am 9.30 manzi
DESCRIPTION
TRANSCRIPT
![Page 1: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/1.jpg)
Lupus in Women: Emerging Strategies
Susan Manzi, MD, MPHChair, Department of Medicine Allegheny General
Professor Medicine Temple UniversityDirector, Lupus Center of Excellence
Pittsburgh, PA
Women’s Health Congress 2012Washington DC
March 2012
![Page 2: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/2.jpg)
Disclosures
• Consultant and Scientific Advisory Board GSK/HGS
![Page 3: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/3.jpg)
What’s on the horizon?
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?
![Page 4: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/4.jpg)
What’s on the horizon?
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?
![Page 5: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/5.jpg)
Disease Female/Male Ratio
Thyroid diseases Diffuse lymphocytic thyroiditis
Primary hyperthyroidism (Graves)
Systemic lupus erythematosus
ages of 15-45
elderly/children
Rheumatoid arthritis
Sjogren’s syndrome
Idiopathic adrenal insufficiency
25-50:1
4-8:1
9:1 12:1 2:1
2-4:1
9:1
2-3:1
Gender Disparity and Autoimmunity
![Page 6: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/6.jpg)
Arch Intern Med. 2004;164:2435-2441
Misdiagnosis of SLE
263 referred for SLE
Diagnostic accuracy80% rheum50% non rheum
- 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
![Page 7: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/7.jpg)
Clinical Pearl
ANA (+) ≠ Lupus
ANA : 95% Sensitive 11% PPV
![Page 8: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/8.jpg)
Misdiagnosis can go both ways.
It takes an average of 4 yrs and 3 physiciansfor the correct diagnosis.
Clinical PearlYou have to think of lupus to diagnosis lupus
![Page 9: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/9.jpg)
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
![Page 10: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/10.jpg)
Autoantibody Determined Clinical Subsets of SLE
RNP
SSA (Ro)SSB (La)
dsDNA
ANA (+)>95% patientsANA + > 90%, nonspecific
Ribosomal-P
phospholipids
![Page 11: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/11.jpg)
Autoantibody Determined Clinical Subsets of SLE
SSA/SSB (rash and neonatal lupus, dry eyes and mouth)
dsDNA (kidney disease)Ribosomal-P(CNS, psychosis)
Phospholipid(clotting and
miscarriage)
RNP(Raynauds)
![Page 12: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/12.jpg)
Diagnostic Challenges
No two patients look alike
Interpretation of criteria
Manifestations not in criteria
Other diseases may mimick lupus
Evolving signs and symptoms over time
![Page 13: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/13.jpg)
Disease Mimickers
Sjogren’s syndrome
Fibromyalgia (+ ANA)
Dermatomyositis
Neoplasms (hematologic)
ITP and TTP
Primary antiphospholipid syndrome
Drug-induced lupus
![Page 14: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/14.jpg)
Pathogenesis of SLE
Genetic
Environmental
Gender
Tissue Damage
Defective Immune Regulation
Break in self tolerance
Autoantibodies
Immune Complexes
Complement activation
![Page 15: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/15.jpg)
Lupus Genetics
Clustering in families (autoimmunity)
Concordance
- monozygotic (identical twins)
25-30%
- dizygotic 5%
![Page 16: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/16.jpg)
BLK
ITGAM
Bank1
![Page 17: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/17.jpg)
Genes increase susceptibility to SLEIn the major histocompatibility complex (MHC)
C2,C4 deficiencyDR2,DR3TNF- polymorphisms
In non-MHCC1q deficiency (rare, but greatest risk!!)Chromosome 1 region 1q41-43 (PARP)
region 1q23 (FcRIIA, RIIIA)Polymorphisms in IL-10, IL-6 and mannose-binding proteinSTAT4 and IRF5
![Page 18: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/18.jpg)
Genes increase susceptibility to SLEIn the major histocompatibility complex (MHC)
C2,C4 deficiencyDR2,DR3TNF- polymorphisms
In non-MHCC1q deficiency (rare, but greatest risk!!)Chromosome 1 region 1q41-43 (PARP)
region 1q23 (FcRIIA, RIIIA)Polymorphisms in IL-10, IL-6 and mannose-binding proteinSTAT4 and IRF5
![Page 19: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/19.jpg)
Homozygous deficiency
C1q 38/41 (93%) C4 14/16 (88%)C2 38/66 (58%)
95% of lupus is polygenic
![Page 20: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/20.jpg)
C1q plays a role in clearly apoptotic blebs
![Page 21: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/21.jpg)
Apoptotic cells are a source of autoantigens
Lupus is characterized bya defect in apoptotic cell
clearance
Pathogenesis of SLE
![Page 22: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/22.jpg)
Why sun exposure may trigger lupus
![Page 23: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/23.jpg)
Clinical Pearl
Photoprotection is important in lupus
Sunblocks, photoprotective clothing
![Page 24: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/24.jpg)
Survival in lupus has improved.
1950 5 year survival 50%
2000 10 year survival 80-90%
![Page 25: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/25.jpg)
Reasons for improved survival
Corticosteroids (1950)
Dialysis
Cyclophosphamide
Anti-hypertensive
Antibiotics
Earlier diagnosis
![Page 26: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/26.jpg)
Causes of morbidity and mortality
lupus kidney infection
Early Late
cardiovascularosteoporosis
cancer
![Page 27: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/27.jpg)
Natural History of SLE
• Disease flares/activity (reversible)
inflammation
• Organ damage (irreversible) from disease or treatment
scarring
![Page 28: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/28.jpg)
Longterm Health Issues in Lupus
Bone
Cancer
Cardiovascular
![Page 29: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/29.jpg)
Longterm Health Issues in Lupus
Bone
Cancer
Cardiovascular
![Page 30: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/30.jpg)
Ramsey-Goldman et al. Arthritis Rheum. 1999;42:882-890.
Expected and Observed Number of Fractures in Women With Lupus
0
10
20
30
40
50
60
70
80
90
100
<18 18-24 25-44 45-64 65-69 70+ Total
Age (years)
Number of fractures
Expected Observed
![Page 31: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/31.jpg)
Osteopenia in women with SLE
Caucasians (n=222)African-Americans (n=77)
Lee C, Arthritis Rheum. 2007;57:585-592
![Page 32: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/32.jpg)
Osteoporosis in Women with SLE
Caucasians (n=222)African-Americans (n=77)
Lee C, Arthritis Rheum. 2007;57:585-592
![Page 33: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/33.jpg)
Adjusted risk factors for low bone mineral density (BMD) in women with SLE *
Risk FactorLow Hip BMD
AdjustedOR (95% CI)
Low Spine BMDAdjusted
OR (95% CI)
Low Forearm BMD
AdjustedOR (95% CI)
African-American race
1.94
(0.93, 4.02)5.49
(2.67, 11.32)
0.56
(0.18, 1.74)
Adjusting for age, BMI, steroid use, thyroid disease, menopausal status
*Low BMD defined as either osteopenia or osteoporosis based on T-score.
![Page 34: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/34.jpg)
Clinical Pearls
African American women with lupus are not protected from this risk (spine)
Fracture rates are greater than expected in
women with lupus
Women with lupus have higher than expected frequencies of osteopenia/osteoporosis
![Page 35: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/35.jpg)
Longterm Health Issues in Lupus
Bone
Cancer
Cardiovascular
![Page 36: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/36.jpg)
Relative Risk for Malignancy in SLEStudy SIR Point Estimate (95% CI)
2.6 (1.5, 4.4)
1.4 (0.5, 3.0)
1.1 (0.7, 1.6)
1.3 (1.1, 1.6)
2.0 (1.4, 2.9)
1.2 (0.5, 2.1)
1.5 (0.8, 2.6)
1.4 (1.3, 1.5)
1.6 (1.1, 2.3)
Peterson 1992
Sweeney 1995
Abu-Shakra 1996
Mellemkjaer 1997
Ramsey-Goldman 1998
Sultan 2000
Nived 2001
Bjornadel 2002
Cibere 2001
0 1 2 3 4 5SIR
SIR, standardized incidence ratio; CI, confidence interval. Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490.
![Page 37: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/37.jpg)
International Study of Cancer Risk in SLE CaNIOS and SLICC Participants
Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490.
Outcomes ● SIR and SMR
(observed/expected rates)
● Linkage to regional tumor registries
![Page 38: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/38.jpg)
International Study of Cancer Risk in Lupus
• 23 sites
• Pooled cohort studies- 2762 patients- 23,696 patient-years
- 9547 patients
- 76,948 patient-years
- Calendar period 1958 - 2000
Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490
![Page 39: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/39.jpg)
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
![Page 40: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/40.jpg)
Hematologic Cancers, Standardized Incidence Ratios
0.8, 3.91.9 3.7 7Leukemia
0.8, 5.52.4 2.1 5HL
2.6, 4.93.611.542NHL
2.1, 3.52.824.467All Heme
95%CI95%CISIRSIRExpectedExpectedObservedObserved MalignancyMalignancy
Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490
![Page 41: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/41.jpg)
Reproductive Cancers, Standardized Incidence Ratios
0.2, 5.81.6 1.3 2Vulva
0.5, 184.9 0.4 2Vagina
0.7, 2.11.311.1 14Cervix
0.3, 1.20.614.5 9Ovary
0.6, 1.00.896.1 73Breast
95% CI95% CISIRSIRExpectedExpectedObservedObservedMalignancyMalignancy
0.1, 0.80.416.9 6Uterus
Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490
![Page 42: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/42.jpg)
Other Cancers, Standardized Incidence Ratios
0.4, 1.81.0Melanoma
0.3, 1.4 0.7Prostate
0.7, 2.11.2Bladder
0.7, 2.81.5Thyroid
0.7, 1.41.0Colorectal
0.5, 2.01.1Gastric0.4, 1.90.9Pancreas
1.1, 1.81.4Lung
95% CI95% CISIRSIRMalignancyMalignancy
1.3, 4.82.6Hepatobiliary
Bernatsky et al. Arthritis Rheum. 2005;52:1481-1490
![Page 43: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/43.jpg)
Clinical Pearls
Increased risk of cancer in SLE compared with general population
Greatest risk:- Hematologic (lymphoma)- Possibly lung and hepatobiliary
![Page 44: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/44.jpg)
Longterm Health Issues in Lupus
Bone
Cancer
Cardiovascular
![Page 45: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/45.jpg)
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 FraminghamAge (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
![Page 46: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/46.jpg)
Prevalence of Coronary Calcification in SLE and Controls
NEJM 2003;349:2407
0102030405060708090
100
<40 40-49 50-59 >60
SLEControl
Freq %
YearsSLE 20/65 (31%): Controls 6/69 (9%)
Calcification score > 0
![Page 47: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/47.jpg)
Prevalence of Carotid Atherosclerosis in SLE and Controls
NEJM 2003;349:2399
0
10
20
30
40
50
60
70
80
<40 50-59 60-69 >70
SLEControls
Years
Freq %
SLE 37.1%: Controls 15.2%
![Page 48: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/48.jpg)
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.
Esdaile JM, Arthritis Rheum 2001
RR = 17 for fatal CHD
![Page 49: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/49.jpg)
Cardiovascular Biomarkers and Surrogate Endpoints Symposium
CRP, MPO, Ox-LDL, Anti-oxLDL
IL-6, IL-1, IL-18, TNF, MMP-9, Lp-PLA2
M-CSF-1, ICAM-1, P-Selectin, VCAM-1
Proposed new biomarkers
Proven biomarkers
LDL, B/PaPL, pro-inflammatory HDL,CECs, complement activation,
iNOS, AGEs
![Page 50: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/50.jpg)
Unpublished data, Pgh
Preventive Cardiology Intervention in SLE
SLE Patients seen at the University of Pittsburgh Lupus Center
0
5
10
15
20
25
30
35
40
45
1 2 3 4 5 6 7 8
# risk factors
%
•89.7% have 3 or more CV risk factors
![Page 51: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/51.jpg)
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
![Page 52: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/52.jpg)
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.
![Page 53: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/53.jpg)
FDA Approved Drugs for SLE
Corticosteroids
Hydroxychloroquine
ASA
Benlysta Approved March 2011
![Page 54: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/54.jpg)
On the Horizon…
![Page 55: Am 9.30 manzi](https://reader038.vdocuments.mx/reader038/viewer/2022102618/5455ca5eaf7959d8748b9919/html5/thumbnails/55.jpg)
• Lupus patients have higher than expected bone loss, cancer risk and CVD (advanced aging)
• Lupus is difficult to diagnose (ANA ≠lupus)
Summary
• Lupus is characterized by a break in defective clearance of apoptotic cells (photoprotection important)
• Drought in drug development in lupus...now with promising biologic therapies in clinical trial