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,