22. Lupus (SLE) Flashcards
SLE: wtf is it?
likely a collection of symptoms, all produced by autoimmune disturbances. not all appear in every patient.
Hallmark = production of autoantibodies
Immune complexes form & are deposited in organs
From notes: The serologic hallmark of SLE is the production of high titered autoantibodies directed against a wide variety of nuclear and other cellular components
SLE: what is age of onset?
F:M ratio?
bonus for ethnicities….
Usually presents at age 20-30
F:M = 8:1
more common in blacks, hispanics, polynesians, & more common in cities
Genetic predisposition?
has a gene been identified?
no obvious hereditary predisposition.
some increase in 1st degree relatives, some twin concordance
Gene ID: it is a multi-gene disease (at least 7 involved). One allele will not yield SLE.
CLinical presentation of SLE?
what are the 3 types?
what organ systems are involved?
No typical clinical presentation (every patient has their own brand!)
3 types: acute/fulminant; slowly progressive; flares/remissions (most common)
any organ system can be involved, often one is predominant.
what are the non-specific disease manifestations seen in over 80% of SLE patients?
-fatigue
-fever
-musculoskeletal disease (may mimic Rheumatoid Arth pattern- but no erosions. morning stiffness, muscle pain.)
what are a few clinical manifestations seen in over 50% of SLE patients (but not as freqently as fever/fatigue/musculoskel sx)?
SKIN: malar rash: 50%; photosensitivity: 50%; alopecia: 50%
(also renal, pulm, cardiac, CNS findings)
The diagnostic criteria he gave are used more for research classification than clnical use, but still helpful. There are 11 categories of SLE findings, of which a patient must have 4 to meet diagnosis. Name a few of these categories?
Malar rash
Discoid rash
photosensitivity
Oral ulcers
arthritis
serositis
renal disorder
neuro disorders
hematologic disorder
immunologic disorder
antinuclear antibodies
what is the most likely mechanism for how autoantibodies are made in SLE?
Antigens that were previously recognized as self are now recognized as non-self. The B cells are fine (they are not pathologic) but are attacking self.
Review: what are the molecules involved in B cell stimulation of CD4+ T cells?
see pic: note CD40/CD40L and B7/CD28 interactions between B cells and CD4+ Tcell
after this interaction, the T cell is activated and will proliferate.
The B cell is activated and will produce autoantibodies.
what is one way we have figured out how to slow autoimmune reactions in mice? does this work in people?
See “X” below… eliminate CD4+ T cells by treating with Anti-CD4+ antibody. –Stops activation of B cells –> less autoantibody production.
Another method: block the CD40-CD40L interactions.
In humans, the latter caused blood clots.
Once you have these circulating autoantibodies, how do they cause disease?
two ways:
- bind cells directly. leads to cell destruction (ex. hemolytic anemia) and cell dysfunction (ex. neuro dysfxn)
- cause circulating immune complexes, which deposit and initiate local immune response, leading to organ injury and dysfxn (“innocent bystander” effect)
not only do lupus patients make excessive amounts of immune complexes – what other issue concerning immune complexes do they have?
they have trouble clearing immune complexes from their circulation
(recall we normally do this via the reticulo-endothelial (RET) system in liver and spleen)
where in the skin layers do immune complexes tend to get stuck? how can we use this to diagnose lupus?
What is the test called?
immune complexes tend to get stuck at dermal-epidermal junction.
we can bind the complexes with fluorescent dye (FITC) and do immunofluorescence staining of skin biopsy. Will see deposits of Ig and C at the dermal-epidermal junction
Test = Lupus Band Test
3 rashes seen in lupus?
- malar rash (spares nasolabial folds)
- discoid rash (scalp involvement, some hypopigmentation)
- photosensitive rash
(Pic is photosensitive, not malar. remember malar spares the nasolabial folds)
List some vascular complications of lupus (4)?
- Raynaud’s
- Nailfold capillary involvement
- Vasculitis (organ ischemia, digital infarct)
- Retinal vasculitis
what is the mechanism by which lupus causes vasculitis?
immune complexes deposit in arterial walls, triggering local inflammation and damage.
vessel wall can necrose and/or thrombose, leading to ischemia/infarct
why is there ulnar deviation with lupus?
is there erosion of the joint spaces?
deviation due to intense articular inflammation: joint becomes loose, flopy –> tendons tug on the sides of the joint and cause deformity.
NO erosion at the joint space.
be able to distinguish RA v SLE with an xray of the hand.
which has joint space erosion?
see Bone Radiology for way better pics of each.
SLE - NO erosion
RA: joint space erosion
very generally, why does lupus cause renal disease?
what is the most common pattern of glomerular injury?
vasculitis: deposits of immune complexes in sub-endotheium. leads to inflammation –> leaky, pockmarked cells.
Pathoma: diffuse proliferative glomerulonephritis is most common pattern.
(Pic: L is normal glomerular tuft; R is lupus)
exactly where in the glomerulus are the immune complexes deposited with lupus renal disease?
-extensive subendothelial deposits (narrowest arrows)
plus subepithelial (A), intramembranous (B), basement membrane (C), foot processes (D)
what is the IF pattern of staining with lupus?
remember this from renal? ;)
Full House pattern (everything you stain for is positive)
Granular deposits rather than linear
what’s this disease? how is it different from lupus in terms of pattern of deposits?
linear immunofluorescence against the basement membrane.
Goodpasture’s Syndrome aka Anti-GBM disease.
In this disease, the glomerular BM is the target of the disease rather than being an innocent bystander, as with lupus
is he seriously going to ask us glomerulus-specific questions? maybe.
so, what is the difference between global and segmental? focal v diffuse?
Global: affects entire glomerulus
Segmental: affects a part of each glomerulus
(Jen’s trick: GlomeruluS uses the words that start with G and S)
Focal: affects less than 50% of all glomeruli
Diffuse: affects more than 50% of all glomeruli
what’s seen at the longer arrows?
shorter arrows?
Long: mesangial cell proliferation
short: immune deposits -> wire loop lesions (upper left)
(there were a few more pics in the lecture that I don’t have time to upload. review if you have time! slides 74-83 or so)
how can immune complex deposition affect the lungs?
can lead to serositis–>
-pleuritis or pleurisy with pleural effusions
Note loss of costo-phrenic angle
how can lupus afect the heart?
serositis again?
- pericarditis with pericardial effusion
- abnormal heart border, less retrosternal heart space.
on ECHO, there is posterior and anterior pericardial effusion (arrows)
heart complications with lupus: what is the term for this? (ie, _________ endocarditis)
non-bacterial endocarditis
Libman-Sacks endocarditis
what’s this?
what can it cause?
Libman Sacks endocarditis.
small, sterile deposits on both sides of the mitral valve (chordae tendonae)
pieces of this vegetation can flick off and cause stroke.
what’s this?
Full House pattern seen with lupus IF staining. positive for everything! (IgG, C3, IgG, C1q…)
(practice quiz)
What labs are positive in a patient that has lupus?
Positive ANA
Positive Ro (SSA)
leukopenia
proteinuria
hypocomplementemia
(practice quiz)
Anti-phospholipid Antibody syndrome may consist of all except:
- Recurrent fetal loss
- prolonged bleeding time
- thrombocytopenia
- venous and arterial thrombosis
- false positive syphilis test
Anti-phospholipid Antibody syndrome may consist of all except:
-Recurrent fetal loss
-prolonged bleeding time (will have prolonged PPT but not prolonged bleeding)
- thrombocytopenia
- venous and arterial thrombosis
- false positive syphilis test
(practice quiz)
a positive anti-dsDNA antibody test is associated with what?
glomerulonephritis
(practice quiz)
BLyS v. Benlysta: do both have an affect on plasma cells? just one?
Only Benlysta has an effect on plasma cells
(I hope I didn’t write this down wrong in lecture: seems like both BLyS and Benlysta would have an effect on plasma cells: BLyS by supporting the B cells that become plasma cells; Benlysta (medication) by being anti-BLyS. Rituximab would definitely not have an effect on plasma cells, maybe that’s what he actually compared against Benlysta?).
(practice quiz)
what is the treatment of choice for severe organ involvement in lupus?
high-dose steroids and Cytoxan
(practice quiz)
lupus patient has PE and APS: what is the treatment?
coumadin
(practice quiz)
Rituxan: what is the effect on B cells? is it effective for lupus?
depletes B cells for 6 months. has never shown efficacy in an lupus randomized controlled trial
(from his notes: Two large RCTs showed no additional benefit of adding Rituxan to standard treatment in SLE, yet its use continues.)
Describe the utility of the ANA for lupus screening or diagnosis
The ANA is highly sensitive, but has low specificity. (so, if ANA is negative, pt is unlikely to have lupus. But if ANA is positive, it’s not super helpful)
ANA is a poor screening test!
Use to confirm a clinical dx of SLE.
In contrast, several antibodies to purified nuclear constituents have a much higher specificity for SLE, but a lower sensitivity.
what is the impact of lupus on pregnancy?
women with SLE have normal fertility
SLE flares occur in 50% of pts during pregnancy (first/third tri, also postpartum)
25-30% of SLE pregnancies end in miscarriage. Overall fetal loss may approach 50%.
what is antiphospholipid antibody syndrome?
does it occur in SLE patients?
common clinical manifestations?
antibody against proteins that are bound to phospholipids.
can occur in the absence of SLE, but occurs in 30% of SLE patients.
causes venous and arterial thrombosis (incl DVT), recurrent fetal loss (due to placental thrombosis), stroke.
what are some common lab findings with anti-phospholipid antibody syndrome? (that you wouldn’t really expect)?
false positive syphilis test
falsely-elevated PTT study (will have prolonged PTT study, but not prolonged bleeding -remember this is more of a clotting problem)
for antiphospholipid antibody syndrome (APS), what are the 2 most important tests?
what is the treatment if someone with APS is having thrombotic events?
tests: lupus anticoagulant, anticardiolipin antibody
treatment if someone with APS is having thrombotic events: warfarin (aka coumadin)
What is the theory of how APS causes clotting?
Antiphospholipid antibodies recognise beta-2 glycoprotein 1, which is involved in the normal immune system. (it’s a cofactor for Lupus Anticoagulant and Anti-Cardiolipin)
when the APS antibodies bind beta-2 glycoprotein, it changes conformation and can bind to other surface receptors, somehow leading to thrombosis.
(red = APS antibody, yellow = B2glycoprotein 1)
Summary of SLE manifestations, explained by the sequence of events on the flip side…..
- A break in tolerance to self-antigens
- The production of autoantibodies to self-antigens
- The formation of autoantibody-autoantigen immune complexes
- Difficulty clearing these immune complexes
- Tissue damage caused by:
a. Autoantibodies directly damaging target tissue, e.g., ITP
b. Autoantibodies directly causing “dysfunction,” e.g., APS
c. Indirect innocent bystander organ damage caused by immune
complex deposition with local complement activation and secondary inflammation, e.g., DPGN (diffuse glomerulonephritis)
what are these?
identify each….
which is specific for CREST?
ANA patterns.
UL: periperal/rim
UR: homogeneous
LL: speckled (sometimes seen in scleroderma)
LR: nucleolar
CREST: centromere (looks speckled)
anti-ds DNA: how relevant is it to SLE? what SLE complication is it associated with?
one of the most specific tests for lupus
highly associated with glomerulonephritis
anti-smith antibody: relevance to lupus?
only positive in 20-30% of patients, but very specific.
If you have anti-smith, you have lupus.
(not sensitive but very specific)
Lupus meds: what are the categories of problems that we use meds for?
what is the treatment of choice for renal disease associated with lupus?
articular symptoms –> NSAIDs, MTX etc
serositis -> NSAIDS, steroids
cutaneous disease –> steroids, plaquenil (anti-malarial)
Hematologic problems -> steroids, IV gamma globuln, splenectomy
Renal disease –> systemic steroids and cyclophosphamide together = treatment of choice
CNS disease -> steroids, anti-seiz, anti-psychotics
rituximab: mechanism of action?
anti-CD20, which is expressed on B cells.
rituximab therefore depletes B cells.
Doesn’t eliminate plasma cells! so there is still production of autoantibodies.
what is BLyS? what is its normal function?
it’s a B cell survival factor.
Signals to B cells that they should keep going! prevents them from apoptosing. Like those volunteers at the sidelines of road races who hand you gatorade.
what is Benlysta? what does it do?
binds BLyS therefore preventing the B cell survival signal.
effective against B cells and also plasma cells- both of these start dying without adequate BLyS
(Benlysta basically kills off the road race volunteer so the runners don’t get their gatorade. which is good if the runners are really, really bad people, ie B cells causing lupus).
Has Benlysta been effective?
(aka Belimumab)
Approved by FDA but treatment effect is MILD.
now that we are slightly better at controlling the acute effects of lupus, what do we need to focus on?
controlling the late musculoskeletal effects and secondary problems
ie osteonecrosis, osteoporosis, atherosclerosis/CAD (from both lupus and chronic steroid use)
what’s Jullet’s memory trick for NEONATAL lupus?
Lupus Likes To Ruin Hearts
Lupus
Leukopenia
Thrombocytopenia
Rash
Heart Block!!!!!
