PEDIATRIC SYSTEMIC LUPUS
ERYTHEMATOSUS
Pediatric Rheumatology
Red Team Resident
Teaching Series
Systemic Lupus Erythematosus
• Episodic, heterogeneous, multisystem
autoimmune disease
– Widespread inflammation of vessels and
connective tissues
– Presence of antinuclear antibodies
– Variable clinical manifestations and course
– Incidence in adults: 2- 7.6 /100,000 per year
• 18% have onset in childhood
• Female to male ratio 8:1
Lupus in Children
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Uncommon before age 4
Incidence 0.5-0.6 /100,000 per year
Females>males
Children have more organ involvement than
adults
• Compliance issues in adolescence
dangerous
• Prognosis guarded; 30% may progress to
renal insufficiency depending on treatment
Current Theories Of
Pathogenesis In SLE
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Etiology unknown
Multiple genes involved
Immune dysregulation of B and T cell responses
Immune complex deposition
Abnormalities of complement
Decreased clearance of apoptotic debris
Hormonal imbalance
Environmental triggers including UV B light, infection
Loss of tolerance to chromatin and other autoantigens
Cross reactivity between bacterial and mammalian DNA
Abnormal response to DNA?
These factors, acting alone or together, may trigger onset
of disease in a genetically predisposed host.
APOPTOSIS
Protease (caspase) cascade
Receptor ligation
ex: TNF, Fas
DNA fragmentation
Chromatin condensation
Cytoplasmic
blebbing
Clearance by phagocytes
Y
AUTOREACTIVITY
Apoptotic bodies
Y
Immune complex disease
• Antibodies can be against self (e.g.
nuclear components in SLE) or foreign
antigens (i.e. drugs or microorganisms in
serum sickness)
• Antibodies and antigens combine to form
immune complexes
• Immune complexes deposit in blood
vessels and tissues and activate
inflammatory response leading to tissue
destruction
Immune complex formation
C’
Y
RBC
Y
Endo
BM
Intima
Complement fixation
RBC
Release of inflammatory,
vasoactive and chemotactic
mediators
Disruption of endothelium
C’
Y
C’
Y
C’
Thickening of BM
Y
Infiltration of
inflammatory
cells
Tissue
damage
1997 ACR CRITERIA FOR THE
CLASSIFICATION OF SLE
• Malar (butterfly) rash:
– Fixed erythema, flat or raised, sparing the
nasolabial folds
• Discoid lupus rash:
– Raised patches, adherent keratotic scaling,
follicular plugging; may cause scarring
• Photosensitivity:
– Skin rash from sunlight
• Oral or nasal mucocutaneous ulcerations:
– Usually painless
1997 ACR CRITERIA FOR THE
CLASSIFICATION OF SLE (cont)
• Inflammatory arthritis:
– Nonerosive, in two or more peripheral joints
• Pleuritis or pericarditis
• Cytopenias:
– Hemolytic anemia, leukopenia (<4,000/mm3),
lymphopenia (<1,500/mm3), or
thrombocytopenia (<100,00/mm3)
• Nephritis:
– Proteinuria >0.5 gm/d
– Cellular casts
1997 CRITERIA FOR THE
CLASSIFICATION OF SLE (cont)
• Encephalopathy:
– Seizures
– Psychosis
• Positive ANA
• Positive immunoserology:
– Antibodies to dsDNA or
– Antibodies to Sm nuclear antigen or
– Positive findings of antiphospholipid antibodies based on:
• anticardiolipin antibodies IgG or IgM, or
• Lupus anticoagulant, or
• False positive test for syphillis for at least 6 months
(RPR/VDRL)
Four of 11 criteria provide a sensitivity of 96%
and a specificity of 100% in children
Clinical Features of SLE
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Constitutional symptoms
Musculoskeletal disease
Mucocutaneous involvement
Renal Disease
Central nervous system disease
Cardiopulmonary disease
Hematologic abnormalities
Gastrointestinal involvement
Musculoskeletal Disease
• Incidence: 76%
– Arthralgias
– Arthritis
• Non-erosive
• Involves small joints of the hands, wrists, elbows,
shoulders, knees, ankles
• Can be migratory, lasting 24-48 hours
– Myalgias/ muscle weakness
• Usually proximal
Mucocutaneous Manifestations
• Frequency: 76%
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Malar rash
Discoid lupus
Vasculitis (purpura, petechiae)
Raynaud’s phenomenon
Nail involvement
Alopecia
Periungual erythema/ Livedo reticularis
Photosensitivity
Oral/ nasal ulcers
Systemic lupus
erythematosus: acute facial
rash
Acute malar rash
Chronic facial
rash
Discoid lupus
Discoid lupus
alopecia
photosensitivity
Systemic lupus
erythematosus: photosensitive
erythematosus rash, upper
back
photosensitivity
Oral ulcer
Malar rash
Systemic lupus
erythematosus: palatal
ulceration
and malar rash
Vasculitic ulcers
Systemic lupus
erythematosus: vasculitis,
fingers
Vasculitis: fingers
Before treatment
After treatment
Systemic lupus
erythematosus: vascultis, toes
Raynaud’s
Phenomenom
Neuropsychiatric Manifestations
Of SLE
• Frequency: 20-40%
• Difficult to diagnose and treat
• Second to nephritis as most common cause
of morbidity & mortality
• Can occur at any time; even at presentation
• Standard lab examinations have not been
helpful in diagnosing or managing CNS sxs
• Imaging modalities are not specific enough
– SLE patients have imaging abnormalities but are
clinically normal
Neuropsychiatric Manifestations
Of SLE
• COMMON: Depression, organic brain
syndrome, functional psychosis,
headaches, seizures, cognitive
impairment, dementia, coma
• OCCASIONAL: Cerebral vascular
accidents (thrombosis or vasculitis),
aseptic meningitis, peripheral neuropathy,
cranial nerve palsies
• RARE: Paralysis, transverse myelopathy,
chorea
Diagnosis Of CNS Lupus
• Cerebritis: CSF analysis shows pleocytosis;
CT, MRI, MRA all may be normal or
nonspecific
• Autoantibodies (anti-neuronal, anticardiolipin, anti-ribosomal P) are not helpful
• Vasculitis: CT, MRI, MRA may or may not be
positive → conventional angiography
• CVA: CT, MRI often positive
• Spectamine (PET) scans positive in mild,
acute, or old disease
• Neurocognitive testing
• Electroencephalography for seizures
Cardiovascular Findings
In SLE
• Pericarditis
• Myocarditis
• Sterile valvular vegetations (rarely clinically
significant except for risk of bacterial
endocarditis)
• Arrhythmias
• Cor pulmonale
• Vasculitis (small vessels)
• Atherosclerosis/ Coronary Heart disease
• Dyslipoproteinemias
Pulmonary Findings In SLE
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Incidence: 5-67%
May be subclinical (abnormal PFTs)
Pleuritis
Pleural effusion
Pneumonitis
Pulmonary hemorrhage
Pulmonary hypertension
Restrictive lung disease & diffusion defects most
commonly observed abnormalities on PFTs
GI INVOLVEMENT IN SLE
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Mild LFT elevation--not significant
clinically--BUT NEED TO EXCLUDE
AUTOIMMUNE HEPATITIS
Colitis
Mesenteric vasculitis
Protein-losing enteropathy
Pancreatitis
Exudative ascites
Hematologic Findings In SLE
• Leukopenia, especially lymphopenia
• Anemia
– mild to moderate, common, due to chronic
disease and mild hemolysis
– severe, uncommon (5%), due to
immune mediated hemolysis (Coombs +)
• Thrombocytopenia
– mild 100-150K, common due to immune
mediated damage
– severe <20K, uncommon (5-10%),
immune mediated damage
• Bone marrow suppression/arrest--very
rare, due to antibodies against precursors
Coagulopathy In SLE
• Hypocoagulable states:
– Anti-platelet antibodies--decreased numbers of
platelets or decreased function (increased
bleeding time)
– Other platelet dysfunction and thrombocytopenia
– Anti-clotting factor antibodies
• Hypercoagulable states:
– Antiphospholipid Antibody Syndrome (APS):
more later
– Protein C and S deficiencies
• Thrombotic thrombocytopenic purpura
Renal Findings In SLE
Most common cause of morbidity & mortality
• Glomerulonephritis – at least 75%
• Microscopic or gross hematuria
• Proteinuria, including nephrotic syndrome
• Hypertension
• Decreased GFR
• Renal failure (up to 30-50% of children prior
to 1980)
• Renal biopsy predictive of potential for renal
damage
– ISN/ RPS classification with NIH activity and
chronicity indices
Laboratory Findings
• Cytopenias (anemia, thrombocytopenia,
leukopenia)
• Elevated ESR, CRP, Immunoglobulins
• Hypoalbuminemia
• Proteinuria; RBCs, casts in urine
• Decreased creatinine clearance
• Low complement levels (C3/ C4)
• Autoantibodies (ANA, APL, Coombs, antiplatelet Ab, rheumotoid factor, etc.)
• (Immune complexes)
Antinuclear Antibodies (ANA)
• Sensitive but not specific, 95-98% pts positive
• Against nuclear components of the cell
• Titer specific- up to 10% of population have +ANA w/o
disease; also see with infections, medications, malignancy
• Subtypes:
– dsDNA: high specificity for lupus (over 80%)
– ENA (extractable nuclear antigen) = RNP/ Smith;
RNP assoc w/ MCTD, Smith specific for SLE
– Ro/ La (SS-a/ SS-b): neonatal lupus, Sjogren’s
– Histone: drug induced lupus
SLE - Treatment
• MILD DISEASE: Rashes, arthralgias,
leukopenia, anemia, arthritis, fever, fatigue
– Treatment: NSAIDs, low dose corticosteroids (<60
mg/day), antimalarials (hydroxychloroquine), low
dose methotrexate
• MODERATE DISEASE: Mild disease + mild
organ system involvement such as: mild
pericarditis, pneumonitis, hemolytic anemia,
thrombocytopenia, mild renal disease, mild
CNS disease
SLE - Treatment
• MODERATE DISEASE (cont.):
– Treatment: Prednisone 1-2 mg/kg/day,
NSAIDS, Antimalarials, Low dose
methotrexate, Azathioprine, MMF
• SEVERE DISEASE: Severe, life-threatening
organ system involvement
– Treatment: High dose corticosteroids (2-3
mg/kg/day or pulse), Immunosuppressives
(IV pulse Cyclophosphamide),
Plasmapheresis, Anticoagulation where
appropriate
SPECIAL CONSIDERATIONS IN
CHILDREN AND ADOLESCENTS
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Life-long burden of renal failure and
(multiple) renal transplant(s)
Steroid toxicity
Immunosuppressive toxicity
Infection risk different in children:
– CMV, EBV
– Bacterial infections, esp. strep
– Fungal infections
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Developmental age and psychosocial issues