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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

Disclosures

• Consultant and Scientific Advisory Board GSK/HGS

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?

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

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

Clinical Pearl

ANA (+) ≠ Lupus

ANA : 95% Sensitive 11% PPV

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

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

Autoantibody Determined Clinical Subsets of SLE

RNP

SSA (Ro)SSB (La)

dsDNA

ANA (+)>95% patientsANA + > 90%, nonspecific

Ribosomal-P

phospholipids

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)

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

Disease Mimickers

Sjogren’s syndrome

Fibromyalgia (+ ANA)

Dermatomyositis

Neoplasms (hematologic)

ITP and TTP

Primary antiphospholipid syndrome

Drug-induced lupus

Pathogenesis of SLE

Genetic

Environmental

Gender

Tissue Damage

Defective Immune Regulation

Break in self tolerance

Autoantibodies

Immune Complexes

Complement activation

Lupus Genetics

Clustering in families (autoimmunity)

Concordance

- monozygotic (identical twins)

25-30%

- dizygotic 5%

BLK

ITGAM

Bank1

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

Homozygous deficiency

C1q 38/41 (93%) C4 14/16 (88%)C2 38/66 (58%)

95% of lupus is polygenic

C1q plays a role in clearly apoptotic blebs

Apoptotic cells are a source of autoantigens

Lupus is characterized bya defect in apoptotic cell

clearance

Pathogenesis of SLE

Why sun exposure may trigger lupus

Clinical Pearl

Photoprotection is important in lupus

Sunblocks, photoprotective clothing

Survival in lupus has improved.

1950 5 year survival 50%

2000 10 year survival 80-90%

Reasons for improved survival

Corticosteroids (1950)

Dialysis

Cyclophosphamide

Anti-hypertensive

Antibiotics

Earlier diagnosis

Causes of morbidity and mortality

lupus kidney infection

Early Late

cardiovascularosteoporosis

cancer

Natural History of SLE

• Disease flares/activity (reversible)

inflammation

• Organ damage (irreversible) from disease or treatment

scarring

Longterm Health Issues in Lupus

Bone

Cancer

Cardiovascular

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

Osteopenia in women with SLE

Caucasians (n=222)African-Americans (n=77)

Lee C, Arthritis Rheum. 2007;57:585-592

Osteoporosis in Women with SLE

Caucasians (n=222)African-Americans (n=77)

Lee C, Arthritis Rheum. 2007;57:585-592

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.

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


Bone

Cancer

Cardiovascular

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.

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

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

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


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


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


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


Clinical Pearls

Increased risk of cancer in SLE compared with general population

Greatest risk:- Hematologic (lymphoma)- Possibly lung and hepatobiliary


Bone

Cancer

Cardiovascular

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

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

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%

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

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

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

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

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.

FDA Approved Drugs for SLE

Corticosteroids

Hydroxychloroquine

ASA

Benlysta Approved March 2011

On the Horizon…

• 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

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Health & Medicine

neonatal lupus

lupus geneticsclustering

systemic lupus erythematosus

sourceof autoantigens

region 1q41

year survival

parp region 1q23 fcriia

c4 deficiencydr2