Transcript systemic lupus erythematosus

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
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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
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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
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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
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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
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ANA
Anti-SSA/Ro and Anti-SSB/La
Complete blood count (CBC)
Liver function tests (LFT)