Transcript Systemic Lupus Erythematosus Cheng-De Yang

Systemic Lupus Erythematosus
Cheng-De Yang, MD, Ph.D.
The Department of Rheumatology,
Renji Hospital.
INTRODUCTION
•
Systemic Lupus erythematosus ( SLE )
is a syndrome of unknown aetiology
most commonly affecting young women.
Virtually any organ of the body may be
involved .
• Typically the course of the disease is a
series of remissions and exacerbations.
• With good management, the ten years
survival may be over 90%.
Etiology and Pathogenesis of SLE
1. Genetic factor
•
•
•
•
Many studies have described familial
aggregation of SLE. 5-13% of lupus have at
least one first or second degree relative with
lupus
It was found a 24-58% concordance in
monozygotic twins.
2-5% concordance in dizygotic twins or
siblings..
The risk of a child developing lupus born
from a mother (or father) with lupus is
calculated to be 3-4% at worst.
•
What are the reasons of Genetic susceptibility?
1. It seems likely that most of the genes
predisposing to SLE are normal.
2. An individual inherits an unlucky combination
of normal genetic polymorphisms, each of
which permit a little immune overreponse, or
presentation of high quantities of target
antigens in certain tissues. The combination of
which is just enough to permit SLE to evolve
after some environmental stimulus.
3. C2, C4, C1q deficiencies, DR2, DR3, 1q41-42
region, Fc-r RIIA, IL10 and Bcl
polymorphisms.
2. Environmental factors
1.
2.
UV light, especially UVB, flares SLE in most patients. It is
unclear whether exposure to UV light can initiate the lupus,
but onset after a sunburn is not unusual. There is good
evidence that exposure of skin to UV light alters the
location and chemistry of DNA as well as the availability of
Ro and RNP antigens.
Drug-induced lupus. Drugs ( hydralazine, procainamide,
beta-blokers, isoniazid, penicillamine) can induce lupus.
Drug-induce lupus may resemble SLE both clinically and
serologically. Usually the disease is mild, and renal and
neurological complications are rare. Generally, lupus that
is caused by a drug exposure goes away once the drug is
stopped.
3. Allergy. Does it induce lupus flare? No direct
evidence.
4. Infection. There has been continuing interest in
the possibility that infectious agents might initiate
or flare SLE. Mechanism might include
molecular mimicry between external Ag and a
self-Ag, epitope spreading, nonspecific activation
of T or B cells. There has been recent interest in
EB, CMV and other virus.
3. Sex hormones
• Female : Male=9:1
• The sex difference is most prominent during
the female reproductive years.
• In mice, castrating females and /or
providing androgens or antiestrogens
protects from disease,whereas castrating
males and providing estrogens accelerates
and worsens SLE.
• The metabolish of sex hormone is abnormal
in some lupus patients. Men and women
with lupus metabolized testosterone more
rapidly than normal, and estrogenic
metabolites of estradial persist longer in
women.
• Neuroendocrine system.
Hyperprolactinemia, abnormalities in
hypothalamic and/or pituitary function.
4. Abnormal immune system
• Sustained presence of autoantigens: increased
apoptosis , impaired clearance of apoptosis
• Hyperactivity in B and T lymphocyte.
• Increased expression of surface molecules
participating in cell activation in both B- and Tcell.
• Overproduction of IL-6 and IL-10
• Defective regulatory mechanism.
Autoantibodies to DNA, RNA, and a host
of other cell nucleus antigens.
Circulating immune complexes are
frequently observed and these may deposit
in the kidney, skin, brain, lung, and other
tissues. It causes inflammation and tissue
damage by a number of mechanism,
notably fixation and activation of the
complement system.
Overview of the pathogenesis of SLE
Infection
UV light
Self Ag
External Ag
Skin cell
Genetic susceptibility
APC
T cell
T cell
IC
APC
Defective IC clearance
B cell
Ab
Target
Clinical manifestations of SLE
The clinical spectrum of SLE is very
broad
It make SLE both fascinating but
potentially difficult to diagnose and
manage.
General symptoms
•
The most common symptoms listed as initial
complaints are fatigue, fever, and weight loss.
Fever: fever secondary to active disease was
recorded from 50% to 86%. No fever curve or
pattern is characteristic. It can be difficult, but
very important to distinguish the fever of SLE
from that caused by complicating infections.
• Fatigue is common in patients with SLE,
especially during periods of disease activity.
It is also often the only symptom that
remains after treatment of acute flares.
Low grade fever, anemia, or any source of
inflammation can result in fatigue.
• Raynaud’s phenomenon
is commonly found in
lupus. It lack specificity.
(a triphasic reaction of distal
digits to cold or emotion, in
which the skin colour
changes from white to blue
to red)
Dermatological involvement
•
•
•
•
•
•
•
•
•
•
Up to 85% of SLE
Butterfly rash
Maculopapular eruption
Discoid lupus
Relapsing nodular non-suppurative
panniculitis
Vasculitic skin lesin
Livedo reticularis
Purpuric lesions
Alopecia
Oral ulcer
• Malar rash: This is a
"butterfly-shaped" red
rash over the cheeks
below the eyes and
across the bridge of the
nose. It may be a flat or
a raised rash.
The rashes are made
worse by sun exposure.
• Maculopapular
eruption
• Discoid lupus
These are red, raised
patches with scaling of
the overlying skin.
• Vasculitic skin lesin
• Alopecia
• Oral ulcer: Painless sores
in the nose or mouth
need to be observed and
documented by a doctor.
Musculoskeletal system
• The arthritis of lupus is usually found on both
sides of the body and does not cause deformity of
the joints. Swelling and tenderness must be
present.
• The most frequently involved joints are those of
the hand, knees, and wrists.
• People with lupus can suffer from a certain type
of low blood flow injury to a joint causing death
of the bone in the joint.
• The muscle involvement was reported in 30-50%
of lupus patients
• Avacular necrosis of
bone.
It may be caused by
prednisone therapy
Kidney system
• Haematuria
• Proteinure (>0.5g protein/d or 3+ )
• Cast
Nervous system
• The brain , nerve problems and psychiatric syndromes
are common in lupus affecting up to two-thirds of
people.
• Potential disorders include seizures, nerve paralysis,
severe depression, and even psychosis.
• Spinal cord involvement in lupus is rare and occurs
primarily when there is clot formation in a critical
vessel that supplies blood to the spinal cord.
Hematological abnormalities
• Red blood cells
a normochromic, normocytic anemia is
frequently found in SLE. They appears to be
related to chronic inflammation, drug-related
haemorrhage.
haemolytic anemia as detected by the Coombs’
test is the feature of SLE.
on rare occasion, a serum antibody may be
produced which impairs red cell production.
• Platelets.
thrombocytopenia (<100*109/L) appears to be
mediated by anti-platelet antibodies or/and
anti-phospholipid antibodies.
• White blood cell
leucopenia (<4.0*109/L), its cause is probably
a combination of destruction of white cells by
autoantibodies, decreased marrow production,
increased or marginal splenic pooling, and
complement activation.
it should also noted that the
immunosuppressive drugs used in the
treatment of SLE may cause a marked
leucopenia.
Pulmonary manifestations
• Pleurisy
it is the most common manifestation of
pulmonary involvement of SLE. The volume of
pleural effusions usually is small to moderate
and maybe unilateral or bilateral. Large
pleural effusion are uncommon. It usually
exudative in character.
Pleural effusions may also occur in SLE patients with
nephrotic syndrome, infection, cardiac failure.
• Lung
1) acute lupus pneumonitis: fever, dyspnea,
cough with scanty sputum, hemoptysis,
tachypnea and pleuritic chest pain.
2) pulmonary hemorrhage
3) chronic diffuse interstitial lung disease.
the diagnosis should not be made until infectious
processes such as viral pneumonia, tuberculosis, and
other bacterial, fungal and pneumocystis carinii
infection have been completely excluded.
Cardiovascular manifestations
• Pericarditis is the most common cardiac
manifestation of SLE.
• Myocarditis (the clinical features of lupus
myocarditis resembles that of viral myocarditis)
• Libman-Sacks endocarditis and valvular disease
• Hypertension, cardiac failure
• Pericarditis
• SLE can be associated
with endocarditis.
Shown here is
Libman-Sacks
endocarditis in which
there are many flat,
reddish-tan
vegetations spreading
over the mitral valve
and chordae.
Gastrointestinal and hepatic manifestation
• Esophagitis, dysphagia, nausea, vomiting:
(drug related in most cases)
• Chronic intestinal pseudo-obstruction,
mesenteric vasculitis, protein-losing
enteropathy
• Pancreatitis
• Lupus hepatitis
Eyes
• The eyes are rarely involved in lupus
except for the retina. People with lupus
often have to be screened by an
ophthalmologist if they are taking the
antimalarial drugs chloroquine or
hydroxychloroquine
Secondary sjogren’s syndrome
• Dry eyes
• Dry mouth
exocrine glands were infiltrated with
lymphocytes
Secondary Antiphospholipid syndrome
• Antiphospholipid syndrome (APS) is
characterized by recurrent arterial and /or
venous thrombosis, fetal loss and
thrombocytopenia. High titer of
Antiphospholipid antibody can be found in
APS patients.
• Deep venous thrombosis
(blood clot). Notice the
contrast between the
involved left leg and the
normal right leg. Redness,
swelling, and warmth
combined with discomfort
in the involved leg are
cardinal manifestations of
a deep venous thrombosis.
Laboratory investigation
Autoantibodies in SLE
• Antibodies to cell nucleus component
ANA, anti-dsDNA, antibodies to extracellular nuclear
antigen (ENA, anti-Sm, anti-RNP, anti-Jo1)
• Antibodies to cytoplasmic antigens
anti-SSA, anti-SSB
• Cell-specific autoantibodies
lymphocytotoxic antibodies, anti-neurone antibodies,
anti-erythrocyte antibodies, anti-platelet antibodies
• Antibodies to serum components
antiphospholipid antibody
anticoagulants antiglobulin (rheumatoid factor)
Anti-nuclear antibodies
• The lupus erythematosus
(LE) cell
it has been superseded by
the ANA and anti-dsDNA
techniques.
• ANA is a screening test
anti-Sm, anti-dsDNA
antibodies are lupus
specific antoantibodies.
• This homogenous pattern
of diffuse bright green
staining of nuclei seen by
immunofluorescence
microscopy with a Hep2
cell substrate is called
homogenous, and is the
most common pattern with
autoimmune diseases
overall.
• This rim (peripheral )
pattern of linear bright
green staining around the
peripheral of nuclei seen
by immunofluorescence
microscopy with a Hep2
cell substrate .
• dsDNA
• Nucleolar pattern
• Speckled pattern
Scl70, SSA, SSB, Sm
• These little Crithidia
organisms have a small
kinetoplast between the
nucleus and the flagella
which glows bright green
under
immunofluorescence
microscopy, and is
indicative of anti-native
DNA antibody that is very
specific for SLE.
• Immu-blotting method
to detect anti-Sm, RNP,
SSA, SSB, Jo1, Scl70
and ribosomal P.
Lupus band test
• Immunofluorescence of skin
with antibody to IgG
demonstrates a band-like
deposition of immune
complexes that is bright green
at the dermal epidermal
junction in this skin biopsy
taken from an area with a
visible rash. With SLE such
deposition can be found in skin
uninvolved by a rash, whereas
with DLE the immune
complexes are found only in
involved skin.
Vasculitis
• Vasculitis in arteries
throughout the body
can account for signs
and symptoms from a
variety of organ
involvements. Seen
here is an artery with
extensive vasculitis
with chronic
inflammatory cells.
• SLE is associated
with a peculiar
periarteriolar
fibrosis in the spleen,
as shown here.
Kidney biopsy
• WHO classification of lupus nephritis is
based on light, immunofluorescence, and
electron microscopic findings.
WHO classification of lupus nephritis
immunofluorence
Pattern
mesangial
Ⅰnormal
ⅡA mesangial deposit
ⅡB mesangial hypercellularity
Ⅲ focal segmental GN
Ⅳ diffuse GN
Ⅴ membranous GN
peripheral
electron microscopy
mesangial
subendothelial subepithelial
0
0
0
0
0
+
0
+
0
0
+
0
+
0
0
++
+
++
+
+
++
++
++
++
+
+
++
+
+
++
Semiquantitative assessment of activity and chronicity
• Active indicators
cellular proliferation, necrosis, karyorrhexis,
cellular crescents, wire loops, hyaline thrombi,
leukocytic infiltration, interstitial infiltration.
• Chronicity indicators
glomerular sclerosis, fibrous crescents, interstitial
fibrosis, tubular atrophy
Indicators are scored on a scale of 0 to 3,with necrosis, karyorrhexis,
and cellular crescents weighted two times. The maximum of activity
is 24, and the maximum of chronicity is 12.
Diagnosis
Criteria for diagnosing lupus
• The diagnosis of lupus is a clinical one
made by observing symptoms. Lab tests
provide only a part of the picture. The
American College of Rheumatology has
designated 11 criteria for diagnosis. To
receive the diagnosis of lupus, a person
must have 4 or more of these criteria:
Criteria of the ARA for the classification of SLE
1. Malar rash:
Fixed erythema over malar areas, sparing nasolabial folds
2. Discoid rash: Erythematous raised patches with keratotic scaling and follicular plugging
3. Photosensitivity: Skin rash after exposure to sunlight, history or physical exam
4. Oral ulcers: Oral or nasopharyngeal, painless, by physical exam
5. Arthritis:Tenderness, swelling, effusion in 2 or more peripheral joints
6. Serositis: A) pleuritis or B) pericarditis
7. Renal disorder A) proteinuria>0.5g/24hour or 3+ or B) cellular casts
8. Neurological disorder: A) seizures or B) psychiatric disorder (having excluded other
causes, e.g. drigs)
9. Haematological disorder: A) haemolytic anaemia or B) leucopenia or C)
thrombocytopenia
10. Immunologic disorder: A) positive LE cells or B) raised anti-native DNA antibdy
binding or C) anti-Sm antibody or D) false positive serological test for syphilis.
11. Positive antinuclear antibody:
Management and treatment
1. Monitoring the lupus patients
• It cannot be emphasized too strongly that
lupus is a disease requiring regular and
careful follow-up.
• Important initial advice should be given
about avoiding UV light, infections,
extreme stress or fatigue
• Laboratory test—blood test, ESR, C3,IC,
liver function tests and anti-dsDNA.
2. Grading clinical activity
• The highly variable nature of the
syndrome
• Evaluation of lupus activity is the base or
beginning of therapy.
• Non-life-threatening features such as
arthralgia, skin rash, RP, alopecia
• Severe complication such as renal,
cerebral and heart involvement.
SLE disease activity index (SLEDAI)
Clinical feature
seizure , psychosis , organ brain syndrome
visual disturbance, cranial nerve disorder
lupus headache, cerebrovascular accidents,
vasculitis
arthritis
myositis
urinary casts, hematuria, proteinure, pyuria
rash, alopecia, mucosal ulcers,
pleurisy, pericarditis
low complement, increased DNA binding
fever
thrombocytopenia, leucopenia
score
8
8
8
8
4
4
4
2
2
2
1
1
3. Clinical therapy
• There are four main groups drugs useful in the
treatment of lupus: the non-steroid antiinflammatory drugs, anti-malarials,
corticosteroid and cytotoxic drugs.
• How to treat lupus is a kind of art. Which and
the dosage of drugs will be used to treat the
patient depend on lupus activity.
Mildly active lupus
• It can be managed with combination of
NSAID and / or anti-malarials.
• Prednisolone remain the drugs of first
choice to control lupus activity.
Low dosage <=10mg/d can be used
Use of corticosteriod to treat various lupus manifestation
Clinical featureinitial
Arthritis (poorly responding to NSAIDs)
pleuritis
Pericarditis
dose of prenisolone
20-30mg/d, reducing
by about 5mg/wk if
symptoms abate
Haemolytic anemia
Thrombocytopenia
1mg/kg/d for about 1M
reduce by 10mg/d if
blood tests improve
Nephritis
1mg/kg/d for about 1M
Neuropsychiatric
controversal!
1-2mg/kg/d,
0.5-1g/d methylprednisolone
Other therapy
•
•
•
•
Plasma exchange
Intravenous Immunoglobulin
Stem cell transplantation
Immune therapy ( anti-IL10, anti-CD20,
and immune tolerance therapy)
SLE and pregnancy
• SLE has been stable for more than 1 year.
• Prednisone is no more than 10mg/d, and
cytotoxic drug has been stopped for more
than 6 moth.
SLE patients can plan to have a baby.
Thanks