on BMD. The HRs of the global index for CEE were relatively balanced across tertiles of summary fracture risk (lowest risk: HR, 0.81; 95% CI, 0.62–1.05; mid risk: HR, 1.09; 95% CI, 0.92–1.30; highest risk: HR, 1.04; 95% CI, 0.88–1.23; interaction, p = 0.42). Conclusions: CEE reduces the risk of fracture and increases BMD in hysterectomized postmenopausal women. Even among the women with the highest risk for fractures, when considering the effects of estrogen on other important health outcomes, a summary of the burden of monitored effects does not indicate a significant net benefit.