Title: Systemic lupus erythematosus: Challenges to Treatment and Diagnosis
1Systemic lupus erythematosus Challenges to
Treatment and Diagnosis
2HORMONAL Female preponderance In mice prone to
lupus clear hormonal role
IMMUNOREGULATORY
GENETIC 1/3 concordance in monoZ twins Single
genes (Complement) Multiple loci, genes (100 or
more genes) SNPS in many genes
ENVIRONMENTAL Infections worsen
lupus Drugs (hydralazine and dozens
more) Molecular mimicry
3Mediators of Cell/Tissue Damage
- Autoantibodies
- Immune complexes
- Autoreactive T cells
- Products of Immune
- Cell Activation
- (lymphokines, other)
4Autoantibodies
- Do nothing, or we do not know whether they are
doing anything - Disease markers (association with disease or
specific clinical manifestation) - Bind to tissue or cell antigens and
- Activate complement
- Alter function
- Inhibit function of agonists
- Mediate ADCC
- Eliminate apoptotic material
- Novel mechanism Bind stressed cells, activate
complement, confer injury.
5Case Report
- 23 yo woman presented with malar rash, pleuritis,
and DPGN-biopsy proven, ANA, high titers of
anti-DNA and anti-cardiolipin Abs. - Received PN and the NIH-developed IV cytoxin
regimen that resulted in complete response. - Age 25 to 28 disease was in clinical remission
was kept on plaquenil anti-DNA and CL Ab titers
remained high. - Immediately after her 28th birthday had an
elective abortion which was performed without any
rheum consultation. - 3 weeks later presented with fever, fatigue, leg
edema, rash, pleuritis and anemia. - Questions
- Why was the disease clinically quiescent despite
the fact that she had high titers of
autoantibodies? - Why did the disease exacerbate following a
tissue-damaging procedure?
6Mesenteric Ischemia/ Reperfusion (IR) model
4
3
Injury Score
2
1
0
Fleming, J. Immunol. 2003, 2004
7Immune Complex Deposition
8(No Transcript)
9Necrotizing vasculitis in a patient with a SLE.
Tissue biopsy may reveal increased expression of
adhesion molecules and infiltrating lymphocytes
10Kidney
Allograft
SLE
11SLE T cells express more CD44 (adhesion molecule)
that confers increased adhesion and migration
AND CD44 siRNA suppresses adhesion and mobility
in SLE T cells
n6
J. Immunol. Feb. 2007
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13J F M A M J J A S O N D J F M A M J J A S O N D J
F M A M J J A S O N D Month
14FDA-approved Drugs for SLE
- Aspirin (baby)
- Glucocorticosteroids
- Hydroxychloroquine.
15Current Treatment
- NIH-established cyclophosphamide protocols for
Lupus Nephritis, - Induction 6 monthly doses of IVCY
- Consolidation quarterly IVCY
16Approach improve existing treatments
- Efforts to use alternates in consolidation phase.
- Efforts to use alternates in induction phase.
Mofetil instead of CY
17Alternative ApproachCapitalize on information
gained from the study of the pathogenesis of the
disease.
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19X
20TLR
IL-6 IL10 BLyS
21- Current Approaches
- Anti-IL-6 Ab
- Anti-IL-6 receptor Ab
- Anti-BLyS
- Future approaches
- TACI-Ig (block the effect of BLyS)
- Anti-IFNa
- Decoy receptors for lymphokines
- Toll-like receptor 9 decoy
- Gene therapy (cell therapy)
22Cognate lymphocyte-lymphocyte and
lymphocyte-endothelial cell interactions
CD40L-------CD40
CD4 TCR-Ag----HLADR2
CTLA4 (-) CD28 () ----------B7
Adhesion
23- CTLA4-Ig (psosiasis, RA)
- Anti-CD40L Ab (x2)
- Some effect but thromboembolism
- No effect
- Anti-CD40 Ab (blocks and depletes)
24Ag (auto-Ag) Tolerance
- B cells
- Deletion
- anti-B cell Abs
- Anergy
- Eliminate surface receptors
- Limited activation
- Engagement of suppressive receptors (Fc)
25LJP-394
B cell Anergic
B cell anti-DNA specificity
26C-dependent lysis
ADCC
B Cells, Be Gone George C. Tsokos, M.D. NEJM,
35025, 2004
27Rituximab in SLEJ. Looney
- Low doses cause B cell depletion in some patients
- FcRIII high affinity phenotype deplete better
12
10
Deplete
8
rs
DISEASE ACTIVITY
6
Non-
Deplete
4
rs
2
0
1
2
3
Month
28T cell
- Understand how SLE T cells are different from
normal T cells - How they function
- Help classify patients to subgroups with distinct
biochemical defects - Design rational treatments
29Tsokos et al, Trends in Immunol. May
2003 Vassilopoulos, Liossis, Nambiar, Enyedy
Krishnan (1995-2006, JI, JCI, JBC, AR)
30In SLE T lymphocytes the production of IL2 is
limited by limited expression of enhancers and
increased expression of repressors
IL-2 Gene
CREM
CD28- RE
AP1
NFAT
NF-?B
AP1
AP1
NFAT
NFAT
NFAT
AP1
NFAT
-285
-275
-160
-150
-135
-125
-205
-90
-85
-45
-180
TATA
Wong, Juang, Solomou, Tenbrock, Kyttaris,
Katsiari J. Immunol. 2001-2007, J. Clin. Invest.
2004-5
31Gene transfer-modified cell therapy
Replenish with PKA p65 TCR z
Eliminate siCREM anti-sense CREM si PP2Ac si
FcRg siCD44
32Assumption levels
- Correction of biochemical defect gtgt
- corrected signaling gtgt
- normal immune effector cell function gtgt
- improve pathology gtgt
- clinical outcome. Cest accompli!
33SLE diagnostic and classification kit.
34patient
35The Future in the Treatment of SLE
- Limitations
- Lack of biomarkers/surrogate endpoints
- Difficulty in conducting trials (number of
patients) - Heterogeneity of the disease
- Control group
- Add-on studies
- Expectations
- Develop suitable biomarkers
- Increase federal funding for multi-center trials
- Increase industry/angel funding
- Better understanding of pathogenic processes
- New biologics/drugs
36Disease Activity
Time
37Disease Activity Indices
Disease activity indices BILAG, ECLAM, LAI, SLAM,
SLEDAI Limitations (preferential weights (organs,
serology) use them all together Antibodies
(aDNA), Complement Novel Complement deposition
on red cells Lymphokines Gene expression Lipid
raft aggregates Biochemical markers End Organ
Damage Markers Kidney CNS Blood etc.
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39- Stephanie Smith was diagnosed with SLE at the age
of 15 in 1959 at the Rockefeller University
Hospital where she presented with arthritis,
rash, pleuritis positive lupus erythematosus
preparation, complement fixing antibodies with
cell nuclei and cytoplasm, elevated sedimentation
rate, gamma-globulin and anemia without renal
disease. - Her serum had anti-Sm antibodies
- Stephanie succumbed to complications of her
disease and treatment 7 years later at the age of
22. - According to one of her physicians, Dr. Eng Tan,
she was very intelligent and talented young
woman. She was a skillful painter.