Introduction:
The recognition of sex and gender as distinct concepts is now widely acknowledged. Sex primarily refers to the biological characteristics determined by chromosomes, reproductive organs, and hormones. At the same time, the term 'gender' pertains to the non-physiological aspects of sex associated with social and cultural norms for males and females. Both sex and gender play a role in influencing the development and manifestation of rheumatic and autoimmune diseases. Genetic and hormonal factors contribute to different immunological responses between males and females to both foreign and self-antigens. Additionally, gender, being linked to behaviors and actions, can affect exposure to microorganisms and access to healthcare services. Recognizing these variations based on sex and gender has significantly improved one's understanding of the differing prevalence and incidence rates between males and females, not only in rheumatic and autoimmune diseases but also in cancers, infectious diseases, and responses to vaccines.
What Is the Incidence of Rheumatic Diseases Among Men and Women?
Prevalence and Incidence: Rheumatic diseases often exhibit gender-based variations in their prevalence and incidence rates. For example, conditions like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are more commonly diagnosed in women, with a female-to-male ratio of approximately 3:1 for RA and up to 9:1 for SLE. On the other hand, ankylosing spondylitis (AS) is more prevalent in men, resulting in a gender ratio of around 3:1 in favor of males. These differences suggest that sex-specific factors, such as hormonal and genetic influences, may contribute to disease susceptibility and development.
What Are the Drug-Related Factors in Which Sex Hormones and Gender Differences Matter?
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Safety of Drugs: It is well-established that sex and gender can have an impact on the safety and effectiveness of drugs in adults due to differences in pharmacokinetics and pharmacodynamics between women and men. Females often experience higher blood drug concentrations and longer drug clearance times compared to males, which can result in a higher occurrence of adverse drug reactions that are more biased toward females.
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Monoclonal Antibodies: In a comprehensive analysis, the focus was on monoclonal antibodies (mAbs), exploring their clinical pharmacokinetic and pharmacodynamic aspects as approved for RA treatment. Notably, the research highlighted that the volume of distribution and clearance of mAbs tend to rise with body size, resulting in higher values for men compared to women. For example, Adalimumab and Rituximab clearance was found to be approximately 40 % higher in men than in women.
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Anti-drug Autoantibodies: The presence of anti-drug antibodies (ADAs) is a significant concern when it comes to the use of monoclonal antibodies (mAbs) for therapeutic purposes. mAbs can sometimes trigger an immune response in the form of ADAs, which may lead to reduced effectiveness of the treatment. However, fully human antibodies like Adalimumab can also be affected. ADAs can contribute to various adverse reactions, including injection site and infusion reactions, thromboembolic events, and serum sickness, which raises safety concerns. A study found that female rheumatoid arthritis (RA) patients treated with Infliximab were more likely to develop ADAs compared to men. Women had a five-fold higher likelihood of having undetectable serum Infliximab levels.
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Compliance With Treatment: When it comes to biological therapies, research suggests that men tend to follow their treatment plan more closely than women. The main reason for stopping therapy is experiencing side effects. A study that looked at data from many countries found that women were more likely to stop biologic therapies for rheumatoid arthritis (RA) compared to men. Interestingly, for RA patients on Janus kinase inhibitors (JAKis), the pain-relieving effects may be more pronounced in men, but overall, treatment response and reaching the therapeutic goal seem to be similar for both men and women.
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Vaccination: People with chronic inflammatory rheumatic diseases, like rheumatoid arthritis (RA), are more prone to infections. To protect against infectious diseases, vaccines are essential preventive measures for these patients. It is known that hormonal and genetic differences between men and women may affect how vaccines work and their safety. Generally, women tend to produce higher levels of antibodies in response to vaccines, but they may also experience more adverse reactions compared to men. In females, local reactions like redness and inflammation at the injection site are more common. Moreover, women tend to report more systemic reactions, such as joint or muscle pain, headache, back and abdominal pain, fever, chills, and hypersensitivity reactions, after vaccination compared to men.
What Impact Do Hormones Have On Rheumatic Diseases?
Hormones are powerful chemical messengers that regulate various physiological processes in the body, including immune responses and inflammation. As such, they can play a crucial role in the development, progression, and severity of rheumatic conditions.
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Estrogen: Research has shown that estrogen (primary female sex hormone) can modulate the immune system, affecting the production and activity of immune cells and inflammatory mediators. In certain autoimmune rheumatic diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), estrogen has been associated with increased disease prevalence and more severe symptoms. Estrogen may promote the production of pro-inflammatory cytokines and autoantibodies, contributing to the chronic inflammation and tissue damage seen in these conditions.
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Progesterone: Progesterone is another female sex hormone that acts in coordination with estrogen during the menstrual cycle and pregnancy. In certain cases, fluctuations in progesterone levels during the menstrual cycle or pregnancy have been associated with changes in disease activity in conditions like RA and SLE.
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Testosterone: Testosterone is the primary male sex hormone, and while it is present in lower levels in females, it plays a crucial role in male physiology. Testosterone has been found to have immunosuppressive properties, dampening immune responses and reducing inflammation. As a result, some autoimmune rheumatic diseases, like RA and SLE, tend to be less prevalent and milder in males compared to females.
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Menopause: Menopause is a significant hormonal milestone in a woman's life when there is a decline in estrogen and progesterone levels due to the cessation of reproductive function. This hormonal shift can impact the course of certain rheumatic diseases that are influenced by estrogen. Women with RA may experience changes in disease activity and symptoms after menopause due to reduced estrogen levels.
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Pregnancy: Pregnancy is a unique phase characterized by significant hormonal changes. Some women with rheumatic diseases, such as rheumatoid arthritis and systemic lupus erythematosus, may experience fluctuations in disease activity during pregnancy. In general, there tends to be a decrease in disease activity during pregnancy, possibly due to the immunosuppressive effects of certain hormones, particularly progesterone.
Conclusion:
Genetics, the environment, and hormonal influences all play crucial roles in the complex and multifactorial etiologies of rheumatic diseases. Hormonal differences between males and females have been identified as a critical factor in shaping the occurrence and presentation of rheumatic diseases. The occurrence and seriousness of these conditions are greatly affected by how hormones and the immune system interact. This leads to differences between men and women in both their prevalence and presentation. It is essential to study how hormones and the immune system interact differently in those with rheumatic diseases. This knowledge can help create personalized treatments and better outcomes for all patients.
