An anti-inflammatory role might explain why the majority of patients are men.
Estrogen was found to suppress the development of arthritis in an SKG mouse model. Estrogen may have an anti-inflammatory role, which might explain why the majority of patients with spondyloarthritis are men.
Hyemin Jeong and colleagues in Korea pointed out that patients with low C-reactive protein (CRP) levels and no radiographic evidence of axial spondyloarthritis in essence have less inflammation and by coincidence are 1 to 1 male to female. Patients with spondyloarthritis who have radiographic inflammation and elevated CRP levels are predominantly male, with a 2:1 ratio.
The difference in pathogenesis in spondyloarthritis between men and women has yet to be described. However, it has been reported that estrogen levels may be lower in patients who have active ankylosing spondylitis when compared with those who have inactive disease.
The authors set out to determine how estrogen affects the development and progression of spondyloarthritis and published their findings relating estrogen to inflammatory cytokines in a recent Arthritis Research & Therapy article.
SKG mice-a mouse strain engineered to develop spontaneous autoimmune arthritis-were divided into 3 groups: a sham group with ovaries intact, mice with ovaries removed, and mice with ovaries removed supplemented with estrogen.
Zymosan A solution was used to induce arthritis in the mice. Serum estrogen levels were measured, postmortem joint tissues were examined, and cytokine levels were quantified.
• Onset of arthritis symptoms was similar among the groups until 24 days.
• After 31 days, the clinical scores of arthritis development were significantly lower in the mice treated with estrogen when compared with the sham group and the ovariectomized mice.
• The incidence of joint arthritis and tail changes was lower in the estrogen treatment group than in the sham and ovariectomized groups.
• Mice treated with estrogen had far fewer inflammatory infiltrations on histologic examination than sham and ovariectomized mice.
• Gut inflammation developed in nearly three-fourths of mice in all 3 groups.
• Gene expression of tumor necrosis factor Î±, interleukin 6, interleukin 17A, and interferon Ï were significantly elevated in the sham and ovariectomized mice compared with wild control mice.
• Mice treated with estrogen had significantly reduced levels of tumor necrosis factor Î±, interleukin 6, interleukin 17A, and interferon Ï compared with the other experimental groups.
• Type 2 T helper cell (Th2) transcription was increased in mice supplemented with estrogen when compared with Th1 expression (Th1 mediates autoimmune diseases, such as rheumatoid arthritis).
Implications for physicians
• Estrogen appears to suppress disease activity in spondyloarthritis.
• The role of estrogen in autoimmune arthritis might explain the male predominance.
• Estrogen may directly suppress tumor necrosis factor Î±, opening the door for investigation into hormone therapy for women who have autoimmune disease.
• A switch from Th1 to Th2 transcription with estrogen may explain why rheumatoid arthritis symptoms improve during pregnancy while lupus may flare during pregnancy (Th1 mediated).
• Estrogen therapy may emerge as a treatment for spondyloarthritis after more investigation.
Financial support was provided by a grant from the Lorea Health Industry Development Institute.
Jeong H, Bae EK, Kim H, et al. “Estrogen attenuates the spondyloarthritis manifestations of the SKG arthritis model.” Arthritis Res Ther. 2017;19:198. doi: 10.1186/s13075-017-1407-1409.