Transcript SYSTEMIC LUPUS ERYTHEMATOSUS

SYSTEMIC LUPUS
ERYTHEMATOSUS
Pardis Nematollahi
June,2014
MD,ACP
SYSTEMIC LUPUS ERYTHEMATOSUS
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Autoimmune multisystem disease characterized by
widespread microvascular inflammation and
production of autoantibodies
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This means wide spectrum of presentation
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Chronic with relapsing and remitting course
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Ranging from indolent to fulminant
The classic presentation of a triad of
fever, joint pain, and rash in a woman
of childbearing age should prompt
investigation into the diagnosis of SLE
Etiology
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Etiology is unknown
Most probable causes
Genetic influence
At least 35 genes are known to increase the risk of SLE.
A genetic predisposition is supported by 40% concordance
in monozygotic twins; if a mother has SLE, her daughter's
risk of developing the disease has been estimated to be
1:40, and her son's risk, 1:250.
Immunological factors Many immune disturbances, both
innate and acquired, occur in SLE
Studies of human leukocyte antigens (HLAs) reveal that
HLA-A1, HLA-B8, and HLA-DR3 are more common in
persons with SLE than in the general population. The
presence of the null complement alleles and congenital
deficiencies of complement (especially C4, C2, and other
early components) are also associated with an increased
risk of SLE
Etiology
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Environmental and exposure-related causes of SLE are
Silica dust and cigarette smoking
Administration of estrogen to postmenopausal women
Photosensitivity is clearly a precipitant of skin disease
Ultraviolet light stimulates keratinocytes, which leads not
only to overexpression of nuclear ribonucleoproteins
Vitamin D deficiency
Drugs
Numerous studies have investigated the role of infectious
etiologies that may also perpetuate autoimmunity.
Patients with SLE have higher titers of antibodies to
Epstein-Barr virus (EBV), have increased circulating EBV
viral loads, and make antibodies to retroviruses
Pathophysiology
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Systemic lupus erythematosus (SLE) is
characterized by a global loss of selftolerance with activation of autoreactive T
and B cells leading to production of
pathogenic autoantibodies and tissue
injury.
Autoimmune reactions directed against
constituents of cell nucleus, DNA
APOPTOSIS
Protease (caspase) cascade
Receptor ligation
ex: TNF, Fas
DNA fragmentation
Chromatin condensation
Cytoplasmic
blebbing
Clearance by phagocytes
Y
AUTOREACTIVITY
Apoptotic bodies
Y
Immune complex formation
C’
Y
RBC
Y
Endo
BM
Intima
Complement fixation
RBC
Release of inflammatory,
vasoactive and chemotactic
mediators
Disruption of endothelium
C’
Y
C’
Y
C’
Thickening of BM
Y
Infiltration of
inflammatory
cells
Tissue damage
EPIDEMIOLOGY
Age : peak 20s and 30s but any age can be affected
before 8 yrs unusual
 Sex :more women affected ,10:1 during childbearing
age
 Prevalence:1/2500
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1 in 700 among women of childbearing age . By
comparison, the female-to-male ratio is only 2 : 1
for disease developing during childhood or after the
age of 65
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Clinical Features of SLE
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Constitutional symptoms
Musculoskeletal disease
Mucocutaneous involvement
Renal Disease
Central nervous system disease
Cardiopulmonary disease
Hematologic abnormalities
Gastrointestinal involvement
Clinical Manifestations
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Ranges from a relatively mild
disorder to rapidly progressing,
affecting many body systems
Most commonly affects the
skin/muscles, lining of lungs, heart,
nervous tissue, and kidneys
General clinical manifestation
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Severe fatigue
Fever
Weight loss
Anorexia
Lymphadenopathy
Mucocutaneous manifestation
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Frequency: 76%
Malar rash
Discoid lupus
Vasculitis (purpura, petechiae)
Raynaud’s phenomenon
Nail involvement
Alopecia
Photosensitivity
Oral/ nasal ulcers
MALAR RASH
 Fixed
erythema, flat or raised,
over the malar eminences
 Tending to spare the nasolabial
folds
 30-60 %
Dermatologic Manifestations
Fig 65-10
MALAR RASH
Photosensitivity
Rash over the sun exposed
areas.Face,neck and V
shaped area of chest.See
rash varies in severity
depending on
exposure.Less under the
orbit protected areas.
DISCOID RASH
Erythematous
raised
patches with adherent
keratotic scaling and
follicular plugging
Atrophic scarring may
occur in older lesions
Oral lesions of SLE
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Erythema of hard
and soft palate,
papules ,vesicles
and petechiae
Erythematous rash
of the tongue.
Oral Ulcers
Oral or
nasopharyngeal
ulceration,
usually painless,
observed by
physician
Joint
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arthralgia, arthropathy, myalgia,
frank arthritis, avascular necrosis
Joint involvement is typically a
nonerosive synovitis with little
deformity, which contrasts with
rheumatoid arthritis
Serositis
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Pleuritis :
convincing history of pleuritic pain ,pleural
rub heard by a physician or evidence of
pleural effusion
or
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Pericarditis:
documented by ECG ,pericardial rub or
evidence of pericardial effusion
Pulmonary Findings In SLE
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Incidence: 5-67%
May be subclinical (abnormal PFTs)
Pleuritis
Pleural effusion
Pneumonitis
Pulmonary hemorrhage
Pulmonary hypertension
Restrictive pulmonary disease & diffusion
defects most commonly observed
abnormalities on PFTs
Cardiovascular Findings
In SLE
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Pericarditis
Myocarditis
Sterile valvular vegetations (rarely
clinically significant except for risk of
bacterial endocarditis)
Arrhythmias
Cor pulmonale
Vasculitis (small vessels)
Atherosclerosis/ Coronary Heart disease
Dyslipoproteinemias
Renal Findings In SLE
Most common cause of morbidity & mortality
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Lupus nephritis affects up to 50% of SLE patients.
The principal mechanism of injury is immune
complex deposition in the glomeruli, tubular or
peritubular capillary basement membranes, or larger
blood vessels
A variety of clinical findings may point toward renal
involvement, including hematuria, red cell casts,
proteinuria, and in some cases the classic nephrotic
syndrome
Neuropsychiatric Manifestations
Of SLE
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Frequency: 20-40%
Difficult to diagnose and treat
Second to nephritis as most common cause of
morbidity & mortality
Can occur at any time; even at presentation
Pathophysiology of CNS
involvement
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The pathologic basis of central nervous system
symptoms is not entirely clear, but antibodies
against a synaptic membrane protein have been
implicated. Neuropsychiatric symptoms of SLE have
often been ascribed to acute vasculitis, but in
histologic studies of the nervous system in such
patients significant vasculitis is rarely present.
Instead, noninflammatory occlusion of small vessels
by intimal proliferation is sometimes noted, which
may be due to endothelial damage by
antiphospholipid antibodies
Neuropsychiatric Manifestations
Of SLE
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COMMON: Depression, organic brain
syndrome, functional psychosis,
headaches, seizures, cognitive
impairment, dementia, coma
OCCASIONAL: Cerebral vascular
accidents (thrombosis or vasculitis),
aseptic meningitis, peripheral
neuropathy, cranial nerve palsies
RARE: Paralysis, transverse myelopathy,
chorea
Hematologic Findings In SLE
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Leukopenia, especially lymphopenia
Anemia
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Thrombocytopenia
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mild to moderate, common, due to chronic
disease and mild hemolysis
severe, uncommon (5%), due to
immune mediated hemolysis (Coombs +)
mild 100-150/micoL, common due to immune
mediated damage
severe <20/microL, uncommon (5-10%),
immune mediated damage
Bone marrow suppression/arrest--very
rare, due to antibodies against precursors
Coagulopathy In SLE
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Hypocoagulable states:
 Anti-platelet antibodies--decreased numbers of
platelets or decreased function (increased
bleeding time)
 Other platelet dysfunction and thrombocytopenia
 Anti-clotting factor antibodies
Hypercoagulable states:
 Antiphospholipid Antibody Syndrome (APS): more
later
 Protein C and S deficiencies
Thrombotic thrombocytopenic purpura
Infection
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because of their underlying
immune dysfunction and treatment
with immunosuppressive drugs
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Fever should be considered serious
Ocular
Conjunctivitis
 Photophobia
 Monocular blindness
transient or permanent
 Blurred vision
 Cotton-Wool spots on retina
due to occlusion retinal blood vessels
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GI INVOLVEMENT IN SLE
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Uncommon SLE manifestations
Mild LFT elevation--not significant
clinically--BUT NEED TO EXCLUDE
AUTOIMMUNE HEPATITIS
Colitis
Mesenteric vasculitis
Protein-losing enteropathy
Pancreatitis
Exudative ascites
1997 ACR CRITERIA FOR THE
CLASSIFICATION OF SLE
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Malar (butterfly) rash:
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Discoid lupus rash:
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Raised patches, adherent keratotic scaling, follicular
plugging; may cause scarring
Photosensitivity:
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Fixed erythema, flat or raised, sparing the nasolabial
folds
Rash as a result of unusual reaction to sunlight, by
patient history or physician observation
Oral or nasal mucocutaneous ulcerations:
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Usually painless
1997 ACR CRITERIA FOR THE
CLASSIFICATION OF SLE (cont)
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Inflammatory arthritis:
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Pleuritis or pericarditis
Pleuritis—convincing history of pleuritic pain or rub heard by a
physician or evidence of pleural effusion, or
Pericarditis—documented by electrocardiogram or rub or evidence of
pericardial effusion
Cytopenias:
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Nonerosive, in two or more peripheral joints
Hemolytic anemia with reticulosis or
leukopenia (<4,000/mm3) or
lymphopenia (<1,500/mm3) or
thrombocytopenia (<100,000/mm3)
Nephritis:
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Proteinuria >0.5 gm/dL or >3+ or
Cellular casts
1997 CRITERIA FOR THE
CLASSIFICATION OF SLE (cont)
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Encephalopathy:
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Seizures
Psychosis
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Positive ANA
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Positive immunoserology:
Anti-DNA antibody to native DNA in abnormal titer, or
Anti-Sm, or
Positive finding of antiphospholipid antibodies based on (1)
an abnormal serum level of IgG or IgM anticardiolipin
antibodies, (2) a positive test for lupus anticoagulant using
a standard test, or (3) a false-positive serologic test for
syphilis known to be positive for at least 6 months and
confirmed by negative Treponema pallidum immobilization
or fluorescent treponemal antibody absorption test
The revised criteria for the classification
of systemic lupus erythematosus
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Serositis
Oral Ulcers
Arthritis
Photosensitivity
Blood disorders:
-Hemolytic anemia
-Leukopenia
(Lymphopenia)
-Thrombocytopenia
6. Renal disorders
7. ANA positive
8. Immunologic
abnormalities:
-Anti-ds- DNA
-Anti- Sm
-Antiphospholipid
-False +ve VDRL
9. Neurologic
abnormalities
10. Malar rash
11. Discoid rash –
rimmed with scaling,
follicular plugging
CLASSIFICATION CRITERIA
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Must have 4 of 11 for Classification
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Sensitivity 96%
Specificity 96%(In children 100%)
Not all “Lupus” is SLE
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Chronic discoid Lupus erythematosus
Drug induced lupus
Subacute Cutaneous Lupus
erythematosus
Chronic Discoid Lupus Erythematosus
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Chronic discoid lupus erythematosus is a disease in
which the skin manifestations may mimic SLE, but
systemic manifestations are rare.
It is characterized by the presence of skin plaques
showing varying degrees of edema, erythema,
scaliness, follicular plugging, and skin atrophy
surrounded by an elevated erythematous border.
The face and scalp are usually affected, but widely
disseminated lesions occasionally occur
Chronic Discoid Lupus Erythematosus
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The disease is usually confined to the skin, but 5%
to 10% of patients with discoid lupus erythematosus
develop multisystem manifestations after many
years.
Approximately 35% of patients show a positive ANA
test, but antibodies to double-stranded DNA are
rarely present.
Immunofluorescence studies of skin biopsy
specimens show deposition of immunoglobulin and
C3 at the dermoepidermal junction similar to that in
SLE.
Subacute Cutaneous Lupus Erythematosus.
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This condition also presents with predominant skin
involvement and can be distinguished from chronic discoid
lupus erythematosus by several criteria.
The skin rash in this disease tends to be widespread,
superficial, and nonscarring, although scarring lesions
may occur in some patients.
Most patients have mild systemic symptoms consistent
with SLE. Furthermore, there is a strong association with
antibodies to the SS-A antigen and with the HLA-DR3
genotype.
Thus, the term subacute cutaneous lupus erythematosus
seems to define a group intermediate between SLE and
lupus erythematosus localized only to skin.
Drug-Induced Lupus Erythematosus
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A lupus erythematosus–like syndrome may develop
in patients receiving a variety of drugs, including
hydralazine, procainamide, isoniazid, and dpenicillamine, Many of these drugs are associated
with the development of ANAs, but most patients do
not have symptoms of lupus erythematosus.
For example, 80% of patients receiving
procainamide test positive for ANAs, but only one
third of these manifest clinical symptoms, such as
arthralgias, fever, and serositis.
Drug-Induced Lupus Erythematosus,cont.
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Although multiple organs are affected, renal and central
nervous system involvement is distinctly uncommon.
There are serologic and genetic differences from classical
SLE, as well. Antibodies specific for double-stranded DNA
are rare, but there is an extremely high frequency of
antibodies specific for histone
Persons with the HLA-DR4 allele are at a greater risk of
developing lupus erythematosus after administration of
hydralazine.
The disease remits after withdrawal of the offending
drug.
DIFFERENTIAL DIAGNOSIS
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Rheumatic: RA, Sjogren’s
syndrome, systemic sclerosis,
dermatomyositis
Nonrheumatic: HIV, endocarditis,
viral infections, hematologic
malignancies, vasculitis, ITP, other
causes of nephritis
Testing
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The following are useful standard
laboratory studies when SLE is
suspected:
CBC with differential
Serum creatinine
Urinalysis with microscopy
Other laboratory tests that may be used
in the diagnosis of SLE are as follows
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ESR or CRP results
Complement levels
Liver function tests
Spot protein/spot creatinine ratio
Autoantibody tests
PROGNOSIS
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Unpredictable course
The outcome has improved significantly, and an
approximately 90% 5-year and 80% 10-year survival
can be expected
Most SLE patients die from renal failure and infection,
probably related to therapy which suppresses immune
system
Recommend smoking cessation, yearly flu shots,
pneumovax q5years
Refrences
1.
2.
3.
4.
Robbins and Cotran,Pathologic basis of disease,8th edition,2010
http://emedicine.medscape.com/article Updated: Feb 19, 2014
Livingston B, Bonner A, Pope J. Differences in clinical
manifestations between childhood-onset lupus and adult-onset
lupus: a meta-analysis. Lupus. Nov 2011;20(13):1345-55.
[Medline]
American College of Rheumatology. 1997 Update of the 1982
American College of Rheumatology revised criteria for
classification of systemic lupus erythematosus. Available at
http://tinyurl.com/1997SLEcriteria. Accessed March 15, 2012
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