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SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) TYPES OF LUPUS ERYTHEMATOSUS • Systemic lupus erythematosus (SLE) • Discoid lupus erythematosus (DLE) • Drug-induced lupus erythematosus (DILE) • Neonatal lupus erythematosus (NLE) CASE STUDY – 16 YEAR OLD FEMALE • Presented to family physician c/o > Fatigue and malaise > Severe sunburn rash on hands and arms following day at beach > Followed by “strange rash” on cheeks and bridge of nose • History and physical > ? of mononucleosis at 15 years > Pain (mild) and stiffness in fingers of both hands and both hips in am beginning at 15 years > Fever (99 F) > No present medications CASE STUDY – 16 YEAR OLD FEMALE • Laboratory testing > CBC with differential – Mild anemia, leukopenia and lymphopenia > Monospot test – Negative > Antinuclear antibody (ANA) – IFA using Hep-2 cells – Positive with homogeneous pattern and titer of 1:1280 > Double-stranded DNA antibodies – IFA using Crithidia luciliae – Positive at a titer of 1:1280 CASE STUDY – 16 YEAR OLD FEMALE • Laboratory Testing > C3 level was 70 mg/dL (85 – 200 mg/dL) > Urinalysis was normal > IgG level was 1820 mg/dL (600 – 1600 mg/dL) • Treatment with > Hydroxychloroquine (Plaquenil) > Avoid direct sunlight • 2 months later > Pain in joints worsened and diffuse swelling > Nightly fever (101 F) and chills > Enlarged lymph nodes behind ears and back of neck CASE STUDY – 16 YEAR OLD FEMALE • Laboratory Testing > C3 level of 45 mg/dL (85 – 200 mg/dL) > Double-stranded DNA antibodies – Positive at titer of 1:2560 • Treated with > Prednisone (20 mg bid) > Naproxen (Naprosyn) (250 mg bid) • Two months later > Asymptomatic with C3 level of 120 mg/dL CASE STUDY – 6 WEEK INFANT GIRL • Referred to dermatologist by pediatrician for skin rash which began 8 days prior • Physical Exam > Irritable but consolable infant in no acute distress • Skin Rash > Initial presentation of erythematous scaling plaque on left cheek > Evolution into numerous plaques on face and scalp with fewer lesions on trunk and extremities CASE STUDY – 6 WEEK INFANT GIRL • Mother > No problems with pregnancy or delivery > Diagnosed with SLE 2 years prior – Asymptomatic with no current therapy – No family history of lupus • Laboratory (infant) > CBC (normal) > Liver function test (normal) > ANA by IFA (positive) – Fine speckled pattern with titer of 1:1280 CASE STUDY – 6 WEEK INFANT GIRL • Cardiology Consultation > Electrocardiogram – Normal sinus rhythm > Echocardiogram – No cardiac malformations or cardiomyopathy • Treatment > Mild topical steroid > Lesion resolution at 4 months of age • Consultation with mother > Present and future concerns SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) • Autoimmune disease affecting multiple organ systems > Relapsing (flares) and remitting course > Protean clinical manifestations • Etiology is unknown • Female to male ratio is 9:1 • Age of onset > 16 to 55 years (65%) > < 16 years (20%) > > 55 years (15%) SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) • Prevalence of 40 to 50 cases / 100,000 • Major causes of mortality > Infections and nephritis (early) > Athrosclerosis (late) • Risk factors > > > > > Genetics (HLA-A1, HLA-B8 and HLA-DR3) Race (AA, Hispanic, Asia > Caucasian) Hormones Chemicals Microorganisms SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) PATHOGENESIS • Defective regulation of apoptosis > Accelerated rate of apoptosis in macrophages mediated (in part) by T cells – T-cell mediated APC apoptosis • Defective clearance of apoptotic cells > Increased cell death with nuclear antigens exposed > Nuclear antigens – DS-DNA, Smith, Sjogren’s syndrome A (SSA) and B (SSB) > Deposition of autoantibody-nuclear antigen complexes CLINICAL MANIFESTATIONS OF SLE • General (Constitutional) > Fever, chills, headache, fatigue, malaise and weight loss • Renal > Hematuria, proteinuria • Skin > Malar “Butterfly” rash > Photosensitivity rash • Cardiac > Myocarditis, pericarditis, endocarditis > Athrosclerosis CLINICAL MANIFESTATIONS OF SLE • Central nervous system > Cognitive dysfunction • Pulmonary > Pleurisy • Musculoskeletal > Myalgias, arthralgias and arthritis • Hematologic > Anemia, leukemia, thrombocytopenia • Lymphatic system > Lymphadenopathy AMERICAN COLLEGE OF RHEUMATOLOGY (ACR) CRITERIA FOR DIAGNOSIS OF SLE • • • • • • • • Serositis (Pleurisy, pericarditis) Oral ulcers Arthritis Photosensitivity Blood disorders (Leukopenia, thrombocytopenia) Renal involvement Antinuclear antibodies (ANA) Immunologic phenomena [false-positive Rapid Plasma Reagin (RPR)] • Neurologic disorder • Malar rash • Discoid rash ANTINUCLEAR ANTIBODY (ANA) TEST • Diagnostic test for autoimmune diseases > Detects autoantibodies against nuclear and cytoplasmic antigens • Nuclear and cytoplasmic antigens > DS-DNA, SS-A, SS-B, Smith, RNP, Scl-70, M2 • Laboratory methods > Enzyme immunoassay (EIA) > Immunofluorescence assay (IFA) – Indirect or direct ANTINUCLEAR ANTIBODY (ANA) BY IFA (PROCEDURE) • Dilute patient serum 1:40 • Add patient serum specimens and controls (positive and negative) to wells of Teflon coated slide > Monolayer of HEp-2 cells (Human carcinoma of larynx) – Interphase and mitotic phase cells • Incubate at RT for 20 minutes, then gently wash with PBS • Add fluorescent conjugate [sheep anti-human IgG with fluorescein isothiocyanate (FITC)] ANTINUCLEAR ANTIBODY (ANA) BY IFA (PROCEDURE) • Incubate at RT for 10 minutes in dark • Gently wash with PBS • Add 1 drop of mounting medium to each well and coverslip • Examination with fluorescent microscopy at 200x > Apple-green fluorescence > Nuclear and /or cytoplasmic patterns > Screen positive (1+ to 2+ fluorescence at 1:40) INTERPRETATION OF ANTINUCLEAR ANTIBODY (ANA) BY IFA IN SLE • Positive specimens > Apple-green fluorescence of nuclear region > Patterns of nuclear fluorescence – Homogeneous or speckled (fine or coarse) • Antigens associated with patterns > Homogeneous (ds-DNA) > Coarse Speckled (SSA and Sm) > Fine Speckled (SSB and SSA) • Specimens are quantified by dilution (2-fold serial) > Interpretation – Negative (< 1:40) – Indeterminate (1:80) – Positive (> 1:160) DISCOID LUPUS ERYTHEMATOSUS • Limited to skin (Face, scalp and ears) > 5% of total lupus cases > 5% develop systemic lupus • Pathophysiology > Genetic predisposition (?) > Heat shock protein – Induced in keratinocytes by UV light – Target for cytotoxic Gamma/Delta T cells • Laboratory diagnosis > Histopathology > ANA (20% positive) DRUG-INDUCED LUPUS ERYTHEMATOSUS (DILE) • Autoimmune disease associated with > Long term use wide spectrum of drugs – 5% of all lupus cases • High risk drugs > > > > > Procainamide (Pronestyl) Hydralazine (Apresoline) Quinidine (Quinaglute) Isoniazid (INH) Minocycline (Minocin) DRUG-INDUCED LUPUS ERYTHEMATOSUS (DILE) • Pathophysiology > Genetic predisposition – HLA DR4 with hydralazine – Rate of acetylation • Fast • Slow » Higher rate of DILE > Oxidative metabolism of metabolites by neutrophils – Creates reactive metabolites which disrupt T cell tolerance DRUG-INDUCED LUPUS ERYTHEMATOSUS (DILE) • Epidemiology > Age of onset > Race > Female/male ratio DILE SLE 50 to 70 years White > Black 1:1 20 to 30 years Black > White 9:1 • Laboratory Diagnosis > ANA > Anti-dsDNA > C3 level 98% < 0.1% Normal 98% 85% Decreased • Clinical Diagnosis > Resolution of symptoms after stopping drug (1 to 2 weeks) NEONATAL LUPUS ERYTHEMATOSUS • Etiology > Passive transfer across placenta of maternal IgG autoantibodies – Anti-SSA/Ro, Anti-SSB/La • Diagnosis in pregnant females > SLE or Sjogrens syndrome • 1% of newborns with maternal autoantibodies develop NLE > Incidence in US of 1:20,000 live births • Clinical manifestations > > > > Cardiac (conduction defects, rhythm abnormalities) Dermatologic (erythematous papules and annular plaques) Hematologic (thrombocytopenia, leukopenia, anemia) Hepatic (hepatitis) NEONATAL LUPUS ERYTHEMATOSUS • Dermatology Manifestations > 90% of cases with skin lesions > 70% present at birth • Cardiac Pathophysiology > Deposition of autoantibodies (anti-SSA) at arterioventricular node • Dermatologic Pathophysiology > Deposition of autoantibody (anti-SSB) at dermal-epidermal junction NEONATAL LUPUS ERYTHEMATOSUS • Congenital complete heart block > 15 to 30% of cardiac manifestations > Develops 18 to 20 weeks gestation > 20 to 30% mortality • Laboratory diagnosis in newborn > > > > ANA Anti-SSA/Ro and Anti-SSB/La Complete blood count (CBC) Liver function tests (LFT)