ANA (Antinuclear Antibody) Test: 5 Pearls Segment

Core IM

Despite knowledge regarding the lack of specificity of ANA positivity, there remain gaps in understanding and practice patterns related to ANA referrals and interpreting ANA positivity.  Given rates of ANA positivity up to 15-20% in the otherwise healthy population, recognizing symptoms and laboratory findings that raise concern for autoimmune disease and warrant ANA testing is critical to understand.   This episode will explore the significance of a positive ANA, including how to interpret ANA titers and patterns.  The Core IM team will review signs, symptoms, laboratory testing and physical exam findings that are concerning for autoimmune disease for which an ANA should be sent. Finally, the episode will review conditions associated with a positive ANA that are not rheumatologic including infections, malignancies and other non-rheumatic autoimmune diseases.  You鈥檙e invited to join the team for 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?
    •  have found 20% 鈥 of the healthy population have a +ANA
    • Poor positive predictive value for connective tissue disorder of less than
    • While a screening test for lupus, also has wide expression in many other rheumatic diseases as well (and other conditions 鈥 see Pearl 4!)
  • Does the titer matter? Yes! 
    • The (level). 
    • One:
      • 1:40 鈥 up to 33% of the healthy pop
      • 1:80 鈥 10-15% of healthy pop
      • 1:160 鈥 5% of healthy pop
      • 1:320 鈥 3% of healthy pop
    •  1% of healthy individuals had titers 鈮 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鈥檚 phenomenon, skin changes, esophageal dysmotility) would suggest scleroderma
    •  was exclusively seen in healthy individuals in some studies, though other data suggest this can be as well
    • 鈥淢onospecific DFS70 may help exclude CTD鈥
  • Keep in mind, ANAs can be positive long before any rheumatological symptoms. 
  •  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 鈥 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
      • 鈥淒o you feel sick when you are in the sun?鈥
    • Dry eyes or dry mouth
    • Oral ulcers (often painless and on the hard palate = more unique to SLE)
    • History of clots or pregnancy losses
    • 搁补测苍补耻诲鈥檚&苍产蝉辫;
  •  with highest odds ratio for  SLE compared to fibromyalgia:
    • Raynaud鈥檚, rash, fever, easing bruising, hair loss
  • Examples of  more 鈥渃lear cut鈥 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 of patients with SLE have fibromyalgia)
    •  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 鈥 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 (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
    • 鈥淕iven the low specificity of ANA for systemic autoimmune disease, it is important to result, particularly if it is requested with low pre-test probability.鈥 
    • 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
      • , primary biliary cirrhosis, autoimmune hepatitis
      •  and 
      • Infections: malaria, tuberculosis,
      • 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鈥檚 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



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


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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