The spectrum of autoimmune phenomena and their clinical presentations as autoimmune disease is very wide and includes more than 20 diseases that pose a greater threat to women than to men (2). In the total patient population, 75% are women. Women have 2.7 times greater risk than men of acquiring an autoimmune disease (2). Autoimmune diseases are among the 10 leading causes of mortality for women of all age groups up to 65 years of age (2). The prevalence of the most common diseases in 1997 in the United States by frequency and sex distribution was strongly in favor of women: Graves’ disease/hyperthyroidism was the most common (1000 women and 150 men per 100 000 inhabitants), followed by rheumatoid arthritis (630 women and 220 men per 100 000 inhabitants) and thyroiditis (750 women and 50 men per 100 000 inhabitants), which taken together comprise the majority of autoimmune diseases (almost 90%) in the general population (in addition to diabetes type 1 and vitiligo) (2). It is estimated that 1 out of 31 inhabitants has an autoimmune disease (2). Other autoimmune diseases such as multiple sclerosis and systemic lupus, which are much rarer than those listed above, are more common in women with glomerulonephritis (which affects both sexes at similar rates) and affect 323 232 persons. The prevalence of other autoimmune diseases is low at 5.14/100 000 inhabitants. It is estimated that every 5 years the number of persons with autoimmune diseases increases by 1 186 015 new cases (2).

Autoimmune disease can affect any organ or part of the body, so their symptomatology is thus varied and unspecific, and diagnosis and treatment represent a challenge for the clinician. Some diseases from this spectrum, if they are not diagnosed and treated, can be life-threatening, such as systemic lupus affecting the kidneys in the form of lupus nephritis and chronic kidney disease (CKD), but also the presence of autoimmune diseases of the heart such as coronaritis, endocarditis, or pericarditis. Some autoimmune diseases such as rheumatoid arthritis are often the cause of invalidity and severely impact quality of life for the patient and their whole family, despite the numerous treatment options available today. Systemic sclerosis requires a life-long search for ways of successful treatment and alleviation of symptoms. Scleroderma crisis, although rare, is extremely critical for the life of the patient and is associated with deterioration of kidney function. There are other autoimmune diseases such as Graves’ disease and chronic thyroiditis that can be successfully treated, but the problem is that they are often not recognized on time due to their gradual and discrete progression, as well as the fact that overlap of more than one autoimmune disease, such as systemic lupus and thyroiditis, is also possible.

Diagnostic procedures are used to sort immunological disorders according to the type of immunological reaction (mediated by immune complexes, autoantibodies, cytotoxic lymphocytes, etc.), and the simplest classification is the one that sorts them into organ-specific (Hashimoto’s thyroiditis, myasthenia gravis, ulcerative colitis, Goodpasture syndrome, autoimmune hemolytic anemia, primary biliary cirrhosis) and organ-nonspecific (systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, polyarteritis nodosa, Sjogren’s syndrome, and inflammatory myopathies).

Women and men clinically differ not only in the incidence of autoimmune disease but in other characteristics as well; for instance, significantly more severe clinical forms of the same disease have been observed in women in comparison with men (3). Sex differences in incidence and severity are the consequence of complex interrelations of genetic, hormonal, epigenetic, and environmental factors, i.e. the overall structure, function, and role of the female and male organisms in nature. There are differences depending on peak incidence, the ratio of women compared with men, and the level of estrogen for diseases such as systemic lupus, rheumatoid arthritis, and systemic sclerosis. Peak incidence for systemic lupus is generative age, perimenopause for rheumatoid arthritis, and age 50-60 for systemic sclerosis. The prevalence ration for women vs. men in systemic lupus is 15:1, 4:1 for rheumatoid arthritis, and 14:1 for systemic sclerosis. High levels of estrogen are associated only with rheumatoid arthritis, while low estrogen levels are negatively correlated with rheumatoid arthritis and systemic sclerosis. Sex differences are constant across the world regardless of education levels, health care service, and participation in clinical trials (3).

Immunological suppression has been observed human males and in the animal world in general (4). Women have superior immunocompetence and stronger immunological reactivity (5, 6). Men have a lower T-lymphocyte count, and women have a reduced number of B-lymphocytes and helper T-cells. Women produce a higher level of circulating antibodies than men. Furthermore, women develop both stronger humoral and stronger cellular immunological responses to stimuli. It has been observed that the prevalence, susceptibility, and severity for parasite infections is higher in men than in women. On the other hand, herpes simplex infection is more common in women due to higher levels of progesterone.

Resident immunological cells in tissues can also be sex-differentiated and influence the oversensitivity of individual target organs, which can be observed in central nervous system diseases, and experimental models have demonstrated the important role of estrogen in the activation of microglia and astrocytes as well as the creation of tolerogenic dendritic cells. It is interesting that migraine, which affects 15% of the total population, is far more common in women and represents a risk factor not only for stroke but for vascular events as well, especially myocardial infarction, and is now clearly associated with elevated cardiovascular (CV) risk (7, 8). Therefore, autoimmunity in isolation is not sufficient for the development of disease without oversensitivity of the target organ. Important functions for target organ immunocompetence are sensitivity to apoptosis, autophagy, mitochondrial function, and the maintenance of biochemical pathways that allow survival such as the Th2 pathway (9, 10).

A higher tendency for sclerosis has been observed with the advent of puberty in comparison with preadolescence, and the risk increases for early puberty. Before puberty, systemic lupus manifests in boys and girls at a ratio of 1:2, but the incidence is much higher for women after puberty (9:1 in favor of women) (11, 12). Long-term treatment adherence is also an issue (13).

Ulcerative colitis is equally represented in both sexes during adolescence, but in early adulthood the ratio increases to 4:1 in favor of men (12).

In pregnancy, the mother is host to the fetus – a carrier of foreign antigens – so the immunological Th1 response to stimuli is necessarily suppressed, and the Th2 lymphocytic response dominates. Additionally, regulatory T-cells mediate active immunological tolerance. Remission of rheumatoid arthritis and ankylosing spondylitis (Th1 mediated diseases) has been observed in pregnancy. Changes associated with pregnancy include the presence of the small protein from the “heat shock” protein family, HSP 10 (chaperonin 10), which has beneficial immunomodulatory effects. Pregnancy does not have a unidirectional effect on the severity of the clinical picture in multiple sclerosis, but remission can be observed in ankylosing spondylitis, multiple sclerosis, and rheumatoid arthritis. Conversely, systemic lupus is exacerbated to a greater or lesser degree in pregnancy. Pregnancy can also induce the first manifestation of autoimmune disease, and the development of fulminant autoimmune diabetes and thyroiditis that becomes evident postpartum has been reported. Autoimmune diseases in pregnancy can result in disease manifestation in the fetus in the form of multiple sclerosis, systemic lupus, thyrotoxicosis, autoimmune thrombocytopenic purpura, and cutaneous lupus. Passive transmission of anti-Ro and anti-La autoantibodies in systemic lupus can lead to the development of congenital block in the newborn, as well as significant arrhythmia. Autoimmune disease can also manifest due to hyperstimulation of the ovaries and in situations related to assisted pregnancy, for instance in women with multiple sclerosis and systemic lupus, and women with antithyroid antibodies have greater risk of abortion in assisted reproduction procedures. Thus, the changes in pregnancy are specific to the form of autoimmune disease. Specific changes noted in pregnancy are also the exchange of cells between the fetus and the mother – microchimerism – which is considered a possible trigger for the development of autoimmune disease. Microchimera cells can persist as inactive dendritic cells and lymphocytes and activate due to exposure to environmental triggers, changes in the cytokine profile, infections, and hormonal changes, causing the development of autoimmune disease.

Menopausal changes influence the reduction of relapse frequency in systemic lupus, but on the other hand also lead to more intensive damage to previously affected organs. Rheumatoid arthritis progresses to a higher degree of physical incapacitation, and the changes to kidneys in rheumatoid arthritis manifest in a spectrum of different diseases (14). Complications can occur, such as secondary amyloidosis affecting the kidneys and manifesting with nephrotic syndrome or affecting the bone marrow with the development of a severe form of secondary anemia, which leads to complications and the development of secondary myocardial infarction or CV complications, which are the most common cause of mortality in this population (15). Other than in puberty, autoimmune hepatitis manifests after menopause as well. Still, early menopause is a special aspect of women which brings the risk of newly-acquired systemic lupus and rheumatoid arthritis (16, 17). There is ample data on the role of the sex hormones estrogen, progesterone, androgen, and prolactin in autoimmunity. In systemic lupus, T-cells are activated through estrogen receptors α and β, unlike in healthy persons. Similarly, the concentration of estrogen in synovial fluid is elevated in rheumatoid arthritis. Progesterone has an anti-inflammatory effect in the immunological system, and the receptors for that hormone can be found on many immunocompetent cells.

Genetic changes concern genes or groups of genes which carry oversensitivity to disease, chromosomal differences, and epigenetic changes. HLA genes (mostly DR and DQ) are associated with many autoimmune diseases such as myasthenia gravis, multiple sclerosis, and systemic lupus and have a central role in the presentation of the CD4+ gene to lymphocytes. The association of the HLA genes and autoimmune diseases is clear in women. Women have a higher prevalence of HLA DR4 than men, and thusly a higher risk of the development of disease associated with that allele – autoimmune hepatitis type 1. There is a strong association of HLA DR2, DQ6 with multiple sclerosis in women. The genotype HLA DRB1*0401/*0401 is associated with the development of rheumatoid arthritis in women. In systemic lupus, the genetic risk from the HLA gene is higher in men. Among non-HLA genes, of importance are the genes that code the molecule CTLA-4 on T-cells, acid phosphatase locus 1, IL-10, and apolipoproteins. Polymorphism of genes for IL-10 is associated with a more severe form of Hashimoto’s thyroiditis, rheumatoid arthritis, and primary Sjogren’s syndrome (18). Genes on the X chromosome also contribute to the development of autoimmunity, since their inactivation has been observed in autoimmune thyroid disease, rheumatoid arthritis, and systemic sclerosis, but not in systemic lupus. The loss of the Y chromosome dependent on age has been observed in primary biliary cirrhosis. Among epigenetic mechanisms, of importance is the loss of microRNA (regulating genes associated with autoimmune diseases), which is differently regulated hormonally and chromosomally in men and women and can contribute to sexual dimorphism in autoimmune diseases.

Patients with autoimmune diseases, especially systemic lupus, can develop secondary antiphospholipid syndrome (APS). This is an autoimmune disorder characterized by the appearance of blood vessel thrombosis, and can also manifest as primary APS in healthy persons (19). The diagnosis of APS is based on clinical manifestations and specific autoantibodies in the blood.

One of the most common manifestations of systemic lupus is to affect the kidneys. More than half of patients with systemic lupus erythematosus (SLE) develop lupus nephritis, which is a negative prognostic factor leading to end stage chronic kidney diseases in 17-25% of patients and requiring renal replacement therapy (20). The course of the disease in proliferative lupus nephritis is unpredictable (13). Pathohistologically demonstrated active kidney damage requires a combination of immunosuppressive medication (cyclophosphamide or mycophenolic acid) and glucocorticoid treatment for proliferative (type III/IV) and membranous lupus nephritis (type V). Rituximab is the secondary line of treatment (21). A unique challenge is the period of pregnancy in patients with systemic lupus. Pregnant women with active lupus nephritis require regular monitoring due to the association with higher incidence of complications for the mother and child. In a cohort study conducted on 166 pregnant women, proteinuria in the first month of pregnancy resulted in 2.6 times higher rate of pregnancy loss. In a study conducted on 65 women, kidney damage defined as proteinuria without preeclampsia, hematuria, or cell detritus in urine was a prognostic factor for intrauterine growth restriction and/or preeclampsia. When choosing the form of treatment in pregnancy, it is necessary to distinguish benefits from harm. Treatment should not be terminated during pregnancy because this can lead to serious morbidity and mortality in the mother and child (22). There is still no alternative form of treatment to anti-inflammatory medication and steroids that are currently applied in the treatment of SLE, but studies have noted the effect of monoclonal antibodies such as tocilizumab (humanized monoclonal antibodies to IL-6) and eculizumab (recombinant fully humanized IgG2/IgG4 monoclonal antibodies to complement C5) (13). Studies support the beneficial role of hydroxychloroquine in the control of disease activity and prevention of progression during pregnancy, recommending an acceptable risk/benefit ratio for oral corticosteroids, azathioprine, and calcineurin inhibitors (cyclosporine A, tacrolimus). Mycophenolic acid, methotrexate, and leflunomide should be avoided due to potential or known teratogenicity in pregnancy. Cyclophosphamides and ACE inhibitors are also contraindicated in pregnancy.

Elevation of serum creatinine and/or proteinuria, the presence of pathological urine sediment, or reduction in estimated glomerular filtration rate (eGFR) are late indicators of deterioration of kidney function (“renal flare”) due to active disease. Relapses occur in 45% of patients, with an incidence of deterioration of 0.1 to 0.2 per patient per year. If the relapses are defined using urine sediment (active >5 white blood cells per visual field) and reduced eGFR, they are an important, though belated, prognosticator for CKD deterioration; consequently, studies that indicate the possibility of early biomarkers of disease progression such as microRNA are especially important (23).

CV risk is elevated in female patients with autoimmune diseases due to the common presence of hypertension, especially masked hypertension that cannot be diagnosed without ambulatory blood pressure monitoring. Hypertension (that can initially manifest as migraines) and hyperlipidemia (low HDL and elevated urate levels in systemic lupus; hypercholesterolemia and insulin resistance is more common in rheumatoid arthritis compared with the healthy population without autoimmune disease) in autoimmune diseases are inadequately recognized and diagnosed, which additionally increases CV risk (24, 25). Patients with systemic autoimmune diseases have higher CV risk that is underestimated and insufficiently recognized. The cardiovascular risk in female patients with systemic lupus and rheumatoid arthritis indicates premature atherosclerosis. Female patients with systemic lupus have a 5-8 times higher incidence of coronary artery disease compared with the general population, which is associated with dyslipidemia, the presence of LDL phenotype-B, and the simultaneous presence of systemic inflammation with other traditional CV risks (2, 25). Autoimmune disease is itself an independent CV factor, which should be taken into account when processing patients with autoimmune diseases, which are far more common in women. It is necessary to estimate total CV risk: screening for high/very high cardiovascular risk with three or more risk factors (pulse pressure, female age >65, cigarette smoking, blood pressure, total cholesterol >5.0 mmol/L, LDL cholesterol >3.0 mmol/L, blood glucose >6.9 mmol/L, obesity, family history of premature cardiovascular disease), with diabetes, hypertension stage 2-3, subclinical target organ damage (left ventricular hypertrophy, carotid plaque, increased arterial stiffness, increased creatinine/ decreased creatinine clearance, proteinuria), present CV disease (myocardial infarction, stroke), or kidney disease. It is necessary to treat risk factors such as hypertension using antihypertensive therapy, hyperlipidemia using statins and fenofibrates, and also treat the underlying autoimmune disease with basic medication and specific treatment measures (25).

The incidence of autoimmune diseases increases with the advent of reproductive capabilities in women and hormonal changes from cycles in reproductive function. We are lacking new biomarkers for timely diagnosis as well as monitoring the activity of autoimmune diseases; in the future, routine measurement of microRNA in the blood, urine, or biopsied tissue could contribute to the reduction of cardiovascular risk in women.