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Systemic Lupus Erythematosus. Epidemiology of SLE. Prevalence - 1/2,000 people Sex - 10:1 female predominance Age at onset 16-55 years: 65% (F:M = 10:1) <16 years: 20% (F:M = 2:1) >55 years: 15% (F:M = 2:1) Race - more common in Blacks and Asians than in Whites.

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epidemiology of sle
Epidemiology of SLE
  • Prevalence - 1/2,000 people
  • Sex - 10:1 female predominance
  • Age at onset

16-55 years: 65% (F:M = 10:1)

<16 years: 20% (F:M = 2:1)

>55 years: 15% (F:M = 2:1)

  • Race - more common in Blacks and Asians

than in Whites

common manifestations of sle
Common Manifestations of SLE

Constitutional Symptoms

  • Fatigue
  • Fever
  • Weight loss

Mucocutaneous Involvement

  • Photosensitive rash
  • Oral ulcers
  • Alopecia

Arthralgias/Arthritis

manifestations of sle con d
Manifestations of SLE (con’d)

Kidneys - Glomerulonephritis

Central Nervous System - Headache, seizures, stroke

Peripheral Nervous System - sensory or motor

Lungs - pleuritis, pneumonitis, hemorrhage

Heart - pericarditis, myocardial infarction, valve disease

GI - serositis, mesenteric vasculitis, pancreatitis

Hematopoietic - lymphadenopathy, autoimmune cytopenias, antiphospholipid antibody syndrome

target antigens in sle
Target Antigens in SLE
  • Nuclear antigens (e.g., dsDNA)
  • Cytoplasmic antigens (e.g., ribosomal proteins)
  • Cell surface antigens (e.g., blood cells)
  • Soluble antigens in sera (e.g., IgG, phospholipids)
anti dsdna antibodies evidence for a pathogenic role
Anti-dsDNA AntibodiesEvidence for a Pathogenic Role
  • Presence correlates with renal involvement
  • Serum levels correlate with disease activity
  • Concentration is enriched in glomerular eluates
  • Some monoclonal anti-dsDNA can produce lupus nephritis
anti dna mediated renal injury proposed mechanisms
Anti-DNA Mediated Renal InjuryProposed Mechanisms
  • Deposition of circulating immune complexes
  • Binding of DNA to GBM (e.g., based on charge)
  • Binding of anti-dsDNA to glomerular antigens(e.g., due to polyspecificity - heparin sulfate, laminin)
autoantibodies in cns lupus degiorgio et al nature med 7 1189 2001
Autoantibodies in CNS Lupus (DeGiorgio et al.: Nature Med 7:1189,2001)

1) Some anti-DNA antibodies bind receptors for glutamate.

2) Glutamate receptors contribute to learning and memory.

3) Overstimulation of glutamate receptors can cause excitotoxic neuron death.

autoantibodies in cns lupus degiorgio et al nature med 7 1189 20011
Autoantibodies in CNS Lupus (DeGiorgio et al.: Nature Med 7:1189,2001)

(continued)

4) Anti-DNA antibodies mediate neuronal cell death.

5) CSF from a patient with CNS lupus contain anti-DNA antibodies that mediate neuronal death.

antiphospholipid antibodies apl antibodies bind complexes of phospholipids and plasma proteins
Antiphospholipid AntibodiesaPL antibodies bind complexes of phospholipids and plasma proteins:
  • Prothrombin-activator complex

(activated factor X, factor V, prothrombin,

calcium, phospholipid)

  • b2-glycoprotein I

(a naturally occurring anticoagulant)

antiphospholipid antibody syndrome aps
Antiphospholipid Antibody Syndrome (APS)
  • Venous thrombosis
  • Arterial thrombosis
  • Recurrent fetal loss
  • Thrombocytopenia
other postulated mechanisms
Other Postulated Mechanisms
  • Defective clearance of apoptotic bodies (persistence of self nuclear antigens)
  • Failure of tolerance (T cells and/or B cells)
  • Activation of B cells and/or dendritic cells by self DNA or RNA through toll-like receptors (i.e., TLR-7 and TLR-9)
special serologic studies in sle
Special Serologic Studies in SLE

Antinuclear Antibodies (ANA)

Anti-dsDNA Antibodies

Anti-ENA Antibodies (RNP, Sm)

Rheumatoid Factor (RF)

Complement (C3, C4, CH50)

acr criteria for sle
1. Malar rash

2. Discoid Rash

3. Photosensitivity

4. Oral ulcers

5. Arthritis

6. Serositis

7. Renal disorder

8. Neurologic disorder

9. Hematologic disorder

10. Antinuclear antibody

11. Immunologic disorder

ACR Criteria For SLE
case history
Case History

Patient: 33-year-old woman

Symptoms: Fatigue, myalgias/arthralgias,

pleuritic chest pain

Signs: T-38.5oC

Nodes - mild diffuse adenopathy

Lungs - dullness at right base

Joints - synovitis at the wrists and MCPs;

small effusions in both knees

differential diagnosis
Differential Diagnosis

Infection

  • Virus (HIV, hepatitis, EBV, Coxsackie)
  • Gonococcus
  • Subacute bacterial endocarditis
  • Pneumonia
  • Tuberculosis
differential diagnosis1
Differential Diagnosis

Infection

  • Virus (HIV, hepatitis, EBV, Coxsackie)
  • Gonococcus
  • Subacute bacterial endocarditis
  • Pneumonia
  • Tuberculosis

Rheumatic Disease

  • Rheumatoid arthritis
  • Systemic lupus erythematosus
differential diagnosis2
Differential Diagnosis

Infection

  • Virus (HIV, hepatitis, EBV, Coxsackie)
  • Gonococcus
  • Subacute bacterial endocarditis
  • Pneumonia
  • Tuberculosis

Rheumatic Disease

  • Rheumatoid Arthritis
  • Systemic lupus erythematosus
  • Mixed connective tissue disease
  • Polymyositis
  • Polyarteritis nodosa
differential diagnosis3
Differential Diagnosis

Infection

  • Virus (HIV, hepatitis, EBV, Coxsackie)
  • Gonococcus
  • Subacute bacterial endocarditis
  • Pneumonia
  • Tuberculosis

Rheumatic Disease

  • Rheumatoid Arthritis
  • Systemic lupus erythematosus
  • Mixed connective tissue disease
  • Polymyositis
  • Polyarteritis nodosa

Malignancy

  • Leukemia
  • Lymphoma
laboratory data
Laboratory Data

Hgb - 11.3 LFTs - wnl

Hct - 34 Creatinine - 1.0

WBC - 3,200 Urinalysis - wnl

Platelets - 220,000 EKG - wnl

X-rays: Chest - small pleural effusion on the right

Hands/knees - swelling, no bony abnormalities

RF - 1:80

ANA - 1:160

serology
Serology

CH50 - low

Anti-DNA - high

laboratory data1
Laboratory Data

Hgb - 11.3 LFTs - wnl

Hct - 34 Creatinine - 1.0

WBC - 3,200 Urinalysis - wnl

Platelets - 220,000 EKG - wnl

*X-rays: Chest - small pleural effusion on the right

Hands/knees - swelling, erosions at MCP joints

RF - 1:80

*ANA - negative

laboratory data2
Laboratory Data

Hgb - 11.3 LFTs - wnl

Hct - 34 *Creatinine - 1.8

WBC - 3,200 *Urinalysis - 2+ protein, RBCs

Platelets - 220,000 EKG - wnl

X-rays: Chest - small pleural effusion on the right

Hands/knees - swelling, no bony abnormalities

*RF - negative

*ANA - 1:160

laboratory data3
Laboratory Data

Hgb - 11.3 LFTs - wnl

Hct - 34 *Creatinine - 1.8

*WBC - 5,600 *Urinalysis - 2+ protein, RBCs

Platelets - 220,000 EKG - wnl

X-rays: Chest - small pleural effusion on the right

Hands/knees - swelling, no bony abnormalities

RF - 1:80

*ANA - negative

laboratory data4
Laboratory Data

Hgb - 11.3 LFTs - wnl

Hct - 34 Creatinine - 1.0

*WBC - 84,000 Urinalysis - wnl

Platelets - 220,000 EKG - wnl

X-rays: Chest - small pleural effusion on the right

Hands/knees - swelling, no bony abnormalities

*RF - negative

*ANA - negative

principles of management
Principles of Management

Careful monitoring

Attention to psychosocial problems

Topical therapy for skin involvement

NSAIDs for arthritis/pleuritis

Treat associated medical problems

Steroids/cytotoxic drugs for refractory symptoms and/or life threatening manifestations

potential biologically based therapeutic interventions for lupus a partial list
B Cell Targets

Anti-BLyS

Anti-CD20

Anti-CD22

Anti-B7

TACI-Ig

T Cell Targets

Anti-CD3

Anti-CD4

Anti-CD40L

CTLA4Ig

Cytokine Targets

Anti-IFN (a or g)

Anti-TNF-a

Anti-IL-10

Anti-IL-6R

Complement System Targets

Anti-C5

C3 convertase inhibitor (Crry-Ig)

Regulatory Cell Targets

CD4+ CD25+ T Cells

Stem Cell Transplantation

Potential Biologically-Based Therapeutic Interventions for Lupus (a partial list)
slide34

Summary

BLISS-52

BLISS-76

a Wallace et al. Presented at the American College of Rheumatology Annual Meeting, Nov 9, 2010, Poster 1172.

slide35

-9.7%

-43.3%

-49.5%

51.9%

38.5%

16.7%

Changes in Serologic Measures

Anti-dsDNA

Median % Change

In Patients Positive at Baseline

C4

% Change Over Time

In Patients With Low Baseline C4

# p <0.001, + p <0.01, * p <0.05