8 April, 2013:

Understanding the impact of menopause and age-related androgen decline on the onset and course of autoimmune diseases, as well as the potential for hormonal interventions, is critically important [1]. In women, the course of systemic lupus erythematosis (SLE) and rheumatoid arthritis (RA) with onset after the age of menopause differs from that with onset before menopause. Early age at menopause is associated with increased disease risk and, after menopause, disease course changes in SLE and RA. This article summarizes what is known about the relationship between reproductive aging and autoimmune diseases in men and women, and highlights areas for further investigation.

Comment

This comprehensive review addresses men and women, and refers to the interactions of sex hormones with disease course and outcome [1]. I will focus only on the relevant data in menopausal women (section 3 of the article). Declining levels of estrogen and DHEA sulfate may be associated with increased production of proinflammatory cytokines (IL1, IL6, TNF-α), and increased physiologic response to these cytokines, decreased secretion of anti-inflammatory cytokines (INF-γ), decreased lymphocyte levels (CD4+ T cells, B cells), and decreased cytotoxic activity of natural killer cells. The author brings data on three diseases which are known to be preponderant in women – SLE, RA, and multiple sclerosis.

In the Nurses' Health Study, an early age at menopause, especially surgical, was associated with an increased risk of developing SLE [2]. Several longitudinal studies, such as LUMINA [3], have noted decreased frequency of flares after menopause, modestly decreased SLE Disease Activity Index, but greater damage accrual in affected organs from individual flares in the postmenopausal period. An increased risk of developing SLE has been associated with postmenopausal hormone use for 2 or more years in the Nurses' Health Study [2], and several publications have pointed at a more severe course in hormone users, mainly in those who took combined estrogen–progestin therapy [4]. However, the LUMINA study did not demonstrate an increased risk for vascular arterial or venous thrombotic events in hormone users, but the cohort was relatively small [5]. Thromboembolism is important in this context since a fraction of SLE patients have anti-phospholipid antibodies and a tendency for blood clots. Another relatively small study from Mexico, where women were randomized to hormone therapy or placebo, concluded that, over 24 months of follow-up, disease activity remained mild and stable and no clinically significant difference was seen between treatment groups [6]. Three patients in the active therapy group developed thromboses, one venous and two arterial, but one of the latter had a history of thrombosis. One patient in the placebo group developed arterial thrombosis; thus nothing much could be deducted from these results.

The data in regard to RA are probably more complex. A large database, presented by Pikwer and colleagues, showed that a later age at menopause was associated with a decreased risk of RA (relative risk 0.64; menopause age > 51 years vs. < 45 years) [7]. This was true both for sero-negative, and perhaps sero-positive RA. But, on the other hand, early menopause was associated with a milder form of RA [8]. These findings suggest that exposure to estrogen may be protective against the onset of disease, yet earlier age at menopause may be associated with a greater proportion of patients presenting with a milder disease course. While an older randomized, placebo-controlled study suggested a potential beneficial effect of hormone therapy (measured as disease activity and pain score) in compliant women [9], the Women's Health Initiative demonstrated a non-significant reduction in the risk of developing RA (hazard ratio 0.74), a non-significant improvement in joint pain scores (odds ratio 4.1) without any change in swelling [10]. The bone-protecting effect of hormones in RA is certainly another beneficial aspect that should be considered.

Lupus erythematosis and rheumatoid arthritis are typically much more prevalent in women than in men. Understanding the complex interplay between reproductive senescence and the course of autoimmune diseases is of great importance. The effects of hormone therapy on the onset and course of lupus erythematosis or rheumatoid arthritis, if any, seem modest.

Amos Pines
Department of Medicine 'T', Ichilov Hospital, Tel-Aviv, Israel

References

1. Bove R. Autoimmune diseases and reproductive aging. Clin Immunol 2013 Feb 28. Epub ahead of print 
http://www.ncbi.nlm.nih.gov/pubmed/23522436 

2. Costenbader KH, Feskanich D, Stampfer MJ, Karlson EW. Reproductive and menopausal factors and risk of systemic lupus erythematosus in women. Arthritis Rheum 2007;56:1251-62. 
http://www.ncbi.nlm.nih.gov/pubmed/17393454 
3. Fernandez M, Calvo-Alen J, Alarcon GS, et al. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA): XXI. Disease activity, damage accrual, and vascular events in pre- and postmenopausal women. Arthritis Rheum 2005;52:1655–64.
http://www.ncbi.nlm.nih.gov/pubmed/15934092 
4. Buyon JP, Petri MA, Kim MY, et al. The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Ann Intern Med 2005;142:953–62.
http://www.ncbi.nlm.nih.gov/pubmed/15968009 
5. Fernández M, Calvo-Alén J, Bertoli AM, et al. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA L II): relationship between vascular events and the use of hormone replacement therapy in postmenopausal women. J Clin Rheumatol 2007;13:261-5.
http://www.ncbi.nlm.nih.gov/pubmed/17921793 
6. Sánchez-Guerrero J, González-Pérez M, Durand-Carbajal M, et al. Menopause hormonal therapy in women with systemic lupus erythematosus. Arthritis Rheum 2007;56:3070-9.
http://www.ncbi.nlm.nih.gov/pubmed/17763408 
7. Pikwer M, Bergström U, Nilsson JÅ, Jacobsson L, Turesson C. Early menopause is an independent predictor of rheumatoid arthritis. Ann Rheum Dis 2012;71:378-81.
http://www.ncbi.nlm.nih.gov/pubmed/21972241 
8. Pikwer M, Nilsson JA, Bergström U, Jacobsson LT, Turesson C. Early menopause and severity of rheumatoid arthritis in women older than 45 years. Arthritis Res Ther 2012;14:R190.
http://www.ncbi.nlm.nih.gov/pubmed/22901865 
9. Hall GM, Daniels M, Huskisson EC, Spector TD. A randomised controlled trial of the effect of hormone replacement therapy on disease activity in postmenopausal rheumatoid arthritis. Ann Rheum Dis 1994;53:112-16.
http://www.ncbi.nlm.nih.gov/pubmed/8129455 
10. Walitt B, Pettinger M, Weinstein A, et al. Effects of postmenopausal hormone therapy on rheumatoid arthritis: the Women's Health Initiative randomized controlled trials. Arthritis Rheum 2008;59:302-10.
http://www.ncbi.nlm.nih.gov/pubmed/18311749