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Dr Elsa van Duuren
FCPSA
May 2012
The adaptive immune system produces antibodies in reaction to antigenic stimuli
We continually produce antibodies against self molecules
IgM,
Weak avidity molecules that cross react with multiple antigens
Autoimmune disease:
Pathogenic autoantibodies produced
High avidity IgG bind specific antigens
Form immune complexes
Defective immune complex clearing
Defective regulation of Ig formation
Persistance
Systemic autoimmune diseases
Widespread deposition of immune complexes and subsequent inflammatory processes
Systemic Lupus Erythematosus
Antiphospholipid antibody syndrome
Scleroderma
Polymyositis/ dermatomyositis
Sjögren syndrome
Mixed connective tissue disease
Rheumatoid arthritis
Vasculitidies
There are no single characteristic features
Common clinical features
Diagnostic or classification criteria
ACR criteria (American Center of Rheumatology, former American Rheumatism Association, ARA)
European criteria
Criteria of single authors/author groups
Prevalence: Percentage of patients in the population
Incidence: New patients per 100,000 population and per year
Disease Prevalence Incidence
Rheumatoid Arthritis 1-3% ca. 30
SLE 0.04-0.05% 6-8
Scleroderma - 0.3-0.4
Polymyositis/Dermatomyositis - 0.2-0.5
Sjögren‘s Syndrome 0.3-1% -
Serological tests are used to further evaluate a patient with a clinical picture of a connective tissue disease
To confirm a specific diagnosis
To guide appropriate management
Assess disease activity (seldom)
Sensitivity
Specificity
Positive or negative predictive value
The likelihood that a patient with a particular clinical picture will have a positive serologic test result
A specific test is more likely to identify a patient with a disease and exclude someone without the disease
A test with a high specificity can rule in/ not rule out a disease
A positive test result provides additional confirmation that the disease is present
Proportion of patients that will test positive or negative who do or do not have the disease
ANA (antinuclear ANTIBODIES)
general name for all autoantibodies which react with nuclear antigens
ANA, anti dsDNA, centromere proteins and histones
ENA (extractable nuclear ANTIGENS)
can be eluted by salt extraction
Sm, U1-snRNP, Ro/SS-A, La/SS-B, Jo-1, Scl-70, PM-1, Mi-2 and Ku
The most popular screening test for ANA is the indirect immunofluorescence assay (IFA) using HEp-2 cells as substrate.
•Detects all ANA with high sensitivity (except for e.g. Ro, Jo1 and Rib-P antibodies).
•Results shown in a certain pattern.
•Staining pattern lacks specificity due to overlap between patterns and diseases
•More specific antibody tests have overtaken staining pattern
A Homogeneous
B Coarse speckled
C Polymorphic
D Centromere
E Multiple nuclear dots
F Nucleolar
G Fine speckled
H Cytoplasm, fine speckled
I Cytoplasm, fine speckled to homogeneous
Pattern target antigen disease association A homogeneous dsDNA SLE
Histones drug-induced SLE
B coarse speckled U1RNP MCTD Sm SLE
C polymorphic PCNA SLE
D centromere CENP CREST, SSc
F nucleolar PM-Scl SSc, PM, Overlap Fibrillarin SSc RNA-Pol III SSc
G fine speckled Ro/SS-A SS, SLE La/SS-B SS, SLE Scl-70 SSc Mi-2 DM
H, I cytoplasm Jo-1 PM/DM Rib-P SLE SRP PM/DM
an
d m
ore ?
Even high titres (1:640) have only a positive predictive value of 35% for connective tissue diseases (CTDs).
ANA in IFA have a predictive value of 11% for SLE and 11% for other CTDs.
4 of 5 ANA positive results cannot be traced back to antigens with known clinical relevance.
IFA results have only a limited clinical usefulness for the doctors
Various autoimmune diseases Connective tissue diseases (CTD) Autoimmune hepatitis Primary biliary cirrhosis Rheumatoid arthritis Addison’s disease Hashimoto thyroiditis Type 1 diabetes mellitus
Non-autoimmune diseases Cancer Gastrointestinal diseases Lung diseases Skin diseases Infections
• ANA are not very specific for certain diseases
• Mainly used to support diagnosis of CTDs
•Healthy population:
• titre 1:40 32%
• titre 1:80 13%
• titre 1:160 5%
• Antibodies directed against small ribonuclear proteins that play a role in mRNA splicing
• Highly specific
• Appropriate to test for in a patient:
• ANA positive + features of a specific CTD
• ANA negative + known CTD
• For diagnostic confirmation
• Do not exclude a specific CTD
• Do not correlate with disease activity and may be found in patients without active disease
• Skin and mucous membranes • Synovium (joints) • Serosal membranes • Kidneys • Central nervous system • Lungs • Heart • Hematopoietic system • Constitutional symptoms:
• Fever, Fatigue, weight loss
Any part of the skin can be involved:
Epidermis
Dermis
Sub-dermal fat
Nailfold capillary
Inflammation
Infarction
Diffuse
Localised
Central nervous system Epilepsy Hemiparesis Cranial nerve lesions Brain stem/ cord lesions Aseptic meningitis Transverse myelitis
Peripheral nervous system Peripheral neuropathies Myasthenia gravis Mononeuritis multiplex
Psychiatric Disorders of mental function
1. Malar rash
2. Discoid rash
3. Photosensitivity
4. Oral ulcers
5. Arthritis
6. Serositis
7. Renal disorder
8. Neurologic
disorder
9. Hematologic
disorder
10. Immunologic
disorder
11. Antinuclear
Antibody
Updating the American College of Rheumatology revised criteria for the classification of
systemic lupus erythematosus, Hochberg MC, Arthritis Rheum 1997, 40: 1725
a) Anti-dsDNA
or
b) Anti-Sm
or
c) Positive finding of
antiphospholipid antibodies
based on:
1. An abnormal serum level of
IgG or IgM anticardiolipin
antibodies
or
2. A positive test result for
lupus anticoagluant using a
standard method
or
3. A false positive serologic
test for syphilis, known to be
positive for at least 6 months
Any of four or more
criteria should be
present, serially or
simultaneously.
> 4 criteria positive: 96
% SLE
• Usually seen in women of childbearing age with: • Constitutional symptoms of fever, weight loss,
malaise, and severe fatigue
• Skin rash and/or stomatitis
• Arthritis
• Renal disease
• Cytopenias
• Although 90% of patients are female, SLE can be seen at any age in either sex
• ANA
• Abnormal titer >1:160
• Clinically significant
• High sensitivity: 93%
• Seen in 95% of SLE
• Not specific for SLE
• Specificity 57%
• Anti-ds DNA
• Seen in 60% of patients with SLE
• Highly specific for SLE
• Low titer rarely seen in other inflammatory conditions
• Strongest clinical association is with nephritis
• Anti-Sm antibodies
• Seen in 10% to 30% of SLE patients
• Highly specific for SLE
Antigen: Phosphoproteins P0 (38 kDa), P1 (19 kDa) and P2 (17 kDa) of the 60S subunit of the ribosomal complex.
Possibly linked to neuropsychiatric manifestations and liver manifestatinos
Highly specific for SLE
SLE 10-20%
Antigens: Histones plus DNA plus other DNA-binding proteins
Is said to be specific for SLE, but data are controversial (question of belief)
Doubtful clinical relevance
Disease Antibody Prevalence
SLE dsDNA
Sm
Rib-P
PCNA
Other:
Phospholipid
Ro/SS-A
La/SS-B
U1-snRNP
C1q
Histone
50-80 % (ACR criterion)
5-30 % (ACR criterion)
10-20 %
2-10 %
40-60 % (SLE with secondary Antiphospholipid
syndrome)
25-60 % (neonatal LE, SLE with limited organ
involvement, SCLE)
19-30 % (SLE with limited organ involvement, SCLE)
13-32 %
Antihistone antibody test:
Sensitive, but non-specific
Positive in 95% of patients with drug induced SLE
Negative result makes drug induced SLE less likely
Also positive in 50% patients with SLE
Most patients asymptomatic
To make diagnosis:
Drug use
High titer ANA, antihistone ab
Negative dsDNA ab
Clinical picture of SLE
Can occur as a primary syndrome or secondary to SLE
Highly variable clinical picture
From benign to the catastrophic antiphospholipid syndrome
Clinical picture due to recurrent venous or arterial thrombosis
Diagnosis made on clinical and serological picture Vascular thrombosis: one or more episode of
Arterial thrombosis
Venous thrombosis
Small vessel thrombosis in any tissue or organ
Pregnancy loss: one or more unexplained deaths of normal foetus at or after 10 weeks
Prem birth before 34 weeks Severe preeeclampsia, eclampsia, or placental
insufficiency
3 or more unexplained consecutive miscarriages
Anticardiolipin antibody (aCL)
IgG and/or IgM in medium or high titer
2 tests 6 weeks apart
AND: Measured by a standardised ELISA for ß2 glycoprotein-1 dependent anticardiolipin
antibody
Abnormality present in plasma at least 2 occasions 6
weeks apart
Autoimmune disease of exocrine glands
Decreased exocrine secretions: Eyes
Mouth
Systemic disease Lungs
Renal
GIT
Skin
Polyarthritis
Primary or secondary
Immunologic alterations in peripheral blood
Relative T-cell lymphopaenia
Increased circulating B-cells
75% SS-A
40% SS-B
60% ANF or RF positive
Polyclonal hypergammaglobulinaemia
IgA has immunopathogenic role in SS
Symptoms of dry eyes Daily persistent, troublesome dry eyes >3mo
Recurrent sensation of sand/gravel in eyes
Use of tear substitutes
Oral symptoms Daily feeling of dry mouth >3 mo
Recurrent or persistent swollen glands
Frequently drink fluid to swallow food
Ocular signs Objective signs of dry eyes:
Schirmer’s test 5mm in 5 mins
Rose Bengal dry eye score
Histopathology Focus score 1
Salivary gland involvement Objective evidence of gland involvement
Unstimulated salivary flow 1.5 ml in 15 mins
Parotic sialography showing presence of sialectasis, without evidence of obstruction of major ducts
Salivary scintigraphy showing delayed uptake, reduced concentration, delayed excretion of tracer
Autoantibodies SS-A or SS-B antibodies
Disorder of connective tissue characterised by degenerative and inflammatory changes that subsequently lead to intense fibrosis
Localised
Generalised
Changes in the blood vessels
Concentric proliferation
Thickening of intima and basement membrane
Organ involvement
Skin
Gastro-intestinal tract
Kidneys
Lungs
ANA Sensitivity: 85%, Specificity 54%
Antibodies against Scl-70 Sensitivity 12%, Specificity 100%
Other ENAs CENP
Fibrillarin
RNA Polymerase III
Calcinosis cutis
Raynaud’s phenomenon
Esophageal dysmotility
Sclerodactyly
Telangiectasis
Defining criteria:
Symmetrical progressive proximal muscle weakness
Muscle biopsy showing inflammatory changes
Elevated muscle enzymes
Electromyographic abnormalities
Characteristic dermatological changes
Progressive proximal weakness
Insidious onset
Intense morning stiffness and pain
Heliotrope rash
Goddron’s patches
ANA can be positive, but not diagnostic
Antibodies against cytoplasmic aminoacyl tRNS synthetase (ARS)
Jo-1:
20% of patients
Mi-2
9% of myositis patients
20% DM patients
Overlap syndrome with features of scleroderma, RA, SLE, and PM/DM
AND characteristic high titre of U1-snRNP antibodies.
First symptoms: Raynaud‘s phenomenon (often many years in advance)
Muscle weakness
Swollen hands and general swelling of the skin
Synovitis
At least 50 % of patients develop a classical connective tissue disease in the course of 10 years
Group of diseases characterised by inflammatory infiltration of blood vessels
• Multisystem inflammatory disease
• Rapidly progressive major organ dysfunction
• Constitutional symptoms (fever, weight loss)
• High ESR, severe anemia, thrombocytosis
• Evidence of small-vessel inflammation: • In the kidneys = active urinary sediment • In the lungs = hemoptysis, dyspnea • In the skin = palpable purpura/hemorrhage
• Acute neurologic changes • Footdrop • Altered mental status
• Tests suggesting immune complex formation and/or deposition • Rheumatoid factor and cryoglobulins
• Antinuclear antibodies (ANA)
• Low C3 or C4 levels
• Tests suggesting necrotizing vasculitis without immune complex deposition • Antineutrophil cytoplasmic antibodies (ANCA)
• Tests suggesting systemic inflammation • Erythrocyte sedimentation rate (ESR)
• C-reactive protein (CRP)
• ANCA by ELISA methods
• Proteinase 3 (PR3)
• Myeloperoxidase (MPO) = MPA
• ANCA by immunofluorescence methods
• c-ANCA:
• Wegener’s disease: 60% to 90%
• p-ANCA
• Microscopic polyangiitis (MPA) : 50% to 80%
• UC : 40% to 80%
• Crohn’s: 10% to 40%
Hoffman GS. Arth Rheum. 1998;41(a):1521–1537.
• Consider tissue biopsy of affected organ to determine
• Vessel size
• Histologic features of vessel inflammation
Vessel wall necrosis
Granulomas/giant cells
Immune complex and/or C3 deposition
• Consider angiography of mesenteric or cerebral vessels as clinically indicated
Vasculitis Vasculopathy
• Infectious diseases
• Bacterial endocarditis
• HIV infections
• Viral hepatitis
• Paraneoplastic syndromes
• Atrial myxoma
• Cholesterol emboli syndrome
• Toxic drug effects
• Ergots
• Cocaine
• Amphetamines
Presence of a heart murmur
Necrosis of lower extremity digits
Splinter hemorrhages
Prominent liver dysfunction
History of recreational drug use
History of high-risk sexual activity
Prior diagnosis of neoplastic disease
Unusually high fevers
The diagnosis of a CTD remains clinical
History
Physical examination
Serologic testing as a diagnostic and disease management tool needs to be
Properly applied
Properly interpreted
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