Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: a prospective study of 103 pregnancies

J. Cortés-Hernández, J. Ordi-Ros, F. Paredes, M. Casellas1, F. Castillo2 and M. Vilardell-Tarres

Departments of Internal Medicine,
1 Obstetrics and Gynaecology and
2 Paediatrics, Vall d'Hebron Hospitals, Barcelona, Spain


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. Our aim was to assess the outcome of pregnancy in a cohort of patients with SLE and to evaluate clinical and laboratory markers for fetal outcome and maternal flares.

Methods. Sixty patients with 103 pregnancies were evaluated prospectively between 1984 and 1999.

Results. There were 68 live births, 15 spontaneous abortions, 12 stillbirths and eight therapeutic abortions. Of liveborn infant births, 19 were premature, 24 had suffered intrauterine growth restriction and one had neonatal lupus. Maternal lupus flares occurred in 33% of pregnancies, mostly in the second trimester (26%) and in the post-partum period (51%). Flares during pregnancy showed a statistically significant association with discontinuation of chloroquine treatment, a history of more than three flares before gestation, and a SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) score of >=5 in these flares. Antiphospholipid antibodies, C3 hypocomplementaemia and hypertension during pregnancy were significantly associated with fetal loss, prematurity and intrauterine growth restriction.

Conclusions. Patients with more active SLE and those with aPL antibodies and hypertension should be monitored and managed carefully during pregnancy.

KEY WORDS: Systemic lupus erythematosus, Pregnancy, Fetal outcome, SLE flares, Antiphospholipid antibodies, Hypertension, Hypocomplementaemia.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
SLE is an autoimmune disease that is well recognized to affect women primarily, especially those of childbearing age. As a consequence, pregnancy and its outcome are of particular importance in this condition. Although advances in the treatment of obstetric complications and improvements in neonatal medicine have allowed women with SLE to have successful pregnancies, SLE remains a disease associated with significant fetal and maternal morbidity [1].

The impact of pregnancy on lupus disease has been investigated but remains controversial, especially with regard to the incidence of disease exacerbations during gestation. Various studies have demonstrated that lupus activity may increase [25], decrease or remain unchanged throughout pregnancy [611]. Several reasons have been proposed to explain this disparity. Differences in the composition of patient cohorts and the use of non-standardized definitions of lupus flare make comparison between studies difficult. Moreover, many complications common to pregnancy may be mistakenly attributed to SLE [9, 12].

In contrast, the impact of SLE on pregnancy is more clearly understood. Women with lupus disease are not less fertile than unaffected women [13], but fetal outcome in lupus pregnancy is characterized by higher rates of fetal loss, preterm delivery and intrauterine growth restriction (IUGR) [1]. Multiple factors have been identified in association with this less successful outcome, including lupus activity during pregnancy, previous nephropathy, maternal hypertension and positivity for antiphospholipid (aPL) antibodies [1, 14].

Finally, SLE may affect the outcome of pregnancy through the development of neonatal lupus, a syndrome that is characterized by fetal and neonatal heart block and subacute cutaneous lupus lesions and is associated with the presence of antibodies to the cytoplasmic ribonucleoproteins SSA (Ro) and SSB (La) [15].

The aim of this prospective survey of pregnant lupus patients was to identify clinical and serological factors that would predict poor maternal and fetal outcomes. We report our results of 103 pregnancies in 60 lupus-affected women.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Between 1984 and 1999, data from 103 consecutive pregnancies in 60 SLE patients attending Vall d'Hebron Hospitals in Barcelona, Spain, were collected prospectively by the combined internal medicine, obstetric and paediatrics services. All patients met at least four of the American College of Rheumatology criteria for the classification of SLE [16].

Patients were seen at least once a month from diagnosis of pregnancy to 8 weeks after delivery or more frequently when needed. At each assessment, a standardized medical history, physical examination and laboratory evaluation was performed. Laboratory tests included full blood count, ESR, serum albumin, creatinine and electrolyte concentrations, urate, liver function tests, urinalysis and 24-h urine collection for measurement of creatinine clearance and protein excretion. In addition, the following immunological evaluations were performed in all pregnancies at the first visit and at 3-month intervals: C3 and C4 complement levels (nephelometry); antibodies to double-stranded DNA (anti-dsDNA) (Farr's ammonium sulphate precipitation technique); antibodies to extractable nuclear antigens, including anti-Ro (SSA), anti-La (SSB), U1RNP and anti-Sm (counterimmunoelectrophoresis); lupus anticoagulant (LA) (coagulation assays); anticardiolipin (aCL) and anti-ß2-glycoprotein I antibodies (ELISA) [17, 18]. Although this last test was introduced in 1995, all samples, which had been kept at –70°C, were tested simultaneously at the end of the study.

Overall disease activity of SLE was evaluated using the SLE Disease Activity Index (SLEDAI) from 1992 onwards [19] and previous pregnancies were assessed retrospectively from clinical notes. A flare was defined as any clinical event attributable to disease activity that required a change in therapy. Patients were advised not to become pregnant when their disease was active or when receiving potentially teratogenic agents. Barrier contraceptive methods were recommended. Flares were treated with prednisone (0.5–1 mg/kg/day) and/or chloroquine (250 mg/day). Standard doses of azathioprine (<=2.5 mg/kg/day) were given for the treatment of severe renal flares during pregnancy. Aspirin prophylaxis (100 mg/day) was prescribed for patients positive for LA and/or aCL antibodies. Patients with antiphospholipid syndrome (APS) previously complicated by thrombotic events or fetal loss received aspirin (100 mg/day) and prednisone 1 mg/kg/day (before 1989) or unfractionated heparin thereafter [20, 21]. In patients with positive anti-SSA/Ro or anti-SSB/La antibodies, no treatment was administered unless there were intrauterine cardiac complications, in which case dexamethasone (4 mg/day) was given [15].

Prenatal assessment consisted of sequential ultrasound studies during the first trimester of pregnancy, at 20 weeks of gestation and at monthly intervals thereafter until delivery. Doppler analysis of uteroplacental circulation was performed at 20 weeks of gestation and every month subsequently. Fetal echocardiography, introduced in 1986, was performed at 18 weeks of gestation; in patients with anti-SS-A/Ro or anti-SS-B/La antibodies, echocardiographic studies were repeated at 24 and 30 weeks of gestation. Fetal condition was assessed by the non-stress test, which was performed every week from 28 to 30 weeks of gestation. When fetal distress was suspected, a contraction stress test was performed and the patient was admitted to hospital for observation. Pregnancy was terminated in case of fetal distress or significant maternal complication.

Spontaneous abortion was defined as the spontaneous loss of pregnancy before 20 weeks of gestation, stillbirth as the death of the foetus in utero after 20 weeks of gestation, and therapeutic abortion as the voluntary termination of pregnancy. Fetal loss was the loss of pregnancy due to spontaneous abortion or stillbirth. Premature birth was a live birth before 37 weeks of gestation and IUGR was defined as birth weight <2500 g. Hypertension was defined as a systolic blood pressure >140 mmHg or a diastolic blood pressure >90 mmHg. Pre-eclampsia was defined as evidence of proteinuria (>3 g/24 h) and hypertension with or without oedema in patients with normal blood pressure and no evidence of proteinuria prior to 20 weeks of gestation.

Statistical analysis
Each pregnancy was treated as a separate observation for analysis. Descriptive statistics, the {chi}2 test, Fisher's exact test and Student's t-test were used. A multiple logistic regression model was applied when the size of the sample groups allowed it. Statistical significance was set at P<0.05.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Sixty patients had 103 spontaneous pregnancies. Thirty-three (55%) patients had had only one pregnancy, 15 (25%) two pregnancies, five (8%) three pregnancies and seven (12%) four or more pregnancies. The mean age at first pregnancy was 28 yr (range 18–42) and the mean duration of disease before first pregnancy was 5.3 yr (range 0–13). In two patients, lupus was first diagnosed during pregnancy. Active disease at conception was present in seven pregnancies.

The clinical and laboratory features of the patients at conception are summarized in Table 1Go. Of the 12 patients with lupus nephritis (LN), three had type III histology (WHO criteria), seven had type IV, one had type V and one had thrombotic nephropathy secondary to APS. These 12 patients had 20 pregnancies. At the time of pregnancy, proteinuria was present in three of these patients, with a mean of 1.9 g/24 h (range 1.5–2.5). Renal impairment was present in three patients, with a mean creatinine level of 3.8 g/dl (range 2.5–7.3) and hypertension controlled by treatment was present in five.


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TABLE 1.  Patient characteristics prior to pregnancy

 
At onset of pregnancy, 38 (63%) patients were taking steroids, with an average prednisone dose of 4.8 mg/day (range 2–20), 29 patients (48%) were taking antimalarials (250 mg/day), three patients (5%) were given 50 mg/day of azathioprine, three patients (5%) were taking 100 mg/day of cyclosporin and one patient (2%) was receiving methotrexate (7.5 mg/week). Chloroquine was stopped in asymptomatic patients (26 out of 29) during the first trimester and was reintroduced after this period to treat subsequent cutaneous or articular flares. When pregnancy was diagnosed, patients taking cyclosporin or methotrexate had these treatments discontinued; azathioprine treatment was continued. During pregnancy, eight patients required an increased dose or initiation of prednisone therapy, with an average dose of 18 mg/day. Aspirin (100 mg/day) was employed in 16 pregnancies. Before 1989, prednisone (1 mg/kg/day) was started in pregnancies of patients with a history of complicated APS (10 pregnancies) and thereafter unfractionated heparin was started (14 pregnancies) in association with aspirin (four pregnancies) or with intravenous immunoglobulin therapy (two pregnancies). Four patients required azathioprine (100 mg/day) for renal flare, and in one case monthly cyclophosphamide pulses were administered for diffuse proliferative glomerulonephritis in the puerperium.

Fetal outcome
Of the 103 pregnancies, 68 (66%) resulted in a live birth, eight (8%) in therapeutic abortion [two of them were due to concomitant treatment with immunosuppressive agents (methotrexate and cyclosporin) and the others were in response to maternal request], 15 (14%) in spontaneous abortion and 12 (12%) in stillbirth.

For the 68 live births, the mean gestational age at delivery was 37 weeks (range 24–41) and the mean birth weight was 2162 g (range 800–4100). Eighty per cent of deliveries were vaginal and 20% by Caesarian section. Prematurity occurred in 19 of 68 live births (28%), IUGR in 24 (35%), with a mean birth weight of 1876.6 g (range 800–2300). Fetal distress, leading to early delivery, was noted in eight pregnancies (12%). One baby was born with an incomplete congenital heart block to a mother positive for anti-Ro/SSA antibodies. No pacemaker was required, although heart block persisted after 8 yr of follow-up.

Fetal outcome in pregnancies of women with LN is shown in Table 2Go. Of 20 pregnancies, one was excluded because of therapeutic abortion. Of the other 19 pregnancies, eight resulted in live births (42%), five in spontaneous abortion (26%) and six in stillbirth (32%). Of the live births, three were premature and with IUGR.


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TABLE 2.  Factors associated with fetal loss and poor fetal outcome in pregnancies of mothers with previous LN

 
Fetal outcomes in each year of the study period were examined to determine whether changes in practice might have affected the results of lupus pregnancy. Although a decreasing trend in the rate of spontaneous abortion was observed, differences were not statistically significant. Yearly rates of stillbirth, prematurity or IUGR were similar over the course of the study. In 1989, treatment of pregnant patients who had aPL antibodies was modified by the introduction of heparin [20, 21]. We therefore specifically compared fetal outcomes in pregnancies in patients with aPL who received treatment before and after this time. An increase in the live birth rate was noted with the introduction of this new regime [three out of 10 pregnancies (30%) before 1989 vs 10 out of 14 (71%) after 1989, P=0.0013 (paired Student's t-test)], which can be explained by individually non-significant changes in the rate of abortion [four out of 10 (40%) vs two out of 14 (14%), P=0.167] and fetal death [three out of 10 (30%) vs two out of 14 (14%), P=0.343]. No statistically significant difference in rates of prematurity or IUGR were noted.

Predictors of fetal loss
Spontaneous abortion and stillbirth were considered separately. By univariate analysis, spontaneous abortion was associated with any of the aPL antibodies (LA, aCL or anti-ß2-glycoprotein I antibodies) (P<0.001) and C3 hypocomplementaemia (P<0.05). However, in the subset of patients with LN, aPL was the only variable significantly associated with spontaneous abortion (P<0.005). No association was found with renal impairment, hypertension or the histological class of the nephropathy, although the small number of patients with nephritis in our cohort may be a confounding factor. Stillbirth was associated with C3 and C4 hypocomplementaemia (P<0.05), previous LN (P<0.005) or hypertension at conception (P<0.001). With respect to aPL, an association with anti-ß2-glycoprotein I antibodies was found (P<0.005), whereas no association was found with LA or aCL antibodies. In the multiple logistic regression analysis, hypertension at conception, C3 hypocomplementaemia and anti-ß2-glycoprotein antibodies were statistically associated (P<0.05) with fetal loss (spontaneous abortion and stillbirth) (Table 3Go).


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TABLE 3.  Factors associated with fetal loss (spontaneous abortion and stillbirth) and poor fetal outcome (prematurity and IUGR) in pregnancies of SLE mothers

 

Predictors of poor fetal outcome
By univariate analysis, prematurity was significantly associated with any aPL antibody (aCL, P<0.001; LA and anti-ß2-glycoprotein antibodies, P<0.05), hypertension during pregnancy (P<0.05) and treatment with prednisone during pregnancy (P<0.005), whereas IUGR was significantly related to maternal age over 35 yr (P<0.05), C4 hypocomplementaemia (P<0.01) and hypertension during pregnancy (P<0.005). By multiple logistic regression analysis, only hypertension during pregnancy and aCL antibodies were associated with poor fetal outcome (P<0.05) (Table 3Go). In the subgroup of patients with LN, hypertension during pregnancy was the only variable associated with poor fetal outcome (P<0.05).

Maternal outcome
Thirty-four (33%) pregnancies were associated with flares (Table 4Go). A total of 39 flares were recorded, with a mean SLEDAI score of 3.6 (range 1–4). Five (13%) flares occurred in the first trimester of gestation, 10 (26%) in the second trimester, four (10%) in the third trimester and 20 (51%) in the post-partum period. Three post-partum flares were preceded by an abortion and three occurred after a stillbirth.


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TABLE 4.  Distribution of SLE flares occurring during pregnancya

 
The joints (69%) and the skin (33%) were the sites involved most frequently. There were four renal flares. Proteinuria, haematuria, hypocomplementaemia, hypertension and elevated anti-dsDNA antibodies characterized each of these flares. Biopsy was performed in one case and histological findings were consistent with type IV glomerulonephritis. Another patient had a previously diagnosed type IV LN and was not rebiopsied. One patient had a renal flare during the second trimester of gestation and, despite improvement after intravenous prednisolone and azathioprine, relapse occurred in the post-partum period. A renal biopsy showed type IV nephritis.

A number of maternal complications were observed. Pre-eclampsia developed in two patients, one of whom had aCL antibodies. Gestational proteinuria was noted in 12 patients and gestational hypertension in five. Four patients with aPL antibodies presented with thrombotic or arterial events in spite of treatment with heparin (one in the third trimester and three in the post-partum period). Three of these patients presented with venous thrombosis, complicated in one case by pulmonary thromboembolism. The arterial event was a stroke in the puerperium, when these antibodies were detectable for the first time.

The effect of pregnancy on renal function in patients with a history of previous LN was studied. In 15 of 19 pregnancies, no changes in renal function were observed. One patient had transient deterioration of renal function and three had a permanent change in renal function, but in two cases this deterioration occurred in patients with previous renal impairment. Five patients presented with new onset of proteinuria and three with hypertension. However, these changes were due to a renal flare in only one case.

Predictors of flare during pregnancy
We noted that pregnancy was associated with enhanced lupus activity, with a mean rate of flares of 0.4 per person-yr before pregnancy, rising to 1.2 during gestation (P<0.0001). As shown in Table 5Go, variables significantly associated with flares during pregnancy were increased number of flares before gestation (P<0.05), a higher SLEDAI index (P<0.05) and previous treatment with chloroquine (P<0.05). Separate {chi}2 analysis revealed that the increased risk of pregnancy flare started to accrue with a history of more than three flares before gestation (P<0.05) or a SLEDAI score of >=5 in these flares (P<0.05).


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TABLE 5.  Characteristics of patients who did and did not experience a flare

 
Flares during pregnancy were more frequent among patients with active disease at conception but differences were not statistically significant.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Although the outcome of pregnancy in patients with SLE has improved considerably in recent years, the frequency of fetal loss remains higher than that in matched pregnant controls. This is due to greater incidences of prematurity, spontaneous abortion and intrauterine death [1, 19]. Excluding pregnancies that terminated in therapeutic abortion, 72% of this series of lupus pregnancies resulted in live births. This percentage is similar to that reported in the literature [10, 13, 1923]. The frequency of fetal loss has been reported as 8–43% in retrospective series and 11–24% in prospective studies [1, 10, 11, 14, 2226]. Our rate of fetal loss of 28% is somewhat higher and may be explained by a higher frequency of aPL positivity in our cohort than in other SLE populations (43% of our patients, accounting for 55% of the pregnancies, presented with positivity to at least one aPL antibody).

Different clinical features and immunological variables have been associated with increased fetal loss in pregnant women with lupus disease, including active disease [26], active renal disease at conception [27], anti-Ro/SSA [28], aPL antibodies [24, 29] and trophoblast-reactive lymphocytotoxic antibodies [30]. However, the underlying pathophysiological mechanisms remain unclear and it is likely that there are several mechanisms that may lead to placental injury in patients with lupus [31]. It is noteworthy that fetal loss was strongly associated with aPL antibodies and C3 hypocomplementaemia in our study. Although patients with positive aPL antibodies constitute a group at high risk of fetal loss, conflicting data regarding the strength of this association have been reported [11, 14, 2224, 26, 32]. This may be due to failure to use optimal laboratory assays for the detection of aPL antibodies during pregnancy, attempts to establish associations from historical data prior to the advent of optimal aPL antibody testing, and the effects of anticoagulation [1]. In 1989, we introduced a change in the treatment of patients with aPL antibodies, and there was a significant improvement in live birth rate following the introduction of heparin (70%) when compared with prednisone and aspirin treatment (30%). This increase in the live birth rate seems to be related to a decrease in the rate of spontaneous abortion and fetal death, although this observation was not statistically significant. Different treatments, including aspirin, steroids, heparin and, more recently, intravenous immunoglobulin, have been used either as single agents or in combination to improve the poor live birth rate amongst women with APS [33]. A rate of live births of 30–100% has been reported in different studies with prednisone and low-dose aspirin treatment [34]. However, steroids have fallen into disfavour as their use is associated with a higher risk of the development of gestational diabetes, hypertension and prematurity, and no evidence has been provided for a decrease in aPL antibody levels with this treatment. Currently, low-dose aspirin together with heparin is considered the treatment of choice. Two prospective randomized studies have reported that this combinations leads to a live birth rate of 70% and is superior to low-dose aspirin alone [35, 36].

The association of hypocomplementaemia and poor fetal outcome has been noted previously [37], but a definite pathophysiological mechanism of placental dysfunction has not been elucidated.

Reported incidences of preterm delivery in SLE pregnancies have ranged between 17 and 49% [14, 2224, 38]. Lupus activity and hypertension are the strongest predictors of preterm birth [8, 22, 23, 25]. However, other factors have been associated, such as a lack of high-school education [23], the presence of Raynaud's phenomenon [23], the use of aspirin, low serum C3 levels, Afro-Caribbean race [2], treatment with prednisone at >20 mg/day [25] and the presence of aPL antibodies [26, 39]. In our study, prematurity occurred in 24% of live births and IUGR in 31%. By multiple regression analysis, only hypertension during pregnancy and aCL antibodies were associated with poor outcome (prematurity and IUGR). We did not observe an association between prematurity, SLE activity and renal disease. This may be related to the fact that most flares were mild and that most of the patients had inactive disease at conception.

Renal disease has been considered as particularly dangerous during gestation. Lupus nephritis imposes haemodynamic constraints on the integrity of the uteroplacental unit, in addition to the immunological events due to lupus and its treatment. Although studies disagree on the effect of lupus nephropathy on fetal loss [4043], it is accepted that there is a better prognosis if disease has been inactive for 3–6 months before conception and in the absence of hypertension [14]. In our study, 12 patients with renal disease had 20 pregnancies, with live births in eight cases and fetal loss in 11. Pregnancies in patients with previous nephritis showed a higher rate of fetal loss than those in women without renal involvement. Our rate of fetal loss of 56% in SLE patients with LN is higher than figures reported in other studies [3739], which may be explained by the fact that 50% of our patients with a history of LN had positivity for at least one aPL antibody. Others have noted the association between these antibodies and fetal loss [44], and we found a statistically significant association between fetal loss and LA, aCL and anti-ß2-glycoprotein I antibodies. In accordance with findings in the study of Ovasiu et al. [45], we observed no relationship between outcome and the severity of initial histological appearance, the presence of proteinuria, creatinine level and treated hypertension. Neither of the two patients with pre-eclampsia had suffered previous LN.

Although studies regarding the effect of pregnancy on SLE activity [26, 811, 46, 47] lack consensus, there are data supporting increased SLE activity during pregnancy. Frequencies of flares during pregnancy have been estimated as 10–30% for patients with non-active disease before gestation and as 60% in patients with active disease [40]. In our study, 34 of 103 pregnancies were associated with a disease flare, accounting for a total of 39 flares. Most flares were moderate in severity and occurred more frequently in the second trimester and in the post-partum period. In agreement with the study of Zulman et al. [3], we observed an increase in lupus flares during pregnancy when the same patients were compared before and during pregnancy. Some studies have demonstrated that lupus patients are more likely to flare during pregnancy if disease is active at conception [26, 27]. In our study, patients with active disease at conception showed more flares than patients with inactive disease; however, differences were not statistically significant, probably because there were only seven patients with active disease. Flares were more frequent in patients who had had more than three flares before conception, with a SLEDAI score >=5 in these flares, and in patients in whom chloroquine treatment had been stopped. Previous studies have determined that patients with SLE may experience flares of their disease if antimalarial drugs are discontinued [48]. Their association with congenital defects has discouraged administration during pregnancy [49]. However, recent studies in SLE patients treated with hydroxychloroquine or chloroquine have shown no adverse effect, either on the pregnancy or on the fetus, suggesting that antimalarials are safe during pregnancy, although the long-term potential effects on offspring are not well known [5053].

In summary, an increase in lupus flares during pregnancy was observed in this cohort of SLE patients, as well as increases in the frequencies of pregnancy loss, preterm birth and IUGR. Poor fetal outcome was associated mainly with aPL antibodies, hypocomplementaemia and hypertension during pregnancy. These findings indicate that patients with more active disease during the course of SLE and with aPL antibodies and hypertension during pregnancy should be monitored and managed carefully.


    Acknowledgments
 
This work was supported by Grant FISS 95/1001 from Fondo de Investigaciones Sanitarias de la Seguridad Social, Spain. We thank Dr P. Choi for critical reading of the manuscript.


    Notes
 
Correspondence to: J. Ordi-Ros, Laboratori de Recerca de Medicina Interna 1, Hospital general Vall d'Hebron, Passeig Vall d'Hebron 119-129, E-08035 Barcelona, Spain. Back


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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 1 May 2001; Accepted 4 December 2001





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Systemic Lupus Erythematosus and Autoimmunity
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