Session Title: Rheumamtoid Arthritis - Human Etiology and Pathogenesis
Session Type: Abstract Submissions (ACR)
Rheumatoid arthritis (RA) is a heterogeneous disease with female predominance. Sex hormones have been suggested to play a part in the pathogenesis. We have previously identified hormonal predictors (breast-feeding and early menopause) that influence predominantly rheumatoid factor (RF) negative RA in women. The increasing incidence with age of RA in men parallels age related drops in androgens. Lower levels of testosterone have been demonstrated in men with RA compared with controls, but it has not been known whether this pattern precedes the disease or if it is a consequence of inflammation.
A nested case-control study was performed, using information and blood samples from a community based health survey performed between 1974 and 1992, which included 22 444 males. Blood samples were drawn between 8.00 and 10.00 a.m. after an overnight fast and stored at -20 degrees Celsius. Height and weight was measured and self-reported smoking habits were noted. Incident cases of RA were identified by linking the cohort to local and national RA-registers, and verified by a structured review of their medical records. Two controls for each validated case, matched for age, sex and year of screening, were selected from the health survey. Testosterone (T), sex hormone-binding globulin (SHBG), follicle stimulating hormone (FSH) and luteinizing hormones (LH) were analysed with standard immunoassays. Free testosterone was calculated from T and SHBG levels.
Serum was available from 105 cases (mean age at diagnosis 59 years; median time from screening to RA diagnosis 12.7 years (range 1-28); 73 % RF positive at diagnosis or later) and 174 matched controls. Mean age at screening was 46 years. Mean free and total T levels were lower in pre-RA cases compared to controls, in particular in the subset who subsequently developed RF negative RA. T correlated negatively with body mass index (BMI), and smokers had significantly higher levels of both free and total T, as well as FSH and LH. In conditional logistic regression models, adjusted for smoking and BMI, lower levels of T were associated with RF negative RA (Odds Ratio (OR): 0.31 per standard deviation (SD), 95% Confidence Interval (CI): 0.12-0.85), with a similar tendency for RA overall (OR: 0. 77 per SD; 95% CI: 0.52-1.12). The same patterns were seen for free T. The differences were more pronounced in individuals screened > 12.7 years before diagnosis. Compared to matched controls and adjusted for smoking, significantly higher levels of FSH were seen in pre-RF-negative RA cases (p=0.02), whereas FSH levels were lower in pre-RF-positive RA cases (p=0.02),
Lower levels of total and free T were predictive of RF negative RA in men, adjusted for smoking and BMI. FSH levels were higher before onset of RF-negative RA, indicating a hypothalamus-pituitary response to testicular dysfunction. By contrast, lower FSH levels were found before onset of RF-positive RA, implicating an impaired hypothalamus-pituitary function as a possible factor in the pathogenesis of RF positive RA. Our results suggest that distinct hormonal patterns are associated with different phenotypes of RA, and that changes in androgens precede the onset of RA in men.
L. T. H. Jacobsson,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/negative-association-between-testosterone-levels-and-risk-of-future-rheumatoid-factor-negative-rheumatoid-arthritis-in-men/