**2. Immunopathogenesis**

The immune system is a multidimensional environment with its main role being to protect the host against foreign pathogens and to remove cellular debris without harming the host. The etiology of SLE is multifactorial which leads to a failure to maintain immune tolerance and immune homeostasis manifested by aberrant immune responses against endogenous nuclear and other self-antigens. The pathogenesis of SLE involves various cells and molecules that intervene in apoptosis, innate and adaptive immune responses [7, 8]. This process involves plasma cells migrating to inflamed tissue where they become long-lived plasma cells that make antibodies and contribute to the formation of immune complexes.

#### **2.1 Genetic predisposition and epigenetics contributions**

The etiology of SLE still remains unknown, but genetic (e.g. major histocompatibility complex (MHC), interferon regulatory factor 5 (IRF5)) components and environmental factors (e.g. Epstein–Barr Virus (EBV), UV light) play an important role in the pathogenesis of SLE [9].

#### **2.2 Coexistence: the interaction of pregnancy and SLE**

The state of pregnancy is a complex and sophisticated one—it requires physiologic adaptions in all maternal systems, including immune and neuroendocrine alterations in the maternal body, in order to adapt and protect the fetus from immunologic attack by the mother [10].

**85**

*Systemic Lupus Erythematosus Pregnancy DOI: http://dx.doi.org/10.5772/intechopen.99008*

mechanism [11].

infection [10].

system [13].

be induced rapidly [12].

The induction and maintenance of tolerance throughout pregnancy involves many different immunoregulatory cell types, including cells that reside in the decidua, which are recruited to the placenta or proliferate locally in the decidua, as well as cell surface receptors and secreted molecules that orchestrate tolerogenic

This modulation of the composition and function of the immune-competent cells and immune-modulatory molecules in the maternal system during pregnancy has the ability to enhance and suppress different immune mechanisms to create a balance that protects the fetus, without compromising the mother's defense against

In harmony, estrogen cells and regulatory proteins exert their effects on decidual

stromal cells and tolerogenic dendritic cells, expand FOXP3+ T regulatory cells (Treg), calibrate the function of the rapidly increasing number of natural killer (NK) cells and downregulate effector T cells. The fetus promotes tolerance to paternal antigens by migration of fetal cells and cell-free fetal DNA to the maternal circulation during normal pregnancy. The fetus is considered a semi-allogeneic graft and to avoid rejection, a tolerogenic state at the feto-maternal interface has to

In a simple schematic way, the physiologic immune response to pregnancy occurs by: (1) stimulation of B cells which occurs with production of antibodies; (2) T helper (Th) cells participate as co-stimulatory cells, inducing a shift at the Th 1 and Th 2 helper cell level; (3) leading to a predominance of Th 2 cells during pregnancy which also suppresses the response of cytotoxic T cells; (4) the shift towards the Th 2 response leads to suppression of anti-fetal antigen-mediated immune responses; (5) the hormonal system participates in the suppression of cell-mediated immunity, and thus immune tolerance; and (6) a tight cooperation for preventing a response to fetal antigens occurs between the trophoblast and the maternal immune

In the case of pregnancy associated with SLE, the main immune abnormality involves the function of T regulatory (Treg) cells, as these are limited in number and in their functions [14]. The main purpose of the Treg cells during a normal pregnancy is to ensure immune tolerance to the fetus, and in the case of SLE, the immune system is confronted with a weaken response which cannot ensure the

Therefore, the problem arises with the number of Treg cells. In a normal pregnancy, the number of Treg cells increases and contrarily decreases in cases of pregnancy loss and pre-eclampsia. On one hand, pregnancy benefits from the contribution of Treg cells, which ensure maternal-fetal tolerance. On the other hand, Treg cells are defective in SLE [15]. It is also possible that this impaired immune tolerance results in complications such as miscarriage, preterm birth or pre-eclampsia. However, in cases of pregnancy associated with inactive SLE, Treg cells might ensure maternal-fetal tolerance because functional Treg cells predominate. This is one of the reasons why women should be in remission prior to pregnancy [13]. The Th 17 cell is a subset of the T helper which is regulated by Treg cells. They possess great plasticity and its function is to produce IL-17 and other interleukins such as IL-21, IL-22, and IL-17F [16]. These cells which mainly produce IL-17A and IL-17F can turn into cells that produce interferon gamma [17]. Th 17 cells have a role in inflammatory processes in autoimmune diseases and abnormal changes in the ratio of Th 17 cells to Treg cells may be related to spontaneous abortion and premature birth [17, 18]. Torricelli et al., found that pregnant women with SLE

*2.2.1 T cell responses in normal pregnancy and in lupus pregnancy*

right settings of the product of conception.

#### *Systemic Lupus Erythematosus Pregnancy DOI: http://dx.doi.org/10.5772/intechopen.99008*

*Lupus - Need to Know*

**1. Introduction**

to improve both maternal and fetal outcomes.

**2.1 Genetic predisposition and epigenetics contributions**

**2.2 Coexistence: the interaction of pregnancy and SLE**

**2. Immunopathogenesis**

role in the pathogenesis of SLE [9].

immunologic attack by the mother [10].

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease characterized by production of autoantibodies and polymorphic manifestations of end-organ damage [1, 2]. The disease can manifest itself in many forms and severity, ranging from mild cutaneous and joint involvement, to devastating ocular complications or lethal renal, cardiac and cerebral involvement [3]. SLE is caused by interactions between susceptibility genes and environmental factors, resulting in irreversible loss of immunologic self-tolerance. Its estimated incidence ranges from 0.3 to 23.2 per 100.000 person-years and it mostly affects women, with a female to male ratio as high as 10–15:1 [4, 5]. In women, prevalence varies between 164 to 406/100.000 [6] and most of them are in childbearing age. For these reasons, reproductive health and family planning are issues of utmost importance for physicians managing SLE patients, including internists, rheumatologists, and gynecologists. Even if fertility is not impaired in SLE, pregnancy represents a high-risk period in the disease course, mainly due to serious potential maternal and fetal complications. On the maternal side, risk of flare is increased during pregnancy, and there is risk of pre-eclampsia (PE) and thrombotic complications, especially in women carrying antiphospholipid antibodies (aPL). On the fetal side, fetal growth restriction (FGR) and preterm birth are feared complications, besides the potential harm caused by maternal antibodies, as it is the case of congenital heart block (CHB) and neonatal lupus in women carrying SS-A and SS-B antibodies. Multidisciplinary approach, preconception counseling, pregnancy planning and increased availability of safe drugs in pregnancy and puerperium have contributed

The immune system is a multidimensional environment with its main role being to protect the host against foreign pathogens and to remove cellular debris without harming the host. The etiology of SLE is multifactorial which leads to a failure to maintain immune tolerance and immune homeostasis manifested by aberrant immune responses against endogenous nuclear and other self-antigens. The pathogenesis of SLE involves various cells and molecules that intervene in apoptosis, innate and adaptive immune responses [7, 8]. This process involves plasma cells migrating to inflamed tissue where they become long-lived plasma cells that make antibodies and contribute to the formation of immune

The etiology of SLE still remains unknown, but genetic (e.g. major histocompatibility complex (MHC), interferon regulatory factor 5 (IRF5)) components and environmental factors (e.g. Epstein–Barr Virus (EBV), UV light) play an important

The state of pregnancy is a complex and sophisticated one—it requires physiologic adaptions in all maternal systems, including immune and neuroendocrine alterations in the maternal body, in order to adapt and protect the fetus from

**84**

complexes.

The induction and maintenance of tolerance throughout pregnancy involves many different immunoregulatory cell types, including cells that reside in the decidua, which are recruited to the placenta or proliferate locally in the decidua, as well as cell surface receptors and secreted molecules that orchestrate tolerogenic mechanism [11].

This modulation of the composition and function of the immune-competent cells and immune-modulatory molecules in the maternal system during pregnancy has the ability to enhance and suppress different immune mechanisms to create a balance that protects the fetus, without compromising the mother's defense against infection [10].

In harmony, estrogen cells and regulatory proteins exert their effects on decidual stromal cells and tolerogenic dendritic cells, expand FOXP3+ T regulatory cells (Treg), calibrate the function of the rapidly increasing number of natural killer (NK) cells and downregulate effector T cells. The fetus promotes tolerance to paternal antigens by migration of fetal cells and cell-free fetal DNA to the maternal circulation during normal pregnancy. The fetus is considered a semi-allogeneic graft and to avoid rejection, a tolerogenic state at the feto-maternal interface has to be induced rapidly [12].

In a simple schematic way, the physiologic immune response to pregnancy occurs by: (1) stimulation of B cells which occurs with production of antibodies; (2) T helper (Th) cells participate as co-stimulatory cells, inducing a shift at the Th 1 and Th 2 helper cell level; (3) leading to a predominance of Th 2 cells during pregnancy which also suppresses the response of cytotoxic T cells; (4) the shift towards the Th 2 response leads to suppression of anti-fetal antigen-mediated immune responses; (5) the hormonal system participates in the suppression of cell-mediated immunity, and thus immune tolerance; and (6) a tight cooperation for preventing a response to fetal antigens occurs between the trophoblast and the maternal immune system [13].

#### *2.2.1 T cell responses in normal pregnancy and in lupus pregnancy*

In the case of pregnancy associated with SLE, the main immune abnormality involves the function of T regulatory (Treg) cells, as these are limited in number and in their functions [14]. The main purpose of the Treg cells during a normal pregnancy is to ensure immune tolerance to the fetus, and in the case of SLE, the immune system is confronted with a weaken response which cannot ensure the right settings of the product of conception.

Therefore, the problem arises with the number of Treg cells. In a normal pregnancy, the number of Treg cells increases and contrarily decreases in cases of pregnancy loss and pre-eclampsia. On one hand, pregnancy benefits from the contribution of Treg cells, which ensure maternal-fetal tolerance. On the other hand, Treg cells are defective in SLE [15]. It is also possible that this impaired immune tolerance results in complications such as miscarriage, preterm birth or pre-eclampsia. However, in cases of pregnancy associated with inactive SLE, Treg cells might ensure maternal-fetal tolerance because functional Treg cells predominate. This is one of the reasons why women should be in remission prior to pregnancy [13].

The Th 17 cell is a subset of the T helper which is regulated by Treg cells. They possess great plasticity and its function is to produce IL-17 and other interleukins such as IL-21, IL-22, and IL-17F [16]. These cells which mainly produce IL-17A and IL-17F can turn into cells that produce interferon gamma [17]. Th 17 cells have a role in inflammatory processes in autoimmune diseases and abnormal changes in the ratio of Th 17 cells to Treg cells may be related to spontaneous abortion and premature birth [17, 18]. Torricelli et al., found that pregnant women with SLE

demonstrated increased levels of IL-17 together with other cytokines, including IL-6, IL-10, and TNF. This may indicate a hyperactive immune system among pregnant women with SLE, and this may be related to the placenta [18].

However, beyond the limited and mal-function of Treg cells, estrogens are also an important part of the immunopathology of SLE, which in pregnancy plays an important part in shaping the immune tolerance.

### *2.2.2 Estrogens and its role in normal pregnancy versus lupus pregnancy*

Estrogens are related to the immune response system and in high concentrations act simultaneously with other reproductive hormones. It is believed to stimulate increased Th2 cytokines during gestation, being a desirable response to normal pregnancy. However, in SLE patient, excessive Th2 responses can lead to increased secretion of IL-17, which may lead to recurrent miscarriages [13, 18]. By promoting Th 2 responses, estrogens in pregnancy tend to worsen Th 2-mediated diseases such as SLE [16, 17]. Torricelli et al., showed high levels of serum IL-17 in pregnant women with SLE [19].

## *2.2.3 B cell response in normal pregnancy versus in SLE*

In SLE, B cells also have an important role in producing antibodies. The B cells participate in maternal immune tolerance to the fetus with secretion of IL-10, which progressively rises during a normal and healthy pregnancy. However, in SLE patients, IL-10 levels are significantly higher at conception and remain elevated throughout pregnancy and postpartum. IL-10 is a pleiotropic cytokine, with both immune stimulatory and immune suppressive functions. Persistent high levels of IL-10 indicate a constitutional overproduction in SLE, resulting in continuous B cell stimulation [12, 13].

## **3. Pregnancy planning and monitoring in SLE**

SLE pregnancies are considered as a high-risk process. The strongest predictor of adverse pregnancy outcomes is an active SLE at time of conception. Patients with active SLE should postpone pregnancy until SLE is under control [20]. In certain cases, pregnancy is contraindicated in patients with severe organ involvement (e.g. severe renal insufficiency or end stage renal disease, congestive heart failure, severe pulmonary fibrosis, and severe pulmonary hypertension) [21]. Women with a past history of thrombotic events have an increased risk for thrombosis during pregnancy and post-partum, and in these cases there should be a switch from warfarin to low molecular weight heparin [22]. Risk stratification should be performed according to the aPL outline, taking into account the type, titer, and persistence of aPL. By doing so, patients can be divided into "high-risk" and "low-risk" profiles and treatment should be given according to each specific case [23]. Women should be started on folic acid preferably 3 months prior to conception; throughout pregnancy, they should be on calcium and vitamin D [24].

Therefore, it is crucial and mandatory the assessment of risk factors for adverse maternal and fetal outcomes in women with SLE who desire to be pregnant – this starts with preconception counseling and implementing appropriate preventive strategies and an individual-tailored monitoring plan before (switch teratogenic medications for non-teratogenic ones, respecting the wash-out of harmful medications, and being in remission for at least 3 to 6 months' prior conception) and during pregnancy [20].

**87**

complications.

**4.2 Presence of anti-Ro antibodies**

cies affected by SLE [26].

*Systemic Lupus Erythematosus Pregnancy DOI: http://dx.doi.org/10.5772/intechopen.99008*

anti-La/SSB antibodies [20].

**4. SLE & other autoimmune diseases**

**4.1 Presence of antiphospholipid antibodies**

treatment is crucial in order to save a patient's life [23].

Once pregnancy is confirmed, a monthly routine need to be ensured and should include: doctor appointments and complete blood analyses, including a complete set of autoantibodies, as well as, specific maternal antibodies such as aPL and anti-Ro/SSA. In the case for patients with current or past renal involvement, blood pressure and 24-h urine proteinuria should be monitored regularly [20, 22].

SLE pregnant should be followed after specific protocols for patients at highrisk of developing hypertensive disorders and/or placental insufficiency. Fetal surveillance should be based on biometric and Doppler findings during the third trimester, and particularly distinguish between early and late FGR, helping to better tailor the time of delivery and reduce perinatal morbidity and mortality. Fetal echocardiography is only indicated if there is suspected fetal dysrhythmia or myocarditis, especially in the context of positive maternal anti-Ro/SSA or

The presence of antiphospholipid antibodies (aPL) during pregnancy is associated with significant risk of maternal and fetal adverse events. The prevalence of aPL in SLE is about 12–44% for anticardiolipin (aCL), 15–34% for lupus anticoagulant (LAC) and 10–19% for anti-beta2 glycoprotein I (β2GPI) antibodies [25]. These antibodies are responsible for an autoimmune hypercoagulable state, known as antiphospholipid syndrome (APS). Even though aPL are present in about a half of patients with SLE, only a fraction of these patients develops antiphospholipid syndrome (APS), which manifests as thrombotic and/or obstetric adverse events, mediated by persistent circulating aPL detected by means of three tests: LAC, aCL and β2GPI antibodies, repeated twice with an interval of 12 weeks apart. A different subset of patients, the so-called "aPL carriers", has been described. These are aPL positive individuals without clinical manifestations, that are at high-risk of prematurity, pre-eclampsia, eclampsia, or HELLP (hemolysis, elevated liver enzyme levels, low platelet count) syndrome. The most severe form of APS is catastrophic antiphospholipid syndrome (CAPS) a potentially fatal and rare condition that women may develop during pregnancy. Its diagnosis is challenging and aggressive

The outcomes of pregnancies in patients with aPL have significantly improved

Anti-Ro/SSA and/or anti-La/SSB autoantibodies are detected in approximately 40% of patients with SLE. The transplacental passage of maternal IgG antibodies (anti-Ro/SSA and anti-La/SSB) may lead to neonatal lupus in 1–2% of all pregnan-

Congenital Heart Block (CHB) is the most severe manifestation, affecting 2% of pregnancies with positive antibodies (especially anti-Ro/SSA) and without a previous history of complicated pregnancies. This usually manifests between the 18th and 24th weeks of gestation. The risk increases significantly 10 to 15% in patients who have a prior history of another neonate affected with cutaneous lupus and up

and live birth rates over 80% are achieved nowadays. The management is based on the risk of profile of aPL and/or previous thrombotic and/or obstetric

to 15–20% in those with a prior neonate affected with CHB [27].

#### *Systemic Lupus Erythematosus Pregnancy DOI: http://dx.doi.org/10.5772/intechopen.99008*

*Lupus - Need to Know*

women with SLE [19].

stimulation [12, 13].

demonstrated increased levels of IL-17 together with other cytokines, including IL-6, IL-10, and TNF. This may indicate a hyperactive immune system among pregnant women with SLE, and this may be related to the placenta [18].

*2.2.2 Estrogens and its role in normal pregnancy versus lupus pregnancy*

important part in shaping the immune tolerance.

*2.2.3 B cell response in normal pregnancy versus in SLE*

**3. Pregnancy planning and monitoring in SLE**

nancy, they should be on calcium and vitamin D [24].

However, beyond the limited and mal-function of Treg cells, estrogens are also an important part of the immunopathology of SLE, which in pregnancy plays an

Estrogens are related to the immune response system and in high concentrations act simultaneously with other reproductive hormones. It is believed to stimulate increased Th2 cytokines during gestation, being a desirable response to normal pregnancy. However, in SLE patient, excessive Th2 responses can lead to increased secretion of IL-17, which may lead to recurrent miscarriages [13, 18]. By promoting Th 2 responses, estrogens in pregnancy tend to worsen Th 2-mediated diseases such as SLE [16, 17]. Torricelli et al., showed high levels of serum IL-17 in pregnant

In SLE, B cells also have an important role in producing antibodies. The B cells participate in maternal immune tolerance to the fetus with secretion of IL-10, which progressively rises during a normal and healthy pregnancy. However, in SLE patients, IL-10 levels are significantly higher at conception and remain elevated throughout pregnancy and postpartum. IL-10 is a pleiotropic cytokine, with both immune stimulatory and immune suppressive functions. Persistent high levels of IL-10 indicate a constitutional overproduction in SLE, resulting in continuous B cell

SLE pregnancies are considered as a high-risk process. The strongest predictor of adverse pregnancy outcomes is an active SLE at time of conception. Patients with active SLE should postpone pregnancy until SLE is under control [20]. In certain cases, pregnancy is contraindicated in patients with severe organ involvement (e.g. severe renal insufficiency or end stage renal disease, congestive heart failure, severe pulmonary fibrosis, and severe pulmonary hypertension) [21]. Women with a past history of thrombotic events have an increased risk for thrombosis during pregnancy and post-partum, and in these cases there should be a switch from warfarin to low molecular weight heparin [22]. Risk stratification should be performed according to the aPL outline, taking into account the type, titer, and persistence of aPL. By doing so, patients can be divided into "high-risk" and "low-risk" profiles and treatment should be given according to each specific case [23]. Women should be started on folic acid preferably 3 months prior to conception; throughout preg-

Therefore, it is crucial and mandatory the assessment of risk factors for adverse maternal and fetal outcomes in women with SLE who desire to be pregnant – this starts with preconception counseling and implementing appropriate preventive strategies and an individual-tailored monitoring plan before (switch teratogenic medications for non-teratogenic ones, respecting the wash-out of harmful medications, and being in remission for at least 3 to 6 months' prior conception) and

**86**

during pregnancy [20].

Once pregnancy is confirmed, a monthly routine need to be ensured and should include: doctor appointments and complete blood analyses, including a complete set of autoantibodies, as well as, specific maternal antibodies such as aPL and anti-Ro/SSA. In the case for patients with current or past renal involvement, blood pressure and 24-h urine proteinuria should be monitored regularly [20, 22].

SLE pregnant should be followed after specific protocols for patients at highrisk of developing hypertensive disorders and/or placental insufficiency. Fetal surveillance should be based on biometric and Doppler findings during the third trimester, and particularly distinguish between early and late FGR, helping to better tailor the time of delivery and reduce perinatal morbidity and mortality. Fetal echocardiography is only indicated if there is suspected fetal dysrhythmia or myocarditis, especially in the context of positive maternal anti-Ro/SSA or anti-La/SSB antibodies [20].
