Ch. 41-Lupus Flashcards
What is the strongest risk factor for SLE?
Gender-Women6:1 ratio for sLE3:1 for cutaneous only
Name risk factors for sLE
female sexethnicity-africana American
Prevalence lupus in caucasian women? Africa-american women?
4 in 1000 AA1 in 1000 caucasian
How does lupus differ in African Americans compared to caucasians
-younger age-more severe disease-more internal organ involvement-higher mortality
What are some environmental factors contributing to lupus
UVRsmokingmedicationsviruses maybe-EBV*may be initial trigger in genetically susceptible host to cause damage and expose nuclear proteins to body
Name the genes most strongly associated with SLE
HLA-DR4PTPN22STAT4IRF5TREX1C1q
What genes are DLE associated with?
HLA-B8-DR3C2/C4 deficiency
What genes is associated with familial chilblain lupus?
TREX1=dysfunction of the exonuclease leads to an accumulation of IFN-stimulatory nucleic acids
What forms of lupus do autoantibodies play the strongest role?
SCLE
Neonatal lupus
Which antibodies are associated with SCLE?
Anti-ro (anti-SSA)
Anti-la (anti-SSB)
What are the 2 Anti-ro antibodies
anti-SSA/Ro60 and anti-SSA/Ro52
Which autoantibodies are associated with neonatal lupus
Anti-ro and anti-la
What role does SSA/Ro60 play in the body?
role in cell survival following UVR, possibly via binding to misfolded non-coding RNAs and targeting them for degradation
Deficiency/antibodies agains SSA thus may prevent this function
What role does SSA/Ro52 play?
SSA/Ro52 has a known regulatory role in inflammation, targeting both interferon regulatory factor 3 (IRF3) and IRF8 for degradationThus: deficiency in this is pro inflammatory
How does UVR cause lupus flare?
-UVR induces apoptosis, which leads to translocation of cellular and nuclear antigens -autoantiboides are thus exposed to the nuclear antigens and cause cascade inflammation
Which cell types make up the infiltrate seen in lupus?
CXCR3-positive CD4+ and cD8+ T cells (lymphocytic) immature plasmacytoid dendritic cells
Describe pathogenesis SLE
- nuclear antigens to be exposed due to lack of clearance of dead cells (e.g. complement factors help macrophages clear these dead cells via opsonization)
- Loss of self tolerance and sensitization to antigens–> causes immature APC to pick up antigen via TLR3. APC presents antigen to naive T helper cells4. IL-4 secreted promotes Th2 maturation
- Th2 promotes B-cell maturation and production
- Plasma cells produce auto-antibodies
How do autoantibodies produce damage in SLE
-Ag-Ab complex binds to Fc receptors of immune cells–> pro inflammatory cytokines like IFN and TNF-Ag-Ab complexes can bind directly to cells and cause complement activation and damage
Most important inflammatory cytokine in SLE?
IFN-alpha
What are the 3 specific cutaneous lesions of lupus? Others?
ACLE-acute cutaneous lupus
SCLE-Subacute cutaneous lupus
CCLE-Chronic cutaneous lupus: DLE, tumid lupus, lupus panniculitis, chilblains
Others:Rowells Syndrome, Bullous SLE
Which lupus forms have interface dermatitis
ACLE, SCLE, CCLE (only DLE, less likely other forms
Where does DLE typically occur on the body?
Head and neck–> face, scalp, ears.
Can be widespread, but unlikely to occur on the body without also lesions on head/neck
Can occur on muscosal surface
What level of the skin does DLE affect?
Superficial and deep dermis
What are the clinical features of DLE?
Erythema, scaly, round/annular plaques often with hypo pigmentation in centre with hyperpigmentation at border scarring, alopecia, atrophy, follicular plugging
Can be photo-distributed (head/neck) but no clear association between sun exposure and their development
firm/indurated
What % DLE develop SLE
10-20% (mostly first 5 yrs)Mostly by mucocutaneous involvementCan have arthralgia in DLEHigher risk if disseminated lesions
Variant of DLE?
Hypertrophic DLE with significant hyperkeratosis, often on extensor arms
Clinical features SCLE?
Photosensitive
Mostly photo exposed areas, mid face often spared, often involves lateral face, extensor arms, shoulders, chest, back
2 types: Annular: raised pink scaly borders with central clearing, or papular bordersPapulosquamous: chronic psoraisiform or eczematous
Minimally palpable
Can get hypo pigmentation or depigmentation but no scarring
What % SCLE are linked to medications?
20-30%
Medications associated with SCLE
“PTHIN DRAGS”
PPI/PUVA
Terbinafine/TNF-alpha inhibitors/Taxanes
HCTZ (#1)
IFN
NSAIDS
Diltirazem + other CCBS/BBs
Ranitidine
Acei, anti-epileptics
Griseofulvin
Statins
What % patients SCLE fulfills SLE criteria
30-50%
What antibody is most associated iwht SCLE? What % have it?
SSA/Anti-Ro
Ranges 60-100%, on avg 70%
Clinical presentation of ACLE?
Malar distribution with sparring of nasolabial fold, can be widespread on body, spares knuckles
Transient (hours to a couple weeks) and photosensitive, resolve with no scarring
Erythema to intense edema, can develop some scale, may have papular component
May show poikiloderma ( atrophy, telengiectasias, dyspigmentation (hypo/hyper), may have erosions
Lupus variants
ACLE, SCLE, DLE (3 major)
Tumid lupus (CCLE)
Lupus panniculitis (CCLE)
Chillblains (CCLE)
Bullous lupus
Rowels
Neonatal (SCLE)
Clinical appearance tumid lupus
Firm, edematous erythematous plaques, urticarial appearing, with no surface change
Mostly on the face, can occur on trunk
*Some think the same as Jessners
Photosensitive
Is tumid lupus associated with SLE?
Majority have no other organ involvement, no serologic markers
10% of those with SLE with have tumid lupus lesions
Clinical presentation Lupus panniculitis
Can start as erythematous indurated plaques, become atrophic and depressed over time situ lipoatrophy
May develop DLE over top= lupus profundus
Located: upper trunk, breasts, buttocks, thighs, upper arms, face scalp
Clinical presentation chilblains lupus
red-purple dusky papules and plaques on toes, fingers, sometimes nose or elbows, knees
May just be ordinary chilblains concurrent with lupus
*over time may become discoid
What genes mutations lead to familial chilblains? What do they encode for ?
TREX1 and SAMHD1
*Exonuclease and nuclease-→lead to accumulation nucleic acids
What is familial chilblains
Chilblains
Arthralgia
+ ANA
But usually no systemic dz
What is Aicardia-Goutieres
AR autoinflammatory disorder
-recurrent sterile fevers, chilblains, developmental delay
What ab is most associated with neonatal lupus
Anti-Ro/SSA
How does neonatal lupus occur?
Mom with SCLE, anti SSA/RO +, transplacentally cross over
What % neonatal lupus are ro+?
Nearly 100%
Also some u1RNP
How does neonatal lupus present
Essentially identical to sCLE (annular erythematous plaques) in adults, predominantly on head/neck though
Photosensitive but can occur without it, can be present at birth
No scarring but can have residual pigmentation and telengiectassis
Can have internal manifestation
What are the internal manifestations of neonatal lupus
Heart block, with or w/o cardiomyopathy
Hepatobiliary
Cytopenias-esp. thrombocytopenia
Other reports DIC, hydrocephalus
When does heart block present in neonatal lupus
At birth
CM may develop a few months after birth but typically also at birth
20% mortality with CM
How does hepatobiliary present in neonatal lupus
Liver failure
Conjugated hyperbilirubenmia
Minor liver enzyme elevations
Workup for suspected neonatal lupus
EKG +- echo
CBC
Liver enzymes ad bili
Repeat q2-3 months x 2-3x (until 9 months wish)
What are the different presentations bullous lesions in lupus?
- Bullous lesions occurring in setting intense basal damage with ACLE or SCLE, rarely DLE.
- Rarely, a dramatic, acute eruption similar to erythema multiforme major or toxic epidermal necrolysis (TEN) may occur in patients with preexisting ACLE or SCLE, or it may appear de novo
- True bullous lupus (next slide)
What is bullous eruption of SLE?
Acquired blistering disorder in patients with SLE
Vesicles and bull that hits path resembles DH with microabsesses in dermal papillae and neutrophils
Bullous SLE targets?
Immunoreactants are often found at the basement membrane zone and antibodies to type VII collagen have been detected in several patient
Most common organ systems in SLE
Joints
Skin
Renal
CNS
Heme
Pleurisy
Constitutional sX: Fevers, joint pain, weight loss, LAD, fatigue
Criteria for SLE
Need 4/11
- Malar rash
- Discoid rash
- Photosensitivity
- Oral ulcers
- Arthritis (non erosive, 2 or more)
- Serositis (pleurites or pericarditis)
- Renal disorder-persistent proteinuria or cellular casts
- Neurologic disorder-psychosis or seizures
- Heme-→ hemolytic anemia, leukopenia <4, lymphopenia <1500, thrombocytop <100 000,
- Antibodies: anti-DNA, anti-sm, APLAS
- ANA
What are the non specific cutaneous findings in lupus?
- Diffuse non scarring alopecia (or discoid lesions)
- Raynauds
- Periungual telengiectasias and erythema (less severe than Scleroderm or DM)
- Vasculitis
- urticarial vasculitis
- small vessel vasculitis w/ palp purport
- PAN-like lesions
- ulcerations
- Cutaneous signs APLAS
- livedo
- necrosis/ulcers
- acrocyanosis
- atrophie blanche
- degos-like lesions
- livedoid vasculopathy
- Palmar erythema and erythromelaglia
- Papular and nodular mucinosis
- Sweets-syndreom of SLE
- Anetoderma
What % patients with papulonodular mucinosis have SLE?
75%
livedo reticularis with ischemic CNS disease has been called?
Sneddon syndrome
What are the core Histopathology findings in lupus?
- basal cell damage (interface dermatitis, vacuolar change)
- Lymphohistiocytic infiltrate
- Dermal Mucin deposition
4.
Name 5 pathological findings in acute cutaneous lupus
- basal cell vacuolization
- Superficial lymphocytic infiltrate
- Apoptotic keratinocytes
- Dermal mucin
- Dermal edema
- focal hemmorhage
In general dermal changes can be quite subtle
Name 7 pathologic findings of SCLE
- Basal cell vacuolization
- apoptotic keratinocytes
- superficial lymphocytic infiltrate (upper dermis)
- Epidermal atrophy
- Dermal mucin
- Dermal edema
- In general compared to DLE less (but still some): follicular plugging, hyperkeratosis, BMZ thickening
Epidermal changes and superficial infiltrate are common
Name 9 findings DLE on path
- Less vacuolar change
- BMZ thickening
- Follicular plugging
- Superficial and deep lymphocytic infiltrate
- Peri-adenxal infiltrate
- Dermal mucin
- Hyperkeratosis
- Pilosebaceous atrophy
- Dermal fibrosis
What does pathology of tumid lupus show
Prominent dermal mucin deposition and superficial and deep lymphocytic infiltrates with a lack of epidermal change
What does pathology for Lupus panniculitis show?
Lymphocytic infiltrate in subcutis, sometimes deep dermis and peri-adnexal
maybe dermal mucin
maybe epidermal atrophy
sometimes vacuolar cahnge
What doe DIF for lupus show?
IgG or IgM granular deposits at dermal-epidermal junction, complement deposits
May be epidermal in SCLE
Though to be anti-ro/SSA
*Lesional skin
What does DIF in normal appearing skin show in SLE?
Ab deposits at DEJ, correlates with disease activity
Workup for suspected SLE patient
CBC
BUn, Cr, UA
ANA, anti-SSA/ro, SSB, ssDNA, histone, U1RNP, APLAS
ESR/CRP
Complement
How does drug induced lupus differ from SLE?
presents as a lupus-like systemic illness with arthralgias, myalgias, pleuritis and fever
lacking nephritis and CNS disease
Skin-typically no findings, sometimes malaria rash and photodistributed erythema
What ab is associated with drug induced SCLE?
anti-SSA/ro
what ab is associated with drug induced SLE?
anti-histone** 95%
What drugs cause drug-induced SLE
“HIP MC”
Hydralazine
Isoniazid, interferon
Procainamide, phenytoin, penicillamine (unmasks true dz)
Minocycline (anti MPO), methyldopa,
Chlorpromazine
Top 2 drugs known to cause SLE
HYdralazine
Procainamide
What ab + in TNF-inhibitor induced SLE ? Wha tis characteristic tnf induced?
anti-dsDNA
More CNS, more renal disease, more skin
Therapy for cutaneous lupus
- sun protection, topical and intra-lesional steroids, topical tacrolimus, topical retinoids
- Systemics: *HCQ (200 mg po daily to BID), chloroquine, quinacrine (can be added)
- Non anti-malarial systemics: oral retinoids, thalidomide, sulfasalazine, dapsone (bullous), MMF, AZA, MTX, ustekinumab, apremilast, systemic steroids
Max dose chloroquine
3.5–4 mg/kg ideal body weight /day
<2.3 mg/kg real weight/day for chloroquin
Max dose of hydroxychloroquine
5 mg/kg REAL weight/day
6.5 mg/kg ideal body weight
Main concerning side effect HCQ
Eye toxicity
Main side effect thalidomide
peripheral neuropathy
Treatment lupus nephritis
Pulse pred x 3 days
MMF >cycle
Treatment SLE
No organ-nsaids
Mild organ-steroids
Moderate: Pulse cychloposhamide +- pulsed steroids
OR: HCQ, mycophenolate mofetil, azathioprine, methotrexate, leflunomide
