FANA ICAP Nomenclature
What is FANA ICAP Nomenclature?
FANA (Fluorescent Antinuclear Antibody) testing using ICAP (International Consensus on ANA Patterns) nomenclature is a standardized system for reporting antinuclear antibody patterns detected by indirect immunofluorescence assay (IIFA) on HEp-2 cells, which includes 28 distinct anticellular (AC) patterns encompassing nuclear, nucleolar, cytoplasmic, and mitotic staining patterns. 1
The ICAP Standardization System
The ICAP nomenclature was developed to address the historical confusion around the term "ANA," which has come to encompass antibodies directed at various cellular compartments including nuclear constituents, components of the nuclear envelope, mitotic spindle apparatus, cytosol, cytoplasmic organelles, and cell membranes. 2
The new terminology uses "anticellular antibodies" (AC) rather than "antinuclear antibodies" to more accurately reflect the diverse targets of these autoantibodies. 2
The standardized nomenclature includes specific pattern designations that correlate with particular autoantibodies and associated autoimmune diseases, improving communication between laboratories and clinicians. 1
Major ICAP Pattern Categories and Clinical Significance
Nuclear Patterns
Homogeneous pattern (AC-1): Associated with anti-dsDNA, anti-histone, and anti-nucleosome antibodies; highly suggestive of systemic lupus erythematosus (SLE) with >95% of SLE patients showing ANA positivity. 3, 4
Fine speckled pattern (AC-4): Associated with anti-SSA/Ro, anti-SSB/La, and anti-topoisomerase-1 antibodies; commonly seen in SLE, Sjögren's syndrome, systemic sclerosis, and inflammatory myopathies. 3, 5
Coarse speckled pattern (AC-5): Associated with anti-U1-SnRNP and anti-Sm antibodies; frequently seen in mixed connective tissue disease (MCTD), SLE, and undifferentiated connective tissue disease. 3, 5
Centromere pattern (AC-3): Associated with anti-CENP antibodies; highly specific for limited systemic sclerosis and Raynaud's phenomenon. 3
Nucleolar Patterns
- Nucleolar pattern (AC-8, AC-9, AC-10): Associated with anti-PM/Scl, anti-RNA polymerase, and anti-U3-RNP antibodies; suggests systemic sclerosis or overlap syndromes. 3
Cytoplasmic Patterns
- The ICAP system includes multiple cytoplasmic patterns that were previously underreported or misclassified, improving detection of antibodies relevant to conditions like inflammatory myopathies. 2, 1
Dense Fine Speckled Pattern
- Dense fine speckled pattern (AC-2): Associated with anti-DFS70/LEDGF antibodies; more commonly found in healthy subjects and other inflammatory conditions rather than systemic autoimmune diseases, and detection of monospecific anti-DFS70 antibodies allows exclusion of SLE diagnosis. 5, 1
Clinical Application and Diagnostic Algorithm
When to Order FANA Testing
IIFA on HEp-2 cells remains the reference standard method for ANA screening, with sensitivity of 90-100% for systemic rheumatic diseases. 2, 6
The test should be ordered when there is clinical suspicion of systemic autoimmune rheumatic diseases, particularly SLE, systemic sclerosis, Sjögren's syndrome, inflammatory myopathies, or MCTD. 2
Interpreting Titer Thresholds
A screening dilution of 1:160 is recommended as the optimal cutoff for adult populations, representing the 95th percentile in healthy controls with 95.8% sensitivity and 86.2% specificity for systemic autoimmune diseases. 3, 7
At 1:80 titer, specificity drops to 74.7%, with 13.3% of healthy individuals testing positive at this dilution. 3, 7
At 1:40 titer, up to 31.7% of healthy individuals may test positive, making this threshold unsuitable for screening in most clinical contexts. 3, 7
Follow-up Testing Based on Pattern
When ANA is positive at ≥1:160 with a homogeneous pattern, order anti-dsDNA antibodies first (using both CLIFT for specificity and solid-phase assays for sensitivity), followed by anti-histone and anti-nucleosome antibodies. 3, 5
For speckled patterns at ≥1:160, order an extractable nuclear antigen (ENA) panel including anti-Sm, anti-RNP, anti-SSA/Ro, anti-SSB/La, anti-Scl-70, and anti-Jo-1. 3, 5
For nucleolar patterns, prioritize testing for anti-RNA polymerase III, anti-PM/Scl, and anti-U3-RNP antibodies, as these suggest systemic sclerosis or overlap syndromes. 3
In cases of high clinical suspicion, specific antibody testing should be performed regardless of ANA result, as some autoantibodies (anti-Jo-1, anti-ribosomal P, anti-SSA/Ro) may be present in ANA-negative patients. 3, 5
Critical Pitfalls and Caveats
Laboratory Method Specification
The testing method must always be specified in the laboratory report, as alternative automated methods (ELISA, chemiluminescence, multiplex assays) have fundamentally different test characteristics compared to IIFA and should not be referred to as "ANA test" or "ANA screen." 2, 3
IIFA requires substantial technical expertise and is only as good as the laboratory performing the assay, necessitating ongoing training programs for laboratory personnel. 2
Avoiding Overinterpretation
Up to 25% of apparently healthy individuals can be ANA-positive by IIFA depending on demographics, serum dilution, and cutoff used, and many will never develop autoimmune disease. 2
A positive ANA test alone is not diagnostic of any specific autoimmune disease and requires clinical correlation with symptoms, additional laboratory abnormalities, and when appropriate, histological findings. 3, 5
ANA testing is intended for diagnostic purposes only and should not be repeated for monitoring disease activity once diagnosis is established; instead, use quantitative anti-dsDNA assays with the same method consistently for monitoring SLE activity. 3, 5
Communication Between Laboratory and Clinic
Both titer and pattern must be reported, as different patterns suggest different autoantibodies and associated conditions. 2, 3, 5
If multiple methods are used for ANA or specific autoantibody testing, results from each method should be reported separately to avoid confusion. 2
Providing detailed clinical information on the laboratory requisition enables the laboratory to assess results appropriately and decide on subsequent reflex testing. 5
Impact on Morbidity, Mortality, and Quality of Life
Early and accurate pattern recognition using ICAP nomenclature enables timely diagnosis of serious conditions like SLE and systemic sclerosis, where specific antibodies may present years before overt disease, allowing for earlier intervention to prevent organ damage. 2
Proper interpretation prevents unnecessary anxiety and testing in patients with low-titer positive results or anti-DFS70 antibodies who are unlikely to develop autoimmune disease. 5, 1
Standardized reporting reduces diagnostic delays and improves bench-to-bedside communication, which is of utmost importance for optimal patient outcomes. 2