Should a patient with symptoms such as joint pain, skin rashes, or neurological abnormalities be tested for Antinuclear Antibody (ANA) and ceruloplasmin?

Testing for ANA and Ceruloplasmin in Patients with Joint Pain, Skin Rashes, or Neurological Symptoms

Test for ANA when evaluating unexplained joint pain, skin rashes, or neurological symptoms, as these are cardinal features of systemic autoimmune rheumatic diseases; test for ceruloplasmin when neurological abnormalities are present, particularly in children and adults through middle age with unexplained hepatic or neurologic symptoms. 1

ANA Testing Indications

When to order ANA:

• Unexplained joint pain with or without swelling, particularly if accompanied by systemic symptoms 2, 3
• Skin rashes suggestive of autoimmune disease (malar rash, photosensitivity, discoid lesions) 2
• Neurological symptoms including movement disorders, cognitive changes, or psychiatric manifestations of uncertain cause 1
• Combination of symptoms: joint pain + rash, or neurological symptoms + systemic features 1

The American College of Rheumatology recommends indirect immunofluorescence assay (IIFA) on HEp-2 cells as the reference method for ANA screening, with a screening dilution of 1:160 representing the 95th percentile of healthy controls. 2, 3 This threshold provides 95.8% sensitivity and 86.2% specificity for systemic autoimmune rheumatic diseases. 2

Critical caveat: Up to 25% of healthy individuals can test ANA-positive depending on demographics and test variables, so clinical context is essential. 2 A positive ANA at low titer (1:40-1:80) occurs in up to 31.7% of healthy individuals. 3

Ceruloplasmin Testing Indications

When to order ceruloplasmin:

• Unexplained neurological abnormalities (movement disorders, tremor, dystonia, parkinsonism) in children and adults through middle age 1
• Unexplained hepatic abnormalities or liver disease at any age 1
• Psychiatric symptoms combined with neurological or hepatic features 1
• Kayser-Fleischer rings on examination 1

The EASL guidelines state that Wilson's disease should be considered in any individual with liver abnormalities or neurological movement disorders of uncertain cause, and age alone should not eliminate the diagnosis. 1 Serum ceruloplasmin should be routinely measured during evaluation of unexplained hepatic, neurologic, or psychiatric abnormalities. 1

Important limitation: A serum ceruloplasmin level <200 mg/L (20 mg/dL) has only a 6% positive predictive value when used alone as a screening test. 1 Approximately 20% of heterozygotes have decreased ceruloplasmin levels, and normal ceruloplasmin does not exclude Wilson's disease. 1

Algorithmic Approach to Testing

For joint pain and skin rashes:

1. Order ANA by IIFA on HEp-2 cells at 1:160 dilution 2, 3
2. If ANA positive, request both titer and pattern reporting 2, 3
3. Order reflex testing based on pattern:
   • Homogeneous pattern: anti-dsDNA, anti-histone 2, 3
   • Fine speckled: anti-SSA/Ro, anti-SSB/La 2, 3
   • Coarse speckled: anti-RNP, anti-Sm 2
4. Include complement levels (C3, C4) and complete blood count 1, 3

For neurological abnormalities:

1. First determine if hepatic involvement is present (check liver enzymes, albumin) 1
2. If hepatic or psychiatric features coexist with neurological symptoms, order ceruloplasmin immediately 1
3. If isolated neurological symptoms in patient <40 years old, strongly consider ceruloplasmin 1
4. Perform slit-lamp examination for Kayser-Fleischer rings 1
5. If ceruloplasmin <50 mg/L (5 mg/dL), this is strong evidence for Wilson's disease 1
6. Also order ANA if autoimmune encephalitis is in differential 1

For combined symptoms (joint pain + neurological + rash):

• Order both ANA and ceruloplasmin simultaneously 1
• Include comprehensive metabolic panel, complete blood count, urinalysis 1, 3
• Consider antiphospholipid antibodies if thrombotic history present 1

Common Pitfalls to Avoid

ANA testing pitfalls:

• Do not use ANA for disease monitoring—it is a diagnostic test only 2
• Do not rely on limited antigen ELISA panels as initial screening—they miss important patterns and have lower sensitivity 3
• A negative ANA does not exclude autoimmune disease; sensitivity is not 100% even at 1:160 2, 3
• In high clinical suspicion, request specific antibodies regardless of ANA result, as some autoantibodies may be present in ANA-negative patients 2

Ceruloplasmin testing pitfalls:

• Normal ceruloplasmin does not exclude Wilson's disease—approximately 10-20% of Wilson's disease patients have normal levels 1
• Ceruloplasmin is an acute phase reactant and may be falsely elevated during inflammation or infection 1
• Immunologic assays may overestimate ceruloplasmin levels compared to enzymatic assays 1
• Do not use ceruloplasmin alone for diagnosis—combine with 24-hour urinary copper excretion and clinical features 1

Additional Baseline Testing When Either Test is Ordered

When ordering ANA or ceruloplasmin, include: 1, 3

• Complete blood count with differential
• Comprehensive metabolic panel (including creatinine, liver enzymes, albumin)
• Urinalysis with protein/creatinine ratio
• Inflammatory markers (ESR, CRP)

For ceruloplasmin testing specifically, add: 1

• 24-hour urinary copper excretion
• Serum copper
• Liver function tests
• Slit-lamp ophthalmologic examination