Laboratory tests - extractable nuclear antigen (ENA)

What it is

A panel of antibodies to nuclear antigens that are "extractable" in saline - historically defined by the assay, not by biology
A reflex test, ordered when the ANA is positive (and specifically requested when anti-Ro is suspected, since some assays miss it)
Standard Australian panel: Ro (SSA), La (SSB), Sm, RNP, Scl-70 (topoisomerase I), Jo-1
- Extended panels add centromere, RNA polymerase III, PM-Scl, Ku, ribosomal P, fibrillarin, Mi-2, MDA5, TIF1-gamma

ENA antibodies are far less common in healthy people than ANA - specificity is the point of the panel
Anti-Ro is the commonest ENA overall and the one most often found outside a defined CTD

Targets are ribonucleoprotein complexes: Ro/La bind small cytoplasmic RNAs; Sm and U1-RNP are spliceosome components; Scl-70 is DNA topoisomerase I; Jo-1 is histidyl-tRNA synthetase
Antigen exposure during apoptosis and NETosis -> nucleic acid-containing immune complexes -> TLR7/9 -> type I interferon
Individual specificities cluster with HLA class II alleles, which is why phenotypes are so tightly antibody-defined

Antibody	Disease	Phenotype it predicts
Anti-Ro (SSA)	Sjogren, SLE	Neonatal lupus and congenital heart block, subacute cutaneous lupus, photosensitivity, lymphopenia, sicca, C2 deficiency, ANA-negative lupus, ILD
Anti-La (SSB)	Sjogren, SLE	Sjogren syndrome and neonatal lupus. Rarely occurs without anti-Ro
Anti-Sm	SLE only	Highly specific (>95%) for SLE; associated with renal and CNS disease. Does not track activity
Anti-U1-RNP	MCTD, SLE	Myositis, Raynaud, puffy hands. High titre + no other antibody = MCTD
Anti-Scl-70 (topoisomerase I)	Systemic sclerosis	Diffuse cutaneous disease + ILD; nucleolar/speckled ANA
Anti-centromere	Systemic sclerosis	Limited cutaneous (CREST) + pulmonary arterial hypertension; lower ILD risk
Anti-RNA polymerase III	Systemic sclerosis	Scleroderma renal crisis, rapidly progressive skin thickening, malignancy association
Anti-Jo-1 (and other anti-synthetases)	Myositis	Antisynthetase syndrome: ILD + myositis + arthritis + mechanic's hands + Raynaud + fever
Anti-ribosomal P	SLE	Psychosis and depression (neuropsychiatric lupus); lupus hepatitis
Anti-PM-Scl, anti-Ku	Overlap	Myositis-scleroderma overlap

A positive ENA in the absence of clinical features does not make a diagnosis
Anti-Sm and anti-dsDNA are the two SLE-specific antibodies in the 2019 EULAR/ACR criteria (6 points)
Anti-Ro is the least specific ENA - occurs in Sjogren, SLE, myositis, systemic sclerosis, PBC, and in ~0.5-1% of healthy people
Isolated anti-Ro52 (as opposed to Ro60) is not disease-specific but predicts ILD when it accompanies a myositis antibody
*ENA titres do not track disease activity* - do not repeat them for monitoring
- Anti-dsDNA and C3/C4 are the monitoring tests in SLE; ENA is not
Once positive, generally stays positive - there is no need to retest a known specificity

Anti-Ro or anti-La in a woman of childbearing age
- Counsel on neonatal lupus: ~1-2% risk of congenital complete heart block; ~15-20% if a previously affected child
- Hydroxychloroquine throughout pregnancy - reduces the risk
- Fetal echocardiography every 1-2 weeks from 16 to 28 weeks
- Complete heart block is irreversible; the neonatal rash and cytopenias resolve as maternal antibody clears
Anti-Scl-70 -> baseline and serial PFTs with DLCO and HRCT for ILD
Anti-centromere -> annual echocardiogram and DLCO for pulmonary arterial hypertension
Anti-RNA polymerase III -> weekly home BP monitoring and immediate presentation for scleroderma renal crisis; ACE inhibitor if it occurs; age-appropriate malignancy screening
Anti-Jo-1 / anti-synthetase -> HRCT and PFTs; treat the lung, not just the muscle
Anti-Sm -> urinalysis and UPCR for lupus nephritis; assess neuropsychiatric features
Anti-U1-RNP high titre -> assess for MCTD; annual echocardiogram for PAH
Anti-ribosomal P -> consider in unexplained psychosis or hepatitis in SLE

After a positive ANA, guided by the pattern
Specifically request anti-Ro if Sjogren, SCLE, ANA-negative lupus or pregnancy planning is the question - solid-phase assays can miss it and some IIF substrates express Ro60 poorly
*Do not order as a screen in non-specific fatigue or arthralgia*

Anti-Ro: Sjogren syndrome, SLE, neonatal lupus and congenital heart block, SCLE, hereditary C2 complement deficiency, primary biliary cholangitis, ILD, sinus node dysfunction and QT prolongation in adults
Anti-La: Sjogren syndrome, neonatal lupus
Anti-Sm: SLE with renal and CNS disease; commoner in African and Asian ancestry
Anti-U1-RNP: MCTD, SLE, Raynaud, PAH
Anti-Scl-70: diffuse systemic sclerosis, ILD, digital ulcers
Anti-centromere: limited systemic sclerosis, PAH, primary biliary cholangitis
Anti-RNA polymerase III: scleroderma renal crisis, coincident malignancy
Anti-synthetases: ILD, mechanic's hands, arthritis
Anti-ribosomal P: neuropsychiatric SLE, lupus hepatitis

ENA antibodies appear years before clinical disease and persist for life once present
Their appearance defines the phenotype the patient is likely to develop, which is the reason to act on them prospectively rather than reactively
Anti-Ro persists through and after pregnancy - the risk of congenital heart block applies to every pregnancy, and is highest with a previously affected child
Scleroderma-specific antibodies (Scl-70, centromere, RNA pol III) are mutually exclusive and each predicts a distinct organ trajectory over the following decade
Isolated ENA positivity without clinical features rarely progresses, but anti-Ro with Raynaud or sicca warrants ongoing review

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