Why Autoimmune Disease is a Women’s Health Issue

The Disproportionate Burden of Autoimmune Disease in Women

Autoimmune disease is a women’s health issue! Autoimmune and autoinflammatory diseases (AIIDs) afflict more than 35 million women in the United States alone¹. According to the National Institutes of Health (NIH), 75-80% of autoimmune patients are female. These disparities are most evident in lupus, multiple sclerosis (MS), Sjogren’s syndrome, rheumatoid arthritis (RA), and thyroid diseases. Understanding why women are more susceptible to these conditions and the challenges they face in the healthcare system is crucial to improving women’s health. This invisible epidemic within an invisible epidemic demands we address AIIDs as a significant women’s health issue.

Biological sex differences, rooted in the presence of a second X chromosome in females, no doubt play a foundational role. Additionally, female-unique downstream factors such as hormones and pregnancy have direct impacts on the immune system. 

Then there are the social factors that make autoimmune disease a women’s health issue. For many reasons, clinicians tend to ignore, gaslight, dismiss or misdiagnose women and girls with autoimmune diseases. To address this, we must first recognize AIIDs as a large, growing, but often neglected aspect of women’s health. The goal should be to speed diagnosis and optimize care to improve overall health outcomes.

Long Frustrating Autoimmune Disease Journeys for Women

Long times to diagnosis or misdiagnosis are a significant problem for women with AIIDs. Several factors contribute to this. AIIDs often present with vague, subjective symptoms, like fatigue and sleep disturbances, which are difficult to use to reach specific diagnoses. Furthermore, primary care providers (PCPs) and even many specialists are often inadequately educated on AIIDs, and do not immediately consider them in differentials. Siloed specialists that usually do not communicate with each other also contribute to uncoordinated care and complex patient journeys.

Women are also especially vulnerable to medical gaslighting. This occurs when providers dismiss or trivialize a patient’s symptoms and struggles, often attributing them to psychological causes. This conveniently allows clinicians to refer patients away or to dismiss them entirely, while neglecting their physical disease. Clinicians are particularly likely to dismiss women of color, older women, LGBTQ+ people identifying as women, and women with existing mental health diagnoses. 

Diagnostic algorithms were historically built around adult white males, but we are now learning that children, women, and people of color may present differently. Most medical education does not teach physicians to pay deep attention to individual patients’ symptom clusters. Instead, clinicians learn to measure patients against a set of diagnostic standards, based on coding for reimbursement. It is difficult to categorize patients with vague symptoms until disease progression ticks off AIID hallmarks (e.g., lupus mask, RA morning joint stiffness) or specific biomarkers. To improve awareness & diagnosis, autoimmune patients, particularly women, must amplify their patient voice. Patient advocacy and receptive medical professionals are critical in reducing medical gaslighting, delayed diagnosis, and misdiagnosis.

Why are Women More Vulnerable to Autoimmune Disease?

Internal Factors

There are several obvious biological factors that contribute to the higher prevalence of AIIDs in women. The root cause is the presence of two X chromosomes in biological females (typically males have one, with a normal genotype XY). The genetic legacy of an extra X chromosome, which contains a large amount of genetic material, combined with epigenetic influences, creates unique downstream impacts on the immune system. 

A Stanford Medicine-led study found significant effects of a second X chromosome. Typically women will have one X chromosome inactivated, but this process is sometimes not completed. This extra, inactivated X chromosome leads to overproduction of certain X-linked proteins, many of which are involved in immunity. This may make women more resistant to infection, but conversely, leaves them more vulnerable to AIIDs.

Incomplete X-Chromosome Inactivation

Incomplete X chromosome inactivation may have evolved because of the unique immune demands of mammalian pregnancy. This phenomenon can trigger overproduction of immune-related proteins. For instance, the Stanford Med study found that the protein Xist was directly related to incomplete X chromosome inactivation and the development of lupus². Other studies have found that proteins produced by the X chromosome can invoke autoantibodies that target the body’s own tissues. Additionally, others have implicated the role of X-linked protein TLR-7 in diseases such as lupus, polymyositis, scleroderma, and Sjogren’s syndrome³.

Interestingly, even genes that are not tied to the X chromosome can have sex-biased effects. For instance, the transcription cofactor VGLL3 is upregulated in women. This sex-bias may be the result of epigenetic effects. VGLL3 is known to promote expression of a number of genes associated with autoimmune diseases, particularly manifesting in the skin⁴. Sjogren’s and lupus both have skin manifestations, and disproportionately affect women.

Pregnancy & Hormones

Beyond direct chromosomal effects, the substantial hormonal changes that females undergo during embryonic development, puberty, pregnancy, and menopause influence immune system function. Estrogen and progesterone, in particular, play significant roles in modulating immune responses.⁵ Estrogen directly affects expression of immunity genes and activates B cells that can produce autoantibodies. Progesterone also has key effects as it interacts with T cells. Many studies have connected increased risk of autoimmune disease development and severity with estrogen exposure⁶.

Researchers have proposed specific pregnancy hypotheses for womens’ vulnerability to AIIDs. For example, cells from the fetus can migrate into the mother’s body and vice versa, a phenomenon dubbed microchimerism. This bidirectional cell transfer may lead to immune system confusing between self and other that can contribute to AIIDs.

Additionally, it may make sense from an evolutionary perspective for reproductive immune system changes. Working out the details of how factors such as age at pregnancy, number of children, and lifestyle could eventually mean proposing hormones as a preventative treatment for autoimmune disease⁷.

The Microbiome

Sitting between intrinsic and extrinsic factors is the microbiome, the billions of microbes that live inside the human gut. The human body microbiome, beyond and including the gut, varies greatly between individuals. The gut and oral microbiomes have emerged as a potential effector of autoimmune disease. 

For example, during pregnancy, the gut microbiome undergoes profound changes⁸. Much like these metabolic and physiological changes, the microbiota and the immune system adapt during different stages of pregnancy. In some cases, loss of immune tolerance can be attributed to changes in microbial composition that affect T cell regulation. Particularly, there is strong evidence for a microbiome association in RA, lupus, and Sjögren’s, all with female predominant prevalence⁹.

External Factors

Environmental exposures and nutritional factors may also play a role in the development of AIIDs. Mercury, pesticides, silica, and tobacco have all been implicated in the pathogenesis of autoimmune diseases. Studies in animals have suggested potential mechanisms for how these environmental triggers affect the onset of AIIDs, which may also differ between triggers. These potential mechanisms include epigenetic modifications, systemic inflammation, or commonly, oxidative stress¹⁰.

Thus, exposome, a composite of environmental and lifestyle factors as another possible  contributor to AIID etiology. For instance, lifestyle and diet directly affect the composition of the gut microbiome, potentially affecting immune function. Additionally, some hypotheses suggest that certain environmental triggers may activate dormant, intrinsic genetic predispositions that can lead to the onset of autoimmune conditions. Although not in this illustration, the exposome also includes infections and their potential long-term effects. For instance, the COVID-19 pandemic, which has triggered a secondary pandemic of long COVID, opened many researchers’ eyes to the long-neglected study of post-viral (and post-bacterial) syndromes.

Overall, the cause of the female bias in AIID is multifaceted, involving intrinsic genetic and hormonal factors as well as external environmental influences.

An Action Plan

The disproportionate impact of AIIDs on girls and women clearly shows the need to improve research, diagnosis, and treatment. Goals include promoting female-targeted research, addressing medical education gaps, discouraging gaslighting and increasing awareness of potential genetic and external factors. Such initiatives can help to improve prevention, care and health outcomes for women with AIIDs. In the meantime, as women, we can help ourselves through self-motivated options, such as learning how to navigate the healthcare system and to speak up to physicians as an autoimmune patient.

Given their disproportionate burden and the 35 million affected, we must frame autoimmune and inflammatory diseases as a women’s health issue among better known ones such as reproductive health or pregnancy care. Check out our upcoming Part II to this post, where we discuss how to address AIIDs in the growing women’s health and FemTech market, particularly as digitally-enabled women’s health start-ups continue to garner more attention and investment.

Authors: DrBonnie360, Ellen M. Martin, & Sydney Hahn

We approach these thought leadership posts from our multi-lens perspectives. 

• DrBonnie360: Digital health consultant, clinical dentist, Wall Street analyst, patient & advocate. 
• Ellen M. Martin: Consultant, editor, life science finance/IR/marcomm, autoimmune caretaker.
• Sydney Hahn: Digital health equity research intern, Human Biology & Society and Mathematical Biology Undergraduate Student at UCLA.

Strategic Consulting & Professional Services

We provide professional consulting services to investment, emerging, and established companies. Our work bridges silos and fills gaps to help our clients improve care for AIID patients and reduce costs. Informed by patient and caretaker perspectives, we urge investors & clients to integrate the best of digital, conventional, and functional medicine into AIID care delivery.

• We help our clients leverage digital innovations into V1C for AIID patients.
• Our subject matter expertise includes: oral health, microbiome, autoimmune patient journeys, competitive landscape analysis, strategic positioning & messaging, digital health, and self-hacking.
• We have decades of experience in finance, marketing, and communications for dozens of healthcare and life sciences organizations, emerging and established.
• Our backgrounds include clinical dentistry, osteology, biotech IR/PR, marcomm, content creation, strategic consulting, and autoimmune advocacy.

Contact us to help you map your market landscape and better understand patients’ unmet needs. Also, we can help you clarify and articulate your company’s market position and differentiators. Long before COVID-19, we were facilitating virtual sessions. We also create compelling content: articles, blog posts, collateral, e-books, web copy, and white papers. Our Autoimmune Connect/DrBonnie360 website showcases our own content.

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