ANA (Antinuclear Antibody) Test: 5 Pearls Segment

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Pearl 1: An ANA does not mean a patient has an autoimmune disease 

• First, what exactly is an ANA?
  • Autoantibodies to antigens in the nucleus
    • The thought is in autoimmune diseases there is dysregulated apoptosis. When the cells breaks down, the contents inside the nucleus come out of the cell. The dendritic cells can present the nuclear antigens to T cells, which then activate B-cells to create antibodies.
  • Can be obtained by 2 different tests
    • IFA (indirect immunofluorescence assay)
    • ELISA
• What are some of the challenges of interpreting a +ANA?
  • Studies have found 20% – 32% of the healthy population have a +ANA
  • Poor positive predictive value for connective tissue disorder of less than 10%
  • While a screening test for lupus, also has wide expression in many other rheumatic diseases as well (and other conditions – see Pearl 4!)
• Does the titer matter? Yes! 
  • The likelihood of disease increases with increasing antibody titer (level). 
  • One study found:
    • 1:40 – up to 33% of the healthy pop
    • 1:80 – 10-15% of healthy pop
    • 1:160 – 5% of healthy pop
    • 1:320 – 3% of healthy pop
  • Study showed that 1% of healthy individuals had titers ≥ 1:2560.
    • For example, a titer of 1:80 has a LR of 0.5 versus 1:640 titer has LR of 19
• The pattern of the ANA is usually non-specific
  • Except for if the pattern centromere in the appropriate clinical setting (Raynaud’s phenomenon, skin changes, esophageal dysmotility) would suggest scleroderma
  • Nuclear dense fine speckled was exclusively seen in healthy individuals in some studies, though other data suggest this can be seen in patients with autoimmune diseases as well
  • “Monospecific DFS70 may help exclude CTD”
• Keep in mind, ANAs can be positive long before any rheumatological symptoms. 
• In one study of military recruits that were ultimately diagnosed with lupus, the earliest antibodies before any clinical symptoms were ANA, dsDNA Anti-Ro and Anti-La.
  • They were found between 3 – 9 years before diagnosis. Then, closer to diagnosis of lupus, anti-Smith and AntidsDNA antibodies were found.
• Experts like Dr. Jonas still counsels patients that the likelihood that developing rheumatological disease with a sole positive ANA is low and counsels regarding symptoms that may need further workup.

Pearl 2: Check an ANA only if suspicion for autoimmune disease, not non-specific pain or fatigue vs. What patient histories should you not get an ANA for and which aspects of the history would raise suspicion for autoimmunity?

• Do not order for fatigue, diffuse joint pain alone (non-inflammatory history), or other mild nonspecific symptoms that have been ongoing for years.
  • If an ANA is ordered, there is a 1 in 5 chance in a woman that the ANA will be positive.
• Ask about:
  • Photosensitivity
    • “Do you feel sick when you are in the sun?”
  • Dry eyes or dry mouth
  • Oral ulcers (often painless and on the hard palate = more unique to SLE)
  • History of clots or pregnancy losses
  • Raynaud’s 
• Symptoms with highest odds ratio for  SLE compared to fibromyalgia:
  • Raynaud’s, rash, fever, easing bruising, hair loss
• Examples of  more “clear cut” histories that warrant checking an ANA/diagnosis of lupus: 
  •  
    • Woman with a positive ANA with a low white blood cell count, anemic, low platelet count and active urinary sediment
    • Prior history of organ involvement such as glomerulonephritis or pericarditis.

Pearl 3: An ANA should be checked only for inflammatory joint pain, which requires a careful history and physical to elicit.

• Arthralgia vs. Arthritis 
  • Arthralgia = joint pain without examination findings
  • Arthritis = swelling and localized tenderness of joints
• Fibromyalgia vs. inflammatory arthritis (overlap up to 22% of patients with SLE have fibromyalgia)
  • Symptoms such as muscle pain, headaches, cognitive problems, paraesthesias, fatigue and abdominal pain more common in fibromyalgia than SLE 
  • Fibromyalgia is characterized by periarticular (around the joints, not at the joints) soft tissue tenderness at characteristic locations: shoulder girdle, lateral epicondyle, etc. 
  • Focal tenderness adjacent to joints (muscles, non-joint areas)
  • Joints may hurt also – but often more diffuse pain, not localized to specific joints
  • No swelling, warmth or erythema
• Inflammatory arthritis is characterized by articular (joint) pain and tenderness. 
  • Joint swelling (feels boggy, especially in RA)
  • Joint tenderness
• Inflammatory joint pain
  • Prolonged (>30 mins) morning stiffness and joint pain worse in the AM or after inactivity, which is more common in RA
  • Lupus inflammatory arthritis may not be always have characteristic morning stiffness.
  • Patients with lupus usually have inflammatory arthritis that is symmetric and involves small joints (such as the MCPs, PIPs of the hands), and classically is NON-erosive (i.e. does not cause joint damage).
    • Most inflamed joints in RA and lupus are NOT usually red/warm and can have subtle inflammation (swelling or tenderness)
    • *Gout and sepsis are only conditions where you usually see warm, red joints

Pearl 4: ANA positivity is seen in other non-rheumatic medical conditions and is not unique to autoimmune diseases.

• How should the general internist counsel patients before ordering ANA?
  • Under the right clinical suspicion, explain to the patient the ANA is a screening test and does not diagnose lupus or other autoimmune disease
  • “Given the low specificity of ANA for systemic autoimmune disease, it is important to counsel the patient about the limitations of a positive test result, particularly if it is requested with low pre-test probability.” 
  • Remind patients that a positive ANA is not diagnostic of lupus or autoimmune disease!  Most patients with a +ANA will NOT develop an autoimmune disease
    • Autoimmune thyroid disease, multiple sclerosis, primary biliary cirrhosis, autoimmune hepatitis
    • Malignancy and lymphoproliferative disease
    • Infections: malaria, tuberculosis, Mycobacterial, syphilis, HIV, and bacterial
    • Drugs induced ANA, even in the absence of drug-induced lupus

Pearl 5: Once an ANA comes back positive, use a CBC and UA to triage how quickly they need to be seen by a rheumatologist. Monitor DsDNA, CBC and complements level as it correlates with disease activity.

• Check CBC and urinalysis (and Cr and LFTs) to see if there is any internal organ involvement
  • Cytopenias 
  • Proteinuria / active urinary sediment ( >5 RBCs and >5 WBCs per high-power field (hpf) and/or cellular casts where none previously existed) that may suggest SLE.
• What does Rheumatology check?
  • Additional autoantibodies on the ENA (extractable nuclear antigen) panel
    • Autoantibodies are not entirely specific as we were often taught in med school:
      • RNP is commonly positive among patients with SLE, though also seen in mixed connective tissue disease (MCTD)
      • SSA/SSB can be seen in primary Sjogren’s Syndrome but also SLE
• Should the ANA be checked again?
  • No!  There is limited utility in rechecking an ANA once it is a known positive (or negative) in most circumstances, similarly with ENA panel antibodies.
• What may correlate with disease activity, particularly in lupus?
  • DsDNA antibodies
    • dsDNA antibodies can increase and decrease over time, and may correlate in some patients with disease activity
  • Complement levels 
  • Lymphocytes

Contributors

Shreya Trivedi, MD, ACP Member – Author/Host
Ann Marie Kumfer MD
Mithu Maheswaranathan MD

Reviewers

Jason Kolfenbach MD
Jacob Mendiertsma, MD

Jason Kolfenbach, MD, consultant: ChemoCentryx

Those named above, unless otherwise indicated, have no relevant financial relationships to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.  All relevant relationships have been mitigated.

Release Date:  October 6, 2022

Expiration Date: October 6, 2025

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