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17 Auto-Immune Disease: Systemic Rheumatic Disease

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
Probable: 3
Possible: 2

Systemic Rheumatic Diseases

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

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
Female : male 10:1 (20-40 years of age)
Polyclonal B cell activation
1st degree relatives: 200x greater than in the general
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
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
b. Anti-Smith (Sm nuclear Ag)
c. Positive finding of anti-phospholipid antibody based
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
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
NB: Increased also in: chronic hepatitis, infectious
mononucleosis, biliary cirrhosis
Auto-antibodies in SLE
Anti-leukocyte antibody
Anti-phospholipid antibody (lupus anticoagulant)
Believed to affect the coagulation cascade
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
Mitotic spindle - anti-SS-A, SS-B, SS-C

In general: very good

100% - 5 yrs; 83% - 10 yrs
Mx: constant monitoring || 1st semester, AY 2011-2012

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:
Jo-1 (histidyl tRNA synthetase) most
frequently detected
Threonyl & alanyl tRNA synthetase
Anti-PM-Scl (specific) also known as PM-1
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
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

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

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

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

NB: Extra-glandular manifestations: lymphadenopathy,

cutaneous vasculitis, interstitial pneumonitis, etc.
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:
ANA (-) lupus
Neonatal lupus || 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
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

Sensitivity Use
Tissue, cell lines
Sensitive, screen
Tissue, cell extract
High specificity
Tissue, cell extract
Higher sensitivity
Cell extract
Very sensitive
Purified Ag
Very sensitive

NB: Rheumatoid Factors: abnormal group of proteins that

interact specifically with the Fc portion of the Ig

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

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 || 1st semester, AY 2011-2012