International Journal of Rheumatic Diseases 2014

SPECIAL ISSUE – SLE IN THE ASIAN PACIFIC REGION

Childhood onset systemic lupus erythematosus: how is it

different from adult SLE?
Amita AGGARWAL and Puja SRIVASTAVA
Department of Clinical Immunology,Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India

Abstract
About 20% of systemic lupus erythematosus (SLE) starts in childhood and children have less gender bias in favor
of females as compared to adults. Systemic manifestations, nephritis, neuro-psychiatric disease and cytopenias are
more common in children at presentation than adults. Since most children develop lupus in their early adoles-
cence, dealing with the diagnosis of an unpredictable lifelong disease during this phase of life is challenging. Physi-
cians must recognise specific medical and social needs of this age group, for optimal long-term outcome. Steroids
and immunosuppressive drugs are the cornerstone for treatment in children as with adults with lupus. The out-
come has improved considerably with these drugs and 10-year survival is nearly 90%. Due to longer life spans
more damage accrues in children as compared to adults. Most of the drugs are associated with significant toxicity
and the goal of having a drug which reduces disease activity and damage without hampering normal growth,
development and fertility is still an elusive one. The current review focuses on clinical and immunological aspects
of childhood SLE and how it differs from adulthood SLE.
Key words: autoantibodies, complications, nephritis, neuropsychiatric, pediatric, systemic lupus
erythematosus.

INTRODUCTION define cSLE, after which the child is transferred to the

adult care physician for follow-up.
Childhood onset systemic lupus erythematous (cSLE) is
a systemic autoimmune disease with remitting-relaps-
ing course where symptoms begin before 18 years of EPIDEMIOLOGY
age, and it accounts for approximately one-fifth of all
cSLE affects children and adolescents all around the
SLE cases.1 SLE is characterized by a wide array of au-
globe; however, incidence and prevalence of disease
toantibodies and clinical manifestations. although the
varies between populations.3 Recent studies suggest that
inflammation and damage is mainly mediated by
cSLE is more frequent and severe in non-white popula-
immune complexes, T cells and monocytes also play a
tions, especially Black, Asian, Hispanic and Native
role. Among the two classification criteria for adults,
American populations, although some studies do not
Systemic Lupus Collaborative Clinics (SLICC) criteria
show any effect of ethnicity.3–7 On an average, 60% of
had higher sensitivity than Amrican College of Rheu-
patients develop cSLE after age 10 years, 35% between
matology (ACR) 1997 criteria in cSLE.2 There is no clear
5 and 10 years, and only 5% before age 5. In studies
age cut-off for cSLE and it varies from 14 to 18 years
from Asia, the mean age at diagnosis was reported to be
but most physicians use onset before 18 years of age to
between 8.6 and 13.5 years.3
Although the prevalence of cSLE is 10–15 times less
in White children as compared to juvenile iopathic
Correspondence: Dr Amita Aggarwal, Professor, Department of
Clinical Immunology, Sanjay Gandhi Postgraduate Institute of
arthritis (JIA),8 the frequency of cSLE is higher and
Medical sciences, Lucknow, India 226014. comparable to JIA in Asian children.4 Also, frequency of
Emails: aa.amita@gmail.com; amita@sgpgi.ac.in cSLE has been reported to be higher in African

© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
A. Aggarwal and P. Srivastava
Americans, Native Americans and Hispanics.3,9 In
Taiwan the incidence of SLE has come down in the last
decade.10
DIFFERENCES IN PATHOGENESIS
The pathogenesis of SLE is multifactorial and results
from a complex interaction between environmental
and genetic factors, leading to a break in immunologic
self-tolerance, thus culminating in autoimmunity.
In the last decade, gene expression profiling has iden-
tified interferon (IFN)-alpha as the major driver for SLE
and the majority of cSLE patients display an ‘IFN signa-
ture’, in peripheral blood mononuclear cells.11 IFN-
alpha is produced by plasmacytoid dendritic cells
(pDC) on stimulation by immune complexes contain-
ing RNA and DNA leading to activation of endosomal
toll-like receptors. Apoptotic bodies can also stimulate
pDCs. Polymorphisms in genes involved in IFN-alpha
pathway, for example IFN regulatory factor 5 and non-
receptor tyrosine-protein kinase (TYK2) also support its
role.12,13 Further, a recent study has shown a direct cor-
relation between SLE Disease Activity Index (SLEDAI)
scores and IFN-alpha levels, suggesting that IFN-alpha
signature can serve as a new biomarker for SLE disease
activity.14,15 Based on the role of IFN in SLE pathogene-
sis, several therapies targeting the IFN-alha pathway are
currently in clinical trials.16
Micro RNAs (miRNA) have also been implicated to
play a role in SLE pathogenesis. Among them miR-
NA-21, miRNA-148a, and miRNA-125a, miRNA-146
are differentially expressed in SLE; some act as a neg-
ative regulator of type 1 IFN pathway and levels of
some other miRNAs correlate with SLE disease
activity.17,18
Children with congenital complement deficiencies
account for about 1% of patients with SLE. Among
these, C1q deficiency has 90% chance of having a
lupus-like illness early in life. Other complement defi-
ciencies, C2, C4 and C1s or C1r deficiency, are also
associated with early onset SLE.19,20
Childhood onset SLE is associated with increased
numbers of SLE risk alleles, which may contribute to
increased disease severity in this subgroup.21 Using
transmission disequilibrium testing and trios of parents
and children with SLE P-selectin gene and interleukin-1
receptor-associated kinase 1 gene, TNFRSF6 and inter-
feron regulatory factor 5 gene were identified as poten-
tial susceptibility genes.22 Other genes have been found
to be present both in cSLE and aSLE.23 In future, with
large consortia it may be possible to identify the
2 International Journal of Rheumatic Diseases 2014
differences in genetic susceptibility and genotypic-phe-
notypic correlation between cSLE and aSLE.
DIFFERENCES IN CLINICAL
PRESENTATION
Childhood onset SLE is associated with more severe dis-
ease phenotype as compared to aSLE. In a large multi-
ethnic cohort study having 1317 SLE patients, it was
shown that cSLE patients had two- to three-fold higher
risk of developing malar rash, hemolytic anaemia,
lupus nephritis and anti-double stranded DNA (anti-
dsDNA) antibody positivity.21
Systemic features, such as fever, fatigue and general-
ised lymphadenopathy are more common in children
with lupus as compared to adults and are seen in nearly
90% of children in most series.24 Mucocutaneous
involvement includes typical malar rash, an erythema-
tous rash seen on both cheeks and bridge of nose spar-
ing the nasolabial folds. In addition, most children
with active disease can have photosensitive rash on
other sun-exposed areas and purpuric rash of vasculitis.
Oral ulcers in lupus are typically painless, and are
located on the hard palate, occasionally nasal mucosa,
and come in crops and heal without scarring. Mucocu-
taneous involvement is more common in cSLE as com-
pared to aSLE.25 Arthritis is present in a significant
proportion of patients with cSLE, and is typically none-
rosive inflammatory polyarthritis.
Serositis in the form of pleuritis, pericarditis and less
frequently peritonitis is seen in about 20% patients
with cSLE. Pericarditis occurs in about 15–30% of SLE
patients and is the most common cardiac manifesta-
tion.26,27 Myocarditis and coronary arteritis are serious
manifestations, but are uncommon in the pediatric age
group. The most common inflammatory lung manifes-
tation is pleuritis; diffuse pneumonitis, alveolar hemor-
rhage and interstitial lung disease are very rare in cSLE
patients.27 Almost any part of the gastrointestinal sys-
tem can be involved but peritonitis, pancreatitis and a-
calculous cholecystitis are the common causes of
abdominal pain in cSLE.28
Renal disease is the main cause of morbidity and
mortality in SLE. Despite large ethnic variations, most
studies report a prevalence of 50–70% of lupus nephri-
tis in childhood series.21,25,29 Although the prevalence
of lupus nephritis is higher in cSLE as compared to
aSLE, kidney damage was found to be unrelated to age
of onset of lupus after adjustment for baseline renal
parameters, therapy given and initial therapeutic
response.30 The 5-year survival rates in cSLE has
 Childhood SLE

improved from 30 to 40% in the 1960s to more than Table 1 Differences in clinical manifestations between child-
90% in the last decade.31,32 Still patients in developing hood and adult systemic lupus erythematosus (SLE)
countries have a poorer outcome.33 Despite improve- More common in childhood SLE Odds ratio (95% CI)
ment in therapy, approximately 10% of children with
Fever 1.48 (1.24–1.76)
proliferative nephritis progress to end-stage renal dis-
Lymphadenopathy 3.67 (1.18–11.45)
ease within 5 years.32 Graft survival after transplant is
Malar rash 1.91 (1.47–2.48)
91% with a living related donor and 78% after cadav- Ulcers/mucocutaneous 1.35 (1.13–1.61)
eric transplant, and these are comparable to the rates in Renal involvement 1.62 (1.21–1.62)
adults.34 Proteinuria 1.49 (1.01–2.20)
Neuropsychiatric involvement in cSLE is at least as Urinary cellular casts 2.35 (1.68–3.29)
common as it is in aSLE, although most children mani- Seizures 2.32 (1.65–3.25)
fest symptoms within 1 year of diagnosis of lupus.35,36 Thrombocytopenia 1.30 (1.10–1.55)
Neuropsychiatric SLE (NPSLE) syndromes are similar in Hemolytic anemia 1.90 (1.44–2.52)
children and adults, although seizures, psychosis, cho- More common in adult SLE
rea and encephalopathy are more common in cSLE, Sicca features 0.42 (0.27–0.64)
Raynaud’s phenomenon 0.56 (0.39–0.80)
whereas cranial neuropathies are more prevalent in
Pleuritis 0.69 (0.54–0.88)
aSLE.25,37 Neurocognitive dysfunction is common in
No significant difference between adults and children
children with SLE and is probably contributed by lupus, Discoid rash 0.98 (0.60–1.60)
corticosteroid use and presence of anti-phospholipid Photosensitivity 0.87 (0.67–1.11)
antibody syndrome.35–37 General cutaneous involvement 1.08 (0.66–1.77)
Anemia of chronic disease is the most common Alopecia 1.02 (0.53–1.95)
form of anemia, regardless of age of onset. Several General musculoskeletal 0.58 (0.33–1.03)
studies have shown that hemolytic anemia is more involvement
prevalent in cSLE than aSLE.25 Leukopenia is found in Hematuria/pyuria 1.52 (0.66–3.48)
42–74% of lupus patients during the course of their Psychosis 1.28 (0.88–1.88)
disease, with similar frequency in cSLE and aSLE.38,39 General neurologic involvement 1.39 (0.94–2.05)
Cerebrovascular accident 1.67 (0.88–3.17)
Lymphopenia correlates with disease activity, anti-
Thrombosis 1.21 (0.80–1.84)
dsDNA titres, and is associated with mucocutaneous
Lung involvement 0.84 (0.59–1.20)
and NPSLE manifestations.40 Thrombocytopenia Heart involvement 0.88 (0.35–2.18)
occurs in two-thirds of children with infantile SLE Leukopenia 1.04 (0.70–1.54)
and one-third of cSLE and aSLE.25 Older girls with Lymphopenia 1.31 (0.9–1.91)
chronic immune thrombocytopenia are more likely to General hematologic 1.17 (0.39–3.48)
evolve full-blown SLE.41 Low platelet counts in lupus involvement
may also be contributed by anti-phospholipid (aPL) General gastrointestinal 1.46 (0.51–4.16)
and anti-platelet autoantibodies. Thrombotic throm- involvement
bocytopenic purpura (TTP), although a rare manifesta- Adapted from Livingston B, Bonner A, Pope J (2011) Differences in
tion of SLE, can be the initial presenting feature of clinical manifestations between childhood –onset lupus and
adult-onset lupus: a meta analysis. Lupus 20, 1345–55. Reproduced
cSLE and one-third of children with TTP may later
with permission from SAGE.
develop lupus.42 The major differences in clinical
manifestations between cSLE and aSLE is summarized
in Table 1. mycophenolate mofetil, cyclosporine and recently
B-cell depleting therapy (Table 2).
Treatment depends on the severity of organ involve-
TREATMENT OPTIONS ment, spectrum of organ involvement, the disease sever-
Corticosteroids and immunosuppressive agents are the ity, background immunosuppressive treatment,
cornerstones of treatment of lupus across all age groups, tolerance to drugs and so on. The ‘ideal drug’ for cSLE
including cSLE. The current armamentarium of drugs would be one which is highly effective in controlling
available for treatment of lupus includes corticoster- disease activity, preventing long-term damage, has min-
oids, non-steroidal anti-inflammatory drugs (NSA- imal effect on growth, fertility and risk of infection;
IDs), hydroxychloroquine, immune-suppressive agents however, to date this has been an elusive goal. Therapy
like azathioprine, methotrexate, cyclophosphamide, in cSLE remains more challenging than aSLE due to

International Journal of Rheumatic Diseases 2014 3

A. Aggarwal and P. Srivastava
Table 2 Drugs used in childhood SLE with their dosage
Drug Dose
Prednisolone 0.25–2.00 mg/kg/day
IV methylprednisone Intravenous 10–30 mg/kg/dose 9
3 days
Hydroxychloroquine 3–5 mg/kg/day, up to 400 mg/day
Azathioprine 0.5–2.5 mg/kg/day
Methotrexate 10–15 mg/m2/week
Mycophenolate mofetil 1.2–2.0 g/m2 in two divided doses
Cyclophosphamide Intravenous 500–750 mg/m2/month
Cyclosporine 2.5–5.0 mg/kg/day
i.v. immunoglobulin Intravenous 400 mg/kg/dose 9 five
doses
Rituximab 375 mg/m2 weekly dose 9 four
doses
more severe and unpredictable disease course, long-
term requirement for therapy, noncompliance and tran-
sition to adult care.43
Overall, children require higher daily steroid doses
for their treatment as compared to adults, as was shown
in a retrospective cohort study of cSLE patients where
children with age of onset < 12 years required higher
steroid doses than those whose disease began in adoles-
cence (0.6 mg/kg vs. 0.2 mg/kg of prednisone equiva-
lent).44 Hydroxychloroquine should be given to all
lupus patients throughout the course of disease, as there
is a high level of evidence that antimalarials increase
long-term survival and moderate evidence of protection
against irreversible organ damage, bone mass loss and
thrombosis.44 Long-term use is also effective in reduc-
ing the number of major flares to almost half.45
Children with significant lupus dermatitis, should be
advised regarding photoprotection with topical sunsc-
reens (SPF > 15) along with physical measures like
protective clothing, umbrellas and so on. Topical gluco-
corticoids and/or tacrolimus can be used in recalcitrant
cases. Methotrexate acts as steroid sparing agent, and
has been shown to be efficacious in management of
resistant skin disease and arthritis in SLE.
Mycophenolate mofetil (MMF) and cyclophospha-
mide CYC) serve as the cornerstones of lupus nephritis
(LN) therapy both in adults as well as children.46 Treat-
ment regimens used for childhood onset LN are gener-
ally derived from adult protocols. Although CYC has
been used for decades and is effective in the induction
of remission, adverse short- and long-term side-effects
which include nausea, bone marrow suppression,
severe infections, hemorrhagic cystitis, alopecia, am-
enorrhoea, infertility and risk of malignancy, warrants
urgent need for an alternative agent. In 2005, a large
4 International Journal of Rheumatic Diseases 2014
randomized controlled trial (ALMS) found MMF to be
as good as CYC for induction treatment of proliferative
LN;47 subgroup analysis of 24 adolescents in this study
showed a trend toward better renal response to 24-week
induction therapy with MMF as compared to CYC
(70% vs. 53%).48 For maintenance, MMF was found to
be superior to azathioprine, although due to small
numbers in cSLE it did not reach statistical signifi-
cance.49 In adults low-dose CYC was found to be as
good as high-dose CYC in a Euro-lupus nephritis trial;
however, no subgroup analysis of cSLE was done.50
Despite lack of evidence in Europe, low-dose CYC is
recommended for use in childhood lupus nephritis.51
CYC is also used in management of diffuse central ner-
vous system (CNS) disease and vasculitis.
Azathioprine has been the traditional steroid-sparing
agent and is used to manage cytopenias, vasculitic man-
ifestations, nephritis, myositis, hepatitis and so on in
SLE. Recently MMF is also being used in place of azathi-
oprine due to its safety profile and similar efficacy.49
Anti-CD20 antibodies have emerged as a salvage
therapy for patients not responding to MMF or CYC as
evidenced by multiple case reports and case series. Anti-
CD20 antibodies are useful in most manifestations of
SLE, including cytopenia, proliferative lupus nephritis,
antiphospholipid syndrome (APS)-related thrombosis,
and so on.52,53 However, these beneficial results could
not be replicated in a randomized controlled trial,
probably due to use of high-dose immunosuppression
in both arms.54 A randomixed clinical trial of rituximab
in cSLE is on and we should have the results in the next
2 years.
Belimumab is an antibody against B lymphocyte
stimulator. ALthough it has been approved by the Food
and Drug Administration (FDA) for treatment of active
nonrenal aSLE, as an add-on therapy55 data in children
is limited.56 There is an ongoing clinical trial assessing
safety and pharmacokinetics of belimumab in cSLE.
SPECIAL ISSUES RELATED TO
ADOLESCENT AGE GROUP
Most children develop SLE during the adolescent per-
iod. At this age, children are trying to adjust to the usual
challenges of adolescence, making their own identity
and are very conscious about their physical appearance.
As it is already a challenging period in life, further stres-
ses and disease manifestations such as alopecia, malar
rash, photosensitivity, cognitive dysfunction and so on,
can make life more miserable for these teenagers. These
issues are further compounded by therapy-related

adverse effects like hirsuitism, moon faces, buffalo
hump, acne, striae, weight gain, mucositis, alopecia and
risk of infertility. Further, accepting the diagnosis of a
new serious and chronic disease is difficult at this age,
and it also strains their family relationships along with
adjustments with their school and peers. Therefore,
many adolescents with SLE are noncompliant with their
medications and reluctant for regular medical follow-
up. Addressing the above issues to some extent along
with special support, both from parents as well as treat-
ing physicians, can help them to cope with the disease
and improve their long-term outcomes.
Another issue in developing countries is the social
stigma associated with chronic disease, which leads to
poor self-esteem, lack of gainful employment and
depression. Further, a significant proportion of girls
and their parents face great difficulty in finding a match
for them. Chronic disease also leads to poor obstetric
outcome and leads to disruption of many marriages.
A recent review on vaccination in juvenile chronic
inflammatory diseases57 confirms that although vac-
cine-induced immune responses are variable due to the
concurrent use of immunosuppressive and biologic
agents, vaccine-related immunogenicity is generally
adequate in most children with cSLE and JIA. All killed
and recombinant vaccinations are safe and should be
administered according to the recommended schedule.
Vaccination against capsulated organisms like Pneumo-
coccus (PCV13 and PPV23), Hemophilus influenzae
(Hib) and meningococci (if not included in national
vaccination programs) are recommended for both chil-
dren and adults with SLE, as many of them have con-
genital complement deficiencies, disease-related
hypocomplementemia and functional asplenia second-
ary to immunosuppressive drugs.57 The 2011 European
League Against Rheumatism (EULAR) recommendation
for vaccination in pediatric rheumatic diseases, sup-
ports the determination of pneumococcal serotype-spe-
cific antibody concentrations after pneumococcal
polysaccharide vaccine (PPV23) vaccination. It recom-
mends conjugate vaccine if antibody concentrations
are found insufficient, as the latter vaccine may be
more immunogenic in immunocompromised
patients.58 The Centers for Communicable Diseases
(CDC) also recommends that children and adults who
are immunosuppressed and are likely to have rapid
decline in protective antibody titres, should get two
doses of PPV23 5 years apart, with a third dose after
they turn 65 (if at least 5 years have passed since the
last dose). It also recommends the use of conjugate
vaccine in pneumococcal conjugate vaccine (PCV13)
International Journal of Rheumatic Diseases 2014
Childhood SLE
na€ıve children with cSLE aged 2 through 18 years.59
All live attenuated vaccines (e.g. bacilli Calmette–
Guerin [BCG], measles, mumps, rubella, chicken pox,
oral polio vaccine [OPV] etc.) are contraindicated in
cSLE patients receiving high-dose systemic immuno-
suppressive agents (including corticosteroids > 2 mg/
kg/day or > 20 mg/day for more than 2 weeks, metho-
trexate > 15 mg/m2/week, cyclosporine 2.5 mg/kg/day,
sulphasalazine 40 mg/kg/day up to 2 g/day, azathio-
prine 1–3 mg/kg, cyclophosphamide 0.5–2.0 mg/kg/
day orally, leflunomide 0.25–0.5 mg/kg/day and/or bi-
ologics) and for 3 months after these drugs are discon-
tinued. However, children who have neither received
varicella vaccine nor had chicken pox in childhood
should be given this live vaccine 4 weeks prior to start
of imunosuppression.58
LONG-TERM OUTCOMES
In cSLE, disease sets in very early in life and tends to
have more severe disease course as compared to adult
onset SLE; these children accumulate significant disease
or therapy-related damage at a relatively young age.23,25
Over the past two decades, mortality rates in lupus has
decreased significantly with 10 and 15 years survival
exceeding 85% in most ethnic populations.29,60 How-
ever, with median age of onset of disease around
12 years, approximately 15% of cSLE patients would
die by 22–27 years of age.61 In a large cohort from Tai-
wan with more than 4500 patients with SLE, cSLE had
the highest mortality and survival rates were only 76%
at 5 years and 64% at 10 years after diagnosis with
cSLE.33,62 Mortality in the initial few years of disease is
related to either disease-related complications or infec-
tions, while delayed mortality is either related to either
severe lupus flare, end stage renal disease or cardiovas-
cular disease.
With improvement in long-term survival rates, multi-
ple co-morbidities related to adverse effects of therapy
and chronic inflammation have to be tackled by
patients with cSLE at a relatively young age. These
include increased risk of premature atherosclerosis with
50-fold increased risk for myocardial infarction in the
third and fourth decade of life,63 osteopenia, osteopo-
rosis and fragility fractures, avascular necrosis of hip
(other joint) and recurrent infections secondary to
immunosuppressive medications. Moreover, SLE also
predisposes to an increased risk of malignancy, particu-
larly lymphoma.64
Of particular concern with regard to children are the
detrimental effects of chronic inflammation and
5
A. Aggarwal and P. Srivastava
corticosteroid use.65 In children, the prescribed dose of
steroids is negatively associated with bone formation as
measured by serum osteocalcin.66 A failure to achieve
adolescent peak bone mass may be associated with pre-
mature osteoporosis and increased risk of fracture. The
prevalence of osteopenia and osteoporosis is similar
among cSLE and premenopausal aSLE patients. In one
cohort of cSLE, low bone mineral density was found to
be more closely associated with increased disease dura-
tion rather than with cumulative corticosteroid dose.67
Although, hypovitaminosis D is more prevalent
among children and adults with SLE as compared to
the general population, there remains conflicting evi-
dence as to whether high SLE disease activity and/or
proteinuria increases the risk of vitamin D deficiency
and vice versa.67,68–71
DAMAGE IN CHILDHOOD ONSET LUPUS
Disease-related damage in lupus patients increases over
time and predicts future mortality. Disease activity, cor-
ticosteroids and immunosuppressive therapy, all con-
tribute to future damage. Cumulative disease activity
over years is the single best predictor of damage across
all age groups.71,72 Certain disease manifestations like
renal and neuropsychiatric involvement predict higher
damage accrual over time.71 Other important risk fac-
tors for damage are presence of anti-phospholipid anti-
bodies and acute thrombocytopenia.71,72 Therapy-
related damage is maximally contributed by high-dose
corticosteroid therapy in children.71 Use of hydroxy-
chloroquine has shown to be protective against disease-
related damage in lupus.8 The risk of ovarian failure as
a complication of cyclophosphamide therapy is signifi-
cantly less in cSLE as compared to aSLE.73–77 Based on
limited data from case series, the average risk of prema-
ture ovarian failure is 11% in females with cSLE who
receive cyclophosphamide before 21 years of age.74
Similarly, semen abnormalities and high gonadotro-
phin levels in males with cSLE is less frequent when
cyclophosphamide therapy is initiated before onset of
puberty.75,76 Cyclophosphamide-induced death of
germ cells in the ovaries or testes is thought to be the
main mechanism of its gonadal toxicity, and the pro-
cess is regarded as cumulative and irreversible. Cur-
rently, most strategies to prevent ovarian toxicity by
chemotherapeutic drugs focus on the prevention of
ovulation in order to decrease metabolic activity and
blood flow and thereby reduce the dose of cyclophos-
phamide that reaches the ovary.78 No such concurrent
protective therapy is applicable for young males, as
6 International Journal of Rheumatic Diseases 2014
spermatogenesis is a continuous process. In prepubertal
children, gonads are in a quiescent state and are thus
exposed to lower doses of toxic drugs, which may
explain less gonadal toxicity in prepubertal children.
Although patients with cSLE are known to have
higher risk for osteonecrosis, risk tends to increase with
age of onset. Nakamura et al. showed that the rate of
osteonecrosis was significantly lower in pediatric
patients than in adolescents or adult patients
(P < 0.0001). They explain this observation by the
hypothesis that prepubertal children tolerate ischemia
better than adults because they have red marrow (with-
out fatty replacement) and abundant blood supply
around growth plates.79 This observation was also con-
firmed in another cohort of cSLE, where only 5% of
patients developed avascular necrosis (AVN) prior to
onset of puberty. They also reported that children with
severe organ involvement, including nephritis and CNS
disease, higher maximal daily doses of prednisone are
more likely to develop symptomatic AVN.80
The SLICC/ACR Damage Index (SDI) for aSLE is a
reliable instrument in the assessment of children with
SLE.81 However, when applied to children, SDI has a
few shortcomings. First, it does not include growth
retardation and delayed puberty which is common in
children with active disease. Second, definition of
nephritic range proteinuria (≥ 3.5 g/day) needs adjust-
ment to weight and height in young children.82 Third,
few items like myocardial infarction, malignancy, pan-
creatic insufficiency, gastrointestinal stricture, ruptured
tendons and so on, which have important places in
SDI, are rarely observed in the pediatric age group, thus
can be omitted. Fourth, definition of ‘premature gona-
dal failure’ should be based on hormonal studies, rather
than history of secondary amenorrhoea as irregular
menstrual cycles are quite common in the adolescent
age group.82
To address these shortcomings in SDI, in 2006 a
group of authors from Pediatric Rheumatology Interna-
tional Trials Organization (PRINTO), proposed the
Pediatric-SDI (Ped-SDI).82 It includes growth failure
and delayed puberty as two additional domains, and
also includes a modified definition of proteinuria
(adjusted for height and weight in young children).
This Ped-SDI was tested on 1015 patients with cSLE
across 39 countries, and 40% of cSLE was found to have
a score of ≥ 1. Growth failure and delayed puberty were
observed in 15.3% and 11.3% of patients, respectively.
According to a recent meta-analysis, there are no signifi-
cant differences in the average SLE damage index scores
between cSLE and aSLE.25

CONCLUSIONS
Childhood SLE, although a lot similar to aSLE, is char-
acterized by higher prevalence of fever, lymphadenopa-
thy, lupus nephritis and anti-dsDNA antibodies.
Prevalence of antiphospholipid syndrome-related
thrombosis, discoid lupus, stroke, Raynaud’s phenome-
non, is less as compared to aSLE. Managing adolescents
with SLE is a challenge and most treatment regimens
are derived from adult protocols. There is a need for
large multinational randomized controlled trials in
cSLE to further tailor these treatments to children. A
compassionate care with balancing the control of dis-
ease activity and drug side-effects can help improve
long-term outcomes with reduction in accrued damage.
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