Arthritis in Systemic Lupus

Erythematosus
Prof. Hermansyah
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.
Damage within SLE
SLICC/ACR Damage Index1
Damage Index Domain N %

Musculoskeletal 121 22%

Neuropsychiatric 110 20%
Renal 79 15%
Ocular 68 13%
Cardiovascular 47 9%
Pulmonary 39 7%
Skin 45 8%
Peripheral vascular 34 6%
Diabetes mellitus 30 6%
Gastrointestinal 19 4%
Malignancy 14 3%
Premature gonadal failure 12 2%
1. Zonana-Nacach et al., 2000
CLINICAL FEATURES
1. May present with any degree of severity
ranging from acute, rapidly fatal to
insidious chronic disability with
multisystem involvement
2. Fever, malaise and weight loss
commonest presenting findings
3. Less commonly, explosive onset with
seizures, diffuse neurological
symptoms, nephritic/nephrotic picture,
arthritis, polysrerositis or combination of
these
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
• HLA’s are loci on genes that code
for certain β 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
 ARTHRITIS
1. Arthritis commonly involves small joints of the
hands, wrists, elbows, shoulders, knees and
ankles – characteristically transient and may
be migratory
2. Pain more severe than evidenced by objective
changes
3. Arthritis almost never erosive and permanent
deformity rare
4. Osteonecrosis, especially femoral head,
common and worsened by steroid therapy
5. Tendinitis can also occur
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
– ζ  εγ
– 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
• Deoxyribonucleopr
otein (DNP)
Ouchterlony Test
• Used to determine
immunological
specificity
• Rules out a false
positive
• Shows the serum
does or does not
have antinuclear
antibodies
DIAGNOSIS
1. Episodic multisystem constellation
of clinical disease
2. Remember SLE in the d/d of any
child with failure to thrive
3. 11 criteria taken as per American
College of Rheumatology
SEROLOGY
1. ANAs present in most children with
SLE, generally high titre and
homogenous pattern
2. Anti Ro ab a- in neonatal lupus
3. Anti Sm ab diagnostic and correlate with
isolated CNS disease
4. Rheumatoid factors and other antitissue
antibodies such as antithryoglobulin
often positive
5. C4 levels drop more than C3 levels in
active disease
DIFFERENTIAL
DIAGNOSIS
1. Other forms of glomrulonephritis
2. Hemolytic anemia
3. Leukemia
4. Allergic or contact dermatitis
5. Epilepsy, psychoses
6. Acute rheumatic fever with carditis
7. Septicemia
CASE SCENARION
1. Our patient has a positive ANA study
2. Her urine examination is normal
3. Chest XRay is normal
She has leucopenia – TC is 400 c/mm
4. She hence has 4 criteria for SLE – 3 clinical as
mentioned before and positive ANA, hence the
diagnosis of SLE is acceptable
CASE SCENARIO
1. 9 year old girl comes with h/o joint pains since
2 years, non migratory, has been worsening
over the past few weeks, she has transient
swelling
2. Joints involved are both knees, right ankle and
small joints of the hands
3. She has chest pain since 2 days, pleuritic in
nature
4. She has a malar butterfly rash, mild swelling of
both knees but significant pain on movement
5. She has a pleural rub right mammary area
6. Her BP is normal
ANALYSIS
1. Young female child with long standing arthritis
involving both small and large joints with pain
more than objective evidence of joint
involvement suggests SLE arthritis
2. The malar rash and pleuritis goes in favour of
this diagnosis
3. Absence of hypertension suggests that renal
involvement has not occurred
4. She has 3 clinical criteria – arthritis, malar
rash and pleuritis for the diagnosis of SLE
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