Systemic Lupus Erythematosus: Diagnosis Laboratory and ...

Systemic Lupus Erythematosus: Diagnosis ? Laboratory and Clinical Presentation

Treatment ? Current Methods and Emerging Biological Treatment

C. Michael Neuwelt, M.D.

Clinical Professor of Medicine University of California, San Francisco,

Chief of Rheumatology Alameda County Medical Center, Oakland, CA

Director of Rheumatology, Core Curriculum St. Mary's Medical Center, San Francisco, CA

UPDATE 2015 AND BEYOND

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Numerous Factors Contribute to Underlying SLE Pathogenesis and Subsequent Organ Damage1,2

Initiate Autoimmunity

Immune Dysfunction

Inflammation and Organ/Tissue Damage

Genetic Susceptibility (Immune-Related)

Stimuli (eg, Environmental,

Hormonal, Infectious)

Immune Reactivity

Innate Immune System Activation

Cytokines

Cytokines

Brain

Lungs Heart Kidneys Skin

Autoantibodies

Adaptive Immune System Activation

Cytokines

Musculoskeletal System

Autoimmune Amplification

1. Tsokos GC. New Engl J Med. 2011;365:2110-2121. 2. Crow MR. Arthritis Res Ther. 2009;11:245-256.

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Multiple Elements of the Immune Response Play a Role in Autoimmunity in SLE1-6 (cont)

Immune Reactivity

Adaptive Immunity

B Cells

Autoantibodies

T Cells Cytokines

IInnffllaammmmaattiioonn

? AInbnnoartmeaImllymacutinviattyed T and B cells

are a feature of SLE pathogenesis1,2

- Overexpression of B- and T-cell costimulatory ligands/receptors1

mDC - HighpeDr CconcentratMioOns of B- and T-cell cytokines1,2

? Increased numCybteorksinoefsantibodyproducing B cells, hypergammaglobulinemia, autoantibody production, and immune-complex formation2

Tissue Damage

mDC=myeloid dendritic cells; pDC=plasmacytoid dendritic cells; MO=macrophages

1. Crow MR. Arthritis Res Ther. 2009;11:245-256. 2. Mok CC, et al. J Clin Pathol. 2003;56:481-490. 3. Tsokos GC. New Engl J Med. 2011;365:2110-2121. 4. Li Y,

et al. Arch Immunol Ther Exp. 2010; 58:355-364. 5. Chan V S-F, et al. Autoimmun Rev. 2012; doi [Epub ahead of print ] 10.1016/j.autrev.2012.03.004.

6. Ronnblom L, et al. Nature Rev Rheum. 2010;6:339-347..

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Autoantibodies Are a Key Feature of SLE

? Characteristic immunologic disturbance in SLE present in almost all patients at some time1-3

? Form immune complexes with nuclear, cytoplasmic, and cell-surface self antigens2,4 ? Amplify immune-system activation through stimulation of innate and adaptive immune

pathways and recruitment of inflammatory cells to immune complexes1,5

Autoantibodies

Autoantibody Detected6

ANA

At Onset 76%

At Any Time 94%

Anti-dsDNA

34%

71%

ANA=antinuclear antibodies; anti-dsDNA=anti-double-strandTeisdsdueeoxDyraibmonaugceleic acid

1. Crow MR. Arthritis Res Ther. 2009;11:245-256. 2. Mok CC, et al. J Clin Pathol. 2003;56:481-490. 3. Heinlen LD, et al. Arthritis Rheum. 2007;56:2344-2351.

4. Chan V S-F, et al. Autoimmun Rev. doi:10.1016/j.autrev.2012.03. 004. [Epub ahead of print]. 5. Tsokos GC. New Engl J Med. 2011;365:2110-2121. 6. ACR

Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Arthritis Rheum. 1999;42:1785-1796.

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Link Between Autoantibodies and Clinical Effects

Autoantibody Associations in SLE

Antigen Specificity

Anti-dsDNA Nucleosomes

Ro La Sm Phospholipids -Actinin C1q

Prevalence (%)

70-80 60-90

30-40 15-20 10-30 20-30

20 40-50

Main Clinical Effects

? Kidney disease ? Skin disease ? Kidney disease ? Skin disease ? Kidney disease ? Skin disease ? Fetal heart problems

? Fetal heart problems

? Kidney disease ? Thrombosis ? Pregnancy loss ? Kidney disease

? Kidney disease

Rahman A, et al. N Engl J Med. 2008;358:929-939.

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