CH300: SYSTEMIC LUPUS ERYTHEMATOSUS o Grade III: proliferative changes in tufts of 10-50%

of glomeruli
DEFINITION AND PREVALENCE o Grade IV: DPGN affecting >50% of glomeruli
- damage mediated by tissue binding autoantibodies o Grade V: predominantly membranous changes
and immune complexes with various degrees of proliferation
- 90% women of child-bearing years o Grade VI: end stage scarred glomeruli
- 15 to 50 per 100,000 - treatment is not recommended for class I or II disease
- Highest in African Americans or with extensive irreversible changes
- aggressive immunosuppression is recommended for
PATHOGENESIS AND ETIOLOGY class III, IV or V inflammatory proliferative lesions,
- interactions between susceptibility genes and because these patients may develop ESRD in 2 yrs if
environmental factors untreated
- abnormal immune response - diagnosis of SLE may be made on the basis of renal
- hyperreactivity and hypersensitivity of T and B histology alone without meeting other diagnostic
lymphocytes and ineffective regulation of Antigen criteria
activity  leukocytoclastic vasculitis is the most common blood
o increased surface expression of HLA-D and CD49L vessel abnormality; not specific
- end result is the sustained production of pathogenic  lymph node biopsy: nonspecific diffuse chronic
autoantibodies and formation of immune complexes inflammation
that bind target tissues resulting in:
o sequestration and destruction of Ig- coated DIAGNOSIS
circulating cells - Classification Criteria for the Diagnosis of SLE (Table
o fixation and cleavage of complement proteins
300-2)
o release of chemotaxins, vasoactive peptides and - DOPAMIN RASH:
destructive enzymes into tissues Eryhtematous circular raised
- many autoantibodies in persons with SLE are directed patches with adherent
against DNA/protein or RNA/protein complexes Discoid rash keratotic scaling and follicular
o nucleosomes, nucleolar RNA, spliceosomal RNA plugging; atrophic scarring
o during apoptosis these cells migrate to cell surfaces may occur
where they are enclosed in blebs Includes oral and
o phospholipids change orientation so the antigenic Oral ulcers nasopharyngeal ulcers;
portions are near the surface observed by physician
o these probably activate the immune system to Exposure to UV light causes
Photosensitivity
produce autoantibodies rash
o complexes persists for long periods of time Nonerosive arthritis of >2
- SLE is a multigenic disease peripheral joints, with
Arthritis
o HLA region (class II DR and DQ genes; HLA class tenderness, swelling or
III encoding C’2 and C’4 effusion
o Clq deficiency confers the highest genetic risk Fixed erythema, flat or
o Fcγ receptors Malar rash raised, over the malar
eminences
o Chromosome 16
Anti-dsDNA, anti-SM,
- SLE is modified by multiple susceptibility genes Immunologic disorder
antiphospholipid
- Protective alleles as well Seizures or psychosis
- These gene combinations influence immune response Neurologic disorder
without other causes
to external environment Proteinuria >0.5g/d or >3+,
o When responses are too high or too prolonged Renal disorder
cellular casts
autoimmunity develops Abnormal titer of ANA by
- Females immunofluorescence or
o Make higher antibody responses Antinuclear antibodies equivalent assay in the
o Exposed to estrogen containing OC pills or absence of drugs known to
Hormone replacement induce ANAs
 Estradiol binds to T and B lymphocyte Pleuritis or pericarditis
receptors favoring prolonged response Serositis documented by ECG or rub
- Environmental stimuli or evidence of effusion
o Exposure to UV light causes flares Hemolytic anemia,
 Increasing apoptosis to keratinocytes leucopenia (<4000/μL),
 Altering DNA and intracellular proteins lymphopenia (<1500/μL) or
Hematologic disorder
- Various infections thrombocytopenia
o Stimulate immune responses (<100,000/μL) in the absence
o EBV of offending drug)

PATHOLOGY - any combination of 4 or more of 11 criteria, well-

Skin Biopsy
- Ig deposition at dermal-epidermal junction (DEJ) of
affected skin (sometimes also of clinically unaffected
skin)
- injury to basal keratinocytes
- inflammation (mostly T lymphocytes) in the DEJ,
around the blood vessels and dermal appendages
Renal Biopsy
- pattern is important in diagnosis and therapy selection
- WHO lupus nephriris grading
o Grade I: no histologic changes
o Grade II: proliferative changes confined to the
mesangium
documented at any time in the patient’s history makes
it likely that the patient has SLE (Sp95% Sn75%)
- (+) ANA in >95%
- high titer IgG antibodies to dsDNA and antibodies to
the Sm antigen are both specific for SLE
- the presence of multiple autoantibodies without clinical
symptoms is not diagnostic of SLE although they are
at an increased risk
- Algorithm for diagnosis and initial therapy (Fig. 300-1
p.1962)
INTERPRETATION OF CLINICAL MANIFESTATIONS
- impt to establish severity and reversibility of illness
- estimate consequences of therapeutic interventions

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Overview and Systemic Manifestations
- may involve 1 or several organ systems
- severity may be mild and intermittent or severe and
fulminant
- most experience exacerbations with periods of relative
quiescence
- permanent complete remissions are rare
- fatigue and myalgias/arthralgias present most of the
time
- severe systemic illness requiring glucocorticoid
therapy may occur with fever, prostration, weight loss
and anemia
Musculoskelatal Manifestations
- mild to disabling intermittent polyarthritis (soft tissue
swelling and tenderness in joints most commonly in
hands, wrists and knees
- visible synovitis suggest active disease
- 10% develop joint deformities in hands and feet
- joint erosions on x-ray are rare; their presence
suggest a non-lupus inflammatory arthropathy (e.g.
RA)
- ischemic necrosis should be considered in persistent
pain in a single joint, particularly if no other
manifestations of active SLE is present
- prevalence of ischemic necrosis is high among SLE
patients esp. those treated with systemic
glucocorticoids
- myositis with clinical muscle weakness, elevated
creatinine kinase levels and biopsy evidence of
muscle necrosis and inflammation may occur
- glucocorticoids and antimalarial agents (rare) can
cause muscle weakness
- adverse effect should be differentiated from active
disease
Cutaneous Manifestations
- rashes may be minor or very severe
- may be the major disease manifestation
- small painful ulcerations on oral and nasal mucosa are
common
- lesions resemble aphthous ulcers and usually indicate
disease activity
- Lupus Dermatitis classifications
o Discoid Lupus Erythematosus (DLE)
 roughly circular with slightly raised, scaly
hyperpigmented erythematous rims and
depigmented, atrophic centers
 all dermal appendages are permanently
destroyed
 can be disfiguring esp. on the face and scalp
 tx: local glucocorticoids and systemic
antimalarials
 only 5% of DLE px have SLE
 50% of DLE px have positive ANA
 20% of SLE px have DLE
o Systemic Rash
 Most common: photosensitive, slightly raised
erythema, occasionally scaly, on the face
(“butterfly” rash on cheeks and nose), ears,
chin, V region of neck, upper back and extensor
surfaces of arms
 worsening of rash often accompanies flare
o Subacute cutaneous lupus erythematosus (SCLE)
 scaly red patches similar to psoriasis or
 attacks of circular red-rimmed lesions
 patients are photosensitive
 most have antibodies to Ro
o Others
 seen less frequently
 recurring urticaria
 lichen planus-like dermatitis
 bullae
 panniculitis (“lupus profundus”)
Renal Manifestations
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- nephritis is the most serious manifestation of SLE
- nephritis and infection is the leading cause of mortality
in 1st decade of disease
- may be asymptomatic so order urinalysis
- renal biopsy aids in therapeutic plans
- most px have proliferative glomerular damage
o microscopic hematuria
o proteinuria (>500mg/24hr)
o ½ develop nephrotic syndrome
o may develop HPN
o if untreated, may have ESRD in 2 years
o aggressive immunosuppression with glucocorticoids
and cytotoxic drugs
- a few px with proteinuria (usually nephrotic) have
membranous GN without proliferation
o outcome is better than DPGN
o less likely to improve on immunosuppression
- lupus nephritis have “flares” and require re-treatment
over many years
- increase risk for accelerated atherosclerosis
- should control BP, hyperlipidemia and hyperglycemia
Nervous System Manifestations
- CNS or PNS
- determine if symptoms are caused by another
condition (e.g.infection)
- diffuse process or vascular occlusive disease
- most common: cognitive dysfunction (difficulty with
memory and reasoning)
- headaches are common; excruciating headaches may
indicate flare
- seizures of any type require anti-seizure drugs and
immunosuppressive therapy
- psychosis should be distinguished from glucocorticoid-
induced psychosis (at >40mg of prednisone)
- myelopathy is common and disabling; may require
high-dose glucocorticoid therapy
Vascular Occlusions
- TIA, strokes, myocardial infarction
- increased in patients with antiphospholipid antibodies
(aPL)
- ischemia in the brain
o by focal occlusion (non-inflammatory or vasculitis)
o emboli from carotid artery plaque
o emboli from fibrinous vegetations of Libman-Sachs
endocarditis
- MI reflect accelerated atherosclerosis
- 50-fold increased risk for vascular events in women
<45 y/o
- associated with increased risk for atherosclerosis:
o older age
o hypertension
o dyslipidemia
o aPL
o repeated high scores for disease activity
o high cumulative doses of glucocorticoids
- initiate long term anticoagulation if event is likely to
result in clotting
- anticoagulation and immunosuppression for
vasculitis + bland vascular occlusions
Pulmonary Manifestations
- most common: pleuritis with or without pleural effusion
- may respond to NSAIDs
- brief course of glucocorticoids when severe
- pulmonary infiltrates also occur; difficult to distinguish
from infection on imaging studies
- life threatening:
o interstitial inflammation leading to fibrosis
o intraalveolar hemorrhage
o require aggressive immunosuppressive and
supportive treatment
Cardiac Manifestations
- most common: pericarditis
 - responds to anti-inflammatory therapy and rarely leads
to tamponade
- more serious: myocarditis and fibrinous endocarditis of
Libman-Sachs
- endocardial involvement may lead to valvular
insufficiencies (mitral or aortic) or embolic events
- usual practice is to give a trial or high-dose steroids
with appropriate supportive therapy for heart failure,
arrhythmia or embolic events
Hematologic Manifestations
- most common: normochromic, normocytic anemia
- rapid onset and severe hemolysis
- require high-dose glucocorticoid therapy
- leucopenia particularly lymphopenia
- thrombocytopenia
o >40,000/μL without abnormal bleeding: no therapy
required
o if severe: high-dose glucocorticoids (1mg/kg/day of
prednisone)
Gastrointestinal Manifestations
- nausea, vomiting, diarrhea and diffuse abdominal pain
(caused by autoimmune peritonitis) may sometimes
indicate a flare
- increased serum AST and ALT are common in active
SLE
- improve with systemic glucocorticoid therapy
- intestinal vasculitis may be life-threatening
- complications: perforations, ischemia, bleeding, sepsis
- aggressive immunosuppressive therapy and high-
dose glucocorticoids for short-term control
Ocular Manifestations
- Sicca syndrome (Sjogren’s syndrome) and nonspecific
conjunctivitis are common and does not threaten
vision
- retinal vasculitis and optic neuritis may cause
blindness in a span of days to weeks
- require aggressive immunosuppression
- complication of glucocorticoid therapy: cataracts and
glaucoma
LABORATORY TESTS
- to diagnose
- to follow course of the disease (detect flare or
developing organ damage)
- to identify adverse effects of therapy
Tests for Autoantibodies
- ANA
o sensitivity specificity
- anti-Ro
o risk for neonatal lupus, sicca syndrome and SCLE
o pregnant women should be screened for anti-Ro
and aPL
- anti-dsDNA
o specific for SLE
o ELISA
o Immunofluorescence
o Farr assay (correlates better with nephritis)
o indicates a flare in nephritis or vasculitis
- anti-Sm
o specific for SLE
o does not reflect disease activity
- aPL
o not specific for SLE
o  risk for venous/arterial clotting, thrombocytopenia
and fetal loss
o at least 2 (+)tests at least 6 weeks apart, clotting,
repeated fetal loss with or without SLE
 Antiphospholipid antibody syndrome (APS)
- ELISA for anticardiolipin
o High titers for IgG anticordiolipin (>50IU) indicate
high risk for clotting
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- Sensitive phospholipids-based activated prothrombin
time
o Dilute Russel venom viper test
- Antibodies to ß2 glycoprotein 1
o target of of most anticardiolipin and lupus
anticoagulants
Standard Tests for Diagnosis
- CBC
- Platelet
- Urinalysis
Tests for Following Disease Course
- to identify status of organ involvement in SLE flares
- Hgb levels
- Platelet counts
- Urinalysis
- Serum Crea
- Albumin
Additional markers
- Anti-DNA antibodies
- Components of complement (C’3 is widely available)
- Activated complement products
- Soluble IL2
- Urinary monocyte chemotactic protein 1
TREATMENT
- no cure and complete remissions are rare
- Goals:
o control acute, severe flares
o develop maintenance strategies to suppress
symptoms
o prevent organ damage
- Depends on:
o whether manifestations are life-threatening to justify
aggressive therapies
o whether manifestations could be reversible
o the best approach to prevent complications
Conservative Therapies for Non-Life-Threatening SLE
- with fatigue, pain and autoantibodies, but without
major organ involvement
- suppression of symptoms by analgesics and
antimalarials
- Analgesics
o NSAIDs for arthritis/arthralgias
o BUT SLE px are at an increased risk for NSAID-
induced aseptic meningitis, elevated serum
transaminases, hypertension and renal dysfunction
o COX-2 inhibitors are not exactly safer, although may
cause fewer adverse GI events
- Antimalarials
o hydroxychloroquine, chloroquine, quinacrine
o reduce dermatitis, arthritis and fatigue
o hydroxychloroquine reduces the number of disease
flares
o should undergo annual ophthalmologic
examinations because of potential retinal toxicity
- dehydroepiandrosterone may reduce disease activity
- low doses of systemic glucocorticoids
Life Threatening SLE: Proliferative Forms of Lupus Nephritis
- systemic glucocorticoids
o mainstay treatment
o 0.5-2mg/kg/day orally or
o 1000mg of methylprednisolone sodium succinate IV
daily for 3 days followed by 0.5-1mg/kg of daily
prednisone or equivalent
o 4-6 weeks of high-doses for severe SLE (40-60mg
prednisone daily)
o subsequently tapered to maintenance dose of 5-
10mg prednisone, prednisolone or equivalent daily
or 10-20mg every other day
o in active lupus nephritis: high doses (1000mg
methylprednisolone IV daily for 3 days) shortens
time to improvement but does not result in better
renal function
 o standard practice for active, life-threatening SLE is
high-dose IV glucocorticoid pulses
o responses are evident after 24 hours of initiation of
treatment
o safety considerations: infection, hyperglycemia,
hypertension, osteoporosis
- Cytotoxic drugs particularly for patients with lupus
nephritis
o Cyclophosphamide (alkylating agent) is the
standard drug for those with renal biopsies showing
WHO grade III, IV and V proliferative or
membranoproliferative nephritis
o used concomitantly with glucocorticoid therapy
o responses begin 3-16 weeks after treatment
o development to ESRD is less frequent
o should be administered to those whose severe
lupus is likely to be reversible
o those with high serum creatinine levels and high
chronicity scores on renal biopsy are not likely to
respond
o recommended duration of therapy is controversial
o glucocorticoid+cyclophosphamide therapy has
many adverse effects disliked by patients
o adverse effects
 irreversible ovarian or testicular failure with
increasing cumulative doses
 nausea and malaise with each IV dose
 alopecia
 frequent infections
o IV intermittent dose has fewer side effects than oral
- Azathioprine (a purine antagonist)
o added to glucocorticoids to reduce flares and
maintenance glucocorticoid dose
o requires several months to be effective
o may have fewer side effects
- Mycophenolate mofetil
o Relative lymphocyte-specific inhibitor of inosine
monophosphate dehydrogenase
o also showed good improvement and fewer side
effects
- Chlorambucil
o alkylating agent substituted for cyclophosphamide
o risk of irreversible bone marrow suppression
- Methotrexate
o folinic acid antagonist
o for arthritis and dermatitis, not in life-threatening
disease
- Leflunomide
o Lymphocyte-specific pyrimidine antagonist
- Cyclosporine
o inhibits production of IL-2 and inhibits T lymphocyte
o potential nephrotoxicity but no bone marrow toxicity
o 3-5mg/kg/day PO in those with steroid resistant
cytopenias of SLE or steroid resistant patients who
have already developed bone marrow suppression
Special Conditions in SLE that May Require Additional or
Different Therapies
- Pregnancy and Lupus
o fertility rates are normal
o fetal loss is increased
o fetal demise is higher in those with high disease
activity, antiphospholipid antibodies and/or nephritis
o should be controlled with prednisone/prednisolone
at the lowest effective dose for the shortest duration
o adverse effects of prenatal exposure to
glucocorticoid (esp. betamethasone)
 low birth weight
 CNS developmental abnormalities
 predilection towards adult metabolic syndrome
o with aPL (on 2 occasions) and prior fetal loss  tx
with standard or LMW Heparin+aspirin
o presence of anti-Ro is associated with neonatal
lupus (rash and congenital heart block)  monitor
fetal heart rates
Page 4 of 5
o women usually tolerate pregnancy without flares
o poor maternal outcomes if with active nephritis or
irreversible kidney, brain or heart damage
- Lupus and APS
o venous or arterial clotting
o repeated fetal losses
o at least 2 positive tests for aPL
o managed with long-term anti-coagulation
o target INR of 3.0
- Microvascular Thrombotic Crisis (Thrombotic
Thrombocytopenic Purpura, Hemolytic Uremic
Syndrome)
o hemolysis, thrombocytopenia, and microvascular
thrombosis in kidneys, brain and other tissues
o high mortality rate
o common in young individuals with lupus nephritis
o identification of schistocytes on peripheral blood
smears and elevated serum levels of lactate
dehydrogenase
o may require plasma exchange or extensive
plasmapheresis
- Lupus Dermatitis
o should minimize exposure to UV light
o proper clothing and sunscreen (al least SPF 15)
o topical glucocorticoids and antimalarials
o systemic treatment with retinoic acid (adverse
effect: fetal abnormalities)
o extensive, pruritic, bullous or ulcerating dermatitides
improve with systemic glucocorticoids
o therapy-resistant lupus dermatitis  topical
tacrolimus, systemic dapsone or thalidomide
Preventive Therapies
- prevent complications with vaccination (those with
influenza and pneumococcal vaccines have the same
flare rates compared to placebo)
- suppress recurrent urinary tract infections
- prevent osteoporosis
- control hypertension
- monitor dyslipidemia, manage hyperglycemia and
obesity to prevent atheroscerosis
Experimental Therapies
- biologics and cytotoxic medications
- strategies targeting T or B lymphocytes
- transplantation of hematopoietic stem cells
PATIENT OUTCOMES, PROGNOSIS AND SURVIVAL
- survival outcome is good!
o 90-95% at 2 years
o 82-90% at 5 years
o 71-80% at 10 years
o 63-75% at 20 years
- poor prognosis
o 50% mortality in 10 years
o associated with (at time of diagnosis)
 high serum crea levels
 hypertension
 nephritic syndrome
 anemia
 hypoalbuminemia
 hypocomplementemia
 aPL
- high incidence of graft rejection in those needing renal
transplant
- disability is commonly due to chronic renal disease,
fatigue, arthritis, pain
- 25% may experience remissions for a few years
- leading causes of mortality
o systemic disease activity
o renal failure
o infections
o thromboembolic events
DRUG-INDUCED LUPUS
- (+) ANA (usually appears before symptoms)
 - fever, malaise, arthritis or intense arthralgias/myalgias,
serositis and/or rash
- appears with certain medications and biologic agents
- rarely involves kidneys or brain
- rarely associated with anti-dsDNA; commonly
associated with antibodies to histones
- resolves over several weeks after discontinuation of
offending medication
- anti-arrhythmics: procaineamide, disopyramide,
propafenone
- anti-hypertensives: hydralazine, some ACE inhibitors
and beta-blockers
- anti-thyroid PTU
- antipsychotics: chlorpromazine and lithium
- anticonvulsants: carbamazepine phyenytoin
- antibiotics: isoniazid, minocycline, macrodantin
- anti-rheumatic: sulfasalazine
- diuretic: hydrochlorothiazide
- antihyperlipidemics: lovastatin, simvastatin
- biologics interferons and TNF inhibitors

--zsazsexy
dedicated to mika, kat, ma and richarded
inspired by prison break and grey’s anatomy
labo
appreciate the reiteration of Harrison
…feel the love

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