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Systemic Lupus

Erythematosus
Sheetal Desai, MD, MSEd
Division of Rheumatology
UC Irvine Medical Center

Questions???
1. What is compound E?
2. Who is Phillip Hench?
3. What are the 11 criteria for lupus?
4. What are the two most common drugs
associated with drug induced lupus?
5. What is the risk of neonatal lupus in a
patient with positive SSA or SSB?

Questions???
6. What is the most common organ
system involved in lupus?
7. How many FDA approved medicines
are there for lupus and what are they?
8. What is the 10 year life expectancy for
lupus?

Case #1
23 year old female comes to rheumatology c/o joint
pains in her PIPs and wrists, fatigue and a rash on her
face. This has been going on for several months. She
denies any fevers, ulcers, CP, SOB, Raynauds. She
does have photosensitivity.
PMH: acne, endometriosis
PSH: none
Meds: OCP, minocycline
PE: VSS, malar rash, TTP to PIPs, no synovitis
Labs: WBC 5, Hg 11, Plt 200, BUN 8, Cr 0.6, ANA pos
1:160, TSH 4.3
What do you do?

History of Lupus
Lupus means wolf in Latin
10th century- case reports appeared in writings
Late 1800s- Sir William Osler initially described the
systemic nature and linked rashes to organ involvement
1949- LE cell described by Malcolm Hargraves at Mayo
Clinic
1954- ANA described
1971- First set of classification criteria proposed for Lupus
1983- Antiphospholipid antibody syndrome described

What exactly is Lupus?


Autoimmune disease where ones immune system
attacks itself
Autoantibody production -> immune complex
deposition -> inflammation -> damage
Chronic disease, characterized by flares and
remission
Pleomorphic with different phenotypic expressions
Multisystem involvement

Types Of Lupus

Drug Induced Lupus


Neonatal Lupus
Cutaneous Lupus
Systemic Lupus Erythematosus

Drug- Induced Lupus


Approximately 80 offending agents can cause
lupus
15,000- 30,000 cases reported annually
Production of autoantibodies more common
than clinical symptoms
99% disappear within 3 months of stopping
the medicine.

DIL Definite Associations

Procainamide (15-20%)
Hydralazine (7-13%)
Enbrel/Remacaide/Humira (2/1000)
Minocycline (5/10,000)
Diltiazem
Penicillamine
INH
Quinidine

Clinical

DIL

Classic SLE

Age of onset

50

20-40

F:M ratio

1:1

9:1

arthralgia

95%

90%

hepatomegaly 25%

25%

Rash

74%

10-20%

Renal disease 5%

53%

CNS disease

0%

32%

ANA

95%

95%

Anti-histone

90%

80%

Case #1
23 year old female comes to rheumatology c/o joint
pains in her PIPs and wrists, fatigue and a rash on her
face. This has been going on for several months. She
denies any fevers, ulcers, CP, SOB, Raynauds. She
does have photosensitivity.
PMH: acne, endometriosis
PSH: none
Meds: OCP, minocycline
PE: VSS, malar rash, TTP to PIPs, no synovitis
Labs: WBC 5, Hg 11, Plt 200, BUN 8, Cr 0.6, ANA pos
1:160, TSH 4.3
What do you do?

Case #2
32 year old female with known Lupus for
five years, on plaquenil 400mg a day and
prednisone 3mg a day, wants to get
pregnant. How do you advise her?
Fertility?
Risk of neonatal lupus?
Medications during pregnancy?

Neonatal Lupus
Rare condition
not true lupus, passively transferred autoimmune
disease
Occurs when mother is SSA/SSB positive
Transplacental transfer of IgG anti SSA or SSB
antibodies
5-7% babies will have a transient rash, resolves by
6-8 months
2% of babies will have cardiac complications with
congenital heart block

Neonatal Lupus

See erythematous,
annular plaques
tends to involve
scalp, face,
periorbital areas

Who gets Lupus?


Prevalence is over 1.5 million Americans
Incidence difficult due to lack of strict
definition
Bimodal peak presentation: ages 20-40 and
again after age 60
Prevalence is higher in African Americans,
Asians, Hispanics
Female to male predominance

Does your sex really matter?

90% of patients with lupus are female


Before puberty F:M ratio is 2:1
During reproductive years ratio 8:1
Post-menopausal ratio 2.3:1
Increased frequency in women attributed to
the hormonal effect of estrogen

Does your sex really matter?


Nurses Health Study
use of estrogen-containing contraceptive agents
associated with an 50 percent increase in risk of
developing SLE
either early onset of menarche (age 10 years) or
administration of estrogen to postmenopausal women
doubles their risk
Treatment of clinically stable SLE with oral
contraceptives for one year does not increase disease
flares

What causes Lupus???


Damage

Genetically
susceptible
individual

Environmental
factors

Inflammation
Auto
antibody
production

Genetics of Lupus

High concordance in monozygotic twins


5-12% or relatives with lupus have the disease
No single lupus gene
Disease is polygenic
At least 30 susceptiblility genes identified
HLADR2, HLADR3, HLADR4, HLADR8 (present
in 75%)
Homozygous deficiency of C1q complement

Environmental Factors
UVA and UVB light can stimulate/ up-regulate
autoimmunity
stimulating keratinocytes to produce cytokines -> activate B
cells to produce ab
Viruses/Bacteria: molecular mimicry
SLE patients have higher titers of antibodies to Epstein-Barr
virus (EBV), increased circulating EBV viral loads; SSA ab
has a sequence similar to EBV nuclear ag 1
Parvovirus B19
Drugs
Silica exposure, tobacco smoke, emotional stress

Lupus
Damage

Inflammation

Genetically
susceptible
individual

Environmental
factors
Auto
antibody
production

Immune dysregulation
Upregulation of innate immunity
Delayed clearance of apoptotic cells, resulting in
antigenic stimulation
Loss of tolerance via failed elimination of
autoreactive T lymphocytes
Abnormalities in B cells
Abnormalities in T regulatory cells (CD4+/CD25+
cells down regulate immune system responses)

Autoantibodies in Lupus
Study of US army recruits revealed lupus autoab
present for up to 9 years prior to dx in 85%
ANA
dsDNA
Anti-Smith
Anti-RNP
Anti-SSA, anti-SSB
Anticardiolipin
Anti B2 glycoprotein

Meaning of ANAs
What exactly are they?
Antibodies that bind to various antigens in
the nucleus of a cell
How is it measured?
Indirect Immunofluorescence

ANA measurement
Indirect Immunofluorescence Assay
1. Take patient serum and add it cells
2. If there are antibodies they will bind
3. Add a fluorochrome tag
4. View under a fluorescent microscope
5. If it lights up in the nucleus then it is positive
6. Dilute sample and repeat steps 1-5 until nuclear
fluorescence disappears

ANA patterns

ANA patterns
Staining Patterns
Observer dependent
Not sensitive
Not specific
Only LOOSELY associated with certain
disease states

ANA associated Diseases


Rheumatic
Conditions

Rheumatic
Conditions

AutoImmune

Misc

Lupus

Polymyositis

Graves

Aging

Drug-induced
Lupus

Dermatomyositis

Primary Biliary Primary


Cirrhosis
Pulmonary
HTN

Scleroderma

RA

Hashimoto
Thyroiditis

Sjogrens

Vasculitis

Autoimmune
Hepatitis

MCTD

MS

ANA and Aging


For every year after age 50, percentage of
ANA positivity increases 1%/year
For example
Age 50
1%
Age 55
5%
Age 60
10%

ANA in Lupus

Sensitivity 93-99% in SLE


Sensitivity 95-100% in drug induced Lupus
Specificity is not great
Higher the titer, higher the specificity
1:40- 30% normal population
1:160- seen in 5% of the population

Clinical Indications for ANA


ANA is NOT a good screening test given its low
specificity
Presence of ANA does NOT mandate the presence
of rheumatologic illness
A negative ANA is more useful and makes Lupus
very unlikely
ANA titers correlate poorly with disease activity so
serial measurements are not recommended
A positive ANA with anti-centromere pattern is very
specific for limited scleroderma

How do patients present?

Myriad of symptoms
Symptoms are often non-specific
No two patients are alike
50% of patients have organ threatening
disease
50% do not have organ threatening disease

Question
What is the most common organ system
involvement in lupus?

How do patients present?

90% malaise and fatigue


90% arthralgia and myalgias
70% photosensitivity/rashes
57% fever
50% arthritis
44% pleuritis
40% alopecia
25% raynauds
25% hypertension
20% oral ulcerations

Malar rash

Malar rash

Discoid Lesions

Oral ulcerations

Raynauds

Jaccouds arthropathy

Laboratory Findings in SLE

97% positive ANA


61% low complement levels (C3, C4)
50% dsDNA ab
46% leukopenia
42% anemia
40% proteinuria, nephritis
35% anticardiolipin antibodies
25% sjogrens syndrome with positive SSA, SSB
12% pleural effusion
Others: thrombocytopenia, anti SM, antiRNP, elevated
LFTs, splenomegaly, thrombophilia, miscarriages

Diagnosis of SLE
Initial criteria proposed by the ACR in 1971,
revised in 1982 and 1997
Criteria designed for research purposes
Need 4 of 11 criteria for diagnosis of SLE
Not perfect, but have over 90% sensitivity
and specificity
Currently two international groups are reevaluating the criteria

ACR 1997 revised criteria

1. malar rash
2. discoid rash
3. photosensitivity
4. oral or nasal ulcers
5. arthritis
6. serositis: pleuritis or pericarditis
7. renal disorder: proteinuria > 500mg/day, cells
8. immunologic: anti SM, anti dsDNA, ACL, lupus ac
9. hematologic: anemia, leukopenia, thrombocytopenia
10. neurologic: seizures or psychosis
11. positive ANA in absence of drugs

2012 SLICC Classification Criteria


Need at least 4 criteria (1 clinical and 1
lab)
Or biopsy proven Lupus Nephritis with
Pos ANA or pos dsDNA

Case #3
A newly diagnosed patient with lupus
asks you what her lifetime prognosis is.
What do you say?

Prognosis
Dramatically improved over time
Normal life expectancy for patients with
drug induced lupus
cutaneous lupus
lupus without organ involvement
Possible increased risk of NHL

Prognosis
Year

5 yr survival

10 yr survival

Prior 1948

50%

1949

Steroids widely accessible

1969

Dialysis widely accessible

1971

77%

1980-present

Increase use of immunosupp

2000-2007

95%

60%

90%

Poor Prognostic Factors

Renal disease (esp DPGN)


Hypertension
Male sex
Young age
Older age at presentation
Poor socioeconomic status
Black race, which may primarily reflect low socioeconomic
status
Presence of antiphospholipid antibodies
Antiphospholipid syndrome
High overall disease activity

Mortality
Bimodal mortality
Early deaths: infection and renal
involvement
Later deaths: atherosclerotic disease
Premenopausal women with lupus have
30-50x higher risk of CAD than their nonlupus counterparts

Treatment
Individualized
Evaluate their risks for organ involvement
dsDNA ab: renal and neurologic
SSA/SSB ab: rashes, pregnancy risks
APL ab: clotting
RNP ab: may develop overlap diseases

Treatment: Patient Education

1. Avoidance sun
2. Use of SPF > 35 sunblocks UVA and UVB
3. Sun-protective clothing
4. Promote exercise
5. Healthy diet (low chol, low sugar, low salt)
6. Smoking cessation
7. Avoidance of stress (animal models)
8. Good sleep hygiene

Treatment: Antimalarials
hydroxychloroquine, quinacrine (available
compounded), chloroquine
Prevent activation of toll like receptors 7 & 9
Used in lupus over 50 years
FDA approved indication
Mildest immunosuppressant
Very safe, risk of retinal toxicity low
Eye exam once yearly

Hydroxychlorquine
Takes 6 weeks to kick in, up to 6 months for
maximal effect
Dose maximum is *** mg/kg/day
Reduces intensity of flares
Increases time to flare
Treats skin and joint manifestations
May prevent renal disease
Mortality benefit
Safe in pregnancy

Treatment: Steroids
Mainstay for organ threatening disease
Work quickly and effectively
dose of 1mg/kg/day
taper over 4-6 weeks, by 10% q week
Long term AE: hyperglycemia, hyperlipidemia,
accelerated atherosclerosis, bone
demineralization, AVN, cataracts, glaucoma,
PUD, skin thinning, emotional lability
Add a steroid sparing imunosuppresant

Immunosuppressive regimens

Methotrexate: used for arthritis and skin


Leflunomide: used for arthritis and skin
Azathioprine: useful for renal disease, autoimmune
hepatitis, pulmonary disease, myositis, cutaneous
manifestations
Mycophenylate Mofetil: lupus nephritis
Cyclosporine: membranous nephritis, aplasias
Cyclophosphamide: used for severe disease- nepritis,
CNS involvement, vasculitis
Rituximab: used for severe organ threatening dz
Belimumab: FDA Approved for Lupus

On the horizon

1. Agents that target B cells


2. Agents that target T/B/APC interaction
3. Agents that target complement
activation
4. Inducers of immune tolerance
5. Agents that target cytokines
6. Inhibition of Toll receptors
7. Stem cell therapies

On the horizon
Only four FDA approved medications for lupusprednisone, plaquenil, aspirin, belimumuab
Many clinical trials ongoing looking at
innovative biologic therapies
Highly likely that the management of lupus will
be totally altered in the next 5-10 years
Outcome, quality of life and prognosis will also
dramatically change