Documenti di Didattica
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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
Types Of Lupus
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
Genetically
susceptible
individual
Environmental
factors
Inflammation
Auto
antibody
production
Genetics of Lupus
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
Rheumatic
Conditions
AutoImmune
Misc
Lupus
Polymyositis
Graves
Aging
Drug-induced
Lupus
Dermatomyositis
Scleroderma
RA
Hashimoto
Thyroiditis
Sjogrens
Vasculitis
Autoimmune
Hepatitis
MCTD
MS
ANA in Lupus
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?
Malar rash
Malar rash
Discoid Lesions
Oral ulcerations
Raynauds
Jaccouds arthropathy
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
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
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
1969
1971
77%
1980-present
2000-2007
95%
60%
90%
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
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
On the horizon
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