A substantial body of data indicates that genetic and neuroendocrine factors play a role in the expression of autoimmune diseases such as rheumatoid arthritis (RA). A detailed understanding of these factors should provide important insights into the prevention and therapy of these diseases. To evaluate genetic factors, we are involved in 2 collaborative studies. The NARAC study is a nationwide consortium that is collecting affected sib pairs with RA for the purpose of conducting a genome-wide scan for susceptibility loci. Genomic areas of interest identified in the initial scans will be then be analyzed with additional techniques. We are also investigating genetic factors in a cohort of patients being evaluated in the context of the ARB synovitis of recent onset study. In addition, we have been conducting studies addressing the role of hypothalamic-pituitary-adrenal (HPA), -gonadal and sympatho-adrenal axes of patients with recent onset RA and other forms of synovitis. We have also been begun studying the role of the HPA and-gonadal axis hormones on immune function during pregnancy and the postpartum periods. We have previously investigated circadian secretion of ACTH, cortisol and interleukin- (IL)-6 in a small group of RA patients compared to age-, sex-, and race-matched controls. Overall, ACTH and cortisol secretion were similar in patients and controls, except that RA patients exhibited higher early morning ACTH secretion. However, RA patients exhibited substantially higher plasma IL-6 levels. Our data suggest that HPA axis activity is inappropriately normal in RA patients. These patients appear to have a relative insensitivity to IL6-stimulated HPA axis activation. OBJECTIVE: The genetic studies have the goal of defining genetic markers and associated biochemical pathways that influence susceptibility, severity, diagnosis, outcome and responses to therapy. Since deficient HPA function probably has pronounced effects on immune function, we are also evaluating these functions in a subset of our patients. We have focused our efforts on patients with recent onset arthritis that are not taking medications. Additional studies are ongoing in pregnant and postpartum subjects. RESULTS. Over the past year, we collected clinical data and DNA samples from 21 RA sibpairs, as part of our efforts in the NARAC collaborative consortium. We also completed an initial evaluation on the association of HLA alleles and clinical features in our cohort of patients with synovitis of recent onset. A paper was published, and additional analyses are in progress. Our data highlight the complex degree of genetic interaction between alleles at several HLA loci. In particular, the shared epitope and HLA-B27, were noted to show an unexpected degree of association with each other, emphasizing the overlapping features of various forms of synovitis in their earliest stages. We also completed an evaluation of hormones in a group patients in the early synovitis cohort (n=32) and a similar number of sex- and age-matched controls. We noted significant differences compared to controls in basal morning levels of cortisol (higher in patients), DHEAS (lower in females age >45), and free testosterone (lower in males age>45), but not in ACTH, DHEA and total testosterone. In addition, we noted that the positive relationships between ACTH-cortisol, ACTH-DHEA, and cortisol-DHEA, observed in the normal controls, were weakened or abolished in the patients (both total and RA subset). An inverse relationship between inflammatory indices (ESR, CRP) and serum androgens (DHEA, testosterone) was also noted. Moreover, acceleration in the age-associated decline in DHEA was observed in the patients with new synovitis. These results provide further evidence for the view that abnormalities in adrenocortical function are present early in the course of RA and non-RA patients. In particular, adrenopause appears to be accelerated. We and others have previously provided evidence that abnormalities of this type may contribute to immune abnormalities. We have also continued to explore the effects of cortisol and other stress mediators on TNF-alpha, IL-12 and IL-10 production by LPS and heat-killed Staph. aureus-stimulated blood monocytes, particularly in the context of pregnancy and the postpartum periods. TNF-alpha and IL-12 are prototypic proinflammatory cytokines, whereas IL-10 is a major anti-inflammatory cytokine. We have previously demonstrated that both cortisol and catecholamines strongly inhibit, through receptor dependent-mechanisms, the secretion of TNF-alpha and IL-12, but cortisol does not significantly suppress secretion of IL-10, and catecholamines powerfully stimulate IL-10. We have also demonstrated similar inhibitory or stimulatory effects are induced with histamine and adenosine. Our studies on pregnant and postpartum patients are in progress but complete analysis of the data are not yet available. CONCLUSIONS: Our genetic studies are just now beginning to expand, but the initial data suggest that these approaches will provide a powerful strategy to dissect pathogenetic mechanisms. Our hormonal studies, demonstrating contrasting effects of these stress mediators and proinflammatory and anti-inflammatory cytokine production have important implications on our understanding of the role of neural and endocrine factors in the regulation of inflammatory processes. These data have relevance to numerous clinical disorders, such as RA, that are influenced by factors such as age, sex, reproductive status and stressful stimuli.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Intramural Research (Z01)
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Special Emphasis Panel (ARB)
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National Institute of Arthritis and Musculoskeletal and Skin Diseases
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