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
• 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
• 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
Apoptotic bodies
AUTOREACTIVITY 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
RBC Y C’
Y
Endo
BM
Intima

Complement fixation
Release of inflammatory,
vasoactive and chemotactic
RBC
C’ mediators
Disruption of endothelium
Y
C’ C’ Thickening of BM
Y 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
• 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%
– 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, anti-
cardiolipin, 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

• 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
• 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, anti-
platelet 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
• 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
• Developmental age and psychosocial issues