Systemic Lupus Erythematosus

Epidemiology of SLE

• Prevalence - 1/2,000 people

• Sex - 10:1 female predominance

• Age at onset16-55 years: 65% (F:M = 10:1) <16 years: 20% (F:M = 3:1) >55 years: 15% (F:M = 7:1)

• Race - more common in Blacks, Hispanics, and Asians than in Whites

Common Manifestations of SLE

Constitutional Symptoms• Fatigue• Fever• Weight loss

Mucocutaneous Involvement• Photosensitive rash• Oral ulcers• Alopecia

Arthralgias/Arthritis

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

• 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 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 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)

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 7:1189,2001)

(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:

• Prothrombin-activator complex (activated factor X, factor V, prothrombin, calcium, phospholipid)

• b2-glycoprotein I (a naturally occurring anticoagulant)

Antiphospholipid Antibody Syndrome (APS)

• Venous thrombosis

• Arterial thrombosis

• Recurrent fetal loss

• Thrombocytopenia

Prevention of Fetal Loss with Crry-Ig(Holers VM…Salmon JE: J Exp Med 195:211, 2002)

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

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

Case History

Patient: 33-year-old woman

Symptoms: Fatigue, myalgias/arthralgias,pleuritic chest pain

Signs: T-38.5oCNodes - mild diffuse adenopathyLungs - dullness at right baseJoints - synovitis at the wrists and MCPs; small effusions in both knees

Differential Diagnosis

Infection• Virus (HIV, hepatitis, EBV, Coxsackie)

• Gonococcus

• Subacute bacterial endocarditis

• Pneumonia

• Tuberculosis

Differential Diagnosis

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

Rheumatic Disease • Rheumatoid arthritis• Systemic lupus erythematosus

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 DiagnosisInfection• 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

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

CH50- low

Anti-DNA - high

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 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 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 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

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

Anti-BLyS (Belimumab)

Summary

BLISS-52 BLISS-76

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

Changes in Serologic Measures

Anti-dsDNA Median % Change

In Patients Positive at Baseline

C4 % Change Over Time

In Patients With Low Baseline C4

-43.3%-49.5%

-9.7%

38.5%

51.9%

16.7%

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

T Cell Costimulation

Inhibition of T Cell Costimulation

Systemic Lupus Erythematosus