Tumor necrosis factor (TNF) inhibits the conversion of dehydroepiandrosterone sulfate (DHEAS) to DHEA in synovial cells from rheumatoid arthritis (RA) patients, but not osteoarthritis (OA) patients, according to a new study. The findings appear in the June 2005 issue of Arthritis & Rheumatism.¹

Clinical and laboratory evidence suggests that androgens play a critical role in human rheumatic diseases and in animal models of arthritis. "Because androgens are anti-inflammatory mediators, TNF-induced inhibition of the local androgen supply is supplementary proinflammatory factor," conclude researchers led by Claudia Weidler, PhD, of the University Hospital Regensburg in Germany. As a result, the balance of androgens to estrogens is severely shifted to estrogens, which most likely supports continuous inflammation in RA synovial tissue. "Consequently, anti-TNF strategies may also exert their positive effects by increasing tissue androgens," they note.

The researchers analyzed synovial tissue from knee joint capsules of 37 RA and OA patients who underwent elective joint replacement surgery, and conversion of DHEAS to DHEA was assessed in populations of mixed cells isolated from these tissue samples. Levels of conversion activity were significantly lower in synovial cells isolated from RA patients than in cells from OA patients. Levels of DHEA in synovial fluid were also significantly lower among RA patients.

Immunohistochemical analysis of these synovial tissue samples indicates that the majority of steroid sulfatase, the enzyme responsible for conversion of DHEAS to DHEA, is located in macrophages, and to a lesser extent in fibroblasts. Since patients with RA tend to have more synovial macrophages than OA patients, the authors suggest that the lower levels of DHEA production indicate that the activity of this enzyme is specifically inhibited in RA synovium and suggest that higher levels of TNF may, in fact, have this effect.

Indeed, a negative correlation was observed between DHEA production and markers of inflammation in tissue from RA patients, but not OA patients. Finally, the investigators found that neutralization of TNF using infliximab enhanced the conversion of DHEAS to DHEA in RA synovial cells, but not OA cells.

Findings may lead to more targeted use of anti-TNF agents

"This looks into one of the pathways where inflammation is governed by hormones that are estrogenic or related to sex hormones," Paul Howard, MD, governor of the American College of Physicians-Arizona and clinical rheumatologist in Scottsdale, Arizona, tells CIAOMed. "It gets to the question of why TNF-blockade may work in certain inflammatory conditions, but not in others."

"There has always been a need to understand why women have more autoimmune disease - particularly RA - than men and why pregnancy has a beneficial effect on RA," he says. Such findings may "help us select more targeted therapy toward inflammatory disease," Dr. Howard suggests. "These are costly drugs and we want to make sure that we're giving the right drug to the right person, [and] that if we can get more focused and targeted, therapies will be more cost-effective, safer, and better for the patient."

Reference:

Weidler C, Struharova S, Schmidt M, et al. Tumor necrosis factor inhibits conversion of dehydroepiandrosterone (DHEAS) to DHEA in rheumatoid arthritis synovial cells: a prerequisite for local androgen deficiency. Arthritis Rheum. 2005;52:1721-1729.