Autoimmune disease in women

See also: Autoimmune disease and Sex differences in medicine

Autoimmunity refers to a pathological immune response of the body's immune system against itself. Autoimmune disease is widely recognized to be significantly more common in women than in men, and often presents differently between the sexes.^[1][2][3] The reasons for these disparities are still under investigation, but may in part involve the presence of an additional X chromosome in women^[3] (given that several genes on the X chromosome are associated with immune system development), as well as the higher presence of female sex hormones such as estrogen (which increases immune system response).^[3] The risk, incidence, and character of autoimmune disease in women may also be associated with female-specific physiological changes, such as hormonal shifts during menses, pregnancy, and menopause.^[4]

Common autoimmune symptoms experienced by both sexes include rashes, fevers, fatigue, and joint pain. Symptoms which are specific to women include irregular menses, pelvic pain, or vaginal dryness, depending on the given disease. Some diseases such as Graves' disease, rheumatoid arthritis, and multiple sclerosis^[5][6] may improve during pregnancy, whereas others such as lupus may worsen.^[5][6][7]

Currently it is not possible to cure autoimmune disease, but many treatments are available. Treatment of autoimmune disease can be broadly classified into anti-inflammatory, immunosuppressive, and palliative – i.e., correcting a functional disturbance related to the condition.^[8] Some medications used to treat autoimmune diseases might not be safe to use during pregnancy.^[2][8]

Common diseases

Autoimmune Disease Cases by Sex

Disease	Ratio of female:male cases
Addison's disease	1.5:1[9]
Ankylosing spondylitis	1:3[10] – 1:4[11]
anti-GBM disease (Goodpasture syndrome)	1:2 – 1:9[12]
Antiphospholipid syndrome	3.5:1[13]
Autoimmune hepatitis	3:1[14]
Behçet's disease	1:5 – 2:1[15]
Celiac disease	1.5:1 – 2:1[16]
Crohn's disease	1:1[17][18] (though F>M after age 25)
Dermatomyositis	2:1 – 3:1[19]
Diabetes type 1	1:1.8[20]
Giant cell arteritis	3:1[21] – 4:1[22]
Graves' disease	5:1[23][24]
Hashimoto's thyroiditis	4:1 – 9:1[25]
Multiple sclerosis	2:1 – 3:1[26]
Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD)	1:1[27]
Myasthenia gravis	3:1[28] (below 40 years of age)
Neuromyelitis Optica (NMOSD)	9:1[29]
Pemphigus vulgaris	2:1[30]
Polymyositis	2:1[31]
Primary biliary cholangitis	9:1[32]
Primary sclerosing cholangitis	1:2[33]
Rheumatoid arthritis	2:1[34]
Sjögren syndrome	9:1[35]
Systemic lupus erythematosus	9:1[36]
Systemic sclerosis (scleroderma)	3:1 – 9:1[37]
Takayasu's arteritis	9:1[38]
Ulcerative colitis	1:1[39] (though M>F after age 45)

There are over 100 autoimmune conditions described, of which the majority are more prevalent in women than in men.^[8] Approximately 80% of all patients with autoimmune disease are women.^[8]

Autoimmune diseases which overwhelmingly affect women include those which affect the thyroid gland (Hashimoto's thyroiditis, Graves' disease), rheumatic diseases (systemic lupus erythematosus, rheumatoid arthritis, scleroderma, and Sjögren syndrome), hepatobiliary diseases (primary biliary cholangitis, autoimmune hepatitis),^[40] and neurological diseases (myasthenia gravis, neuromyelitis optica spectrum disorders (NMOSD), and multiple sclerosis). For men who may develop these conditions, epidemiological and symptomological differences may still exist. For example, when multiple sclerosis and rheumatoid arthritis do occur in men, they tend to develop later in life for men (around age 30–40) than for women, when incidence rises after puberty.^[3]

Some autoimmune diseases affect both sexes at roughly equal rates, or have only a slight female predominance.^[40] These conditions include inflammatory bowel disease (ulcerative colitis, Crohn's disease), immune thrombocytopenic purpura (ITP), and MOG antibody disease, among others. Although the lifetime incidence of these diseases may be similar, they may still exist a difference in disease onset, course, complications, and prognosis which vary based on sex. For example, men are more likely to develop Crohn's disease in the upper GI tract compared to women.^[41] Males and females are equally as likely to be affected by Crohn's disease until around age 25, when women become overrepresented as Crohn's disease patients.^[39] Women and men are equally likely to develop ulcerative colitis until age 45, after which this shifts to a significant male predominance.^[39]

Very few autoimmune diseases are thought to be more common in men than in women. Examples of these may include ankylosing spondylitis, primary sclerosing cholangitis, type 1 diabetes, and certain vasculitides including anti-GBM disease (Goodpasture syndrome) and Behçet's disease (though whether this represents an autoimmune disease vs autoinflammatory disease remains unclear.) On closer inspection, some diseases initially thought to be overrepresented in men have trended towards sex neutrality over time. For example, early studies of ankylosing spondylitis reported a ratio of 10:1 male to female patients, but more recent reports have indicated this is closer to 3:1.^[10] This may reflect a true increased incidence in women over time, or may be due to improvements in diagnostic testing.

Additionally, sex ratios of affected patients can vary widely between geographic regions. For instance, Crohn's disease is slightly more common in women in Western countries, whereas it is slightly more common in men in Asian countries.^[41] Behçet's disease is more common in males in regions along the historic Silk Road, but is more common in women in the United States.^[15] This suggests that the risks of developing autoimmune disease are multifactorial, and may vary based on race and environment as well as sex.

Signs and symptoms

Autoimmune diseases can result in systemic or localized symptoms, depending on the given disease.^[8] Typical systemic symptoms include fevers, fatigue, muscle aches, joint pain, and rashes; these can be seen in diseases such as lupus or rheumatoid arthritis. Other autoimmune diseases have localized effects on specific organ or tissue types. For instance, alopecia areata presents with patchy baldness due to autoimmune destruction of hair follicles, whereas multiple sclerosis presents with neurological symptoms due to autoimmune demyelination of the central nervous system.

Both systemic and localized disease can present with symptoms which are exclusive to women. Women with Sjögren syndrome (an autoimmune disease characterized by destruction and inflammation of the salivary and lacrimal glands) are 2–3 times more likely to report vaginal dryness than other postmenopausal women.^[42]

Causes

The causes of autoimmunity are still the subject of extensive research, and include genetic as well as environmental factors. However, the clear overrepresentation of women as persons with autoimmune disease suggests that sex-specific factors are highly instrumental in the development of these conditions. Posited reasons for this disparity include the differential effects of sex hormones (especially estrogen) on immune response, X-chromosome inactivation, changes associated with pregnancy, and evolutionary pressures that affect the sexes differently.^[6] Due to biological development, many of these elements are inextricably linked, and it can be difficult to isolate the individual effects of each factor.

X chromosome inactivation

See also: Lyonization

Many genes involved in the immune response reside on the X chromosome, of which most women have two copies, whereas men typically only have one. During cell division in embryological development, one of the two X chromosomes is inactivated at random, in a process called lyonization. This ensures that the expression of X chromosome genes is randomly suppressed on one of the two copies in females in order to compensate for the extra copy of these genes.^[43] Incomplete suppression of the extra copies of these genes may lead to overexpression of some genes involved in the immune response resulting in a more robust immune response and an increased risk of developing autoimmune diseases.^[43]

Additional support for this hypothesis can be illustrated by the higher rates of autoimmune disease in men with Klinefelter syndrome (47,XXY).^[44] Like women, males with Klinefelter syndrome also have two copies of the X chromosome, which may predispose them to increased risk of autoimmune disease through the same mechanism.^[44] This risk is highest in autoimmune diseases which are female-predominant (e.g., Addison's disease, multiple sclerosis, Sjögren syndrome).^[44] With the exception of Type 1 diabetes, which affects both sexes at roughly equal rates, Klinefelter syndrome was not correlated with increased risk of autoimmune diseases which occur in males with greater or equal frequency^[44] (e.g., ankylosing spondylitis, psoriasis.)

Despite having only one copy of the X chromosome, women with Turner syndrome (45,XO) are still twice as likely as the general female population to develop autoimmune diseases.^[45] Interestingly, the autoimmune diseases for which Turner syndrome patients are at greater risk include inflammatory bowel disease, type 1 diabetes, alopecia areata, and several other autoimmune disorders which tend to affect the sexes at roughly equal rates. This suggests that the development of autoimmune disease is not solely mediated by differential expression of genes on the X chromosome.

Sex hormones

Sex hormones are instrumental in nearly every aspect of human biology, including the development and response of the adaptive immune system. Sex hormones such as estrogen, progesterone, and testosterone are all present in healthy men and women, albeit at different levels. Estrogen and progesterone are considered primary female sex hormones, while testosterone is the primary male sex hormone. Broadly speaking, estrogen is understood to be immune-activating, while testosterone is considered to be immune-suppressing. The ideal immune system response must be alert enough to recognize and destroy foreign antigens, while also being selective enough to avoid attacking the self. There exists a necessary trade-off between immune system hyperactivity (autoimmunity) versus hypoactivity (immune deficiency). Since men and women have different levels of these sex hormones, they necessarily incur unequal risk for developing these conditions. Very broadly speaking, men are more predisposed to infectious disease, but are less likely to develop autoimmune disease. Women conversely are at higher risk for developing autoimmune disease, but are more protected from infectious disease than men. Women have a greater number of circulating antibodies than do men,^[46] which has implications for their development of autoimmune disease, as well as their increased resistance to infectious disease.

Estrogen

Estrogen has significant effects on the response of the adaptive immune system.^[47] Higher levels of estrogen are correlated with higher levels of circulating antibodies, which are responsible for mounting an immune response.^[46] In addition to short-term changes, the immune system may also be influenced by longer-term changes, such as total lifetime exposure. The course of disease may also be related to hormonal fluctuations, especially those of puberty, pregnancy, and menopause.

Testosterone

The immunocompetence handicap hypothesis proposes that testosterone may have utility as a secondary sexual characteristic which signals fitness to prospective mates.^[48][49] As males have higher levels of testosterone, which suppresses immune system activity, signaling fitness in spite of this handicap is a demonstration of mate quality in spite of this handicap. Additional proof-of-concept can be demonstrated through testosterone supplementation. Men with Klinefelter syndrome (47,XXY) naturally make very little testosterone; androgen supplementation has been shown to decrease serum levels of all immunoglobulins in these men.^[50]

Pregnancy

Pregnancy has both short- and long-term effects on the immune system, and these changes may persist even after the completion of pregnancy. These effects on the course of autoimmune diseases vary widely, and are dependent on the specific disease, as well as the individual patient. Conditions such as rheumatoid arthritis often improve over the course of pregnancy, especially in the second and third trimesters; however, women often relapse within three months of giving birth.^[7] Other conditions, such as lupus, often become much worse over the course of pregnancy.^[5][7]

During pregnancy, the hormone estrogen spikes; additionally, hormonal fluctuations may continue long after childbirth.^[51] These changes could trigger, improve or even worsen an autoimmune disease. In addition to estrogen, other hormones like progesterone and prolactin may trigger these illnesses.^[46]

The mother's immune system tends to be suppressed during pregnancy, to prevent fetal rejection from foreign antibodies in the fetus.^[51] As stated before, pregnancy causes an increase of estrogen in the female body. The increase of this hormone weakens the functioning of immune cells, thus debilitating the mother's immune system.^[47] In addition, it is possible that fetal cells continue to circulate in the mother's body for years after childbirth, making it a possible trigger for autoimmune disease.^[52]

Diagnosis

Autoantibodies with commonly-associated autoimmune diseases

Autoantibody	Condition
ANA*("anti-nuclear antibody")	Lupus
AHA ("anti-histone antibody")	Drug-induced lupus
ds-DNA ("anti-double stranded DNA antibody")	Systemic lupus erythematosus with renal involvement
SMA ("anti-smooth muscle antibody")	Autoimmune Hepatitis
AMA ("anti-mitochondrial antibody")	Primary Biliary Cirrhosis
ACA ("anti-centromere antibody")	Scleroderma (CREST)
SS-A/Ro Ab ("anti-Sjögren syndrome A"/"anti-Ro" antibody)	Sjögren syndrome
CCP ("anti-cyclic citrullinated peptide")	Rheumatoid Arthritis
RF (rheumatoid factor)	Rheumatoid Arthritis
Jo ("anti-Jo antibody")	Polymyositis
anti-Scl-70 ("anti-topoisomerase I antibody")	Systemic Scleroderma

Diagnosis of autoimmune disease is based upon clinical and laboratory evidence.^[8] In order to diagnose autoimmune disease, typical symptoms of a given disorder must be present, along with laboratory evidence of autoantibodies. Autoantibodies develop throughout the course of autoimmune disease, as the immune system mistakenly forms specific antibodies to its own tissues, resulting in inflammation. The presence of autoantibodies alone is not sufficient for diagnosis, as autoantibodies may arise for a variety of other reasons, including malignancy, infection, or injury, and may be present even in persons who are completely healthy.^[8] However, it is possible for persons to have detectable autoantibody levels prior to clinical development autoimmune disease; this state may be characterized as pre-autoimmunity.^[8] Additionally, it is possible to display clinical signs of autoimmune disease before autoantibody levels are detectable.^[8] Most autoantibody assays are more sensitive than they are specific; that is, a negative autoantibody test is better at excluding a given disease, than a positive autoantibody test is at diagnosing a disease.

Generally, autoantibody results are reported in the form of titers, with higher titers (e.g., 1:160) indicating greater autoantibody concentration than lower titers (e.g., 1:8). Different autoantibody assays will have different criteria for determining whether a given test is positive, negative, or indeterminate. Other laboratories ordered in the workup of autoimmune disease may include a white blood cell count (WBC), CRP (C-reactive protein), ESR (erythrocyte sedimentation rate), and C3/C4 (complement levels), among others.

Additional circumstantial evidence to indicate likely autoimmune disease include family history and clustering of autoimmune diseases within a given family, presence of HLA haplotypes associated with a given disease, sex bias, and proof-of-concept through response to immunosuppressive therapy.^[8]

Treatment

See also: Autoimmune disease § Treatment

See also: Pregnancy category

Currently, it is not possible to fully cure any autoimmune disease. However, treatments exist which can improve the course of a given disease and/or result in long periods of remission.^[8] Pharmacological treatment of autoimmune disease can be broadly classified into anti-inflammatory, immunosuppressive, and palliative – e.g., correcting a functional disturbance related to the condition. The overall goals of such treatment are to limit the severity of flare-ups of disease, as well as to limit the total number of flares – that is, to extend periods of disease remission.

Anti-inflammatory

Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used to reduce inflammation associated with flares of autoimmune illness. NSAIDs work by inhibiting COX-1 and COX-2 enzymes,^[53] which are responsible for generating prostaglandins which cause inflammation. They additionally may inhibit chemotaxis, stop neutrophil aggregation, and decrease levels of pro-inflammatory cytokines.^[53] They are not considered immunosuppressive agents, as they do not directly target immune cells. Examples of NSAIDs include ibuprofen, naproxen, and diclofenac. These drugs are not recommended past the 20th week of pregnancy, as they may have adverse effects on development of the fetal circulatory system and kidneys.^[53]

Corticosteroids

Corticosteroids also have both anti-inflammatory and immunosuppressive effects,^[54] and are used widely in the treatment of autoimmune disease. They work through promoting the synthesis of multiple proteins such as lipocortin-1 and annexin A1, which stop the downstream production of prostaglandins and leukotrienes which promote inflammation.^[54] Examples of corticosteroids used in autoimmune disease include prednisone and methylprednisolone. There are no robust randomized controlled studies in humans regarding the safety of corticosteroid use in pregnancy.^[55] Corticosteroid use may be associated with cleft palate formation in the 1st trimester,^[55][56] but the data on this is limited. There is little evidence to suggest that material corticosteroid use is associated with early delivery, low birth weight, or preeclampsia. Prednisone and methylprednisolone have been classed as pregnancy category C, in that they should only be used in the maternal benefits outweigh potential risks to the fetus.^[55]

Immunosuppressive

Optimal treatment of autoimmune disease addition to quelling the generalized inflammation which may occur with autoimmune disease, treatment is also focused on specifically targeting the adaptive immune system. The goal of direct immunosuppression is to treat flares as well as extend the period of remission between episodes. Immunosuppressive drugs are categorized into DMARDs (disease-modifying anti-rheumatic drugs), as well as^{[clarification needed]}

DMARDs (Disease-Modifying Anti-Rheumatic Drugs)

DMARDs can be further classified into conventional-synthetic, targeted-synthetic, and biologic agents.

Palliative

Some autoimmune diseases with targeted effects on endocrine organs can result in an inability to produce hormones necessary to maintain normal physiology. Palliative treatment of autoimmune disease involves treating the secondary condition, by replacing vital hormones which are no longer being produced. Examples of this include the treatment of type-1 diabetes with exogenous insulin. Though this does not cure the primary autoimmune disease, it effectively treats the lack of hormone caused by it.

Non-pharmacological

Non-pharmacological treatments are effective in treating autoimmune disease and contribute to a sense of well-being. Women can:

• Eat healthy, well-balanced meals. A healthy diet limits saturated fat, trans fat, cholesterol, salt, and added sugars.^[2] People may alleviate symptoms of inflammation by following the Autoimmune Protocol Diet, which focuses on eliminating food that may trigger inflammation.^[57] Those with autoimmune diseases should focus on consuming foods that are very fresh and nutritious.^[57]
• Engage in regular physical activity without overdoing it. Patients should speak with a clinician about what types of physical activity is appropriate. A gradual and gentle exercise program often works well for people with long-lasting muscle and joint pain. For example, yoga or tai chi may be helpful.^[2]
• Get enough rest. Rest allows body tissues and joints the time they need to repair. Sleeping is a great way to maintain health of the mind and body. Lack of sleep, along with elevated stress levels may cause symptoms to worsen. Without proper rest, the body's immune defense remains inadequate. Many people need at least seven to nine hours of sleep each day to feel well-rested.^[2]
• Reduce stress. Stress and anxiety can trigger symptoms to flare up with some autoimmune diseases. Simplifying daily stressors will help alleviate symptoms and contribute to a sense of well-being. Meditation, self-hypnosis, and guided imagery, may be effective in reducing stress, pain, and boost people's ability to cope with other effects of autoimmune diseases. Instructional materials can guide people in learning these activities. Some include self-help books, audio sources, tapes, or consulting with an instructor. Joining a support group or talking with a counselor might also help manage stress and cope with the disease.^[2]

Complementary

Some complementary treatments may be effective and include:

• Listening to music
• Taking time to relax in a comfortable position
• Using imagery throughout the day
• Imagining confronting the pain and watching it be destroyed.^[2]
• Journaling and daily affirmations
• Traditional herbal medicine^[58]

During pregnancy

Concerns about fertility and pregnancy are present in women with autoimmune diseases. Talking with a health care provider before becoming pregnant is recommended. They may suggest to wait until the disease is in remission or suggest a change in medication before becoming pregnant. There are endocrinologists that specialize in treating women with high-risk pregnancies.^[2]

Some women with autoimmune diseases may have problems getting pregnant. This can happen for many reasons such as medication types or even disease types.^[59] Tests can tell if fertility problems are caused by an autoimmune disease or an unrelated reason. Fertility treatments are able to help some women with autoimmune disease become pregnant.^[2]

Changes in the severity of the disease seem to vary depending on the type of disease. There is an observable trend in pregnant women with rheumatoid arthritis, where the condition seems to improve during pregnancy.^[7] Differently, expecting mothers with systemic lupus erythematosus (SLE) may be more likely to have worsened symptoms through pregnancy; however, this is difficult to predict.^[7]

Medications have an influence on female fertility a well; furthermore, fertility has an impact on pregnancy. There are certain medications that can hinder women's ability to get pregnant, such as cyclophosphamide or corticosteroids.^[59] For this reason, it may be extremely helpful for women with autoimmune diseases to seek treatment when conceiving.

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External links

• American Thyroid Association
• National Endocrine and Metabolic Diseases Information Service, NIDDK, NIH, DHHS