REVIEW

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The management of pediatric systemic lupus

erythematosus
Stacy P Ardoin and Laura E Schanberg*

INTRODUCTION

S U M M A RY
Most children and adolescents with systemic lupus erythematosus
(SLE) now survive into adulthood, leading the pediatric rheumatology
community to focus on preventing long-term complications of SLE,
including atherosclerosis, obesity, and osteoporosis, and their treatment.
Unfortunately, because of the paucity of data in pediatric SLE, little is known
about epidemiology, long-term outcome, and optimal treatment. Most
research focuses on adults with SLE, but pediatric SLE differs significantly
from adult SLE in many aspects, including disease expression, approaches
to pharmacologic intervention, management of treatment toxicity, and
psychosocial issues. Children and adolescents with SLE require specialized,
multidisciplinary care. Treatment can be optimized by early recognition of
disease flares and complications, minimizing medication toxicity, educating
families about prevention, promoting school performance, addressing
concerns about reproductive health, and negotiating the transition to
adult-centered medical care. Developmentally appropriate concerns about
pain, appearance, and peers often affect treatment adherence and must be
addressed by the health-care team. Research in pediatric SLE is desperately
needed and provides a unique opportunity to understand how developmental
immunology and the hormonal changes associated with puberty affect the
pathophysiology of SLE.
KEYWORDS adolescent, child, pediatric systemic lupus erythematosus,
prevention, treatment

REVIEW CRITERIA
A PubMed search of English-language journals from 1960 to the present
was performed using the terms pediatric and SLE in combination with
epidemiology, outcome, immunology, treatment, atherosclerosis,
osteoporosis, sunscreen, gonadal failure and names of specific medications.
Some abstracts from the American College of Rheumatology that were published
in Arthritis and Rheumatism were reviewed. In addition, the authors used their
private libraries, and authors communicated with specific researchers including
Dr Christy Sandborg and Dr Virginia Pascual. Focused internet searches to look
for transition checklists were also performed, and the American Academy of
Pediatrics website was reviewed.

S Ardoin is a Senior Fellow in Adult and Pediatric Rheumatology

and L Schanberg is the Cochief of the Division of Pediatric Rheumatology
and an Associate Professor of the Department of Pediatrics at Duke
University Medical Center, Durham, NC, USA.
Correspondence
*Duke University Medical Center, DUMC 3212, Durham, North Carolina 27710, USA
schan001@mc.duke.edu
Received 20 June 2005 Accepted 5 September 2005
www.nature.com/clinicalpractice
doi:10.1038/ncprheum0046

82 NATURE CLINICAL PRACTICE RHEUMATOLOGY

Approximately 1520% of all cases of systemic

lupus erythematosus (SLE) are diagnosed in
childhood.1 No diagnostic criteria specific for
pediatric SLE exist, so the disease is generally
defined using the adult American College of
Rheumatology criteria, with age of onset prior
to 18 years of age;2,3 however, this approach fails
to take into account differences in presentation
and prognosis between adults and children with
SLE. There is a paucity of data addressing the
epidemiology of pediatric SLE. The incidence of
SLE appears to be increased in Hispanic, Asian,
and AfricanAmerican pediatric populations,
but large-scale, population-based studies have
not been performed.4 Finnish, Canadian, US,
and Japanese registries and surveys suggest an
incidence of pediatric SLE between 0.360.60
per 100,000 population per year.4
Fortunately, advances in our understanding of
the biology, diagnosis, treatment and supportive
care of SLE over the past 50 years have dramatically improved the prognosis of children and
adolescents with SLE. Five and ten year survival
rates have increased from less than 40% in the
1960s5,6 to 8090% in the 1980s and 1990s.79
In 2002 the Centers for Disease Control and
Prevention performed a retrospective analysis
of death certificate data from 1979 to 1998. The
results showed no increase in mortality in children
with SLE less than 15 years of age, but highlighted
rising mortality rates in adults aged 45 years and
older.10 While a cure for SLE remains elusive,
most children and adolescents now look forward
to an adulthood of living with SLE. Improved
outcomes compel pediatric rheumatologists to
focus on prevention of later complications of
SLE and its therapy, including accelerated atherosclerosis, obesity, and osteoporosis. Because glucocorticoids remain a mainstay of therapy, efforts to
limit cumulative steroid toxicity, including effects
on growth, are crucial. In addition, attention to
psychosocial issues of the family, child, and adolescent, and managing the transition from pediatric to
adult care significantly improve health outcome.

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CHILDREN ARE NOT LITTLE ADULTS

Although the biology of pediatric and adult SLE

is similar in many ways, disease expression in children and adolescents with SLE is different from
their adult counterparts and requires specialized
care. At diagnosis, organ-system involvement
is often more severe and widespread in children compared with adults.1113 Treatment of
children with SLE requires special attention to
growth and development, family dynamics, effects
of disease and medication on body image, adjustment to diagnosis, peer relations, and fostering
the independence necessary for a successful
transition to adulthood. Promoting school attendance and performance enhance health outcome.
The health-care team can promote success in
school by being knowledgeable about government resources available to schoolchildren
(including 504 Plans and Individual Educational
Plans in the US) and by advocating for patients
within the school system. The health-care team
can provide specific suggestions to schools,
including symptom recognition, recommendations concerning neurocognitive testing, occupational and physical therapy, adaptive physical
education, and specific accommodations based
on disability. Even in healthy, well-adjusted
adolescents, increased risk-taking behavior, pressure from peer groups, nonadherence to medical
regimens, and heavy emphasis on appearance
and body image complicate medical care; these
issues are more prevalent and problematic in
children with chronic illness. Lethargy and
fatigue, common findings in healthy adolescents, can reflect disease activity or depression
and require evaluation. Mood and personality changes characteristic of adolescence
make recognition of neuropsychiatric lupus
particularly challenging.
The developing immune and endocrine
systems in children and adolescents can
provide insight into the pathophysiology of
SLE. A childs immune system differs from an
adults in several ways. For example, children
have an increased total number of antigenspecific T cells, which decrease to adult levels
by late childhood; immunoglobulin A levels are
reduced in childhood, but reach adult levels by
68 years of age; and the B-cell and T-cell repertoires undergo significant differentiation and
maturation during childhood.14 In addition, as
girls mature into puberty, the incidence of SLE
increases, suggesting a possible role of hormonal
factors in onset of SLE.

For several reasons, the study of children with

SLE provides an ideal opportunity to better
understand SLE in all populations. Children
lack the confounding comorbidities present
in adults, families of children are often more
available for genetic studies, and the cumulative
burden of disease and treatment provide ample
opportunity to study long-term outcomes of
disease and therapy. In addition, the developing
immune system and hormonal influences of
puberty can provide unique opportunities for
translational research investigating pathogenesis
and mechanisms of intervention.
LABORATORY MONITORING AND CLINIC
VISITS

Management of SLE in children requires frequent

examination and laboratory monitoring, usually
at least every 3 months in patients who are
doing well and more frequently for those with
uncontrolled disease. Routine monitoring includes
measurement of lupus serologies and laboratory
assessment for organ involvement and medication toxicity. The presence of ANTICARDIOLIPIN
ANTIBODY and LUPUS ANTICOAGULANT can
suggest thrombophilia and the need for chronic
anticoagulation. Meticulous examinations, use of
a standardized growth chart, thorough symptom
reviews, and careful attention to psychosocial
status are crucial for early detection of disease
flares and complications. Fear of pain associated
with venipuncture, intravenous line placement,
or subcutaneous injection can be relieved by
experienced pediatric nurses and phlebotomists.
Distraction and relaxation techniques and topical
anesthetics can relieve anxiety and discomfort.
Several clinical tools that were developed to
measure SLE disease activity in adults have also
been validated in children, including the SLE
DISEASE ACTIVITY INDEX (SLEDAI), SYSTEMIC
LUPUS ACTIVITY MEASURE (SLAM), European
Consensus Lupus Activity Measurement
(ECLAM), and British Isles Lupus Activity
Group Index (BILAG).15 The SLE International
Collaborating Clinics/American College of
Rheumatology Disease Index (SLICC/SDI) has
been used to assess cumulative organ damage
from SLE in children. These outcome measures
are used primarily in clinical research but can
also be helpful in the clinical setting. As none
of these outcome measures were created specifically for children and adolescents, they might
not capture the full spectrum of disease in
this population.

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GLOSSARY
ANTICARDIOLIPIN
ANTIBODY
Antibody against cardiolipin;
associated with thrombotic
events in systemic lupus
erythematosus
LUPUS ANTICOAGULANT
Heterogeneous
antiphospholipid antibodies
associated with thrombotic
events in systemic lupus
erythematosus
SYSTEMIC LUPUS
ERYTHEMATOSUS (SLE)
DISEASE ACTIVITY INDEX
A formal measure of disease
activity over the preceding
10 days, which provides a
score based on 24 separate
disease characteristics
SYSTEMIC LUPUS
ACTIVITY MEASURE
A measure of disease
activity over the preceding
month; assesses organsystem involvement and
incorporates laboratory
abnormalities

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GLOSSARY

PHARMACOLOGIC THERAPIES

ANTIPHOSPHOLIPID
ANTIBODIES
Immunoglobulins initially
thought to recognize
anionic phospholipids;.
associated with thrombotic
events in systemic lupus
erythematosus

The choice of immunosuppressive therapy

in children and adolescents depends on the
patients specific disease manifestations.
Unfortunately, the medical literature provides
little evidence-based guidance on which to base
therapeutic decisions in the pediatric population. The limited available data are often from
retrospective or noncontrolled studies in children and adolescents, or inferred from adult
studies. In children, selecting a medication also
requires consideration of convenience (e.g.
thrice-daily dosing requires giving a dose at
school) and discomfort (e.g. oral versus parenteral administration). Specific medication
toxicities, dosing regimens, and monitoring
practices are outlined in Table 1.
Glucocorticoids

Glucocorticoids remain the mainstay for initial

treatment of significant organ-system involvement in pediatric SLE. The numerous toxicities
associated with chronic glucocorticoid therapy
mandate careful use, and the best approach for
reducing toxicity is the use of steroid-sparing
agents to minimize total glucocorticoid exposure.
In children, particularly important concerns
include effects on growth (Figure 1) and body
image, bone toxicity (loss or inadequate accrual
of bone mass and avascular necrosis), and
risk of mood disorders. Rapid tapering of the
glucocorticoid dose can result in disease flares.
Use of alternate-day dosing of prednisone in
stable SLE is a frequent practice, but no clinical
trial data proves that it is superior or equal to
daily dosing of prednisone. Small studies have
shown that glucocorticoids reduce dendritic cell
numbers and interferon expression in patients
with SLE;16,17 intravenous glucocorticoid pulse
therapy appears to enhance this effect (V Pascual,
personal communication). The safest dose,
route, frequency, and duration of glucocorticoid
therapy remain unknown.
Hydroxychloroquine

It is standard practice in the pediatric rheumatology community to maintain children and

adolescents with SLE on hydroxychloroquine.
While no studies have been performed in the
pediatric population, a double-blind, placebocontrolled withdrawal study in adults with SLE
showed a lower disease-flare rate in those taking
hydroxychloroquine compared with those on
placebo.18 Hydroxychloroquine improves lipid

84 NATURE CLINICAL PRACTICE RHEUMATOLOGY

profiles in adults with SLE, especially those

taking glucocorticoids.1921 The drug appears to
be safe during pregnancy;22,23 levels of hydroxychloroquine are low in breast milk, suggesting
that use during lactation might be safe, although
further study is warranted.24
Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs)

are used in pediatric SLE primarily to treat
musculoskeletal symptoms. Recent data have
highlighted the potential cardiovascular risk
associated with chronic use of cyclo-oxygenase 2
(COX2)-specific inhibitors in adults,25,26 but it
is not clear whether this risk is specific to COX2
inhibitors or applicable to all NSAIDs. The longterm cardiovascular consequences of chronic
NSAID use in childhood remain unknown
and are particularly worrisome in a population
predisposed to premature atherosclerosis. A
Childhood Arthritis and Rheumatology Research
Alliance survey of 95 pediatric rheumatologists
with 1,546 years of cumulative clinical experience reported only one cardiovascular event
(pulmonary embolism in a child with multiple
risk factors for thrombophilia) in NSAID-treated
rheumatology patients (C Sandborg, personal
communication). Low-dose, prophylactic
aspirin is commonly prescribed for adult and
pediatric SLE patients with ANTIPHOSPHOLIPID
ANTIBODIES but no history of thrombotic events.
No large-scale trials have addressed the safety or
efficacy of this practice.
Methotrexate

Weekly oral or subcutaneous methotrexate is

prescribed to treat mucocutaneous and articular
manifestations refractory to hydroxychloroquine
or NSAIDs. Data evaluating methotrexates efficacy in pediatric SLE are limited and mixed.
While an open-label study of 10 children showed
improvement in disease activity and decreased
use of glucocorticoid in eight subjects,27 a retrospective assessment of 11 patients with refractory
pediatric SLE (seven of whom also had nephritis)
demonstrated only transient improvement.28
Methotrexate improves cutaneous and articular
disease and reduces steroid exposure in adults.29
Azathioprine

Azathioprine is often used as a steroid-sparing

therapy in pediatric SLE; however, no controlled
clinical trials have assessed the efficacy of
azathioprine in this population. Azathioprine

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Table 1 Toxicities associated with medications used to treat pediatric systemic lupus erythmatosus.
Medication

Commonly prescribed
dose

Toxicities

Suggested monitoring/prevention

Glucocorticoids

Pulse methylprednisolone
(30 mg/kg up to 1 g/day for
3 or more days) for initial
treatment of severe
disease

Weight gain
Growth retardation
Striae
Effects on body image
Sleep disruption
Affective disorders
Psychosis
Hypertension
Dyslipidemia
Impaired glucose tolerance
Immunosuppression
Inadequate gain of bone mass
Avascular necrosis
Myopathy
Gastrointestinal irritation
Cataracts, glaucoma

Nutrition counseling
Blood-pressure monitoring
Assessment of lipid levels
Calcium and vitamin D supplementation
Annual bone mineral densitometry in
postpubescent patients
Regular ophthalmology follow-up

Oral or intravenous
glucocorticoids
(12 mg/kg/day prednisone
equivalent once daily
or in divided doses followed
by slow taper)

Hydroxychloroquine

57 mg/kg/day, orally

Retinal toxicity
Rare: Hepatitis
Neuromyopathy
Cardiomyopathy

Ophthalmic examination every 612 months

NSAIDS

Preparation-dependent

Headache, aseptic meningitis

Fatigue
Change in personality or school
performance
Gastrointestinal irritation/ulcer
Constipation
Hepatitis
Renal toxicity
Possible cardiovascular risk

CBC, liver chemistry, serum creatinine at least

every 6 months
Patients instructed to take medications with food
Test stool for occult blood if indicated

Methotrexate

0.31 mg/kg/week orally

or subcutaneously
(maximum of
2530 mg/week)

Nausea, diarrhea
Immunosuppression
Bone-marrow suppression
Hepatotoxicity
Rare: Pulmonary toxicity
Possible malignancy risk

Subcutaneous administration can reduce nausea

Folic acid supplementation can reduce toxicity
CBC, liver chemistries every 48 weeks
Baseline PPD, CXR

Azathioprine

12.5 mg/kg/day, orally

Immunosuppression
Bone-marrow suppression
Hepatotoxicity
Rare: Possible malignancy risk

CBC, liver chemistry every 48 weeks

Consider assessing TPMT status to predict
toxicity

Mycophenolate
mofetil

Titrate up to 600 mg/m2

twice daily orally (maximum
of 1500 mg twice daily)

Nausea, diarrhea
Immunosuppression
Bone-marrow suppression
Hepatotoxicity

At least monthly CBC, liver chemistries

Cyclophosphamide

Titrate to 1 g/m2 intravenous

injection monthly (maximum
of 1500 mg/dose)
12 mg/kg/day daily orally

Nausea
Immunosuppression
Bone-marrow suppression
Hemorrhagic cystitis (particularly
with oral cyclophosphamide)
Gonadal failure
Hair loss
Malignancy
(bladder and hematologic cancers)

Prophylactic antiemetics
Frequent CBC
Aggressive intravenous hydration
Mesna
Frequent urinalyses
GnRH agonists
Consultation with a reproductive endocrinologist
Urine cytology

CBC, complete blood count; CXR, chest X-ray; GnRH, gonadotropin-releasing hormone; NSAID, nonsteroidal anti-inflammatory drug; PPD, purified protein
derivative; TPMT, thiopurine methyltransferase.

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SLE disease activity index scores and renal function in membranous nephritis, but MMF therapy
did not significantly improve renal function
in diffuse proliferative glomerulonephritis.33
The role of MMF in the treatment of pediatric
lupus nephritis remains unclear but MMF is
an attractive option because of its oral route of
administration, relative tolerability, and lack
of affect on fertility.

Age (years)
Date

Height Growth
rate

Taking
prednisone

Cyclophosphamide

Stature

Weight

Figure 1 Typical growth chart for female

adolescent with systemic lupus erythematosus
receiving glucocorticoid therapy. The growth chart
shows weight gain (kg) and decrease in height
velocity (cm/year) coinciding with initiation of
prednisone therapy. Height and weight begin to
normalize when prednisone is discontinued.

can be helpful in managing hematologic manifestations of SLE, cutaneous disease refractory to hydroxychloroquine and methotrexate,
stable pneumonitis, or pleuritis and following
standard cyclophosphamide therapy for
diffuse proliferative glomerulonephritis. Some
advocate its use as first-line therapy in diffuse
proliferative glomerulonephritis, although this
remains controversial.30
Mycophenolate mofetil

Mycophenolate mofetil (MMF) has recently

gained popularity as a therapy for lupus
nephritis. Studies in adults with lupus nephritis
suggest that MMF, when used as induction or
maintenance therapy, has short-term efficacy and
safety at least equal to cyclophosphamide.31,32 A
noncontrolled trial involving 11 children with
SLE showed MMF (average dose 22 mg/kg body
weight daily) was steroid-sparing and improved

86 NATURE CLINICAL PRACTICE RHEUMATOLOGY

Because of its potential toxicity, cyclophosphamide is reserved for the most severe
manifestations of pediatric SLE, including
diffuse proliferative glomerulonephritis, severe
neuropsychiatric lupus, significant interstitial
lung disease, and pulmonary hemorrhage.
Monthly intravenous pulses or daily oral cyclophosphamide are prescribed depending on
the indication. Standard treatment for diffuse
proliferative lupus nephritis in children has
generally been monthly intravenous pulse cyclophosphamide for 6 months, followed by quarterly
infusions for 2 years or longer. This regimen is
based on NIH trials in adults showing improved
renal survival at 10 years compared with prednisone treatment alone.34,35 One noncontrolled
trial in 16 children with lupus nephritis who
were followed up after 1 year showed that cyclophosphamide (7501,000 mg/m2 intravenous
monthly for 7 months, followed by 3 month
interval dosing for a minimum of 6 months)
decreased proteinuria, improved renal function,
and had a good safety profile.36
Concern about gonadal failure, a distressing
potential complication of cyclophosphamide
therapy, often leads patients or parents to refuse
treatment. Women under 26 years of age and
prepubertal girls are less likely to develop permanent gonadal failure than their older counterparts; however, the risk is still 17%.37,38 In adult
women with SLE who were receiving cyclophosphamide treatment, gonadotropin-releasing
hormone (GnRH) agonists reduced the incidence
of ovarian failure.39,40 Potential side effects of
GnRH therapy include menopausal symptoms,
loss of bone mass, depression, and delay of
pubertal development.41 No studies have assessed
the safety and efficacy of GnRH agonists in pediatric SLE, but a double-blind, placebo-controlled
trial of triptorelin in girls with SLE who are
receiving cyclophosphamide therapy is currently
underway. In males, sperm banking is a reliable
option for preserving child-bearing potential,

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but the issue must be discussed with sensitivity,

especially in younger boys. Other, more controversial, options for preserving fertility include
in-vitro fertilization with embryo preservation
and investigational cryopreservation of oocytes
or ovarian tissue. Preservation of ovarian tissue,
oocytes, or sperm in minors raises ethical issues,
including insurance coverage and ownership in
event of a childs death. Before starting cyclophosphamide therapy in boys and girls with SLE,
consultation with a reproductive endocrinologist
is strongly recommended.
Rituximab

Rituximab, a B-cell-depleting therapy, seems an

attractive therapy for SLE, a disease characterized
by the presence of autoantibodies. A phase I/II
trial of a single rituximab infusion in 18 adults
with SLE showed B-cell depletion and improvement in SLE activity measure scores at 2 and
3 months.42 Several case series have reported
successful treatment of a variety of manifestations of SLE with rituximab; however, only a
few have included children or adolescents.4345
Controlled trials are now underway to assess the
efficacy of rituximab in treating adult renal and
nonrenal SLE.
Other

In noncontrolled trials, cyclosporin has shown

some promise for treatment of SLE;46,47 however,
concerns about toxicity, including hirsutism,
hypertension, renal toxicity, and dyslipidemia,
limit its use. Leflunomide,48,49 intravenous
immunoglobulin,50,51 plasma exchange,52 and
stem-cell transplantation53 have been shown to be
effective in SLE in case reports or small studies, but
none of these therapies has yet gained widespread
acceptance as standard treatment in pediatric SLE.
Chronic anticoagulation with warfarin or heparin
is indicated for children and adolescents with
antiphospholipid antibody syndrome.54
PREVENTION AND ANTICIPATORY
GUIDANCE

The important long-term health consequences of

SLE and treatment toxicity need to be discussed
frequently with families, because even healthy
children and adolescents are unable to fully
comprehend future consequences. Emphasizing
what children and their families can do to
reduce complications can be empowering,
although compliance with preventative measures
is often variable.

Sun protection

In adults, exposure to ultraviolet (UV) A and B

irradiation has been shown in photoprovocation
testing to worsen cutaneous manifestations of
SLE.55 Because UV exposure leads to release of
DNA and other nuclear antigens from damaged
keratinocytes, the risk of triggering the production of autoantibodies and, therefore, SLE
activity is a concern. Education of children and
their families about how sun protection might
control disease activity can improve compliance. Regular use of sun-protective clothing
and avoiding times of maximal sun exposure
are strongly recommended in all SLE patients.
Regardless of the season, daily use of sunscreen
with a sun-protection factor of 30 or greater, is
recommended, even when indoors because UV
exposure from fluorescent lighting (ubiquitous
in schools) also poses a risk. An ideal sunscreen
contains both physical (titanium or zinc oxide)
and chemical (Parsol 1789, Givaudan-Roure
Corporation, New Jersey, or Mexoryl, LOral,
Paris, France) agents with broad-spectrum UVA
and UVB protection. Compliance with chronic,
daily sunscreen application can be challenging.
Children and adolescents might need to try
several brands and varieties to find appropriate
products for different activities. Cosmetics
containing sunscreen might be appealing to
teenage girls. The use of tanning beds is emphatically discouraged, and self-tanning lotions are an
option if a tan is strongly desired.
Osteoporosis prevention

Because glucocorticoids and SLE increase the risk

of osteoporosis and because peak bone mass is
achieved in young adulthood (Figure 2), early
education focusing on maximizing bone health
is essential for children and adolescents with SLE.
A diet history can assess whether the minimum
recommended, age-specific daily requirements of
calcium and vitamin D are being achieved. Diet
alone is often inadequate in supplying calcium
and vitamin D; however, the wide variety of
supplements that are available allows children
and their parents to find a palatable supplement,
if required. Weight-bearing exercise is encouraged
to maintain bone mass.Annual bone mineral
densitometry can assess trends in bone mass in
postpubertal patients, although interpretation
of results is complicated in growing adolescents.
When severe osteoporosis is present, especially
in the presence of nontraumatic or multiple
fractures, bisphosphonates are considered. The

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1.3 -

Total body BMD (g/cm2)

1.2 1.1 1.0 0.9 0.8 -

10

20

30

40

50

Age (years)

Figure 2 Bone mineral density versus age in Caucasian females. Peak bone
density is achieved during late adolescence, making it important to optimize
bone mass during childhood and adolescence, particularly in those at risk
of osteopenia/osteoporosis. Reproduced with permission from reference 75
American Society for Clinical Investigation. Permission conveyed through
Copyright Clearance Center, Inc. BMD, bone mineral density.

should be routine in the care of children and

adolescents with SLE. Control of proteinuria
is essential because nephrotic-range proteinuria is linked with ultrasonographic evidence
of premature atherosclerosis in pediatric SLE.63
Angiotensin-converting enzyme inhibitors
can reduce proteinuria and have been shown
to provide cardiovascular protection in adults
with coronary artery disease.64 It is important
to monitor for side effects, including cough,
hyperkalemia, and predisposition to azotemia,
when angiotensin-converting enzyme inhibitors
are used. As mentioned previously, hydroxychloroquine has lipid-lowering properties, and
folic acid and aspirin should be considered for
cardiovascular protection.65 The Atherosclerosis
Prevention in Pediatric Lupus Erythematosus
(APPLE) trial, investigating the efficacy of
atorvastatin in preventing progression of carotid
intimal thickening (a surrogate marker of atherosclerosis) is currently underway. The results of
APPLE trial will provide guidance on the use
of statins as a preventative therapy in children
and adolescents with SLE.
Contraception

GLOSSARY
FRAMINGHAM RISK
FACTORS
Coronary artery disease
risk factors defined by the
Framingham risk study,
which include age, gender,
blood pressure, and
diabetes mellitus

consequences of long-term use of bisphosphonate

therapy are not fully known and the long half-life
of the drug raises concerns about potential effects
on fetal development during future pregnancy,
so informed consent must be obtained before a
patient starts bisphosphonate therapy.
Cardiovascular risk management

An ever-growing number of studies show that

SLE increases the risk of accelerated atherosclerosis and its complications.5658 SLE itself,
beyond the traditional Framingham risk
factors, is an independent risk factor for
atherosclerosis.59 The actual prevalence of
premature atherosclerosis and its risk factors in
pediatric SLE remains unknown. In one cohort,
dyslipidemia, a risk factor for coronary artery
disease, was present in 71% of adolescents with
SLE.60 Subclinical myocardial perfusion defects
were detected in 16% of children and adolescents with SLE.61 Because atherosclerosis begins
in childhood even in healthy children, early
education about cardiovascular risk and modification of risk factors are essential62 Aggressive
control of blood pressure, lipid monitoring with
dietary and pharmacologic intervention when
indicated, weight control, promotion of aerobic
exercise, and counseling on tobacco avoidance

88 NATURE CLINICAL PRACTICE RHEUMATOLOGY

The potential teratogenicity of medications used

to treat SLE and the risk of SLE flares during
pregnancy provide additional impetus to prevent
teen pregnancy. Counseling about contraception
and the risks of pregnancy should begin well
before puberty because risk-taking behavior
is a normal part of adolescence. Reliance on
barrier methods is problematic, but hormonal
contraception (using either progesterone only
or progesteroneestrogen combinations) is an
option. Preliminary data from the Safety of
Exogenous Estrogens in Lupus Erythematosus
National Assessment (SELENA) trial suggest
that oral contraceptives containing low-dose
estrogen do not increase the incidence of SLE
flares in adult women with SLE.66 It is important to note that women with a moderate to high
titer of anticardiolipin antibodies or a positive
lupus anticoagulant assay were excluded from
the SELENA trial. Lingering concerns about
an increased risk of thrombotic events from
estrogen exposure, particularly in children with
antiphospholipid antibodies, make injectable
medroxyprogesterone an attractive therapeutic
option; however, chronic use of medroxyprogesterone has been associated with loss of
bone density.67 Referral of patients to a high-risk
obstetrician can be useful for adolescents seeking

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information about the risks of pregnancy, who

are contemplating marriage, or who become
pregnant.
Immunization

Because infections impart significant morbidity

and mortality in pediatric SLE, vaccination
is an important opportunity for prevention.
Concerns about immunization in SLE have
persisted because of anecdotal reports linking
vaccination to the development of SLE or disease
flares and worries about the efficacy of vaccines
in the setting of active disease and immunosuppression.68 Several adult studies, however,
have suggested that immunization in SLE is safe
and effective.6971 The American Academy of
Pediatrics recommends withholding live, attenuated vaccines from children on chronic prednisone therapy at doses greater than 2 mg/kg
body weight daily (or doses greater than 20 mg
daily for those over 10 kg) until glucocorticoids
have been discontinued for at least 1 month.72
Otherwise, routine age-specific vaccinations are
advised for all children and adolescents with
SLE, including annual influenza vaccination.
Pneumococcal vaccines, now routinely administered to all infants in the US, should be provided
to children and adolescents who were not previously immunized. Recent American Academy of
Pediatrics guidelines recommend immunizing all
adolescents with the meningococcal vaccine.73
Transition from pediatric to adult
rheumatology care

The transition from child-centered to adultcentered care for SLE is an important and often
difficult milestone for providers, patients, and
parents. Young adults with SLE are at higher
risk for delayed psychosocial, cognitive, and
physical development than their healthy peers,
contributing to a high incidence of drop-out
and nonadherence with therapy during the
time of transition. Without regular medical
care, young adults with SLE can incur significant morbidity and mortality. The transition
is a prolonged process, not a single event, and
should begin several years before the actual
change of providers. Transition is staggered so
that providers do not all change simultaneously.
Physicians caring for children and adolescents
with SLE need to provide the ongoing education
necessary for successful transition, focusing on
fostering independence and normal separation
from parents and pediatric providers. The

Box 1 Provider checklist for successful

transition from pediatric to adult medical care.
Medical
Understands medical condition
Knows names of medications, side effects,
how to take medications
Makes appointments and refills medications
Knows how medications and disease interact
with use of alcohol, illicit drugs, tobacco
Takes medications reliably
Performs required self care
Participates in medical visits
Social
Has living arrangements
Performs activities of daily living
Self-advocate in medical system
Has reliable transportation to medical visits
Aware of effects of disease process,
medications on reproductive health
Educational and vocational
Has plans for education, training or
employment beyond high school
Has work experience: volunteering,
work-study, part-time or full-time job
Aware of Family Medical Leave Act, disability
resources available through school/employer
Financial
Can pay for medical care
Knows how to pay bills
Can cover living expenses
Knows how to budget
Adapted from the Adolescent Transition Tool developed by
the Childrens Hospital Massachussetts Initiative for Youth
with Disability, the Transition Worksheet from the Division
of Specialized Care for Children at University of Illinois at
Chicago, IL; and the Rheumatology Transition Checklist for
Teenagers from the Childrens Hospital of Philadelphia, PA.

optimal time to change providers depends on

the developmental stage, maturity, and readiness
of each child and family, preferably occurring
during a period of relative disease and psychosocial stability. Before transition, it is important to assess the young adults understanding
of SLE and its complications, medication side
effects, self-care requirements, means of effective communication with health-care providers,
and the importance of compliance. Educational
and vocational goals, as well as concerns about
reproductive health, need to be addressed. A
written checklist can be useful (Box 1). Ideally,
the adult provider is experienced with the special
concerns of young adults with SLE. Barriers to
a successful transition can include the patients

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limited knowledge and insight, inadequate selfadvocacy skills, apathy, and reluctance to leave
the pediatric providers. Parental and pediatric
providers unwillingness to let go, gaps in
heathcare financing and services, and the adult
providers limited knowledge or availability can
also be problematic.74 Rheumatologists with
internal medicine and pediatrics training are
well-positioned to assist children and adolescents with the transition from childhood
to adulthood.
CONCLUSION

Children and adolescents with SLE represent

a vulnerable population deserving specialized
medical care. The health-care team must pay
particular attention to the special physiologic,
developmental, and psychosocial needs of
affected children. The optimal, evidence-based
management of pediatric SLE is hampered by the
absence of robust data concerning epidemiology,
long-term outcomes, and efficacy and safety of
therapeutic interventions. Further research in
pediatric SLE is desperately needed to improve
the care and outcome of children and adolescents
with SLE.

Note added in proof While this review was in

press an open-label study addressing the use of
rituximab in pediatric SLE patients has been
published. Seven children with refractory SLE
showed improvement in BILAG global scores
after treatment with rituximab and suffered
no significant toxicity over a median of 1 year
of follow up.76

KEY POINTS

Emphasis is now placed on treatment of

systemic lupus erythematosus (SLE) and preventing
long-term complications

Much has been inferred from adult studies

because of a paucity of data on pediatric SLE

Age-related differences affect the pattern

of disease expression and the psychosocial impact
of SLE

A specialized, multidisciplinary health-care

team improves family education, treatment, and
outcome of pediatric SLE

Research in pediatric SLE is required to

understand how the developing immune system
and puberty affect the pathophysiology of SLE

90 NATURE CLINICAL PRACTICE RHEUMATOLOGY

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