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Differences Between the Sexes in Rheumatic Disease

April 27, 2023 | Rheumatic Disease


Generally, rheumatic diseases affect women more than men, although few exceptions exist. The ratio of women to men can be anywhere from 3:1 in rheumatoid arthritis and upwards of 7:1 or more for lupus or Sjögren’s syndrome, depending on which part of the world and study you are looking at. The exception to this female predominance is in a disease called ankylosing spondylitis, where there is male dominance. Not only do sex differences influence the overall prevalence of disease, but also influence onset and severity of autoimmune disease.

Why is there a difference?

This question is more difficult to answer, but an evolutionary explanation has been proposed. The birth mother of the baby or offspring has a biological role to safeguard the developing baby, both in utero and post-partum, from danger. In fact, she will passively transfer her antibodies and immunoglobulins (a process known as passive immunity) to prepare the newborn’s immune system and protect the newborn from infectious agents they will encounter upon birth. Having this responsibility affords the mother a stronger immune system and, consequently, a more active immune system that, on the other hand, can have a greater tendency to activate, sometimes inappropriately, resulting in autoimmune diseases.

What is the role of the environment and how does it interact with the effects of different sexes?

Exposure to certain infections and chemicals such as those found in pesticides, organic solvents have been suggested to trigger autoimmunity. Vitamin D is an environmental factor with immunomodulatory effects and low levels have been implicated in increasing the risk of autoimmune disease. Differences in sex-specific exposure to any of these environmental factors can therefore contribute to the differences observed.

How do sex differences result in a higher prevalence of women with autoimmune disease?

Research has focused on chromosomes, genes, and hormones such as the female hormone estrogen to understand the mechanism of the sex difference observed. Estrogen has complex effects on the immune system and can have a stimulatory or inhibitory role. Furthermore, estrogen levels can change during a woman’s lifetime as she moves from puberty into adulthood, pregnancy, and postmenopausal years. The type of response will depend not only on the woman but also on the disease and what part of the immune system is playing a dominant role in the disease. Pregnancy is an example of this complex interaction whereby the mother’s immune system, in order to avoid rejection of the fetus, will suppress some aspects of her own immune system but also activate another arm of the immune system to produce more antibodies to transfer to the baby for protection. Hence, autoimmune diseases such as lupus can flare, while others, such as rheumatoid arthritis, tend to remain quiescent and physiologically immune suppressed during pregnancy.

Some of the mechanism of how female hormones modulate the immune system has been elucidated while other pathways are incompletely understood, and more work lies ahead in understanding this complex system.

It is clear, however, that differences exist, and hormones, in addition to genes and the environment, have complex and profound effects on the development of autoimmune disease.

Kristen Lee, MD

About the Author

Kristen Lee, MD

Kristen Lee, MD, is the Rheumatology Team lead in Medical Affairs, North America at Pfizer. She trained at NYU School of Medicine and was Assistant Professor there before she joined industry. At NYU, she saw a diverse group of patients with complicated autoimmune diseases and contributed to the education of fellows and faculty. She is also a fellow of the American College of Rheumatology (ACR) and serves on the Communications and Marketing Committee for the ACR. Dr Lee’s interests include the pathogenesis of inflammatory arthritis and novel therapies for the treatment of autoimmune diseases. She is committed to the education of patients, fellows, and the rheumatology community. She lives in New York City.

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