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

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 - nephritis is the most serious manifestation of SLE
Overview and Systemic Manifestations - nephritis and infection is the leading cause of mortality
- may involve 1 or several organ systems in 1st decade of disease
- severity may be mild and intermittent or severe and - may be asymptomatic so order urinalysis
fulminant - renal biopsy aids in therapeutic plans
- most experience exacerbations with periods of relative
quiescence - most px have proliferative glomerular damage
- permanent complete remissions are rare o microscopic hematuria
o proteinuria (>500mg/24hr)
- fatigue and myalgias/arthralgias present most of the
time o ½ develop nephrotic syndrome
- severe systemic illness requiring glucocorticoid o may develop HPN
therapy may occur with fever, prostration, weight loss o if untreated, may have ESRD in 2 years
and anemia o aggressive immunosuppression with glucocorticoids
and cytotoxic drugs
Musculoskelatal Manifestations - a few px with proteinuria (usually nephrotic) have
- mild to disabling intermittent polyarthritis (soft tissue membranous GN without proliferation
swelling and tenderness in joints most commonly in o outcome is better than DPGN
hands, wrists and knees o less likely to improve on immunosuppression
- visible synovitis suggest active disease - lupus nephritis have “flares” and require re-treatment
- 10% develop joint deformities in hands and feet over many years
- joint erosions on x-ray are rare; their presence - increase risk for accelerated atherosclerosis
suggest a non-lupus inflammatory arthropathy (e.g.
RA)
- should control BP, hyperlipidemia and hyperglycemia
- ischemic necrosis should be considered in persistent
Nervous System Manifestations
pain in a single joint, particularly if no other
- CNS or PNS
manifestations of active SLE is present
- determine if symptoms are caused by another
- prevalence of ischemic necrosis is high among SLE condition ([Link])
patients esp. those treated with systemic - diffuse process or vascular occlusive disease
glucocorticoids - most common: cognitive dysfunction (difficulty with
- myositis with clinical muscle weakness, elevated memory and reasoning)
creatinine kinase levels and biopsy evidence of - headaches are common; excruciating headaches may
muscle necrosis and inflammation may occur indicate flare
- glucocorticoids and antimalarial agents (rare) can
cause muscle weakness
- seizures of any type require anti-seizure drugs and
immunosuppressive therapy
- adverse effect should be differentiated from active
disease - psychosis should be distinguished from glucocorticoid-
induced psychosis (at >40mg of prednisone)
Cutaneous Manifestations - myelopathy is common and disabling; may require
- rashes may be minor or very severe high-dose glucocorticoid therapy
- may be the major disease manifestation
- small painful ulcerations on oral and nasal mucosa are Vascular Occlusions
common - TIA, strokes, myocardial infarction
- lesions resemble aphthous ulcers and usually indicate - increased in patients with antiphospholipid antibodies
disease activity (aPL)
- Lupus Dermatitis classifications - ischemia in the brain
o by focal occlusion (non-inflammatory or vasculitis)
o Discoid Lupus Erythematosus (DLE)
o emboli from carotid artery plaque
 roughly circular with slightly raised, scaly
o emboli from fibrinous vegetations of Libman-Sachs
hyperpigmented erythematous rims and
depigmented, atrophic centers endocarditis
- MI reflect accelerated atherosclerosis
 all dermal appendages are permanently
- 50-fold increased risk for vascular events in women
destroyed
<45 y/o
 can be disfiguring esp. on the face and scalp
- associated with increased risk for atherosclerosis:
 tx: local glucocorticoids and systemic o older age
antimalarials
o hypertension
 only 5% of DLE px have SLE
o dyslipidemia
 50% of DLE px have positive ANA
o aPL
 20% of SLE px have DLE
o repeated high scores for disease activity
o Systemic Rash
o high cumulative doses of glucocorticoids
 Most common: photosensitive, slightly raised
- initiate long term anticoagulation if event is likely to
erythema, occasionally scaly, on the face
result in clotting
(“butterfly” rash on cheeks and nose), ears,
- anticoagulation and immunosuppression for
chin, V region of neck, upper back and extensor
vasculitis + bland vascular occlusions
surfaces of arms
 worsening of rash often accompanies flare Pulmonary Manifestations
o Subacute cutaneous lupus erythematosus (SCLE) - most common: pleuritis with or without pleural effusion
 scaly red patches similar to psoriasis or - may respond to NSAIDs
 attacks of circular red-rimmed lesions - brief course of glucocorticoids when severe
 patients are photosensitive - pulmonary infiltrates also occur; difficult to distinguish
 most have antibodies to Ro from infection on imaging studies
o Others - life threatening:
 seen less frequently o interstitial inflammation leading to fibrosis
 recurring urticaria o intraalveolar hemorrhage
 lichen planus-like dermatitis o require aggressive immunosuppressive and
 bullae supportive treatment
 panniculitis (“lupus profundus”)
Cardiac Manifestations
Renal Manifestations - most common: pericarditis

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 - responds to anti-inflammatory therapy and rarely leads - Sensitive phospholipids-based activated prothrombin
to tamponade time
- more serious: myocarditis and fibrinous endocarditis of o Dilute Russel venom viper test
Libman-Sachs
- endocardial involvement may lead to valvular - Antibodies to ß2 glycoprotein 1
insufficiencies (mitral or aortic) or embolic events o target of of most anticardiolipin and lupus
anticoagulants
- usual practice is to give a trial or high-dose steroids
with appropriate supportive therapy for heart failure,
Standard Tests for Diagnosis
arrhythmia or embolic events
- CBC
- Platelet
Hematologic Manifestations
- Urinalysis
- most common: normochromic, normocytic anemia
- rapid onset and severe hemolysis
Tests for Following Disease Course
- require high-dose glucocorticoid therapy
- to identify status of organ involvement in SLE flares
- leucopenia particularly lymphopenia
- Hgb levels
- thrombocytopenia
- Platelet counts
o >40,000/μL without abnormal bleeding: no therapy
- Urinalysis
required - Serum Crea
o if severe: high-dose glucocorticoids (1mg/kg/day of - Albumin
prednisone) Additional markers
- Anti-DNA antibodies
Gastrointestinal Manifestations - Components of complement (C’3 is widely available)
- nausea, vomiting, diarrhea and diffuse abdominal pain - Activated complement products
(caused by autoimmune peritonitis) may sometimes - Soluble IL2
indicate a flare - Urinary monocyte chemotactic protein 1
- increased serum AST and ALT are common in active
SLE TREATMENT
- improve with systemic glucocorticoid therapy - no cure and complete remissions are rare
- intestinal vasculitis may be life-threatening - Goals:
- complications: perforations, ischemia, bleeding, sepsis o control acute, severe flares
- aggressive immunosuppressive therapy and high- o develop maintenance strategies to suppress
dose glucocorticoids for short-term control symptoms
o prevent organ damage
Ocular Manifestations - Depends on:
- Sicca syndrome (Sjogren’s syndrome) and nonspecific o whether manifestations are life-threatening to justify
conjunctivitis are common and does not threaten aggressive therapies
vision o whether manifestations could be reversible
- retinal vasculitis and optic neuritis may cause
blindness in a span of days to weeks
o the best approach to prevent complications
- require aggressive immunosuppression
- complication of glucocorticoid therapy: cataracts and Conservative Therapies for Non-Life-Threatening SLE
glaucoma - with fatigue, pain and autoantibodies, but without
major organ involvement
LABORATORY TESTS - suppression of symptoms by analgesics and
- to diagnose antimalarials
- to follow course of the disease (detect flare or - Analgesics
developing organ damage) o NSAIDs for arthritis/arthralgias
- to identify adverse effects of therapy o BUT SLE px are at an increased risk for NSAID-
induced aseptic meningitis, elevated serum
Tests for Autoantibodies transaminases, hypertension and renal dysfunction
- ANA o COX-2 inhibitors are not exactly safer, although may
o sensitivity specificity cause fewer adverse GI events
- anti-Ro - Antimalarials
o risk for neonatal lupus, sicca syndrome and SCLE o hydroxychloroquine, chloroquine, quinacrine
o pregnant women should be screened for anti-Ro o reduce dermatitis, arthritis and fatigue
and aPL o hydroxychloroquine reduces the number of disease
- anti-dsDNA flares
o specific for SLE o should undergo annual ophthalmologic
o ELISA examinations because of potential retinal toxicity
- dehydroepiandrosterone may reduce disease activity
o Immunofluorescence - low doses of systemic glucocorticoids
o Farr assay (correlates better with nephritis)
o indicates a flare in nephritis or vasculitis Life Threatening SLE: Proliferative Forms of Lupus Nephritis
- anti-Sm - systemic glucocorticoids
o specific for SLE o mainstay treatment
o does not reflect disease activity o 0.5-2mg/kg/day orally or
- aPL o 1000mg of methylprednisolone sodium succinate IV
o not specific for SLE
daily for 3 days followed by 0.5-1mg/kg of daily
o  risk for venous/arterial clotting, thrombocytopenia prednisone or equivalent
and fetal loss o 4-6 weeks of high-doses for severe SLE (40-60mg
o at least 2 (+)tests at least 6 weeks apart, clotting, prednisone daily)
repeated fetal loss with or without SLE o subsequently tapered to maintenance dose of 5-
 Antiphospholipid antibody syndrome (APS) 10mg prednisone, prednisolone or equivalent daily
- ELISA for anticardiolipin or 10-20mg every other day
o High titers for IgG anticordiolipin (>50IU) indicate o in active lupus nephritis: high doses (1000mg
high risk for clotting methylprednisolone IV daily for 3 days) shortens
time to improvement but does not result in better
renal function
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 o standard practice for active, life-threatening SLE is o women usually tolerate pregnancy without flares
high-dose IV glucocorticoid pulses o poor maternal outcomes if with active nephritis or
o responses are evident after 24 hours of initiation of irreversible kidney, brain or heart damage
treatment - Lupus and APS
o safety considerations: infection, hyperglycemia, o venous or arterial clotting
hypertension, osteoporosis o repeated fetal losses
- Cytotoxic drugs particularly for patients with lupus o at least 2 positive tests for aPL
nephritis o managed with long-term anti-coagulation
o Cyclophosphamide (alkylating agent) is the o target INR of 3.0
standard drug for those with renal biopsies showing - Microvascular Thrombotic Crisis (Thrombotic
WHO grade III, IV and V proliferative or Thrombocytopenic Purpura, Hemolytic Uremic
membranoproliferative nephritis Syndrome)
o used concomitantly with glucocorticoid therapy o hemolysis, thrombocytopenia, and microvascular
o responses begin 3-16 weeks after treatment thrombosis in kidneys, brain and other tissues
o development to ESRD is less frequent o high mortality rate
o should be administered to those whose severe o common in young individuals with lupus nephritis
lupus is likely to be reversible o identification of schistocytes on peripheral blood
o those with high serum creatinine levels and high smears and elevated serum levels of lactate
chronicity scores on renal biopsy are not likely to dehydrogenase
respond o may require plasma exchange or extensive
o recommended duration of therapy is controversial plasmapheresis
o glucocorticoid+cyclophosphamide therapy has - Lupus Dermatitis
many adverse effects disliked by patients o should minimize exposure to UV light
o adverse effects o proper clothing and sunscreen (al least SPF 15)
 irreversible ovarian or testicular failure with o topical glucocorticoids and antimalarials
increasing cumulative doses o systemic treatment with retinoic acid (adverse
 nausea and malaise with each IV dose effect: fetal abnormalities)
 alopecia o extensive, pruritic, bullous or ulcerating dermatitides
 frequent infections improve with systemic glucocorticoids
o IV intermittent dose has fewer side effects than oral o therapy-resistant lupus dermatitis  topical
- Azathioprine (a purine antagonist) tacrolimus, systemic dapsone or thalidomide
o added to glucocorticoids to reduce flares and
maintenance glucocorticoid dose Preventive Therapies
o requires several months to be effective - prevent complications with vaccination (those with
influenza and pneumococcal vaccines have the same
o may have fewer side effects flare rates compared to placebo)
- Mycophenolate mofetil - suppress recurrent urinary tract infections
o Relative lymphocyte-specific inhibitor of inosine - prevent osteoporosis
monophosphate dehydrogenase - control hypertension
o also showed good improvement and fewer side - monitor dyslipidemia, manage hyperglycemia and
effects obesity to prevent atheroscerosis
- Chlorambucil
o alkylating agent substituted for cyclophosphamide Experimental Therapies
o risk of irreversible bone marrow suppression - biologics and cytotoxic medications
- Methotrexate - strategies targeting T or B lymphocytes
o folinic acid antagonist - transplantation of hematopoietic stem cells
o for arthritis and dermatitis, not in life-threatening
disease PATIENT OUTCOMES, PROGNOSIS AND SURVIVAL
- Leflunomide - survival outcome is good!
o Lymphocyte-specific pyrimidine antagonist o 90-95% at 2 years
- Cyclosporine o 82-90% at 5 years
o inhibits production of IL-2 and inhibits T lymphocyte o 71-80% at 10 years
o potential nephrotoxicity but no bone marrow toxicity o 63-75% at 20 years
o 3-5mg/kg/day PO in those with steroid resistant - poor prognosis
cytopenias of SLE or steroid resistant patients who o 50% mortality in 10 years
have already developed bone marrow suppression o associated with (at time of diagnosis)
 high serum crea levels
Special Conditions in SLE that May Require Additional or  hypertension
Different Therapies  nephritic syndrome
- Pregnancy and Lupus  anemia
o fertility rates are normal  hypoalbuminemia
o fetal loss is increased  hypocomplementemia
o fetal demise is higher in those with high disease  aPL
activity, antiphospholipid antibodies and/or nephritis - high incidence of graft rejection in those needing renal
o should be controlled with prednisone/prednisolone transplant
at the lowest effective dose for the shortest duration - disability is commonly due to chronic renal disease,
o adverse effects of prenatal exposure to fatigue, arthritis, pain
glucocorticoid (esp. betamethasone) - 25% may experience remissions for a few years
 low birth weight - leading causes of mortality
 CNS developmental abnormalities o systemic disease activity
 predilection towards adult metabolic syndrome o renal failure
o with aPL (on 2 occasions) and prior fetal loss  tx o infections
with standard or LMW Heparin+aspirin o thromboembolic events
o presence of anti-Ro is associated with neonatal
lupus (rash and congenital heart block)  monitor DRUG-INDUCED LUPUS
fetal heart rates - (+) ANA (usually appears before symptoms)

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 - 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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