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Review Article

Neonatal Lupus: An Update

Sathish Kumar
Department of Pediatrics, Christian Medical College, Vellore, Tamil Nadu, India

Received: September, 2016

Accepted: November, 2016
Published: November, 2016
Address for correspondence:
Dr. Sathish Kumar,
Department of Pediatrics,
Christian Medical College,
Vellore ‑ 632 004, Tamil Nadu, India.
E‑mail: sathishkumar@cmcvellore.ac.in
Abstract
Neonatal lupus erythematosus (NLE) is a syndrome that usually presents in the fetus or
neonates that is caused by transplacental passage of autoantibodies from the mother. It is a
clinical spectrum of cutaneous, cardiac, and systemic abnormalities observed in the newborn
or infants whose mothers have autoantibodies against Ro/SSA and/or La/SSB. Congenital
complete heart block is the most serious manifestation of NLE that can develop in utero
or after birth. Multidisciplinary team involvement is indicated. This article will provide an
overview the presentation of NLE and will review the evidence for current therapies.
Key Words: Anti‑La antibodies, anti‑Ro antibodies, congenital atrioventricular block, neonatal
lupus erythematosus

Introduction Neonatal Lupus Erythematosus

Neonatal lupus erythematosus (NLE) is a syndrome
characterized by skin, cardiac, and systemic abnormalities
seen in newborn infants whose mothers have
autoantibodies against Ro/SSA and/or La/SSB.[1] The
condition was first described almost 60  years ago by
McCuistion and Schoch, who noted the presence of
characteristic skin lesions on a baby born to a mother who
suffered from lupus.[2] By the late 1970s, NLE was found
to be caused by maternal transplacental passage of the
anti‑SSA/Ro antibodies from mother to fetus.[3] The term
NLE was initially selected because of the similarity of skin
lesions with those that can occur in subacute cutaneous
lupus. However, the disparities between the NLE and
those living with systemic lupus, especially for cardiac
involvement, highlight the inappropriateness of the term,
and only minorities of mothers have defined systemic
lupus erythematosus. Furthermore, many of the mothers
have or go on to develop primary Sjogren’s syndrome
or undifferentiated autoimmune disease, and many of
them are totally asymptomatic. This article will provide
an overview of NLE including clinical presentations,
pathogenesis, and treatment. Much of the current
knowledge about this syndrome based on the study of the
American Neonatal Lupus Registry[4,5] and a recent large
French study.[6]
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Clinical manifestations that present in the fetus,
neonate, or infant due to the transfer of anti‑SSA/Ro,
and/or anti‑SS‑B/La and/or rarely anti‑RNP antibodies
are termed NLE.[7] These antibodies may be found in
mothers who have been diagnosed with SLE, primary
Sjogren’s syndrome, antiphospholipid syndrome or other
autoimmune disorders but only cause clinical disease
in a minority of babies born to mothers with these
autoantibodies.[8] The most common manifestations of NLE
are permanent cardiac and transient cutaneous disease.
Congenital complete heart block  (CHB) due to congenital
atrioventricular block  (CAVB) in the absence of structural
cardiac abnormalities is usually detected during the
second trimester. CAVB is almost universally associated
with maternal autoantibodies reactive with the 52‑kD Ro,
60‑kD Ro, or 48‑kD La antigens.[8] The skin rash usually
appears during the first 2  months after birth and appears
preferably over the scalp and periorbital region.[2] Skin
rash is also strongly linked to Ro/La maternal antibodies
as well as to antibodies against U1 RNP. The skin rash
seen in these babies often resemble the rash of subacute
cutaneous lupus.[2] Despite its rarity, NLE has attracted
great attention since it is a model of autoimmune disease
acquired “passively” due to placental transfer of maternal
antibodies to the fetus.
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DOI:

How to cite this article: Kumar S. Neonatal lupus: An update. Indian J

10.4103/0973-3698.194548
Rheumatol 2016;11:139-44.

S139 © 2016 Indian Journal of Rheumatology | Published by Wolters Kluwer - Medknow

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Kumar: Neonatal lupus
Epidemiology of Neonatal Lupus
In systemic lupus erythematosus, the generally accepted
prevalence of anti‑SSA/Ro is from 25% to 30% and
anti‑SSB/La antibodies from 5% to 15%.[1] The frequency
of CAVB in women with anti‑Ro antibodies is estimated
between 1% and 2%.[8] When a woman has had a child
with CAVB, the risk of recurrence of CAVB in a subsequent
pregnancy is about 19% (data on 257 pregnancies resulting
from US observatories, French and a European series).[9]
Pathophysiology
The CAVB is characterized by the presence of immune
complex deposition, inflammation, and calcification of
fibrosis at the fetal atrioventricular (AV) node.
However, to date, the molecular mechanisms that connect
placental transfer of autoantibodies to abnormalities in
fetal intracardiac conduction, and the process leading to
myocarditis or fibrosis of the AV node are not completely
understood. Recent literature suggests that factors such
as maternal Vitamin D deficiency or hypothyroidism,
immunological abnormalities in the fetus: Dysfunctions
of toll‑like receptors  (TLRs), all in a context of increased
physiological apoptosis including heart fetal cells are
involved in pathophysiology of NLE. The normally
intracellular antigens, Ro52 and Ro60, are expressed
during apoptosis on the surface of fetal cells, and maternal
anti‑Ro and anti‑La antibodies may well bind to these
antigens and create inflammation and fibrosis, or target
calcium channels on the surface of cardiomyocytes by
cross‑reaction or maternal chimerism, and cause fetal
heart rhythm disorders. Inflammation and fibrosis, in turn,
may be responsible for intracardiac conduction disorders,
and for endomyocardial fibrosis and other disorders that
occur occasionally. The team of Jill Buyon reported the
existence of an excess of apoptosis and the presence of
infiltration by macrophages in the hearts of fetuses died
of CAVB.[10] They showed that apoptotic cardiomyocytes
opsonized by maternal antibodies induce secretion by
phagocytes of proinflammatory and profibrotic cytokines,
responsible for the acquisition by cardiomyocytes of a
fibrotic phenotype of.[11] In vitro, anti‑Ro52 antibodies
including those that recognize the p200 peptide can
attach to the surface of cardiomyocytes and thus disturb
the spontaneous movements of calcium, resulting in
intracellular accumulation of calcium, loss of contractility,
and finally a cell apoptosis. In animal models, the transfer
of anti‑Ro52 anti‑p200 antibody specificity is associated
with a greater frequency of CAVB presenting with sinus
bradycardia in newborn than the other types of anti‑Ro52
antibody but the importance of the anti‑p200 specificity
has not been confirmed in humans and testing for these
specific antibodies is not routinely available.
The anti‑Ro antibodies although important are neither
necessary, nor sufficient to cause congenital heart block,
Indian Journal of Rheumatology  ¦  Supplement 2 2016
as only 1%–2% of fetuses whose mothers’ have anti‑Ro
antibodies are affected, anti‑La antibodies alone are
occasionally responsible and twins discordant for CAVB
have been described. Other players in the pathogenesis
of congenital heart block are not well understood
but may include environment factors contributing to
a seasonal pattern in some cases and an association
with other autoimmune conditions including maternal
hypothyroidism.[12,13]
Microchimerism is a mechanism by which maternally
derived cells crossed the placenta during pregnancy and
remain in fetal tissues without being destroyed. They are
thus able to survive in symbiosis. Jill Buyon raised the
possibility that a maternal microchimerism phenomenon
may contribute to the pathophysiology of CAVB.[14]
Innate immune mechanisms involving TLRs may be involved in
neonatal lupus. Reaction between TLRs and nuclear material
resulting from apoptosis could induce an inflammatory
reaction in certain tissues causing the clinical symptoms
observed particularly at cardiac level. In this case, the immune
complexes formed of the fetal antigen Ro and the maternal
autoantibodies to Ro may be internalized and react with
endosomal TLR7. Activation of TLRs resulting in activation
of autoreactive B‑cells and macrophages and the generation
of interferon α, could be responsible for the stimulation of
macrophages capable of secreting the transforming growth
factor β and endothelin 1, that play a role in inflammation
and leading to cardiac fibrosis.[15] This hypothesis is supported
by the observations that hydroxychloroquine  (HCQ) can
inhibit TLR7 signaling and HCQ can significantly reduce the
risk of recurrence of CAVB in babies born to mothers with a
previously affected baby.[9]
The contribution of genetic factors involved in the
immune response is supported by some studies of
patient populations and animal models have shown
that the HLA‑DRB1*04 and Cw*05 were associated with
susceptibility to CAVB whereas the HLA DRB1*13 and
Cw*06 appeared to be protective. More recently, Clancy
et  al. showed a strong association between certain HLA
polymorphisms and the occurrence of CAVB, in a study of
genomic SNP.[16] However, these studies do not currently
have implications for prevention or treatment.
Diagnosis
NLE can be detected either in utero or during the postnatal
period. In utero, the diagnosis is suspected in a fetus that
exhibits any degree of CHB on a fetal echocardiogram.
The presence of CHB in a fetus of a mother with a known
autoimmune disorder is usually assumed to be due to the
presence of maternal autoantibodies. CHB may develop
in utero, once transplacental passage of immunoglobulins
starts in the second trimester at about week 16. Postnatally,
NLE is most often recognized based on the characteristic
skin manifestations. If the baby manifests the characteristic
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Kumar: Neonatal lupus
skin rash, measurement of maternal serum autoantibodies
is indicated to help confirm the diagnosis. Persistent
neonatal bradycardia also suggests the presence of CHB.
An echocardiogram and Doppler study of the heart is
important to confirm CHB, to rule structural heart disease
that can cause heart block, and to look for any other
associated cardiac findings. A  skin biopsy in the fetus may
be necessary if one has doubt regarding the diagnosis of
NLE or in the mother if the maternal diagnosis of subacute
cutaneous lupus erythematosus needs confirming.
Clinical Manifestations
Cutaneous
Cutaneous lesions appear most commonly between the
4th  and 6th  week of life or sometimes at birth and recover
spontaneously without sequelae in more than three‑fourth
of the cases.[17] Lesions of NLE appears over sun‑exposed
areas, especially around the eyes, face, and scalp.[17,18] They
are erythematous macules, or papules which are rounded,
annular or elliptical in shape with erythema, and scaling
sometimes covered with fine scales.[18] Lesions are superficial
and resemble subacute cutaneous lupus erythematosus
of the adult. Mucosa is not involved.[18] In some cases,
the skin lesions can involve the almost the entire body.
New lesions often appear over several weeks and they
disappear by 6–8 months of age at the time when maternal
autoantibodies clears from the baby’s circulation.[17] Skin
biopsy shows interface dermatitis and vacuolar alterations
at the dermoepidermal interface and adnexal structures.[19]
These findings on skin biopsy are seen on those infants who
have the typical erythematous desquamative lesions.
Another type of skin biopsy findings which correlate with
cutaneous urticaria‑like lesions are a superficial and deep
perivascular and periadnexal lymphocytic infiltrates.[19]
Immunofluorescence staining often shows deposits of IgG,
IgM, IgA, or C3 at the dermo‑hypodermic junction.
Cardiac Neonatal Lupus
Congenital atrioventricular block
Heart block can present in utero or rarely in the after
birth.[20] Cardiac involvement can present as first, second,
or third‑degree heart block. The finding of persistent sinus
bradycardia in a fetus may be the first clue that prompts
investigation into CHB, especially in the absence of history
of an autoimmune disease in the mother. The CAVB is
usually found between 20 and 24  weeks of gestation
during a routine ultrasound or when fetal bradycardia
is observed on auscultation of the heart sounds but it
can occur at any time from week 16 to term and may
present occasionally after birth.[20] CAVB is mostly complete
and irreversible, manifested as bradycardia below 100/min.
Sometimes, evidence of a first‑  or second‑degree heart
block is found which does not cause clinical bradycardia.
This may sometimes be spontaneously reversible but can
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progress to complete block before or after birth warranting
systematic regular supervision.[20]
Other Heart Damage
During the last decade, the occurrence of dilated
cardiomyopathy has been reported, which may occur later
with a rated frequency between 5% and 28.6%.[21] Children
with CAVB should be monitored not only in terms of heart
rate but also in terms of overall heart function. Fetal hydrops
is a devastating consequence of autoantibodies causing
CAVB and affecting the myocardium resulting in dilated
cardiomyopathy in some babies. The spectrum of neonatal
lupus has also expanded with the description of cases of
endomyocardial fibroélastoses. Recently, a histological
study of 18 children hearts explants or fetus with CAVB
showed abnormalities  (including lesions fibroelastosis,
endomyocardial) more extensive or more frequent than
had been suggested by echocardiography.[22] Cimaz et  al.
have demonstrated QT prolongation in 21 children born to
mothers with anti‑SSA/Ro.[23]
Hepatobiliary Disease
The liver injury can be isolated or secondary to heart
failure in the context of CAVB. Hepatobiliary disease is rare
and probably underestimated, its prevalence is estimated
between 9% and 27%.[5] Hepatic involvement can manifest
as hepatic failure presenting during gestation or in the
neonatal period. It can also present with conjugated
hyperbilirubinemia in the first few weeks of life with little
or no elevations of aminotransferases. Or it could present
with mild elevations of aminotransferases, which occurs
approximately at 2–3 months of life. Prognosis depends on
the severity of hepatic involvement.
Hematological Neonatal Lupus
Hematological abnormalities may involve any of the
three cell lines and include Coombs’ positive hemolytic
anemia, neutropenia, and thrombocytopenia.[3] There
is a recent report of an infant with neutropenia and
mild abnormalities of liver functions who was born to a
mother with anti/Ro‑/La antibodies.[24] In this report, the
neutropenia resolved over  2–3  months, and the baby did
not have any infection during that time.
Other Rare Manifestations of Neonatal Lupus
In Boros et  al.,[25] series of 47 NLE babies, five were
reported to have hydrocephalus. Lung damage[26] or bone
type chondrodysplasia punctate[3] have been exceptionally
described in NLE.
Treatment
Screening for congenital heart block
The most common time to develop CHB is 18–30  weeks
in 82% of the cases, but it can occur up to 38  weeks
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Kumar: Neonatal lupus
(18% of the cases) and after birth.[20] Therefore, monitoring
the fetal heart rate is currently recommended between
16  weeks and term, every week in babies whose mothers
have anti‑Ro and/or anti‑La antibodies. Monitoring for
the development of the first‑  or second‑degree heart
block and by fetal echocardiography is only available in
a few specialist centers but may be done every 2–7  days
if available and if the mother has had a previously
affected baby with CAVB and poor outcomes. The logic
of this screening is based on the possibility of treating
patients at the earliest opportunity to prevent progression
of incomplete heart block or intermittent block to
permanent CHB. However, this seems unlikely since
Friedman et  al., who studied 95  patients with anti‑SSA/
Ro antibodies by measuring the PR interval, during weekly
ultrasounds performed between the 16th  and 26th  weeks
of gestation  (PRIDE study) have found no abnormality
in PR in the weeks before diagnosis of CAVB.[27] More
recently, Ruffatti et  al. have shown limited evidence
that weekly plasmapheresis, fortnightly intravenous
immunoglobulins  (IVIG), and daily 4  mg betamethasone
will be efficacious in stabilizing second‑degree heart block
and preventing progression to third‑degree heart block.[28]
There is no evidence that established third‑degree
CAVB can be reversed by any of these treatments, but
it has been hoped that early detection and treatment of
CHB with fluorinated steroids might reduce the risk of
complications that affect cardiac contractility, the risk of
developing hydrops, and death of the fetus.
Preventive treatment of congenital atrioventricular
block
The risk of CAVB is 1%–2% in the presence of anti‑Ro
antibodies, and no prophylactic treatment has been
recommended in the past to women with no relevant
medical history. The risk is however higher  (16%–19%) in
women with anti‑Ro antibodies who already had a child
with CAVB,[8,20] and various treatments have been tried
for the secondary prevention in this situation. Prednisone,
prednisolone, and methylprednisolone only cross the
placenta in low concentrations and are not effective. The
fluorinated steroids are no longer recommended as they
are not effective at preventing progression of myocardial
disease, cannot reverse third‑degree heart block, and
may be associated with obstetric complications or
neuropsychiatric development abnormalities in the child.[29]
Administration of fluorinated steroids may reverse first‑and
second‑degree AV block, but this remains debatable and
is not an option in centers that cannot monitor the fetus
for incomplete block before bradycardia develops due to
third‑degree block. Friedman et  al. found that steroids
as a single agent failed to prevent the conversion of
second‑degree AV block to third‑degree AV block.[27]
Jaeggi et  al. found that cardiac complications of NLE
were associated with moderate or high titers of maternal
Indian Journal of Rheumatology  ¦  Supplement 2 2016
anti‑Ro antibodies.[30] The event of CHB was 5% for fetuses
with high Ro values compared to 0% for fetuses with low
titers anti‑Ro. Therefore, it is suggested that in future
preventive therapies for cardiac NLE treatment should be
aimed to develop agents that would decrease the levels
of autoantibodies. In this context, HCQ is a promising
agent. Maternal HCQ has been shown to decrease the risk
of recurrence of CAVB in fetuses of mothers with anti‑Ro
antibodies and SLE and a previously affected child.[31]
Izmirly et  al. have also shown that infants born to women
with anti‑Ro/La antibodies  (with or without lupus) and a
previously affected child who are treated with HCQ have a
significantly reduced rate of re‑occurrence of CAVB.[9]
Theoretically IVIG could decrease transplacental passage
of anti‑Ro and anti‑La antibodies from mother to
fetus. However, in one study, IVIG failed to prevent the
development of CHB in the fetus when given at 3rd weekly
intervals to anti‑Ro and/or anti‑La pregnant women who
had a previous pregnancy in which CHB developed.[32]
Outcomes and Recurrences
The majority of women with high anti‑Ro levels and no
other significant disease manifestations ultimately have
normal pregnancy outcomes, and the babies have a good
prognosis. Apart from CAVB which is permanent the skin,
liver, and hematologic manifestations of NLE resolve within
6  months because this is the lifespan of the maternal IgG
antibody in the infant.[3] Skin and heart findings can manifest
after discharge from the hospital. Persistent telangiectatic
lesions and hyperpigmented macules can be treated with
laser therapy.[3,32] The cutaneous lesions are photosensitive
and can get exacerbated by ultraviolet light exposure;
hence, strict photoprotection is recommended.[17,3]
Children with third‑degree block usually require pacing if
they are symptomatic.[6,20] On long‑term follow‑up, babies
with cardiac NLE have a risk of developing cardiomyopathy
(18%).[6] Cardiomyopathy can develop despite early
institution of permanent pacemaker.[21] In the French
study after 7  years of follow‑up, 79% had a pacemaker,
18% had cardiomyopathy, and 11% had died.[6] These
babies may also develop an autoimmune disorder later in
childhood.[17] The risk factors for poor outcomes (neonatal
deaths) are hydrops, prematurity, and low birth weight.
Having a pacemaker, prenatal and postnatal cardiomyopathy
are risk factors for death during childhood.[6]
Diagnosis of NLE in a baby does not predict that the
mother will progress to systemic autoimmune disease.
Mother continues to possess these antibodies and may
develop clinical features over the next 10  years even if
asymptomatic at the time of the baby’s birth.[17]
Conclusion
NLE is a rare disease the clinical manifestation classically
involves congenital CHB in the fetus and/or typical skin rash
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Kumar: Neonatal lupus
recognizable at birth. More recently, other manifestations
of the syndrome including neutropenia, thrombocytopenia,
or elevated liver enzymes have been described. While
the rash is transient, CHB is irreversible and majority of
affected infants will require pacemaker. There is evidence
that HCQ administration to anti‑Ro positive mothers with
or without SLE can prevent development CHB in the infant.
Further work is required to establish effective treatment
regimen to prevent or reverse third‑degree heart block of
NLE.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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Kumar: Neonatal lupus

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Indian Journal of Rheumatology  ¦  Supplement 2 2016 S144