Autoantibodies encountered in patients with autoimmune connective tissue diseases Flashcards
What does the ANA test for?
Tests for a group of Anti-nuclear antibodies commonly defined as autoantibodies that target primarily nuclear components including DNA, small nuclear ribonucleoproteins (snRNP) and are detected by the fluorescent antinuclear antibody test
What diseases are increased ANA titers seen in ?
Systemic lupus erythematosus, systemic sclerosis, and dermatomyositis
Pathogenic potential of ANA antibodies?
These reflect basic inflammatory events in tissue but rarely care pathogenic potential
Fluorescent antinuclear antibody (FANA) vs ELISA test?
Elisa is less expensive, more convenient, but has increased density and decreased specificity.
The FANA can also give you titers
What does the ANA titer represent?
The last dilution at which the ANA pattern is detectable.
The higher the number, the higher the levels of the autoantibody that is being picked up
Importance of ANA for SLE?
High titers of ANA have high sensitivity (98%), and low specificity (90%) and the NPV is high (99%). The PPV though is only 30-40% for SLE.
- ~2/3 of + ANAs in a general medical population will be a/w dz other than SLE
- Rare that a negative ANA will have SLE
What percent of patients w/ SLE are negative for ANA?
1-2%
What is the PPV of ANA for the detection of SLE?
30-40% and NPV is 99%
What is the most sensitive serologic test for SLE?
ANA
What ANA patterns are a/w SLE?
Homogenous and peripheral
How often is ANA + in SCLE and what type of ANA pattern is seen?
60-80% and speckled/particulate ANA pattern
What percentage of patients w/ DLE have + ANA
5-25%
Significance of the ssDNA antibody?
This one can suggest a risk for developing SLE in DLE patients.
also seen in linear morphea
Significance of the C1q antibody?
Severe SLE and hypocomplementemic urticarial vasculitis
Significance of the dsDNA antibody?
Highly specific test for SLE, a/w LE nephritis. Useful for monitoring nephritis activity
What is the significance of the U1RNP antibody?
It is always + in mixed connective tissue dz (required for dx)
What is the significance of the Ro/SSA antibody?
+ in neonatal LE/congenital heart block (99%); SCLE (75-90%), primary SjS (70); a/w photosensitivity
Which antibody is + in 99% of cases of neonatal LE/congenital heart block
Ro/SSA
Significance of the cardiolipin antibody?
Antiphospholipid syndrome in SLE.
- Recurrent abortions, thrombocytopenia, hypercoagulable state, livedo reticularis, leg ulcers, acral infarction, hemorrhagic cutaneous necrosis
Significance of the anti-histone antibody?
Drug-induced SLE
Significance of the anti-smith antibody?
Highly specific for SLE; higher prevalence in African Americans and Asians (30-40%)
Significance of the anti beta2 glycoprotein antibody?
High risk of thrombosis in SLE; primary antiphospholipid syndrome
Significance of the anti rRNP antibody?
Highly specific for SLE; a/w neuropsychiatric LE
What is the significance of the anti-Ku antibody?
Overlap syndromes with DM/PM and systemic sclerosis. Thought to be potentially associated with myositis in SLE cases
Which antibodies are high specific for SLE?
dsDNA, Smith, rRNP
What two proteins make up the Ro antigen?
Ro52 and Ro60
Which of the Ro antigens is cytoplasmic and which is nuclear?
Ro52 is cytoplasmic and the 60kD (Ro60) is nuclear
Which of the Ro antigens is more pathogenic?
Ro52 is more pathogenic and clinically significant
What happens if the patient is negative for 60kD (nuclear) but + for the 52kD (cytoplasmic) antigens?
Then the interpreter may report a negative ANA
What do the anti-SSA/ro and Anti-SSB/La antibodies react against and where are they located in the cell?
These react against proteins present in human cytoplasmic RNP that are found in both the cytoplasm and nucleus
Why are the Ro and La antibodies often both positive?
These are a “linked set” of autoantigens b/c both are present on the same RNP particles
Both are often + due to epitope spreading
Even though the Anti-SSA/ro and Anti-SSB/La antibodies are often both present which one is more likely to be present first/alone?
the Anti-SSA/Ro is the one that is more commonly + by itself or present first.
What antigens and diseases are a/w the homogenous phenotype of the ANA?
Antigen: dsDNA, Histones
Disease: SLE, DLE, RA
What antigens and diseases are associated with the rim/peripheral phenotype of the ANA?
Antigen: native DNA or deoxynucleoprotein
Disease: Most consistent with SLE
What antigens and diseases are associated with the speckled pattern of ANA?
Antigens: Ro/SSA, La/SSB, RNP, Sm, Scl-70
Disease associations: SS, MCTD, SLE, scleroderma
What antigens and diseases are associated with the speckled look of the ANA?
Antigens: PM/Scl
Diseases: Scleroderma
What antigens and diseases are associated with the Cytoplasmic phenotype of the ANA?
Antigens: tRNA synthetases, Jo-1, Mitochondria, Smooth Muscle
Diseases: polymyositis/dermatomyositis, primary biliary cirrhosis, autoimmune hepatitis
What drugs are a/w drug-induced-ANA/SLE?
Procainamide, Hydralazine, Isoniazid, Chlorpromazine, Phenytoin, Quinidine, Methyldopa, Minocycline
What antibodies are + in Drug-induced SCLE?
Anti-Ro/SS-A (80%), Anti-La/SS-B)
What does the skin eruption in Drug-induced SCLE look like?
Skin ALWAYS involved; photosensitive papulosquamous eruption (psoriasiform to lichenoid); rare to have systemic involvement
What drugs commonly cause drug-induced SCLE?
HCTZ, terbinafine, griseofulvin, NSAIDs, CCBs, Antihistamines, PPI’s, docetaxel, ACE inhibitors, TNF-a inhibitors (etanercept most common)
What type of antibodies develops in the use of TNF-a inhibitors?
So TNF-a blockade is associated with induction of autoantibody: often ANA and dsDNA
Clinical significance of this is unknown
How long does it take on TNF-a inhibitors before autoantibodies form usually?
8-20 months
Which TNF-a inhibitor is most likely to cause autoantibodies?
Infliximab, then adalimumab/entancercept
What sx’s occur with the autoantibodies generated by TNF-a blockade?
Antibodies = ANA and dsDNA –> lupus-like syndrome: butterfly rash (ACLE), SCLE, and DLE as well as small vessel vasculitis and chilblains
Also: phlebitis (with anti-cardiolipin antibodies), leukopenia, thrombocytopenia, serositis, fever, weight loss, asthenia. Arthritis is a common, renal involvement is rare
How does TNF-a inhibitor-induced lupus differ from typical drug-induced lupus?
Skin manifestations are more prominent
ANA and dsDNA + are more common than anti-histone +
Development of aAb seems to be clinically insignificant
Should you screen for an ANA before starting a TNF-a inhibitor?
NOT recommended
What is the significance of p155/140 (TIF-1y) antibodies?
Clinically amyopathic DM and cancer-associated DM in adults. It is also associated with severe dz in adults and kids.
What is the significance of the NXP-2 antibody?
Juvenile DM w/ calcinosis
What antibodies are associated w/ anti-synthetase syndrome, myositis, mechanics hands, arthritis, Raynaud’s phenomenon, severed ILD?
Aminoacyl tRNA syntheases: Anti-Jo1, Anti-PL7, Anti-Pl12, EJ/OJ
What are the 4 aminoacyl tRNA synthetase antibodies?
Anti-Jo1, Anti-PL7, Anti-PL12, EJ/OJ
What is the significance of the anti-Mi-2 antibody?
It is against helicase–> classic DM skin findings, mild muscle disease, good response to treatment
Significance of the MDA5/CADM-140 antibodies?
Against MDA5 (anti-melanoma differentiation-associated gene 5), clinically amyopathic dermatomyositis with rapidly progressive ILD in adults and kids.
also distinctive skin findings: skin/oral ulcers, palmar papules, mechanics hands, panniculitis
What are the unique skin findings associated w/ Anti-MDA5/CADM-140 (anti-melanoma differentiation-associated gene 5) antibodies?
Skin/oral ulcers, palmar papules, mechanic’s hands, panniculitis
Significance of the SRP antibody?
Fulminant dermatomyositis/polymyositis w/ cardiac involvement, poor prognosis
What is the significance of the centromere antibody?
Most specific antibody for CREST or limited cutaneous systemic sclerosis.
a/w pulmonary HTN
Significance of the Scl-70?
Against DNA topoisomerase I
Most strongly associated with systemic sclerosis with pulmonary fibrosis
Significance of the RNA polymerases I/II?
High levels correlate with severe skin involvement and renal crisis in primary systemic sclerosis
What is the significance of the Anti-RNA polymerase III autoantibody?
Increased risk of internal malignancies, associated w/ paraneoplastic systemic sclerosis
Significance of the anti-Fibrillarin (U3RNP) antibody?
A/w internal organ involvement in systemic sclerosis
What is the significance of the ssDNA in morphea?
A/w the linear type, correlates w/ disease severity/activity
What is the significance of the anti-histones antibodies in morphea?
Most prevalent in linear and generalized morphea correlates w/ disease severity/activity
What is the molecular target of the rheumatoid factor?
Fc portion of the IgG
What are the key associations of the rheumatoid factor?
Low levels: very nonspecific, may be seen in other connective tissue dz, infections, liver dz, sarcoid, systemic vasculitides
High levels: a/w severe, crippling, erosive RA and extra-articular manifestations of RA like systemic vasculitis, neuropathy.
Mixed cryoglobulinemia types II and III secondary to hep C infection
What are the molecular targets of the cyclic citrullinated proteins antibodies (CCP)?
CCP proteins in skin like filaggrin and joints
What is the significance of the cyclic citrullinated proteins antibodies?
A/w severe RA; also a predictor for the development of RA
What is the most specific antibody for Sjogren’s syndrome?
Alpha-fodrin
What is the target of the alpha fodrin antibody?
Actin-binding protein (involved in secretion)
Significance of the Ro/SSa antibody?
Neonatal LE (99% of cases) and SCLE (may be a/w photosensitivity)
What antibody defines mixed connective tissue disease?
U1RNP
What are the hallmarks of DM w/ MDA5 antibodies?
Palmar papules, deep cutaneous ulcerations, and oral mucosal pain.
Often amyopathic disease, high risk for ILD
What antibody is associated with having Gottron papules, Gottron sign, and shawl sign?
Anti-Mi-2
Which antibody is a/w patients with dermatomyositis that have concomitant arthritis, Raynaud’s and ILD?
Anti-Jo-1
Which antibody in dermatomyositis is associated with a higher risk of malignancy and cutaneous sx’s like a heliotrope rash, Gottron’s papules, and flagellate erythema?
Anti-p155 (TIF-1y)
Which antibody in dermatomyositis is associated with severe symmetric proximal muscle weakness
Anti-SRP (signal recognition particle)
