PEDIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS

1. PEDIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS Pediatric Rheumatology Red Team Resident Teaching Series

2. 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

3. 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

4. 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.

5. Y Y Y AUTOREACTIVITY Y Y Y APOPTOSIS Protease (caspase) cascade Death signal Receptor ligation ex: TNF, Fas DNA fragmentation Chromatin condensation Cytoplasmic blebbing Clearance by phagocytes Apoptotic bodies

6. Immune complexdisease • 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

7. Immune complex formation Y C’ Y Y RBC Y Y Y Y Endo BM Intima Complement fixation Release of inflammatory, vasoactive and chemotactic mediators RBC C’ Y Disruption of endothelium Y Y Y Y C’ Y C’ Thickening of BM Y Y Y Y Y Y Infiltration of inflammatory cells Tissue damage

8. 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

9. 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

10. 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

11. Clinical Features of SLE • Constitutional symptoms • Musculoskeletal disease • Mucocutaneous involvement • Renal Disease • Central nervous system disease • Cardiopulmonary disease • Hematologic abnormalities • Gastrointestinal involvement

12. 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

14. 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

21. Systemic lupus erythematosus: acute facial rash Acute malar rash

22. Chronic facial rash

23. Discoid lupus

24. Discoid lupus

25. alopecia

26. photosensitivity

27. Systemic lupus erythematosus: photosensitive erythematosus rash, upper back photosensitivity

28. Oral ulcer Malar rash

29. Systemic lupus erythematosus: palatal ulceration

31. Vasculitic rash and malar rash

32. Vasculitic ulcers

34. Systemic lupus erythematosus: vasculitis, fingers

35. Vasculitis: fingers

36. Before treatment After treatment

37. Systemic lupus erythematosus: vascultis, toes

38. Raynaud’s Phenomenom

39. 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

40. 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

41. 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

42. 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

43. 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

44. 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

45. 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 Hematologic Findings In SLE

46. 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

47. 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

48. 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)

49. 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

50. 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