Laboratory tests - anti-double stranded DNA (anti-dsDNA)

What it is and why it matters

IgG autoantibody against double-stranded DNA - one of the two highly specific antibodies in SLE (with anti-Sm)
*The only routine lupus antibody that TRACKS DISEASE ACTIVITY - and the one tied to lupus nephritis*
Assays differ, and the difference matters:

Assay	Characteristics
Crithidia luciliae immunofluorescence (CLIFT)	*Most SPECIFIC* - the kinetoplast is pure dsDNA with no protein contamination
Farr radioimmunoassay	Detects high-avidity antibodies; best correlation with nephritis and activity
ELISA / multiplex	Most SENSITIVE, used for screening; picks up low-avidity antibodies -> more false positives

Positive in ~60-70% of SLE at some point in the disease
Specificity ~95% for SLE
In lupus NEPHRITIS: positive in ~80-90%
Present up to 9 years before SLE is diagnosed (ANA first, then anti-Ro/La, then anti-dsDNA and anti-Sm closest to onset)
Found in <1% of healthy controls

Defective clearance of apoptotic debris -> nuclear antigen exposure -> loss of B-cell tolerance
Immune complex disease
- dsDNA-anti-dsDNA complexes deposit in the glomerular basement membrane (and some antibodies cross-react directly with alpha-actinin and nucleosomes bound to the GBM)
- -> complement activation -> CONSUMPTION of C3 and C4 -> inflammation
- *This is why a rising anti-dsDNA with FALLING C3/C4 is the serological signature of an impending flare*
DNA-containing immune complexes -> plasmacytoid dendritic cells via TLR9 -> type I interferon - the central amplification loop, and the target of anifrolumab
Drug-induced: *TNF inhibitors characteristically induce anti-dsDNA (unlike classical drug-induced lupus from hydralazine/procainamide, which causes ANTI-HISTONE antibodies*)

Antibody	Sensitivity	Meaning
ANA	>95%	*Screening test - a negative ANA effectively excludes SLE*
Anti-dsDNA	60-70%	Specific; tracks activity; NEPHRITIS
Anti-Sm	20-30%	*Most specific (>99%)*, does NOT track activity
Anti-Ro/SSA	30-40%	Neonatal lupus + congenital heart block, subacute cutaneous lupus, photosensitivity, Sjogren
Anti-La/SSB	10-15%	With Ro; reduces congenital heart block risk when isolated
Anti-RNP	25-40%	MCTD if high titre and isolated
Anti-histone	50-80% SLE	*>95% of classical DRUG-INDUCED lupus*
Anti-ribosomal P	10-20%	Neuropsychiatric lupus, lupus hepatitis
Antiphospholipid	30-40%	Thrombosis, pregnancy morbidity

2019 EULAR/ACR: entry criterion ANA >=1:80, then weighted domains
- Anti-dsDNA OR anti-Sm scores 6 points; low C3 AND C4 scores 4 (low C3 or C4 alone = 3)
- Biopsy-proven class III or IV lupus nephritis = 10 points - classifies on its own with a positive ANA
- Total >=10 with at least one clinical criterion

Positive anti-dsDNA + compatible clinical features -> SLE
*ALWAYS pair with C3 and C4* - the combination is far more informative than either alone
- Rising titre + falling complement -> impending flare (especially renal)
- Persistently high titre with normal complement and no symptoms -> do not treat the number
Check urinalysis (active sediment), urine protein:creatinine ratio and creatinine at every visit - serology never replaces the urine
Renal biopsy remains the only way to determine ISN/RPS class and guide immunosuppression
Negative anti-dsDNA does not exclude SLE, nor lupus nephritis
Monitoring frequency: 3-6 monthly in stable disease, more often with active nephritis

Urinalysis with microscopy, uPCR, creatinine, FBE, ESR/CRP
- *A high CRP in SLE suggests INFECTION or serositis, not lupus activity (CRP is characteristically low in a lupus flare*)
Renal biopsy if proteinuria >0.5 g/day, active sediment, or unexplained renal impairment
Pre-emptive escalation in asymptomatic serological activity is controversial - hydroxychloroquine optimisation and closer follow-up are reasonable; immunosuppression usually is not

Hydroxychloroquine for EVERYONE with SLE - reduces flares, thrombosis, damage accrual and mortality; <=5 mg/kg/day to limit retinopathy, with baseline and annual ophthalmology screening from 5 years
Glucocorticoid at the lowest effective dose, with an early steroid-sparing agent
Lupus nephritis (class III/IV)
- Mycophenolate OR low-dose IV cyclophosphamide (Euro-Lupus) + glucocorticoid
- *Add-on therapy is now standard rather than reserve: belimumab (BLISS-LN) or voclosporin (AURORA)* added to standard care
- ACE inhibitor/ARB, and SGLT2 inhibitor for residual proteinuria
Severe non-renal disease: belimumab, anifrolumab (type I interferon receptor blocker), rituximab
Taper glucocorticoids toward <=5 mg/day prednisolone or off - the current EULAR target

TNF inhibitor -> anti-dsDNA in 10-15%, but overt lupus in <1%
*Do not stop the biologic for a positive antibody alone* - stop it for clinical lupus
Symptoms resolve on withdrawal; hydroxychloroquine or a short steroid course if needed

Lupus nephritis - the strongest clinical association
SLE disease activity, serositis, cutaneous and haematological flares
Hypocomplementaemia (low C3 and C4)
TNF inhibitor therapy - infliximab > adalimumab > etanercept
Autoimmune hepatitis, mixed connective tissue disease, occasionally Sjogren
Chronic infection - hepatitis C, infective endocarditis, TB (usually low titre, ELISA-detected)
A high-avidity (Farr or Crithidia) positive result is far more likely to be genuine SLE than an ELISA-only positive

Titres fluctuate with disease activity - the only routine lupus antibody that does
A rise commonly precedes a clinical flare by weeks to months, especially renal
Falls with effective treatment (and after rituximab/belimumab); persistently high after induction predicts renal relapse
Anti-Sm, anti-Ro and anti-RNP, by contrast, are fixed and should not be repeated
Serologically active, clinically quiescent (SACQ) patients - a recognised group; *many never flare - treating the serology alone causes harm*
Long-term outcome in SLE is driven by renal disease, cardiovascular disease, infection and accrued glucocorticoid damage - not by the antibody titre

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