What Are Anti-Histone Antibodies?
Anti-histone antibodies are autoantibodies that target histone proteins (the structural proteins around which DNA wraps to form chromatin), and they serve as a key diagnostic marker primarily for drug-induced lupus erythematosus (DILE) and are also found in systemic lupus erythematosus (SLE), particularly in patients with lupus nephritis. 1
Primary Clinical Significance
Anti-histone antibodies should be ordered primarily when drug-induced lupus is suspected, particularly in patients presenting with lupus-like symptoms who are taking medications known to cause DILE 1. The presence of anti-histone antibodies with negative or low anti-dsDNA titers strongly suggests drug-induced lupus rather than idiopathic SLE 1.
Key Distinguishing Features:
- In drug-induced lupus: Anti-histone antibodies are present in the majority of symptomatic patients, with higher titers than asymptomatic patients who develop drug-induced antinuclear antibodies (DANA) 2
- In idiopathic SLE: Anti-histone antibodies are found in approximately 25% of patients, associated with a variety of antigenic specificities including histones, double-stranded DNA (15%), chromatin, and ribonucleoprotein complexes 3, 4
- Temporal pattern: Anti-histone antibody titers gradually fall after discontinuation of the offending drug in DILE cases 1, 2
Diagnostic Testing Approach
Anti-histone antibodies are NOT part of the standard lupus antibody panel recommended by the European League Against Rheumatism (EULAR), which includes ANA, anti-dsDNA, anti-Ro, anti-La, anti-RNP, anti-Sm, anti-phospholipid antibodies, C3, and C4 1.
When to Order Anti-Histone Testing:
- Primary indication: Suspected drug-induced lupus in patients on high-risk medications 1
- Secondary indication: Confirmed lupus nephritis patients who remain anti-dsDNA negative, as anti-histone antibodies are more prevalent in lupus nephritis than in SLE without kidney disease 1
- Testing algorithm: Begin with ANA as first-level screening; if positive, proceed with specific antibody testing including anti-histone antibodies when DILE is specifically suspected 1
Molecular Characteristics
Anti-histone antibodies can target five different histone classes (H1, H2A, H2B, H3, H4) and various histone-histone and DNA-histone complexes 5. In SLE, there is higher preponderance for antibodies targeting H1, H2A, and H2B 4. The concomitant appearance of both IgG and IgM anti-histone antibodies is observed predominantly in SLE patients 4.
Important Clinical Caveats
- Specificity considerations: While anti-histone antibodies were historically considered highly specific for DILE, emerging evidence suggests they may be less prevalent with modern biological agents compared to older DILE-inducing drugs 6
- Not disease-specific alone: Anti-histone antibodies can appear in various autoimmune conditions, though at significantly lower frequencies (6%) compared to SLE (25%) 4
- Interpretation context: The fine specificities of anti-histone antibodies can be assay-dependent, and results may vary based on histone preparation quality and testing methodology 5