SYSTEMIC LUPUS ERYTHEMATOSUS

OUTLINE Definition Epidemiology Pathophysiology Classification and diagnosis Clinical Features Lupus related syndromes Treatment Prognosis

DEFINITION Inflammatory autoimmune disorder affecting multiple organ systems characterized by the production of autoantibodies directed against cell nuclei”

EPIDEMIOLOGY Prevalence influenced by age, gender, race, and genetics Peak incidence 14-45 years Black > White (1:250 vs. 1:1000) Female predominance 10:1 HLA DR3 association, Family History Severity is equal in male and female

Etiology Genetic (HLA DR3 association) Environmental Abnormal immune response Environmental UV Viruses Hormones (Estrogen)

PATHOPHYSIOLOGY

CLINICAL FEATURES: Mucocutaneous Malar Rash (butterfly erythema) Discoid rash Photosensitive rash Subacute cutaneous LE Livedo reticularis Alopecia Raynaud’s Vasculitic ulceration Oral ulceration Nasal septal perforation Nailfold capillary changes

MALAR RASH Fixed erythema, flat or raised, over the malar eminences Tending to spare the nasolabial folds

DISCOID RASH Erythematous raised patches with adherent keratotic scaling and follicular plugging; Atrophic scarring may occur in older lesions

Alopecia

Subacute Cutaneous Lupus

Acute Cutaneous: Malar Rash Note Sparing of Nasolabial Folds Chronic Cutaneous:Discoid Note Scarring, Hyperpigmentation

Follicular Plugging Livedo Reticularis ACR

ORAL ULCERS Oral or nasopharyngeal ulceration Usually painless, observed by a physician

SLE - VASCULOPATHY Small vessel vasculitis Raynaud’s phenomenon Antiphospholipid antibody syndrome

CLINICAL FEATURES: Musculoskeletal Arthritis is NONEROSIVE, transient, symmetrical, affecting small joints, seldom deforming, less severe than RA Most common presenting feature of SLE

Jaccoud’s Arthopathy: Nonerosive, Reducible Deformities

CLINICAL FEATURES: Musculoskeletal Synovitis-90% patients, often the earliest sign Osteoporosis From SLE itself and therapy (usually steroids) Osteonecrosis (avascular necrosis) Can occur with & without history of steroid therapy

CLINICAL FEATURES: Ocular Conjunctivitis Photophobia Monocular blindness-transient or permanent Blurred vision Cotton-Wool spots on retina-degeneration nerves fibers due to occlusion retinal blood vessels

CLINICAL FEATURES: PLEUROPULMONAR Pleuritis/Pleural effusion Infiltrates/ Discoid Atelectasis Acute lupus pneumonitis Pulmonary hemorrhage “Shrinking lung” - diaphragm dysfunction Restrictive lung disease

CLINICAL FEATURES: Cardiac Pericarditis –in majority of patients Libman Sacks endocarditis Cardiac failure Cardiac Arrythmias-common Valvular heart disease Coronary Artery Disease

Lupus - Endocarditis Noninfective thrombotic endocarditis involving mitral valve in SLE. Note nodular vegetations along line of closure and extending onto chordae tendineae.

CLINICAL FEATURES: HEMATOLOGIC DISORDER A) Hemolytic anemia - with reticulocytosis OR B) Leukopenia - less than 4,000/mm3 total on 2 or more occasions C) Lymphopenia - less than 1,500/mm3 on 2 or more occasions D) Thrombocytopenia - less than 100,000/mm3 in the absence of offending drugs

CLINICAL FEATURES: Neurologic Behavior/Personality changes, depression Cognitive dysfunction Psychosis Seizures Stroke Chorea Pseudotumor cerebri Transverse myelitis Peripheral neuropathy Total of 19 manifestations described May be difficult to distinguish from steroid psychosis or primary psychiatric disease

CLINICAL FEATURES: Renal (Lupus Nephritis) Develops in up to 50% of patients 10% SLE patients go to dialysis or transplant Hallmark clinical finding is proteinuria Advancing renal failure complicates assessment of SLE disease activity Nephritis remains the most frequent cause of disease-related death.

CLINICAL FEATURES: Renal (Lupus Nephritis) Usually asymptomatic Gross hematuria Nephrotic syndrome Acute renal failure Hypertension End stage renal failure

WHO CLASSIFICATION OF LUPUS NEPHRITIS Class I Normal Class II Mesangial IIA Minimal alteration IIB Mesangial glomerulitis Class III Focal and segmental proliferative glomerulonephritis Class IV Diffuse proliferative glomerulonephritis Class V Membranous glomerulonephritis Class VI Glomerular sclerosis

CLINICAL FEATURES: Gastrointestinal & Hepatic Uncommon SLE manifestations Severe abdominal pain syndromes in SLE often indicate mesenteric vasculitis, resembling medium vessel vasculitis (PAN) Diverticulitis may be masked by steroids Hepatic abnormalities more often due to therapy than to SLE itself

Laboratory Findings Complete blood count Urine Analysis Anemia Leukopenia Lymphopenia Thrombocytopenia Urine Analysis Hematuria Proteinuria Granular casts

Immunological findings ANA - 95-100%-sensitive but not specific for SLE Anti -ds DNA-specific(60%)-specific for SLE, but positive to other non lupus conditions 4 RNA associated antibodies Anti-Sm (Smith) Anti Ro/SSA-antibody Anti La/SSB-antibody Anti-RNP Antiphospholipid antibody Biologic false + RPR Lupus anticoagulant-antibodies tocoagulation factors. risk factor for venous and arterial thrombosis and miscarriage. Prolonged aPTT Anti-cardiolipin Depressed serum complement Anti hystones antibodies

THE 1982 REVISED CRITERIA FOR CLASSIFICATION OF SLE 1. Malar rash 2. Discoid rash 3. Photosensitivity 4. Oral ulcers 5. Arthritis 6. Serositis 7. Renal disease. > 0.5 g/d proteinuria ≥ 3+ dipstick proteinuria Cellular casts 8. Neurologic disease. Seizures Psychosis (without other cause) 9. Hematologic disorders. Hemolytic anemia Leukopenia (< 4000/uL) Lymphopenia (< 1500/uL) Thrombocytopenia (< 100,000/uL) 10. Immunologic abnormalities. Positive LE cell Anti-ds- DNA Anti- Sm Any antiphospholipid 11. Positive ANA ( 95-100% )

CLASSIFICATION CRITERIA Must have 4 of 11 for Classification Sensitivity 96% Specificity 96% Like RA, diagnosis is ultimately clinical Not all “Lupus” is SLE Discoid Lupus Overlap syndrome Drug induced lupus Subacute Cutaneous Lupus

DIFFERENTIAL DIAGNOSIS Almost too broad to consider given number of clinical manifestations Rheumatic: RA, Sjogren’s syndrome, systemic sclerosis, dermatomyositis Nonrheumatic: HIV, endocarditis, viral infections, hematologic malignancies, vasculitis, ITP, other causes of nephritis “Overlap Syndrome” (UCTD, MCTD)

LUPUS RELATED SYNDROMES Drug Induced Lupus Classically associated with hydralazine, isoniazid, procainamide Male:Female ratio is equal Nephritis and CNS abnormalities rare Normal complement and no anti-DNA antibodies Symptoms usually resolve with stopping drug

LUPUS RELATED SYNDROMES Antiphospholipid Syndrome (APS) Hypercoagulability with recurrent thrombosis of either venous or arterial circulation Thrombocytopenia-common Pregnancy complication-miscarriage in first trimester Lifelong anticoagulation warfarin is currently recommended for patients with serious complications due to common recurrence of thrombosis Antiphospholipid Antibodies Primary when present without other SLE feature. Secondary when usual SLE features present

LUPUS RELATED SYNDROMES Raynaud’s Syndrome: -Not part of the diagnostic criteria for SLE - Does NOT warrant ANA if no other clinical evidence to suggest autoimmune disease

SLE – treatment I. Mild cases (mild skin or joint involvement): NSAID, local treatment, hydroxy-chloroquin Cases of intermediate severity (serositis, cytopenia, marked skin or joint involvement): corticosteroid (12-64 mg methylprednisolon), azathioprin, methotrexat

SLE – treatment II. Severe, life-threatening organ involvements (carditis, nephritis, systemic vasculitis, cerebral manifestations): high-dose intravenous corticosteroid + iv. cyclophosphamide + in some cases: plasmapheresis or iv. immunoglobulin, or, instead of cyclophosphamide: mycophenolate mofetil (not registered in the EU) Some cases of nephritis (especially membranous), myositis, thrombocytopenia: cyclosporine

TREATMENT Antiphospholipid Syndrome Lupus and Pregnancy Anticoagulation with warfarin (teratogenic) subcutaneous heparin and aspirin is usual approach in pregnancy Lupus and Pregnancy No longer “contraindicated” No changes in therapy other than avoiding fetal toxic drugs Complications related to renal failure, antiphospholipid antibodies, SSA/SSB

TREATMENT ESR, CRP probably useful as general markers of disease activity Complement and anti-DNA antibodies may correlate to disease activity but often impractical turnaround time from lab Patient history

PROGNOSIS Unpredictable course 10 year survival rates exceed 85% Most SLE patients die from infection, probably related to therapy which suppresses immune system Recommend smoking cessation, yearly flu shots, pneumovax q5years, and preventive cancer screening recommendations