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BrainSalivary, Parotid glands
Thyroid
Heart, LungsSerous linings of Heart, Lungs, GI tractKidneys
Special Complications of Pregnancy
Joints
Blood Vesselsand Blood ProteinsInflammation vs Coagulation
Skin
LUPUS
Variable from patient to patientWaxing and WaningUnpredictableChronic Illness and Disability
Prevalence of Lupus vs Other Diseases
JDRF SocietyNat Inst Neur Dis and StrokeLupus Foundation of AmericaSusan Komen Foundation
( in USA x 1000)
Disease-Specific Funding per year by NIH(normalized to patient numbers)
Millions/year/pt
www.nih.gov.news
Wallace in Arthr and Allied Cond, 13th Ed V2, p1319 Koopman, ed
%
YEARS
IMPROVED SURVIVAL IN SLE: 1955-1990
Epidemiologic Data Based on SLE Cause of Death
The Major Difference has been due to Steroids
Antibiotics: 20th Century Miracle Drugs
Many Faceted DisordersMany Causes for Each SymptomUnpredictable Flares of DiseaseWaxing and Waning Activity
Problems: Treatment SelectionOptimizing the DoseOutcome Measurement
Impediments to Drug Development In the 21st Century
Lupus
• Not an Infection• Disorder of the Immune System• Inflammation in Various Organs• Complicated Causes and Course• Like the others even more so…..
• No new Treatment Approved in > 40 years
• But there is one small population with lupus we can cure
0
5
10
15
20
P1 P2 P3 P4 P5 P6
Biop
lex
Uni
ts
Six Lupus Patients with “Arthritis”
0
2
4
6
8
10
12
P1 P2 P3 P4 P5 P6
IL10
0
50
100
150
200
250
300
P1 P2 P3 P4 P5 P60
20406080
100120140160
P1 P2 P3 P4 P5 P6
IL8
IFN ALPHA TNF ALPHA
HUMANS ARE NOT MICE
Adapted from: Ramanujam M, Davidson A. Arthritis Research and Therapy 2004; 197
Make inflammatoryProteins
Activate other cells
B
IFN-
T
M
Makeantibodies
D B1INF alpha
Adapted from: Ramanujam M, Davidson A. Arthritis Research and Therapy 2004; 197
B
IFN-
T
M
RituximabOcrelizumabEpratuzumab
Abatacept
Lymphostat B, TACI Ig
Riquent, EdritideTLR inhibitors INF alpha inhibitors
D
TNF inhibitors
Cellcept, AsleraAnti IL6
IDEC 131Biogen
T cell activation anddecreased apoptosis
Congenic Dissection of Lupus Pathogenesis
2
B6.Sle2
B cell hyperactivity
B6 strainLupus-resistant
1 3
NZM2410Lupus-prone
2
3
B6.Sle3
1
B6.Sle1
Loss in immune tolerance to chromatin
Mohan C, et al. J Clin Invest. 1998;101:1362-1372.
Mohan et al., J. Immunology, 1998
NZM2410
B6
Re-assembly of Lupus Pathogenesis by various combinations of congenic
intervals
B6.Sle2
B6.Sle3
1
B6.Sle1
Re-assembly ofcongenic intervals
13 2
B6.Sle1,2,3
1 2
B6.Sle1,2
1 3
B6.Sle1,3
2 3
B6.Sle2,3
>90% Fatal lupus
~15% Fatal lupus
~50% Fatal lupus
0% Fatal lupus
Morel et al. PNAS 97:6670-6675, 2000
2
3
0
5
10
15
20
25
30
35
anti-dsDNA
discoid renal
Caucasiann=185
Native Amern=40
African Amern=67
Lupus in People From Different Genetic Backgrounds: Risk is not Destiny
SLE Genes: Ethnic Differences
GENE CAUC AFR references
TNF alpha X Hum Immunol 65:622
16q12-13 X E J Hum Gen 12:668
12q24 X Am J Hum Gen 74:73
FcgRIIIa X Rheum (Ox) 42:446
FcgRIIa X J Clin Invest 95:1348
11p13 (discoid) X J Inv Derm Sym 9:64
NO synth prom X J Rheum 30:60
FasL 1q23 X J Immun 170:132
Harley JB…. Langefeld CD Nature Genetics 40:152, 2008
ITGAMPXKKIAA1542
Whole Genome Scanning
Hom G….Behrens T New England J of Med 358:900, 2008
C8orf13-BLK and ITGAM-ITGAX
Whole Genome Scanning
Nath S….Harley JB Nature Genetics 40:152, 2008 ITGAM Functional variant in
integrin CR3 identified
Kelly JA….Edberg JC IRF5 African Americans
Kawasaki A…. Behrens T Arthritis Rheumatism 58:826, 2008 IRF5 Japanese Population
2008: From Genome to Gene
Pharmacogentics of Cyclophosphamide
• Cyclophosphamide is activated by cytochrome P450 (CYP) enzymes (genetic variants)
• 62 patients with proliferative nephritis• Relative risk of ovarian failure 0.10 with CYP2C19*2
(combined hetero/homozygous)• Increased risk of ESRF or doubled serum creat.
with CYP2B6*5 or CYP2C19*2
Takadak Arth Rheum 2004;50:2202
AZATHIOPRINE OPTIMIZATION
• Imuran (AZA) - derivative of 6-mercaptopurine• AZA metabolized in cells by thiopurine S-
methyltransferase (TPMT) to active thiopurine nucleotides: genetic variants of TPMT differentiate response– 6-thioguanine (6-TG) (too low: AZA ineffective, too
high: bone marrow suppression)– 6-methylmercaptopurine (6-MMP) too high:
hepatotoxicity
Appropriate level of 6-TG is associated with therapeutic effects in Inflammatory bowel disease
• Dubinsky. Gastroenterology 2000; 118:705
Were any of these concepts applied to the clinical trials?
Will the new biologic trials be more focused and strategic?
Many Faceted Disorder (even more than most)Many Causes for Each Symptom (more than most)Unpredictable Flares of Disease (more than most)Waxing and Waning Activity (more than most)
Problems: Treatment Selection/Patient Selection/Timing of SelectionOptimizing the Dose/Earlier Outcome MeasuresNo approved treatments in > 40 yearsOutcome Measurement IS A CRISIS!!!!Poorly trained clinical trialists and we need MORE!!!!
Impediments to Drug Development Specifically for Lupus
Focus on practical Need, based on a multi-disciplinary perspective from biotech, IT, academic, foundation partners
Bring Basic Science Down the Hall to the Clinic Develop a More Sophisticated Immune Pharmacology Develop Individualized Medicine for a multi-faceted disease Pave the way for new approaches to other such diseases
Bringing Down the Barriers to Treatment Development for Lupus
LFA PROGRAM Lupus Biomarkers
Clinical Consortium
Industry-Sponsored
Trials
Pharmaco-genomics
Shared Community Data/Sample
Resource
SLICCand
FLARE
Biomarkers
Lupus Foundation
of America
Bedside to Bench
Patient Selection
New Drugs
Optimize Rx Pt selection, guide Rx objective outcomes
Improve Clinical Tools
Education, International Site Development, Public Awareness, FDA, Govt Agencies,