Systemic Lupus Erythematosus Pregnancy

Abstract

Systemic Lupus Erythematosus (SLE) is an autoimmune disease of unknown etiology that often affects women during childbearing age. Pregnant women with SLE are considered high-risk patients, with pregnancy outcomes being complicated by high maternal and fetal mortality and morbidity. Obstetric morbidity includes preterm birth, fetal growth restriction (FGR), and neonatal lupus syndromes. Active SLE during conception is a strong predictor of adverse pregnancy outcomes and exacerbations of disease can occur more frequently during gestation. Therefore, management of maternal SLE should include preventive strategies to minimize disease activity and to reduce adverse pregnancy outcomes. Patients with active disease at time of conception have increased risk of flares, like lupus nephritis, imposing a careful differential diagnosis of pre-eclampsia, keeping in mind that physiological changes of pregnancy may mimic a lupus flare. Major complications arise when anti-phospholipid antibodies are present, like recurrent pregnancy loss, stillbirth, FGR, and thrombosis in the mother. A multidisciplinary approach is hence crucial and should be initiated to all women with SLE at childbearing age with an adequate preconception counseling with assessment of risk factors for adverse maternal and fetal outcomes with a tight pregnancy monitoring plan. Although treatment choices are limited during pregnancy, prophylactic anti-aggregation and anticoagulation agents have proven beneficial in reducing thrombotic events and pre-eclampsia related morbidity. Pharmacological therapy should be tailored, allowing better outcomes for both the mother and the baby. Immunosuppressive and immunomodulators, must be effective in controlling disease activity and safe during pregnancy. Hydroxychloroquine is the main therapy for SLE due to its anti-inflammatory and immunomodulatory effects recommended before and during pregnancy and other immunosuppressive drugs (e.g. azathioprine and calcineurin inhibitors) are used to control disease activity in order to improve obstetrical outcomes. Managing a maternal SLE is a challenging task, but an early approach with multidisciplinary team with close monitoring is essential and can improve maternal and fetal outcomes.

The Complement System, T Cell Response, and Cytokine Shift in Normotensive versus Pre-Eclamptic and Lupus Pregnancy

“…Interestingly, recent evidence showed that serum levels of complement fractions implicated in the classical activation pathway such as C1q, C4a, and C4b are decreased in both early and late stages of pre-eclampsia, supporting data from experimental models where C1q has a protective role against pre-eclampsia and C1q deficiency associates with endothelial dysfunction, decreased placental vascular endothelial growth factor, and elevated levels of sFlt-1 [19]; thus, C1q and C4 may prevent the onset of pre-eclampsia [1,2,20,[39][40][41].…”

“…Diverse studies emphasized risk factors for adverse pregnancy outcomes such as active lupus and particularly high disease activity in the six months before conception, active nephritis at conception or history of nephritis, use of anti-hypertensive medications or proteinuria more than 1 g daily, serological activity, hypocomplementemia during gestation, previous pregnancy complications, glucocorticoid use (prednisone considered a surrogate marker for active disease), and excessive complement activation through an alternative pathway [16][17][18][19][20]. Risk stratification of lupus pregnancy complications classically relies on maternal characteristics (age, smoking, previous pregnancy complications), disease characteristics (activity and organ damage, presence of specific anti-Ro/La and antiphospholipid antibodies, low complement levels) as well as medication (embryotoxic drugs).…”

“…Systemic lupus erythematosus (SLE) is an inflammatory autoimmune multisystem disease underpinned by unpredictable evolution (relapsing-remitting, prolonged remission, persistently active disease), immunologic, genetic and therapeutic heterogeneity, high morbidity, and mortality [16][17][18][19]. As the prototype of autoimmune conditions, systemic lupus remains a multifaceted and multifactorial disease resulting from a complex interplay between environmental factors, hormonal status, as well as overwhelming immunological abnormalities acting on a specific genetic background (polygenic disease).…”

“…As the prototype of autoimmune conditions, systemic lupus remains a multifaceted and multifactorial disease resulting from a complex interplay between environmental factors, hormonal status, as well as overwhelming immunological abnormalities acting on a specific genetic background (polygenic disease). Aberrant immune regulation comprises the activation of both innate and adaptive immunity with impaired clearance of self-nucleic acids related to the induction of type I interferon, lym-phocyte activation and signaling, defective T regulatory processes, autoantibody synthesis, complex immune formation and deposition, and multivisceral tissue damage [16][17][18][19][20][21][22]. Several pathways are actually proposed to explain the aberrant immunity in SLE, focusing on the imbalance between production and clearance of apoptotic debris, activated innate and adaptive immunity, inflammatory cell recruitment and tissue injury mediated by the augmented synthesis of pro-inflammatory cytokines derived from activated macrophages (TNFα, IL-6, IL-8), T cells (IL-17) and B cells (IL-10 and IL-6 as a result of IL-21 costimulation), loss of T and B cell tolerance and, finally, excessive autoantibody synthesis partially dependent on a specific type I IFN signature [16][17][18][19].…”

“…Aberrant immune regulation comprises the activation of both innate and adaptive immunity with impaired clearance of self-nucleic acids related to the induction of type I interferon, lym-phocyte activation and signaling, defective T regulatory processes, autoantibody synthesis, complex immune formation and deposition, and multivisceral tissue damage [16][17][18][19][20][21][22]. Several pathways are actually proposed to explain the aberrant immunity in SLE, focusing on the imbalance between production and clearance of apoptotic debris, activated innate and adaptive immunity, inflammatory cell recruitment and tissue injury mediated by the augmented synthesis of pro-inflammatory cytokines derived from activated macrophages (TNFα, IL-6, IL-8), T cells (IL-17) and B cells (IL-10 and IL-6 as a result of IL-21 costimulation), loss of T and B cell tolerance and, finally, excessive autoantibody synthesis partially dependent on a specific type I IFN signature [16][17][18][19]. Extreme patient heterogeneity as well as lupus endotypes rely on immunological heterogeneity comprising the activation of different cell subtypes (B and T cells, plasmablasts, NK cells, neutrophils, and myeloid cells), type I interferon response, and aberrant cytokine profile [16][17][18][19][20][21][22].…”