Prof.

Hermansyah
Arthritis in Systemic Lupus
Erythematosus
 History
1948 Malcolm Hargraves discovers the
lupus erythematosus (LE) cell.
1957 The first anti-DNA antibody is
identified.
 Systemic Lupus Erythematosus

Inflammatory autoimmune disease of

unknown etiology
Morbidity
Disease associated
Corticosteroid associated
Corticosteroid use as high as 89% 1-2

Mortality 5-10% at 10 years

Early - active disease and infections
Late - atherosclerosis
1. Zonana-Nacach et al., 2000 2. Urowitz et al., ACR meeting 2000
(Abstract)
 LE Cell
The LE cell is a
neutrophil that has
engulfed the antibody-
coated nucleus of
another neutrophil.
LE cells may appear in
rosettes where there
are several neutrophils
vying for an individual
complement covered
protein.
 Michael Jackson has been diagnosed
with lupus, Fox News is reporting:

*Systemic lupus erythematosus (SLE

or lupus) is a chronic
 Damage within SLE
SLICC/ACR Damage Index1
Overview of Clinical Trial Design
Process

Collaborative process between

Genelabs, FDA and Consultants
1995 Arthritis Advisory Committee
Two efficacy per-patient endpoints
steroid reduction
improved disease activity
1999 Arthritis Advisory Committee
Clinical trial endpoints discussed
Primary Efficacy Endpoint (Responder)

Sustained prednisone
reduction:
Prednisone decreased to 7.5
mg/day
For 2 consecutive months
Including last visit
1) Reduction in Corticosteroid
Requirements
If SLEDAI was stable or improved,
an algorithm dictated steroid taper
2) Improvement or Stabilization of SLE
Based upon improvement or
stabilization in each of SLEDAI,
SLAM, KFSS and Patient VAS,
without clinical deterioration
 Genetic Associations
HLAs are loci on genes that code for
certain chain on the MHC complex
HLA-DR2
HLA-DR3
HLA-DQB1 Involved in mediating
production of antibodies to ds-DNA
 Burden of Disease
Most patients have either recurrent
flares or continuously active disease 1
Flares remain common in established
disease 2
Morbidity also associated with
corticosteroid use 3

1. Barr et al., 1999 ; 2. Petri et al., 1991; 3. Zonana-Nacach, et al., 2000

 Symptoms
Non-specific:
Fatigue
Weight loss
Malaise = generally feeling ill
Fever
Anorexia (over time)
Arthritis
90% of patients experience arthritic symptoms
Symmetrical
Appears in hands, wrists, and knees mainly
 Skin Manifestations
Malar or
Butterfly Rash
Discoid Rash
Stimulated by
UV light
Skin
manifestations
only appear in
30-40% of lupus
patients.
Renal (Kidney) Manifestations
50-70% of all lupus
patients experience
renal developments.
Most Dangerous:
Glomerulonephritis
where at least 50% of
the glomeruli have
cellular proliferation
Glomeruli capillary
beds in the kidney
that filter the blood.
Normal
Renal Failure because
of Glomerulonephritis
is the leading cause of
death among lupus
patients.

Glomerulonephritis
 Other Manifestations
Cardiac
Central Nervous System
Hematological
 Main Pathology
The plasma cells are producing antibodies
that are specific for self proteins, namely
ds-DNA
Overactive B-cells
Suppressed regulatory function in T-cells
Lack of T-cells
Activation of the Complement system
 Overactive B-cells
Estrogen is a stimulator of B-cell activity
Lupus is much more prevalent in females of
ages 15-45
Height of Estrogen production
IL-10, also a B-cell stimulator is in high
concentration in lupus patient serum.
High concentration linked to cell damage
caused by inflammation
 T-cell Malfunctions
Fc region switch

Leads to malfunction in signaling and
decreased IL-2 production
Increased levels of Ca2+
Leads to spontaneous apoptosis
T-cell Signal Transduction
Activation of Complement System

Complement system is activated by

the binding of antibodies to foreign
debris.
In this case its over activation
RBCs lack CR1 receptor
Decreasing the affective removal of
complexes
 IgG Pathogen
IgG is the most pathogenic
because it forms intermediate sized
complexes that can get to the small
places and block them.
 DNA is the Main man
DNA is the main antigen for which
antibodies are formed.
Extracellular DNA has an affinity for
basement membrane where it is
bound by autoantibodies.
Classical thickening of the basement
membrane
 Testing
ESR
Urinalysis
Complement Test
Tests levels of C3, C4, CH50
Low levels indicates possible presence of
disease
FANA Fluorescent antinuclear antibody
Ouchterlony Test shows interactions
 FANA
ELISA Test
Generally test
for:
ds-DNA
antibodies
Antihistone
antibodies
Binds to DNA,
major
constituent of
chromatin
Deoxyribonucleo
protein (DNP)
 Ouchterlony Test
Used to
determine
immunological
specificity
Rules out a false
positive
Shows the serum
does or does not
have antinuclear
antibodies
 Summary
Lupus = Autoimmunity
Systemic and affects connective tissue
Caused by malfunctions of:
T-cells
B-cells
Complement System
Signal Transduction
Can be lethal or not
Unique to each individual