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11
SLE

Dr. Sarmiento July 3, 2015

o Antigens, autoantibodies, and immune complexes persist
TOPIC OUTLINE for prolonged periods of time, allowing inflammation and
I. Background and Epidemiology disease to develop
II. Pathogenesis and Etiology  Sustained production of pathogenic autoantibodies. Activation
A. Autoantibodies in SLE of complement and immune cells leads to release of
III. Pathology chemotaxins, cytokines, chemokines, vasoactive peptides,
A. Skin and destructive enzymes
B. Renal (Lupus Nephritis)  Chronic inflammation  accumulation of growth factors and
C. Autoantibodies in SLE products of chronic oxidation  irreversible tissue damage in
IV. Diagnosis glomeruli, arteries, lungs, and other tissues.
A. 2006 Criteria for Diagnosis of SLE  Immune cell activation is accompanied by increased secretion
B. Approach to Diagnosis of proinflammatory type 1 and 2 interferons (IFNs), tumor
V. Interpretation of Clinical Manifestations necrosis factor α (TNF-α), interleukin (IL)-17 and B cell–
VI. Laboratory Tests maturation/survival cytokines B lymphocyte stimulator
VII. Treatment (BLyS/BAFF), and IL-10.
A. Treatment for Women with SLE  Upregulation of genes induced by interferons is a genetic
VIII. Antiphospholipid Antibody Syndrome "signature" in peripheral blood cells of SLE in approximately
IX. Prevention 50% of patients
X. Prognosis  Decreased production of other cytokines also contributes to
SLE:
BACKGROUND AND EPIDEMIOLOGY o Lupus T and natural killer (NK) cells fail to produce
enough IL-2 and transforming growth factor β (TGF-β) 
 Autoimmune disease
induce and sustain regulatory CD4+ and CD8+ T cells.
 Organs and cells undergo damage mediated by tissue-binding
 The result of these abnormalities is sustained production of
autoantibodies and immune complexes
autoantibodies and immune complexes; pathogenic subsets
 Ninety percent (90%) of patients are women of child-bearing
bind target tissues, with activation of complement, leading to
years
release of cytokines, chemokines, vasoactive peptides,
o Females make higher antibody responses than males
oxidants, and destructive enzymes.
o Child-bearing age are exposed to estrogen-containing oral
 This is accompanied by influx into target tissues of T cells,
contraceptives or hormone replacement
monocyte/macrophages, and dendritic cells, as well as
 Estradiol binds to receptors on T and B lymphocytes,
activation of resident macrophages and dendritic cells.
increasing activation and survival of those cells, thus
 In the setting of chronic inflammation, accumulation of
favoring prolonged immune responses
growth factors and products of chronic oxidation contribute to
 In most patients, autoantibodies are present for a few years
irreversible tissue damage, including fibrosis/sclerosis, in
before the first clinical symptom appears
glomeruli, arteries, brain, lungs, and other tissues.
o Clinical manifestations are heterogenous
AUTOANTIBODIES IN SLE
PATHOGENESIS AND ETIOLOGY
Antibody Antigen Clinical Utility
Prevalence

Recognized
,%

Antinuclear 98 Multiple Best screening test;

antibodies nuclear repeated negative
(ANA)* tests make SLE
unlikely. Sensitive,
but not specific
Anti-dsDNA* 70 DNA (double- High titers are SLE-
stranded) specific and in some
patients correlate with
disease activity,
nephritis, vasculitis. If
the ANA is negative,
but you have a high
suspicion of SLE,
request this test.
Anti-Sm* 25 Protein Specific for SLE; no
complexed to definite clinical
6 species of correlations; most
 Interactions between susceptibility genes and environmental nuclear U1 patients also have
factors result in abnormal immune responses such as: RNA anti-RNP; more
o Activation of innate immunity (dendritic cells) by CpG common in blacks and
DNA, DNA in immune complexes, and RNA in RNA/protein Asians than whites.
self-antigens Anti-RNP 40 Protein Not specific for SLE;
o Lowered activation thresholds of adaptive immunity cells complexed to high titers associated
(antigen-specific T and B lymphocytes) U1 RNAγ with syndromes that
o Ineffective regulatory and inhibitory CD4+ and CD8+ T have overlap features
cells of several rheumatic
o Reduced clearance of apoptotic cells and of immune syndromes including
complexes. SLE; more common in
 Self-antigens (nucleosomal DNA/protein; RNA/protein in Sm, blacks than whites
Ro, and La; phospholipids) are available for recognition by
Anti-Ro (SS- 30 Protein Not specific for SLE;
the immune system in surface blebs of apoptotic cells
A) complexed to associated with sicca
hY RNA, syndrome, predisposes

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primarily 60 to subacute cutaneous CLASSIFICATION OF LUPUS NEPHRITIS

kDa and 52 lupus, and to neonatal (INTERNATIONAL SOCIETY OF NEPHROLOGY AND RENAL
kDa lupus with congenital PATHOLOGY SOCIETY)
heart block; associated CLASS DESCRIPTION
with decreased risk for
nephritis I Minimal  Normal glomeruli by light
Mesangial microscopy (LM)
Anti-La (SS- 10 47-kDa Usually associated
Lupus  Mesangial immune deposits by
B) protein with anti-Ro;
Nephritis immunofluorescence (IF)
complexed to associated with
hY RNA decreased risk for II Mesangial  LM: mesangial hypercellularity or
nephritis ProliferativeLu matrix expansion with mesangial
pus Nephritis immune deposits
Antihistone* 70 Histones More frequent in drug-
 IF/EM: few isolated subepithelial or
associated induced lupus than in
subendothelial deposits
with DNA (in SLE
nucleosome, III Focal Lupus  <50% of all glomeruli
chromatin) Nephritis
Antiphosphol 50 Phospholipids, Three tests available— III (A)  Active lesions—focal proliferative
ipid β2 ELISAs for cardiolipin III (A/C)  Active and chronic lesions—focal
glycoprotein 1 and β2G1, sensitive proliferative and sclerosing
cofactor, prothrombin time III (C)  Chronic inactive lesions - focal
prothrombin (DRVVT); predisposes sclerosing
to clotting, fetal loss, IV Diffuse Lupus  50% of all glomeruli
thrombocytopenia Nephritis o Diffuse segmental (IV-S) to
Antierythroc 60 Erythrocyte Measured as direct diffuse global (IV-G)
yte membrane Coombs' test; a small o Segmental: glomerular lesion
proportion develops involves <1/2 of the glomerular
overt hemolysis tuft lesions
Antiplatelet 30 Surface and Associated with V Membranous  LM/IF/EM: Global or segmental
altered thrombocytopenia but Lupus subepithelial immune deposits with
cytoplasmic sensitivity and Nephritis or without mesangial alterations
antigens on specificity are not
platelets good; this is not a VI Advanced  >90% of glomeruli globally
useful clinical test Sclerotic Lupus sclerosed without residual activity
Antineuronal 60 Neuronal and In some series a Nephritis
(includes lymphocyte positive test in CSF  Class I: abnormkality only at IF not on LM.
anti- surface correlates with active  Class II: there is starting abnormality seen even at LM
glutamate antigens CNS lupus.  Class III: refers to focal lupus nephritis when <50% of all
receptor) glomeruli are affected
Antiribosoma 20 Protein in In some series a  Class IV: diffuse lupus nephritis when more than 50% of all
lP ribosomes positive test in serum glomeruli are affected. It may range from diffuse segmental
correlates with (IV-S) to diffuse global (IV-G)
depression or  Class V: Global or segmental subepithelial immune deposits
psychosis due to CNS with or without mesangial alterations
lupus  Class VI lupus nephritis – characterized by Advanced
PATHOLOGY Sclerotic when >90% of glomeruli globally sclerosed
SKIN without residual activity
This is based on renal biopsy.
Deposition of immunoglobulins at the dermal-epidermal junction
For Class I-III, you can give aggressive treatment, however for
(DEJ)
Class IV-VI, treatment is not indicated
o Injury to basal keratinocytes
I-III are reversible changes
o Inflammation (influx of T lymphocytes in the DEJ and
IV- VI – end stage renal disease; 2 years nalang to develop
around blood vessels and dermal appendages)
Clinically unaffected skin may also show Ig deposition at the
DEJ DIAGNOSIS
RENAL (LUPUS NEPHRITIS) Based on characteristic clinical features and autoantibodies
Any combination of  4 of 11 criteria, well documented at any
 World Health Organization (WHO) classification of lupus
time during an individual’s history
nephritis
o Specificity:~95%
 International Society of Nephrology (ISN) Renal Pathology
o Sensitivity: ~75%
Society (RPS)- new classification
 In renal biopsies, the pattern and severity of injury are
important in diagnosis and in selecting the best therapy 2006 CRITERIA FOR DIAGNOSIS SLE
 An advantage of the ISN/RPS classification is the addition of CRITERIA DESCRIPTION
"a" for active and "c" for chronic changes, giving the Malar rash or Fixed erythema, flat or raised, over
physician information regarding the potential reversibility of “Butterfly” Rash the malar eminences
disease.
 Imporatnce of using this classification is for prognostication: Discoid rash Erythematous circular raised patches
o In general, class III and IV disease, as well as class V with adherent keratotic scaling and
accompanied by III or IV disease, should be treated with follicular plugging; atrophic scarring
aggressive immunosuppression if possible, because there may occur
is a high risk for end-stage renal disease (ESRD) if Photosensitivity Exposure to ultraviolet light causes
patients are untreated or undertreated. rash. Prolonged exposure to
o Class I or II disease or those with extensive irreversible computers.
changes (class VI). – Treatment not recommended. Oral Oral and nasopharyngeal ulcers,
Though according to the lecturer, we can give aggressive ulcers(Painless) observed by physician(a report of
treatment to patient with Class I-III Lupus Nephritis the patient of the occurrence of these
is not enough)

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Arthritis Nonerosive arthritis(radiologic Most of the autoantibodies, present at the

finding) of two or more peripheral
joints, with tenderness, swelling, or
effusion
Serositis Pleuritis or pericarditis (ECG or rub or
evidence of effusion)
Renal disorder Proteinuria >0.5 g/d or 3+, or cellular
casts
Neurologic Seizures or psychosis without other
causes
Hematologic Hemolytic anemia or
disorder leukopenia (<4000/L) or
lymphopenia (<1500/L) or
thrombocytopenia (<100,000/L)
**in the absence of offending drugs
Immunologic Anti-dsDNA, anti-Sm, and/or anti-
phospholipid
Antinuclear immunofluorescence or an equivalent
antibodies assay at any point in time in the
absence of drugs known to induce
ANAs
 Mnemonics: MD, RN. SOPHIAA2
 High-titer IgG antibodies to double-stranded DNA and
antibodies to the Sm antigen are both specific for SLE and 
favor the diagnosis in the presence of compatible clinical
manifestations.
 The presence in an individual of multiple autoantibodies
without clinical symptoms should not be considered
diagnostic for SLE, although such persons are at increased
risk
APPROACH TO DIAGNOSIS
time clinical manifestations appear
Exacerbations interspersed with periods of
relative quiescence
Permanent complete remissions – rare
Other systemic manifestations:
o Fatigue and myalgias/arthralgias
o Fever
o Prostration
o Weight loss
o Anemia
MUSKULO Can be the first manifestation of the disease
SKELETAL Case: A 25 year-old female with these
manifestations; consider immunologic
diseases e.g. SLE
Intermittent polyarthritis (joints in the
hands, wrists, and knees)
Joint deformities (hands and feet) – occur
only in 10%
X-ray- nonerosive joints
Myalgia is more common than myositis
o Glucocorticoid and antimalarial
therapies can also cause muscle
weakness; thus must be distinguished
from active disease.
RENAL Nephritis - most serious manifestation of
SLE
o Usually asymptomatic, hence ordering
of UA for suspected/diagnosed SLE
patients should be routine
If diffuse proliferative glomerulonephritis
(DPGN) is untreated, virtually all patients
develop end-stage renal disease (ESRD)
within 2 years of diagnosis
Aggressive immunosuppression is indicated,
unless damage is irreversible (Class VI)

NERVOUS Cognitive dysfunction (difficulties with

SYSTEM memory and reasoning): most common
manifestation of diffuse CNS lupus
Excruciating headaches: often indicate
SLE flare
Seizures
Psychosis (distinguished from
glucocorticoid-induced psychosis)
Myelopathy

VASCULAR Vascular events are increased in, but not

exclusive to, SLE patients with antibodies
to phospholipids (aPL).
In SLE, myocardial infarctions are primarily
manifestations of accelerated
atherosclerosis
SLE patients are seven- to tenfold increased
risk for vascular events e.g. Myocardial
infarction. Strict monitoring of blood
pressure and cholesterol levels are
suggested.
Antiphospholipid antibodies - associated
with hypercoagulability and acute
thrombotic events, whereas chronic
disease is associated with accelerated
atherosclerosis.
PULMO Pleuritis with or without pleural
effusion: most common
Life-threatening pulmonary manifestations:
INTERPRETATION OF CLINICAL MANIFESTATIONS o Interstitial inflammation leading to
 When a diagnosis of SLE is made, it is important to establish fibrosis
the severity and potential reversibility of the illness and to o Shrinking lung syndrome
estimate the possible consequences of various therapeutic o Intraalveolar hemorrhage
interventions CARDIO Pericarditis - Most frequent cardiac
MANIFESTATIONS manifestation
o Usually responds to anti-inflammatory
SYSTEMIC Involves one or several organ systems at
therapye.g. steroids and aspirin
the start but over time, additional
o Rarely leads to tamponade
manifestations may occur
Myocarditis and fibrinous endocarditis of

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Libman-Sacks: More serious Arthritis/arthralgias NSAIDs

manifestations SLE patients are at
Increased risk for myocardial infarction - increased risk for
usually due to accelerated NSAID-induced aseptic
atherosclerosis, which probably results meningitis, elevated
from chronic inflammation and/or chronic serum transaminases,
oxidative damage to lipids and to organs hypertension, and renal
HEMA Most frequent- normochromic normocytic dysfunction
anemia Increase risk for
Hemolysis myocardial infarction
Leukopenia-almost always consists of LIFE-THREATENING OR ORGAN-THREATENING
lymphopenia MANIFESTATIONS(LUPUS NEPHRITIS AND HEART
Rarely predisposes to infections INVOLVEMENT)
Thrombocytopenia Methylprednisolone Systemic glucocorticoids
CUTANEOUS sodium succinate 0.5–
Discoid Roughly circular with slightly raised, scaly 2 mg/kg per day PO or
Lupus hyperpigmented erythematous rims and 1000 mg of IV daily for
Erythematou depigmented, atrophic centers 3 days
s (DLE) 5% of people with DLE have SLE Then Prednisone 0.5–1
Among those with SLE, as many as 20% mg/kg daily
have DLE Cyclophosphamide (an Induction of improvement in
It does not follow that all patients presenting alkylating agent) or severely ill patients
with DLE has SLE. Remember that you mycophenolate mofetil
need to fulfill at least 4 of the 11 criteria (a lymphocyte-specific
Systemic Butterfly" rash inhibitor of inosine
Rash o Photosensitive monophosphatase and
o Photosensitivity means exacerbation therefore of purine
of flare synthesis)
o slightly raised erythema, occasionally Azathioprine (a purine May be effective but is slower
scaly, on the face (particularly the analogue and cycle- to influence response
cheeks and nose) specific
o Rashes are also seen at the ears, chin, antimetabolite)
V region of the neck, upper back, and
extensor surfaces of the arms TREATMENT FOR OTHER MANIFESTATIONS
Worsening of this rash - flare of systemic
Discoid lupus Topical or locally injected
disease
erythematosus (DLE) glucocorticoids and
Subacute Scaly red patches or circular flat red-rimmed
systemic antimalarials
Cutaneous lesions; photosensitive
Lupus o (+) antibodies to Ro (SS-A)
Nervous System Glucocorticoids
Erythematos Other rashes:
Manifestations
us (SCLE) o Recurring urticaria
o Lichen planus–like dermatitis Pulmonary Glucocorticoid to more
o Bullae Manifestations aggressive
o Panniculitis ("lupus profundus") immunosuppressive
Alopecia therapy
ISN grade III or IV Glucocorticoids and
Cyclophosphamide (500–
LABORATORY TESTS
750 mg/m2 intravenously,
Tests for Autoantibodies monthly for 3–6 months)
o ANA- most important; positive in >95% of patients; Mycophenolate (or
usually at he onset of symptoms azathioprine) after a 6-
o Anti double-stranded DNA (dsDNA)- specific test month induction phase.
Screening tests
o Complete blood count- check anemia
o Urinalysis – check proteinuria TREATMENT FOR WOMEN WITH SLE
Tests for Follow-up Increased (approximately two- to threefold) rate of fetal loss
o Hemoglobin levels Poor maternal outcomes - with active nephritis or irreversible
o Platelet counts organ damage in kidneys, brain, or heart
o Urinalysis Small proportion develops severe flares
o Serum levels of creatinine or albumin DOC: prednisone/prednisolone - at the lowest effective
None is uniformly agreed upon as a reliable indicator of flare doses for the shortest time required due to possible adverse
Repeat antibodies – for normal test but symptoms persists effects of steroids on fetus
o Adverse effects of prenatal glucocorticoid exposure
TREATMENT (primarily betamethasone) on offspring may include low
birth weight, developmental abnormalities in the CNS,
Reassure your patient that if they adhere to the management of
and predilection toward adult metabolic syndrome.
their disease, they can live a normal life.
SLE patients with aPL (on at least two occasions) and prior fetal
No cure for SLE
losses- heparin (standard or low-molecular-weight) plus
Complete sustained remissions are rare
low-dose aspirin
Goal: control acute, severe flares and suppress symptoms to
presence of anti-Ro (which can induce neonatal lupus ) -
prevent organ damage
requires vigilant monitoring
Analgesics and antimalarials (hydroxychloroquine,
chloroquine, and quinacrine) are mainstays for symptomatic
treatment ANTIPHOSPHOLIPID ANTIBODY SYNDROME
Patients with SLE with:
o Venous or arterial clotting
o Repeated fetal losses
At least two positive tests for aPL
Treatment:

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 Acute Respiratory Distress Syndrome 1.09

o Long-term anticoagulation
Target INR:
o 2.0–2.5- patients with one episode of venous clotting
o 3.0–3.5- patients with recurring clots or arterial clotting

PREVENTION
 Vaccinations (influenza and pneumococcal)
 Suppressing recurrent urinary tract infections
 Prevent osteoporosis
 Control of hypertension
 Monitoring and treatment of dyslipidemias
 Management of hyperglycemia and obesity

PROGNOSIS
 Survival: 95% at 5 years, 90% at 10 years, and 78% at 20
years
 Poor prognosis:
o high serum creatinine levels [>124 mol/L,hypertension
o nephrotic syndrome anemia [hemoglobin <124 g/L
(<12.4 g/dL)]
o hypoalbuminemia
o hypocomplementemia
o aPL
o male sex
o ethnicity (African American, Hispanic, and mestizo
heritage)
 Systemic disease activity, renal failure, and infections -
leading causes of death in the first decade:
 Subsequently: thromboembolic events(10-20 years)

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