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: /100,000 per year 18% have onset in childhood Female to male ratio 8:1

Lupus in Children Uncommon before age 4 Incidence /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 fragmentation Chromatin condensation Cytoplasmic blebbing Apoptotic bodies APOPTOSIS Clearance by phagocytes Y Y Y Y Y Y AUTOREACTIVITY

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 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y C’C’ C’C’ C’C’ Immune complex formation C’C’ Endo BM Intima Complement fixation Release of inflammatory, vasoactive and chemotactic mediators Disruption of endothelium Thickening of BM Infiltration of inflammatory cells Tissue damage 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/mm 3 ), lymphopenia (<1,500/mm 3 ), or thrombocytopenia (<100,00/mm 3 ) 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 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; Vasculitic lesions Alopecia Post treatment: cushoingoid, but rash gone

alopecia

photosensitivity

Systemic lupus erythematosus: photosensitive erythematosus rash, upper back photosensitivity

Oral ulcer Malar 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 K, 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

The Classification of Glomerulonephritis in SLE Revisited International Society of Nephrology and Renal Pathology Society Working Group on the Classification of Lupus Nephritis Kidney International, Vol. 65 (2004), pp

International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 Classification of Lupus Nephritis Pathology Society (ISN/RPS) 2003 Classification of Lupus Nephritis Class IMinimal mesangial lupus nephritis Normal glomeruli by light microscopy, but mesangial immune deposits by immunofluorescence Class IIMesangial proliferative lupus nephritis Purely mesangial hypercellularity or mesangial matrix expansion Class IIIFocal proliferative lupus nephritis Active or chronic focal, segmental or global endo- or extracapillary glomerulonephritis involving <50% of all glomeruli

International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 Classification of Lupus Nephritis Class IV Diffuse proliferative lupus nephritis Active or chronic diffuse, segmental or global endo- or extracapillary glomerulonephritis involving ≥ 50% of all glomeruli.

International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of lupus nephritis Class V Membranous lupus nephritis Global or segmental subepithelial immune deposits, with or without mesangial alterations Class V lupus nephritis may occur in combination with class III or IV in which case both will be diagnosed C lass VI Advanced sclerosis lupus nephritis >90% of glomeruli globally sclerosed without residual activity

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

Emergencies in SLE Fever: always r/o infection Renal disease: uremia, hypertension Cytopenias: acute hemolytic anemia, thrombocytopenia CNS: seizures, coma Pleural effusion/ pneumonitis/ pulmonary hemorrhage Pericarditis/ myocarditis Peritonitis/ pancreatitis/ GI bleed Raynaud's: digital necrosis Ocular: retinal vein thrombosis, hemorrhage, edema Thrombotic events, catastrophic antiphospholipid antibody syndrome, microangiopathic syndromes “Lupus Crisis”

Morbidity and Mortality in SLE Life-threatening organ system involvement: –Renal Failure (HTN, dialysis, transplant) –Cardiovascular: accelerated, premature atherosclerotic disease (CAD, MI’s), dyslipoproteinemias –CNS: Cognitive defect Treatment Toxicities: –Long-term steroid use: growth/ pubertal delay, avascular necrosis of bone, osteoporosis/ fractures, cataracts, glaucoma –Cytoxan: Fertility issues, risk of malignancy –Infectious: In immunocompromised patients- PCP, Varicella zoster, opportunistic infections

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