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17 Auto-Immune Disease: Systemic Rheumatic Disease

Generalities
Presence of one or more auto-antibodies
Directed against: membrane, cytoplasm, nucleus
ANA: hallmark of SRD
Many of the diseases have distinctive profiles of
auto-antibodies with diagnostic specificities
Inflammatory process: non-infectious in nature

Criteria for SLE diagnosis


Definite: A person shall be said to have SLE if any 4
(or more) of the 11 criteria are present, serially or
simultaneously, during any interval of observation
(definite)
Probable: 3
Possible: 2

Systemic Rheumatic Diseases


Systemic Lupus Erythematosus
Sjogrens Syndrome
Progressive Systemic Sclerosis
Rheumatoid Arthritis
Mixed Connective Tissue Disease
Polymyositis

ANA (anti-nuclear antibody)


Initial screening test for SLE..
A (-) test with a confirmed clinical diagnosis does not
rule out SLE
Therefore, not specific for SLE
Sensitive in detecting SLE, about 95%

(other A-I diseases:

AS, MG, GS, GD, HT, Type I DM)

Systemic Lupus Erythematosus


Clinical manifestation: protean
Primarily pathology: vasculitis, multi-organ
involvement but NON organ specific
Tissue injury: mediated primarily by immune complex
deposition
Female : male 10:1 (20-40 years of age)
Polyclonal B cell activation
1st degree relatives: 200x greater than in the general
population
Diagnostic Criteria for SLE (1997 updated)
1. Malar rash (40% of patients)
2. Discoid rash
3. Photosensitivity
4. Oral ulcers
5. Non-erosive arthritis
6. Serositis (pleuritis or pericarditis)
7. Renal disorder (persistent proteinuria)
8. Neurologic disorder
9. Hematologic disorder*
10. Immunologic disorder*
11. Positive antinuclear antibody*
NB. For the diagnosis of SLE, there should be four or more
of the above criteria
Hematologic Disorder*
a. Hemolytic anemia with reticulocytosis or
b. Leukopenia <4000/mm3 on > 2 occ
or
c. Lymphopenia <1500/mm3 on > 2 occ or
d. Thrombocytopenia <100,000/mm3
(in the absence of offending drug)
Immunologic Disorder*
a. Anti-DNA in abnormal titer
or
b. Anti-Smith (Sm nuclear Ag)
or
c. Positive finding of anti-phospholipid antibody based
on:
1. Anti-cardiolipin IgG or IgM
2. Lupus anticoagulant
3. False (+) test for syphilis (to be confirmed)

NB: (+) LE cell prep & (+) ANA test : SLE is strongly
suspected
Anti-dsDNA (native)
Confirmatory test for SLE (about 2/3 of patients)
Also: to monitor SLE patients in response to therapy
Reference level: <25 IU/mL (considered negative for
SLE)
NB: Increased also in: chronic hepatitis, infectious
mononucleosis, biliary cirrhosis
Auto-antibodies in SLE
ANA
Anti-ds-DNA
Anti-Sm
Anti-leukocyte antibody
Anti-phospholipid antibody (lupus anticoagulant)
Believed to affect the coagulation cascade
o
by interfering with anti-coagulation factors,
as a result, the patient has a tendency to
form clots
ANA Fluorescent pattern
Homogenous - antideoxynucleoprotein
Peripheral - anti-ds-DNA
Nuclear membrane - DNA
Speckled - anti-ss-DNA
Pseudo ACA - anti-histone
Anticentromere - anti-Smith
Nucleolar - anti-RNP
Cytoplasmic - anti-nucleolar
Anti-nuclear lamins - anti-Scl-70
Anti-ribosomal - anti-proliferating nuclear Ag
Anti-centriole/centrosome/midbody - anti-mitotic
spindle
Mitotic spindle - anti-SS-A, SS-B, SS-C
Prognosis
-

In general: very good


100% - 5 yrs; 83% - 10 yrs
Mx: constant monitoring

rainwater@mymelody.com || 1st semester, AY 2011-2012

Polymyositis
Primarily affects females (young to late middle age)
Clinically: muscle weakness with pain & tenderness
(shoulders, hips, neck)
Characterized by: inflammatory infiltrates in skeletal
muscle with necrosis & degeneration
NB: Dermatomyositis: when accompanied by skin changes
(maculo-papular or eczema-like skin lesion)
Serologically - presence of a number of auto-antibodies
directed against different tRNA synthetases
E.g., Antibodies to:
o
Jo-1 (histidyl tRNA synthetase) most
frequently detected
o
Threonyl & alanyl tRNA synthetase
Anti-PM-Scl (specific) also known as PM-1
o
Laboratory Findings
Increase in ESR (correlates with disease activity)
Increased in CPK (MM & MB) & aldolase (reflect
muscle injury & disease activity)
LDH & AST usually elevated
Increase LDH2 to LDH5 (esp LDH5): (indicates active
muscle necrosis)
Muscle biopsy: inflammation & muscle degeneration
& regeneration
Scleroderma
Antigen is not known
Female: male 3:1 (20-60y/o)
Most common symptom: Raynauds phenomenon*
(90% of patients)
CREST syndrome: milder form of scleroderma
Primarily: skin, but can lead to multi-organ
involvement (GIT, heart, lung, etc.)
NB: Scl-70: an ANA, 15-20%
-

Spontaneous production of auto-antibodies against:


nucleus, nucleolus, mitochondria
With rapidly progressive & diffuse cutaneous
involvement: at greater risk of developing early
visceral involvement
Skin fibroblasts reproduce faster & secrete more
collagen

NB: 40% of death: malignant hypertension & renal failure


Pathogenesis
Immune complex-mediated injury to small blood vessels &
capillaries vascular occlusion decreased blood flow
injury to surrounding connective tissues stimulating
fibroblast proliferation increased collagen deposition
NB: 20-30 % of all scleroderma patients have CREST syndrome:
Calcinosis cutis
Raynauds phenomenon
Esophageal dysmotility
Sclerodactyly
Telangiectasia

Anti-Centromere Antibody
Very high percentage in patients with CREST
syndrome, (a variant, and milder form of
scleroderma)
Present only in a small minority of patients with
Scleroderma
Anti-Scleroderma Ab (Scl-70)
Diagnostic for scleroderma, present in 20-30% of
patients
Occasionally seen in: SLE, MCTD, SS, RA, Polymyositis
Increased levels in: INH, methyldopa, penicillin,
streptomycin, tetracycline, aspirin & propylthiouracil
usage
NB: Positive also for CREST syndrome
Sjogrens Syndrome
Most often occurs secondary to RA, SLE, scleroderma,
polymyositis
Partial or complete destruction of the salivary
&lacrimal glands by lymphocytes & plasma cells
In its primary form: manifested as
Keratoconjunctivitis sicca
o
o
Xerostomia
NB: Presence of RF & ANA , indicative of a systemic
disease
Antigenic alteration of salivary gland tissue sensitization,
lymphocytic infiltration, production of auto-antibodies against
the salivary & lacrimal glands damage
-

Biopsy: affected salivary or lacrimal glands are


infiltrated with aggregates of lymphocytes
Occurs primarily after age 45, with female to male
ratio of 10:1
Can affect any of the bodys glands that produce
sweat, saliva or oil
Often associated with:RA, SLE, PBC, scleroderma
HLA: HLA-DR3

NB: Extra-glandular manifestations: lymphadenopathy,


cutaneous vasculitis, interstitial pneumonitis, etc.
Classification
Primary SS not associated with other CTD
Secondary SS associated with other CTD eg. RA, SLE
NB: Auto-antibodies in SS are usually restricted to
SS-A (Ro) & SS-B (La) Ag
Anti SS-A (Ro) & Anti SS-B (La)
Produced in Sjogrens syndrome
Anti SS-A found in about 60-70% of pts with primary SS
Anti SS-B found in about 50-60% of pts with primary SS
NB: Also increased in:
o
Scleroderma
ANA (-) lupus
o
o
Neonatal lupus

rainwater@mymelody.com || 1st semester, AY 2011-2012

Mixed Connective Tissue Disease


Initially reported in 1972
20 patients: initially reported
Characterized by combined clinical features of:
SLE, RA, scleroderma, polymyositis
Serologically high titer of auto-antibodies to a nuclear
RNP (in all of the patients)
The concept of MCTD as a separate group has
changed with time
Consensus: MCTD represents an overlap of:
systemic sclerosis, SLE, & polymyositis

Autoantibody Markers associated with RA


Rheumatoid Factor (RF) - directed against the Fc
portion of the IgG molecule; not specific for RA
Anti-keratin antibody (AKA) - a fairly specific but not
very sensitive marker for RA
Anti-perinuclear factor (APF) - a sensitive but less
specific than AKA in RA patients
Antibody to RA-associated Nuclear Antigen (RANA)
(Anti RANA) - was demonstrated in SS patients
associated with RA
Anti RA 33 - highly specific for RA

NB: A group of patients originally diagnosed as MCTD


eventually evolved to one disease: scleroderma being
the most prevalent

NB: The first 3 (and possibly anti-RA33) may precede the


onset of clinical RA

Anti-Nuclear RNP
One of the 4 anti-ENA (SS-A, SS-B and Smith)
Increased in: MCTD, SLE, discoid lupus
Antigens consist of RNA & protein
Rheumatoid Arthritis
Chronic, symmetric, erosive arthritis of the peripheral
joints
Female to male ratio 3:1 (30-50 years of age)
All patients: morning stiffness & joint pains that
improves through the day
Excessive production of Type 1 cytokines
RF: IgM (or IgG/IgA) to the Fc portion of IgG (these
are not specific but may enhance immune complexes)

Diagnostic Methods in Autoantibody Detection


Method
Antigen
Sensitivity Use
IF
Tissue, cell lines
Sensitive, screen
DI
Tissue, cell extract
High specificity
CIE
Tissue, cell extract
Higher sensitivity
IB
Cell extract
Very sensitive
ELISA
Purified Ag
Very sensitive

NB: Rheumatoid Factors: abnormal group of proteins that


interact specifically with the Fc portion of the Ig
molecule
-

SS & Feltys syndrome: commonly occur with RA


Most patients: have the major histo-compatibility
complex (MHC) Class II alleles DR 4, DR 1 (or both)

NB: Antigen is not known


Pathogenesis
Unknown antigenic stimulus synovial tissue in
susceptible patient (+) IgG production reacts with
unknown antigen altered & unrecognized as self
formation of IgM (RF) which becomes the antibody against
the altered IgG (+) soluble immune complexes in
synovium activation of complement system
chemotactic factors (+) leukocytes leukocytes ingest
immune complexes triggers enzymes (e.g. colagenase) &
mediators of inflammation inflammation of synovial
lining intermittent course or proliferative synovitis
bone-cartilage erosion or tendon destruction
permanent joint damage

rainwater@mymelody.com || 1st semester, AY 2011-2012