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Clinical Infection & Immunity

Review

Volume 7, Number 2, September 2022, pages 31-36

Hydroxychloroquine in Lupus Pregnancy: What Do We Know?

Systemic lupus erythematosus (SLE) is a multisystem autoimmune condition most commonly affecting women of childbearing age. In North America, the overall estimated incidence of SLE is between 3.7 and 49 for every 100,000 person-years in the Medicare population [1], and its prevalence is estimated to be between 48 and 366.6 per 100,000 individuals [1-3]. A three-fold higher mortality rate has been reported in SLE patients compared to the general population [4].

Pregnancy is of significant concern for SLE patients of childbearing age because SLE is associated with increased maternal and fetal morbidity [5]. However, the increase in SLE activity during pregnancy remains uncertain and debatable, though it has been found that the total flare rate ranges from 30% to 50% during pregnancy and the first year postpartum [5-7]. If the patient has active lupus in the 6 months before conception, the risk of significant SLE activity during pregnancy can be up to seven-fold higher [8]. Furthermore, the postpartum SLE patient continues to be at risk for lupus flares up to 3 months after delivery [9]. Therefore, it has been advised to delay pregnancy until the disease has been in remission for at least 6 months [5, 10].

Increased SLE activity during pregnancy may affect maternal and fetal health. Lupus nephritis is a notorious complication during SLE pregnancy [11], though it can occur de novo, or more commonly as an exacerbation in patients with a history of nephritis. For lupus nephritis during pregnancy, intravenous or oral corticosteroids are started initially for rapid onset compared to other immunosuppressants [10]. The appearance of other conditions further complicates health status. Pregnant SLE patients who take 10 g or higher doses of prednisone may have an increased risk of diabetes mellitus [10]. Pre-eclampsia is increased up to 13-35% in lupus pregnancy compared to 5-8% in the general population [10]. This pre-eclampsia risk in SLE pregnancy has been associated with lupus nephritis and prednisone, and a soluble fms-like tyrosine kinase-1 antagonist of vascular endothelial growth factor found to be elevated in SLE patients with pre-eclampsia [12, 13]. Active lupus is a risk factor for pregnancy loss, preterm birth, preterm premature rupture of membranes, and intrauterine growth restriction which are also commonly found in SLE pregnancy. However, the causative factors behind these adverse effects remain elusive [10, 14, 15].

Therapeutic options utilizing antimalarials, most notably hydroxychloroquine (HCQ) and other immunosuppressants, such as azathioprine and tacrolimus, are compatible with pregnancy. HCQ should be continued throughout pregnancy as recent evidence shows benefits for both mother and neonate, and discontinuation can significantly increase SLE disease activity [10, 16].

Antimalarial agents such as chloroquine (CQ) and HCQ are commonly used in autoimmune diseases like SLE and rheumatoid arthritis [17]. HCQ was initially recommended for cutaneous and articular manifestations in SLE patients, and since it has demonstrated to reduce the occurrence of flares by about half and subsequently improve survival [18-20]. HCQ is approved by the United States Food and Drug Administration for SLE treatment [18, 21]. Many multifaceted beneficial effects of HCQ are reported in the literature. Though particularly effective in treating arthritis and cutaneous diseases [22, 23], HCQ is an independent predictor of complete renal remission in patients treated with mycophenolate mofetil in lupus nephritis [24].

HCQ is a weak lipophilic base, which accumulates in acidic subcellular compartments such as lysosomes and endosomes, where it remains trapped in a protonated state [25]. The resulting increase in pH from 4 to 6 inhibits lysosomal enzymes, causing impairment of antigen processing and presentation by major histocompatibility complex (MHC)-II complex on surfaces of macrophages and dendritic cells [26-28] (Fig. 1a), weakening adaptive immune response [29].

Click for large image

Figure 1. HCQ is a weak lipophilic base. (a) Increases pH in acidic subcellular compartments and inhibits lysosomal enzymes, causing impairment of antigen processing and presentation by MHC-II complex on surfaces of macrophages and dendritic cells. (b) HCQ inhibits endosomal TLRs via impairment of endosomal acidification, inhibiting TLR signaling and decreasing pro-inflammatory cytokines produced by mononuclear cells in the blood. (c) HCQ inhibits T- and B-cell receptor-mediated intracellular Ca++ mobilization from both intracellular and extracellular compartments. This inhibits the NFAT nuclear translocation and decreases gene expression of CD154, leading to the inhibition of T cells and B cells. (d) HCQ also blocks the assembly of the NOX complex by preventing translocation of gp91phox catalytic subunit into the endosome and subsequent formation of an active NOX complex. Inhibition of NOX-mediated signaling decreases the production of pro-inflammatory cytokines and nitric oxide bioavailability. HCQ: hydroxychloroquine; MHC: major histocompatibility complex; TLR: Toll-like receptor; NFAT: nuclear factor of activated T cells; NOX: NADPH oxidase.

A hallmark of rheumatic autoimmune disorders (RADs), such as SLE, primary Sjogren’s syndrome, and rheumatoid arthritis, is increased production and secretion of proinflammatory cytokines via activation of Toll-like receptor (TLRs) in macrophages, monocytes, helper T cells, neutrophils, and endothelial cells [30]. HCQ or CQ can inhibit endosomal TLRs, specifically TLR3, TLR7, TLR8, and TLR9, by impairing endosomal acidification [30-32] (Fig. 1b). By inhibiting endosomal TLR signaling, HCQ and CQ can decrease proinflammatory cytokines produced by mononuclear cells in the blood, including interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, and IL-2 [33-37].

HCQ can also impair Ca⁺⁺ release from the endoplasmic reticulum (ER). Specifically, HCQ inhibits T and B-cell receptor-mediated intracellular Ca⁺⁺ mobilization from both intracellular stores and the extracellular environment in a dose-dependent manner [38, 39]. By impairing Ca⁺⁺ mobilization from the ER, HCQ inhibits the nuclear factor of activated T cells (NFAT) nuclear translocation and decreases CD154 gene expression (Fig. 1c) [39]. CD154 is a transcription factor on T cells needed for B-cell activation and depends on Ca⁺⁺ release from the ER [39], leading to a multilevel inhibition of T cells and B cells.

An increase in the Th17 cells to regulatory T cells (Tregs) ratio has been linked to autoimmune diseases such as SLE [40, 41]. This imbalance increases the secretion of proinflammatory cytokines such as IL-17 and IL-6, and reduces levels of circulating factors like TGF-β, which suppresses inflammation and autoimmunity [40, 42]. In lupus MLR/pr mice, HCQ rebalancing the ratio of Th17 to Tregs, dampens the autoimmune response [40].

HCQ blocks the NADPH oxidase (NOX)-mediated signaling cascades activated by TNF-α and IL-1β in monocytes [43]. HCQ prevents the formation of an active NOX complex in the endosomes. Activation of endosomal NOX generates reactive oxygen species (ROS) [43]. HCQ-mediated NOX inhibition can impair the production of proinflammatory cytokines and the correct distribution of TLR8, suppressing the immune response (Fig. 1d) [43]. Furthermore, low ROS levels from HCQ treatment have been shown to increase nitric oxide bioavailability in mice, preventing endothelial dysfunction and reducing thrombus formation, a well-known clinical manifestation in SLE [43-45].

HCQ is the first-line treatment in SLE pregnancy, and its use has been recommended throughout pregnancy to control active SLE activity [10, 16]. HCQ improves pregnancy outcomes in SLE [46, 47], reduces the risk of congenital heart block in neonate of patients with positive anti-Ro/SSA antibody [48, 49], and delays SLE onset in patients who develop undifferentiated connective tissue disease [50]. HCQ reduces the risk of thrombosis due to antiphospholipid antibodies, and is not associated with increased risk of congenital defects, spontaneous abortions, fetal death, prematurity or decreased numbers of live births. In addition, HCQ is safe for the treatment of other autoimmune diseases during pregnancy [51, 52].

Cesarean delivery may be increased in pregnancies with SLE due to a higher risk of preeclampsia [9]. Yet spontaneous vaginal delivery has been shown to be significantly higher in patients taking HCQ [53]. A randomized clinical trial showed fewer patients with preeclampsia in the HCQ group, and fetal exposure in utero did not lead to any visual or hearing defects [54].

The serious adverse effects of HCQ exposure, such as cardiac and retinal toxicities, are rare [47]. A meta-analysis of SLE patients showed no concerns for retinopathy in human pregnancies [55]. In fact, only 0.1% of HCQ-related retinopathies have been associated with a median duration of HCQ treatment of > 10 years [21]. Despite cardiac toxicity being controversial, a large prospective study reported that the rate of heart conduction disorders during the 12-month follow-up was similar to that of the general population [56]. CQ and HCQ can cross the placental barrier, raising concerns of ototoxic and retinotoxic defects, primarily based on animal studies [57], but may reduce the risk of congenital heart block in high-risk populations [58] and have no significant risk of congenital malformations [57, 59]. Though detected in breast milk, HCQ is safe to use while breastfeeding. A study on breastfeeding SLE mothers treated with HCQ showed that all breastfed infants had normal development and visual function [58]. In addition, the risk of adverse effects with less than 12 months of HCQ exposure is negligible, making HCQ a safe medication during SLE pregnancy [53]. As such, the European Alliance of Associations for Rheumatology has also recommended its use for SLE management [60] (Table 1).

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Table 1. Clinical Aspects of Hydroxychloroquine Usage in Lupus During Pregnancy

Coronavirus disease 2019 (COVID-19) can have severe implications on maternal and fetal health, sometimes leading to extreme prematurity [61]. Konig et al identified 80 patients with SLE and COVID-19 in the global physician-reported registry and concluded that SLE patients with HCQ treatment are not protected from COVID-19 [62]. Although data remain scant, there is no evidence that pregnancy increases susceptibility and severity to COVID-19 [61]. A case series of nine pregnant women with COVID-19 pneumonia in the third trimester had clinical presentation similar to nonpregnant adults, with no evidence of intrauterine transmission of SARS-CoV-2 [63]. Large-scale studies, however, are needed to determine the absence of vertical transmission. High concentrations of cytokines are detected in critically ill patients with COVID-19 due to a cytokine storm that contributes to disease severity [64]. It has been shown in vitro that HCQ is less toxic than CQ and efficiently inhibits SARS-CoV-2 infection by blocking the transport of SARS-CoV-2 from endosomes to endolysosomes, preventing the release of the viral genome [65]. Furthermore, HCQ is a successful anti-inflammatory agent that can significantly decrease cytokine and pro-inflammatory factor production [65]. A randomized clinical trial of 685 patients demonstrated that HCQ did not show any significant benefit for reducing COVID-19-associated hospitalization or other secondary clinical outcomes [66].

Further large-scale clinical outcomes studies are required to study the long-term effects of HCQ on pregnancy and the infant after delivery. Moreover, data are scarce on the concentration of HCQ in breastmilk and the long-term implications for infants. It is also important to investigate the optimal therapeutic range of HCQ in serum during SLE pregnancy, balancing where the risk is adverse effects on maternal and fetal health is the lowest.

Acknowledgments

None to declare.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Author Contributions

NL, AK, and JC wrote the manuscript.

Data Availability

The authors declare that data supporting the findings of this study are available within the article.

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