1. Lupus in Women:
Emerging Strategies
Women’s Health Congress 2012
Washington DC
March 2012
Susan Manzi, MD, MPH
Chair, Department of Medicine Allegheny General
Professor Medicine Temple University
Director, Lupus Center of Excellence
Pittsburgh, PA

2. Di s cl os ures
• Consultant and Scientific Advisory Board GSK/HGS

3. Topics for Discussion
What is lupus?
Why is diagnosis so difficult..even for rheumatologists?
What are the recent updates on pathogenesis?
What happens to patients with lupus?
Why are current treatments suboptimal?
What’s on the horizon?

4. Topics for Discussion
What is lupus?
Why is diagnosis so difficult..even for rheumatologists?
What are the recent updates on pathogenesis?
What happens to patients with lupus?
Why are current treatments suboptimal?
What’s on the horizon?

5. Gender Disparity and Autoimmunity
Disease Female/Male Ratio
Thyroid diseases
Diffuse lymphocytic thyroiditis 25-50:1
Primary hyperthyroidism (Graves)
4-8:1
Systemic lupus erythematosus
9:1
ages of 15-45
12:1
elderly/children
2:1
Rheumatoid arthritis
2-4:1
Sjogren’s syndrome
9:1
Idiopathic adrenal insufficiency 2-3:1

6. Misdiagnosis of SLE
263 referred for SLE
- 134 (51%) SLE
- 4 (1.5%) Systemic sclerosis
- 7 (2.6%) Sjogrens
- 1 (<1%) PM/DM
- 14 (5%) Fibromyalgia
- 76 (29%) Antinuclear Antibody (ANA) (+)
- 27 (10%) Non-rheumatic disease
Diagnostic accuracy
80% rheum
50% non rheum Arch Intern Med. 2004;164:2435-2441

7. Clinical Pearl
ANA (+) ≠ Lupus
ANA : 95% Sensitive
11% PPV

8. Misdiagnosis can go both ways.
It takes an average of 4 yrs and 3 physicians
for the correct diagnosis.
Clinical Pearl
You have to think of lupus to diagnosis lupus

9. Classification Criteria for SLE
(As revised in 1997 by the American College of Rheumatology)
A person is said to have SLE if four of these criteria are present at any time:
Skin criteria
• Butterfly rash (lupus rash over the cheeks and nose)
• Discoid rash (thick rash that scars, usually on sun-exposed areas
• Sun sensitivity
• Oral ulcerations
Systemic criteria
• Arthritis
• Serositis
• Proteinuria or cellular urinary casts
• Seizures or psychosis with no other explanation
Laboratory criteria
• Hemolytic anemia, leukopenia, or thrombocytopenia
• Antiphospholipid antibodies, lupus anticoagulant, anti-DNA antibodies, false positive
Syphilis test, or anti-Sm antibodies
• Antinuclear antibody

10. Autoantibody Determined Clinical
Subsets of SLE
SSA (Ro)
SSB (La)
RNP
phospholipids
Ribosomal-P
dsDNA
ANA (+)>95% patients
ANA + > 90%, nonspecific

11. Autoantibody Determined Clinical
Subsets of SLE
SSA/SSB (rash and neonatal lupus,
dry eyes and mouth)
RNP
(Raynauds)
Phospholipid
(clotting and
miscarriage)
Ribosomal-P dsDNA (kidney disease)
(CNS, psychosis)

12. Diagnostic Challenges
Interpretation of criteria
Manifestations not in criteria
Other diseases may mimick lupus
Evolving signs and symptoms over time
No two patients look alike

13. Disease Mimickers
Fibromyalgia (+ ANA)
Sjogren’s syndrome
Dermatomyositi
s and TTP
ITP
Primary antiphospholipid syndrome
Neoplasms (hematologic)
Drug-induced lupus

14. Pathogenesis of SLE
Tissue Damage
Environmental
Complement activation
Genetic
Gender
Immune Complexes
Defective Immune
Regulation
Autoantibodies
Break in self
tolerance

15. Lupus Genetics
Clustering in families (autoimmunity)
Concordance
- monozygotic (identical twins)
25-30%
- dizygotic 5%

16. ITGAM
BLK
Bank1

17. Genes increase susceptibility to SLE
In the major histocompatibility complex (MHC)
C2,C4 deficiency
DR2,DR3
TNF-α polymorphisms
In non-MHC
C1q deficiency (rare, but greatest risk!!)
Chromosome 1 region 1q41-43 (PARP)
region 1q23 (FcγRIIA, RIIIA)
Polymorphisms in IL-10, IL-6 and
mannose-binding protein
STAT4 and IRF5

18. Genes increase susceptibility to SLE
In the major histocompatibility complex (MHC)
C2,C4 deficiency
DR2,DR3
TNF-α polymorphisms
In non-MHC
C1q deficiency (rare, but greatest risk!!)
Chromosome 1 region 1q41-43 (PARP)
region 1q23 (FcγRIIA, RIIIA)
Polymorphisms in IL-10, IL-6 and
mannose-binding protein
STAT4 and IRF5

19. Homozygous deficiency
C1q 38/41 (93%)
C4 14/16 (88%)
C2 38/66 (58%)
95% of lupus is polygenic

20. C1q plays a role in clearly apoptotic blebs

21. Pathogenesis of SLE
Apoptotic cells are a source
of autoantigens
Lupus is characterized by
a defect in apoptotic cell
clearance

22. Why sun exposure may trigger lupus

23. Clinical Pearl
Photoprotection is important in lupus
Sunblocks, photoprotective clothing

24. Survival in lupus has improved.
1950 5 year survival 50%
2000 10 year survival 80-90%

25. Reasons for improved survival
Corticosteroids (1950)
Dialysis
Cyclophosphamide
Anti-hypertensive
Antibiotics
Earlier diagnosis

26. Causes of morbidity and mortality
Early Late
lupus cardiovascular
kidney osteoporosis
infection
cancer

27. Natural History of SLE
• Disease flares/activity (reversible)
inflammation
• Organ damage (irreversible) from
disease or treatment
scarring

28. Longterm Health Issues in
Lupus
Bone
Cancer
Cardiovascular

29. Longterm Health Issues in
Lupus
Bone
Cancer
Cardiovascular

30. Expected and Observed Number of
Fractures in Women With Lupus
Expected Observed
100
90
80
70
60
50
40
30
Number of fractures
20
10
0
<18 18-24 25-44 45-64 65-69 70+ Total
Age (years)
Ramsey-Goldman et al. Arthritis Rheum. 1999;42:882-890.

31. Osteopenia in women with SLE
Caucasians (n=222)
African-Americans (n=77)
Lee C, Arthritis Rheum. 2007;57:585-592

32. Osteoporosis in Women with SLE
Caucasians (n=222)
African-Americans (n=77)
Lee C, Arthritis Rheum. 2007;57:585-592

33. Adjusted risk factors for low bone mineral density (BMD) in
women with SLE *
Low Forearm
Low Hip BMD Low Spine BMD
BMD
Risk Factor Adjusted Adjusted
Adjusted
OR (95% CI) OR (95% CI)
OR (95% CI)
African- 1.94 5.49 0.56
(0.93, 4.02) (2.67, 11.32) (0.18, 1.74)
American race
Adjusting for age, BMI, steroid use, thyroid disease, menopausal status
*Low BMD defined as either osteopenia or osteoporosis based on T-score.

34. Clinical Pearls
Fracture rates are greater than expected in
women with lupus
Women with lupus have higher than expected
frequencies of osteopenia/osteoporosis
African American women with lupus are not
protected from this risk (spine)

35. Longterm Health Issues in
Lupus
Bone
Cancer
Cardiovascular

36. Relative Risk for Malignancy in SLE
Study SIR Point Estimate (95% CI)
Peterson 1992 2.6 (1.5, 4.4)
Sweeney 1995 1.4 (0.5, 3.0)
Abu-Shakra 1996 1.1 (0.7, 1.6)
Mellemkjaer 1997 1.3 (1.1, 1.6)
Ramsey-Goldman 1998 2.0 (1.4, 2.9)
Sultan 2000 1.2 (0.5, 2.1)
Nived 2001 1.5 (0.8, 2.6)
Bjornadel 2002 1.4 (1.3, 1.5)
Cibere 2001 1.6 (1.1, 2.3)
0 1 2 3 4 5
SIR
SIR, standardized incidence ratio; CI, confidence interval.
Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490.

37. International Study of Cancer Risk in SLE
CaNIOS and SLICC Participants
Outcomes
● SIR and SMR
(observed/expected
rates)
● Linkage to regional
tumor registries
Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490.

38. International Study of Cancer Risk in Lupus
• 23 sites
- 9547 patients
- 76,948 patient-years
- Calendar period 1958 - 2000
• Pooled cohort studies
- 2762 patients
- 23,696 patient-years
Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490

39. Total Number of Cancers Observed and Expected,
with Standardized Incidence Ratios
Malignancy Observed Expected SIR 95% CI
Total 431 373.3 1.2 1.1, 1.3
Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490

40. Hematologic Cancers,
Standardized Incidence Ratios
Malignancy Observed Expected SIR 95%CI
All Heme 67 24.4 2.8 2.1, 3.5
NHL 42 11.5 3.6 2.6, 4.9
HL 5 2.1 2.4 0.8, 5.5
Leukemia 7 3.7 1.9 0.8, 3.9
Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490

41. Reproductive Cancers,
Standardized Incidence Ratios
Malignancy Observed Expected SIR 95% CI
Breast 73 96.1 0.8 0.6, 1.0
Ovary 9 14.5 0.6 0.3, 1.2
Cervix 14 11.1 1.3 0.7, 2.1
Vagina 2 0.4 4.9 0.5, 18
Vulva 2 1.3 1.6 0.2, 5.8
Uterus 6 16.9 0.4 0.1, 0.8
Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490

42. Other Cancers,
Standardized Incidence Ratios
Malignancy SIR 95% CI
Lung 1.4 1.1, 1.8
Hepatobiliary 2.6 1.3, 4.8
Pancreas 0.9 0.4, 1.9
Gastric 1.1 0.5, 2.0
Colorectal 1.0 0.7, 1.4
Thyroid 1.5 0.7, 2.8
Bladder 1.2 0.7, 2.1
Prostate 0.7 0.3, 1.4
Melanoma 1.0 0.4, 1.8
Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490

43. Clinical Pearls
Increased risk of cancer in SLE compared
with general population
Greatest risk:
- Hematologic (lymphoma)
- Possibly lung and hepatobiliary

44. Longterm Health Issues in
Lupus
Bone
Cancer
Cardiovascular

45. Incidence rates of myocardial infarction in 498 women
with SLE (Pittsburgh) and 2208 women from the
Framingham Offspring Study: 1980-1993
Myocardial Infarction (per 1000 person- years)
SLE Framingham
Age (years) Rate Rate Rate Ratio 95%CI
15-24 6.33 0.00 ∞ −
25-34 3.66 0.00 ∞ −
35-44 8.39 0.16 52.43 [21.6, 98.5]
45-54 4.82 1.95 2.47 [0.8, 6.0]
55-64 8.38 1.99 4.21 [1.7, 7.9]
Manzi, et al. Am J Epidemiol, 1997

46. Prevalence of Coronary Calcification in
SLE and Controls
100
90
80
70
60
50 SLE
Freq %
40 Control
30
20
10
0
<40 40-49 50-59 >60
Years
SLE 20/65 (31%): Controls 6/69 (9%)
NEJM 2003;349:2407
Calcification score > 0

47. Prevalence of Carotid Atherosclerosis in
SLE and Controls
80
70
60
50
Freq % 40 SLE
30 Controls
20
10
0
<40 50-59 60-69 >70
Years
NEJM 2003;349:2399
SLE 37.1%: Controls 15.2%

48. Role of Traditional Risk Factors
After adjusting for baseline CHD risk using the
Framingham risk factor estimate, patients with
SLE still had a 7- to 10-fold increased risk of
CHD and stroke.
RR = 17 for fatal CHD
Esdaile JM, Arthritis Rheum 2001

49. Cardiovascular Biomarkers and Surrogate
Endpoints Symposium
Proven biomarkers
aPL, pro-inflammatory HDL,
LDL, B/P CECs, complement activation,
Proposed new biomarkers iNOS, AGEs
CRP, MPO, Ox-LDL, Anti-oxLDL
IL-6, IL-1, IL-18, TNFα, MMP-9, Lp-PLA2
M-CSF-1, ICAM-1, P-Selectin, VCAM-1

50. Preventive Cardiology Intervention in SLE
SLE Patients seen at the University of Pittsburgh Lupus Center
45
40
35
30
25
%
20
15
10
5
0
1 2 3 4 5 6 7 8
# risk factors
¥89.7% have 3 or more CV risk factors
Unpublished data, Pgh

51. Clinical Pearl
SLE patients are at significant risk for
atherosclerotic CVD
This risk cannot be fully explained by
traditional risk factors alone
Awareness and practical approaches to
management

52. Clinical Pearls
HRT and OCPs do not increase the risk of
significant disease activity in lupus
Caveat: Lupus women have increased risk of
CVD and thrombosis.

53. FDA Approved Drugs for SLE
Corticosteroids
Hydroxychloroquine
ASA
Benlysta Approved March 2011

54. On the Horizon…

55. Summary
• Lupus is difficult to diagnose (ANA ≠lupus)
• Lupus is characterized by a break in defective clearance
of apoptotic cells (photoprotection important)
• Lupus patients have higher than expected bone loss,
cancer risk and CVD (advanced aging)
• Drought in drug development in lupus...now with
promising biologic therapies in clinical trial