3. • 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%.
INTRODUCTION
5. 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.
6. • 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.
7. 2.. Environmental factors
1. 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.
2. 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.
8. 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.
9. 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.
10. • 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.
11. 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 T-
cell.
• Overproduction of IL-6 and IL-10
• Defective regulatory mechanism.
12. 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.
13. Overview of the pathogenesis of SLE
Skin cell
T cell T cell
B cell
APC
APC
Defective IC clearance
UV light Infection
External AgSelf Ag
Ab
IC
Target
Geneticsusceptibility
15. The clinical spectrum of SLE is very
broad
It make SLE both fascinating but
potentially difficult to diagnose and
manage.
16. 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.
17. • 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.
18. • 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)
20. • 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.
25. • Oral ulcer: Painless sores
in the nose or mouth
need to be observed and
documented by a doctor.
26. 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
29. 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.
30. 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.
32. • 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.
33. 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.
34.
35. 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
37. • 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.
38. 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
39. 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
41. 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.
42. • 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.
44. 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)
45. 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.
46. • 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.
47. • This rim (peripheral )
pattern of linear bright
green staining around the
peripheral of nuclei seen
by immunofluorescence
microscopy with a Hep2
cell substrate .
• dsDNA
50. • 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.
52. 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.
53. 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.
54. • SLE is associated
with a peculiar
periarteriolar
fibrosis in the spleen,
as shown here.
55. Kidney biopsy
• WHO classification of lupus nephritis is
based on light, immunofluorescence, and
electron microscopic findings.
58. 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.
59. DIFFERENTIAL DIAGNOSIS
• Almost too broad to consider given number
of clinical manifestations
• Rheumatic: RA, Sjogren’s syndrome,
systemic sclerosis, dermatomyositis
• Nonrheumatic: HIV, endocarditis, viral
infections, hematologic malignancies,
vasculitis, ITP, other causes of nephritis
• “Overlap Syndrome” (MCTD)
61. Diagnosis
• The diagnosis of SLE is based on a
combination of clinical findings and
laboratory evidence.
• Familiarity with the diagnostic criteria helps
clinicians to recognize SLE and to subclassify
this complex disease based on the pattern of
target-organ manifestations
• .
62. Diagnosis
• The American College of Rheumatology
(ACR) criteria, proposed in 1982 and revised
in 1997, summarize features that may aid in
the diagnosis.
• The presence of 4 of the 11 ACR criteria yields
a sensitivity of 85% and a specificity of 95%
for SLE.
63. 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:
Criteria of the ARA for the classification of SLE
64. 1. Malar rash: Fixed erythema over malar areas, sparing nasolabial folds
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:
Criteria of the ARA for the classification of SLE
65. 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:
Criteria of the ARA for the classification of SLE
66. • When the Systemic Lupus International
Collaborating Clinics (SLICC) group revised
and validated the ACR SLE classification
criteria in 2012, they classified a person as
having SLE in the presence of biopsy-proven
lupus nephritis with ANA or anti–double-
stranded DNA (anti-dsDNA) antibodies or if 4
of the diagnostic criteria, including at least 1
CLINICAL and 1 IMMUNOLOGIC
criterion, have been satisfied.
68. CASE 1
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
71. • THE 4 CRITERIA NOT INCLUDING AT
LEAST 1 IMMUONOLOGICAL
CRITERION
72. 1. URINE ANALYSIS
A) proteinuria 0.6g/24hour B) cellular casts
2. CBC SHOWED PANCYTOPENIA
A) leucopenia B) haemolytic anaemia C) thrombocytopenia
3. RAISED ANTI-DOUBLE-STRANDED DNA
ANTIBODY.
4.POSITIVE ANTINUCLEAR ANTIBODY
CASE 2
83. • RENAL BIOPSY SHOWED LUPUS
NEPHRITIS WITH POSITIVE
IMMUNOLOGICAL CRITERION
FULFILLING (SLICC) REQUIREMENT
FOR DIAGNOSIS
84. LUPUS RELATED SYNDROMES
1- Drug Induced Lupus
– Classically associated with hydralazine,
isoniazid, procainamide
– Male:Female ratio is equal
– Nephritis and CNS abnormalities rare
– Normal complement and no anti-DNA
antibodies
– Symptoms usually resolve with stopping drug
85. LUPUS RELATED SYNDROMES
2- Antiphospholipid Syndrome (APS)
– Hypercoagulability with recurrent thrombosis of either
venous or arterial circulation
– Thrombocytopenia-common
– Pregnancy complication-miscarriage in first trimester
– Lifelong anticoagulation warfarin is currently
recommended for patients with serious complications
due to common recurrence of thrombosis
– Antiphospholipid Antibodies
– Primary when present without other SLE feature.
– Secondary when usual SLE features present
86. LUPUS RELATED SYNDROMES
3- Raynaud’s Syndrome:
-Not part of the diagnostic criteria for SLE
-Does NOT warrant ANA if no other clinical
evidence to suggest autoimmune disease
87. 3-Systemic Lupus Erythematosus
and Pregnancy
• Systemic lupus erythematosus (SLE) is one of the
most common autoimmune disorders that affect
women during their childbearing years. Typical
clinical symptoms of SLE include fatigue, fever,
arthritis, a photosensitive rash, serositis,
Raynaud phenomenon, glomerulonephritis,
vasculitis, and hematologic abnormalities. Flares
of SLE are uncommon during pregnancy and are
often easily treated. The most common symptoms
of these flares include arthritis, rashes , and
fatigue.
88. • SLE increases the risk of spontaneous abortion,
intrauterine fetal death, preeclampsia, intrauterine
growth retardation, and preterm birth. Prognosis
for both mother and child are best when SLE is
quiescent for at least 6 months before the
pregnancy and when the mother’s underlying renal
function is stable and normal or near normal.
Lupus nephritis can get worse during pregnancy.
• The mother’s health and fetal development should
be monitored frequently during pregnancy. In
addition, an obstetrician with experience in high-
risk care should conduct the follow-up of pregnant
women with SLE.
90. 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.
91. 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.
92. 3. Clinical therapy
• There are four main drug groups useful in the
treatment of lupus:
• Non-steroidal anti-inflammatory drugs
(NSAIDs).
• Anti-malarials (Hydroxychloroquine).
• Corticosteroids.
• Cytotoxic drugs.
Immunomodulators (Novel Therapy).
• 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.
93.
94. 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
95. 1- Nonsteroidal Anti-inflammatory
Drugs (NSAIDs)
• Ibuprufen (Advil, Addaprin,……)
• Naproxin (Anaprox,Naprelan,Naprosyn,
…..)
• Diclofenac (Voltaren XR, Cataflam)
• Main mechanism: Inhibition of
prostaglandin synthesis.
• Usually used for relief of mild to moderate
pain.
96. 2-Antimalarials
• Hydroxychloroquine ( Plaquenil )
• This agent inhibits chemotaxis of eosinophils
• locomotion of neutrophils
• Impairs complement-dependent antigen antibody reaction
Dose:
400 mg ( 310 mg base ) PO once or twice daily ;
maintenanance : 200-400 mg (155-310 mg base) PO daily.
with prolonged therapy optain CBCs periodically.
97. 3-Corticosteriods :
used to treat various lupus manifestations
Clinical featureinitial dose of prenisolone
Arthritis (poorly responding to NSAIDs) 20-30mg/d, reducing
pleuritis by about 5mg/wk if
Pericarditis symptoms abate
Haemolytic anemia 1mg/kg/d for about 1M
Thrombocytopenia 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
99. Treatment of certain conditions:
• Antiphospholipid Syndrome
– Anticoagulation with warfarin (teratogenic)
– subcutaneous heparin and aspirin is usual approach in
pregnancy
• Lupus and Pregnancy
– No longer “contraindicated”
– No changes in therapy other than avoiding fetal toxic
drugs
– Complications related to renal failure, antiphospholipid
antibodies, SSA/SSB
104. 1- Belimumab (Benlysta )
• Belimumab inhibits the biological activity of B-
lymphocyte stimulator (BLyS); BLyS is a naturally
occurring protein required for survival and for
development of B-lymphocyte cells into mature plasma B
cells that produce antibodies. In autoimmune diseases,
elevated BLyS levels are thought to contribute to
production of autoantibodies.
• This agent is indicated for active, autoantibody-positive
SLE in patients in whom standard therapy, including
corticosteroids, antimalarials, immunosuppressives, and
nonsteroidal anti-inflammatory drugs, is failing.
105. • Indicated for active, autoantibody-positive lupus (systemic
lupus erythematosus) who are receiving standard therapy,
including corticosteroids, antimalarials,
immunosuppressives, and nonsteroidal anti-inflammatory
drugs
• Limitations of use: Efficacy has not been evaluated in
patients with severe active lupus nephritis or severe active
central nervous system lupus, and has not been studied in
combination with other biologics or IV cyclophosphamide;
not recommended in these situations
• 10 mg/kg IV q2Weeks x3 doses, then q4Weeks thereafter
106. 2-Rituximab ( Rituxan )
• B-cell depletion with rituximab has been used
successfully for rheumatoid arthritis but has
shown mixed results for the treatment of SLE.
One open study using rituximab showed excellent
results as rescue therapy for patients with active
SLE and unresponsive to standard
immunosuppressant therapy.However, a placebo-
controlled study failed to show an overall
significant response
107. • 1000 mg IV infusion, repeat after 2 weeks
(2 infusions separated by 2 weeks is 1
course)
• Repeat course q24weeks or based on
clinical evaluation (but no sooner than 16
weeks)
• Used in combo with methotrexate
• Premedicate with glucocorticoids 30
minutes before infusion to reduce infusion
rxn
• Not to exceed 1000 mg/dose
108. PROGNOSIS
• Unpredictable course
• 10 years survival rates exceed 85%
• Most SLE patients die from infection,
probably related to therapy which
suppresses immune system
• Recommend smoking cessation, yearly flu
shots, pneumovax q5years, and preventive
cancer screening recommendations