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.

Receptor ligation ex: TNF, Fas

Protease (caspase) cascade

DNA fragmentationChromatin condensation

Cytoplasmic blebbing

Apoptotic bodies

APOPTOSIS

Clearance by phagocytesY

Y

Y

YY

YAUTOREACTIVITY

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

Y

YYY

Y

YY

YY

Y

Y

Y

Y

YY

Y

Y

Y

Y

C ’ C ’

C ’Immune complex formation

C ’

EndoBM

Intima

Complement fixation

Release of inflammatory, vasoactive and chemotactic

mediatorsDisruption of endothelium

Thickening of BM

Infiltration of inflammatory

cellsTissue damage

RBC

RBC

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 ulcerMalar rash

Systemic lupus erythematosus: palatal

ulceration

Vasculitic rash 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 SLEMost 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

• 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

SLE - Treatment

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