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, Raynaud’s. 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 one’s 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, Raynaud’s. 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 get’s 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
Genetically
susceptible
individual
Environmental
factors
Inflammation
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
Grave’s
Aging
Drug-induced
Lupus
Dermatomyositis
Primary Biliary Primary
Cirrhosis
Pulmonary
HTN
Scleroderma
RA
Hashimoto
Thyroiditis
Sjogren’s
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% raynaud’s
25% hypertension
20% oral ulcerations
Malar rash
Malar rash
Discoid Lesions
Oral ulcerations
Raynaud’s
Jaccoud’s 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% sjogren’s 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%
60%
1980-present
Increase use of immunosupp
2000-2007
95%
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
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 diseasenepritis, CNS involvement, vasculitis
 Rituximab: used for severe organ threatening
dz
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