ANA panels: A comprehensive approach to early autoimmune diagnosis

Primary care providers (PCPs) play a critical role in the early identification and evaluation of autoimmune diseases—often long before patients reach a rheumatologist. As referral criteria become more stringent and antinuclear antibodies (ANA) testing alone proves insufficient, clinicians can order a more comprehensive and clinically relevant workup. Explore the value of expanded autoimmune blood testing, how it integrates into primary care practice, and when to order it to ensure timely, appropriate specialty care.

In this article:

Clinical challenge | Why it matters | Ordering recommendations | Interpreting test results | Next steps | Supporting resources

Clinical challenge: Right-time autoimmune screening and referrals for rheumatology 

Primary care providers are often the first to suspect autoimmune disease in patients. At this initial suspicion, an ANA test is typically ordered because these antibodies are a common marker of autoimmune disease. If the ANA test is positive, patients are guided directly to a specialty referral. However, rheumatologists are now requesting that patients have more than just a positive ANA screening result before the referral.  

This presents a new opportunity for PCPs. Through earlier advanced testing in the primary care setting, PCPs can also be the first to diagnose an autoimmune disorder and initiate a faster, more informed referral to a rheumatology specialist for further care.

Why it matters: Positive ANA isn’t always enough

Before now, an ANA blood test had been the gold standard to test for rheumatoid arthritis (RA) and other autoimmune conditions. But it’s not enough for many patients.

Antinuclear antibodies are neither universally present in all autoimmune patients nor specific to a particular condition. In fact, they are not always present in patients with even common disorders such as RA or autoimmune thyroid disease (ATD). Therefore, relying on positive ANA results alone leads to additional testing requirements and delayed diagnosis, as well as over-referral for patients who may not truly need it. 

To close this gap, providers should seek more comprehensive testing that analyzes disease-specific markers in addition to the traditional antinuclear antibody test. The added benefit of this cotesting approach means that rheumatologists receive targeted referrals that are accompanied by more thorough documentation and lab workups, thus moving the patient into an appropriate specialty care plan sooner and with fewer steps.

Comprehensive autoimmune testing now reduces steps later 

Comprehensive autoimmune screening 

1 blood draw, fewer steps to treatment^a

Screening with ANA alone

Multiple blood draws, more steps to treatment^a

^aThe number of visits, referrals, and ordered tests may vary based on the specific patient case and the clinician’s decisions.

Ordering recommendations: ANA panel streamlines autoimmune diagnosis with 1 blood draw

Symptoms for autoimmune conditions vary across patients and can overlap across individual conditions, making diagnosis difficult with just an ANA screening. Alternatively, the Quest Diagnostics ANAlyzeR™ panel combines multiple tests—using only 1 specimen—to screen for 25 analytes that indicate a variety of autoimmune diseases, including:

• Antiphospholipid syndrome (Hughes syndrome)
• Autoimmune thyroiditis (Graves disease, Hashimoto thyroiditis)
• CREST syndrome
• Mixed connective tissue disease
• Neuropsychiatric SLE
• Polymyositis/dermatomyositis
• Rheumatoid arthritis
• Sjögren syndrome
• Systemic lupus erythematosus (SLE)
• Systemic sclerosis
• Thrombocytopenia

The comprehensive ANAlyzeR™ ANA panel delivers a full-picture view of results to support differential diagnosis. Its enhanced sensitivity leverages immunofluorescence assay (IFA) for ANA and double-stranded DNA (dsDNA) tests. 

Recommended test: ANAlyzeR™ ANA panel

ANAlyzeR™ ANA, IFA with Reflex Titer/Pattern, Systemic Autoimmune Panel 1

• Test code: 36378
• CPT codes: 86038, 86255, 86235 (x9), 86160 (x2), 86147 (x3), 86146 (x3), 83520 (x4), 86200, 86376

Note: Each of the component tests may also be ordered individually.

Includes

• ANA Screen, IFA, with Reflex to Titer and Pattern (249)
• Beta-2-Glycoprotein I Antibody (IgA) (36552)
• Beta-2-Glycoprotein I Antibody (IgG) (36554)
• Beta-2-Glycoprotein I Antibody (IgM) (36553)
• Cardiolipin Antibody (IgA) (4661)
• Cardiolipin Antibody (IgG) (4662)
• Cardiolipin Antibody (IgM) (4663)
• Centromere B Antibody (16088)
• Chromatin (Nucleosomal) Antibody (34088)
• Complement Component C3c (351)
• Complement Component C4c (353)
• Cyclic Citrullinated Peptide (CCP) Antibody (IgG) (11173)
• DNA (ds) Antibody, Crithidia IFA with Reflex to Titer (37092)
• Jo-1 Antibody (5810)
• Mutated Citrullinated Vimentin (MCV) Antibody (13238)
• Rheumatoid Factor (IgA, IgG, IgM) (19705)
• RNP Antibody (19887)
• Scleroderma Antibody (Scl-70) (4942)
• Sjögren’s Antibody (SS-A) (38568)
• Sjögren’s Antibody (SS-B) (38569)
• Sm Antibody (37923)
• Sm/RNP Antibody (38567)
• Thyroid Peroxidase Antibodies (TPO) (5081)

Who should be screened with the ANAlyzeR™ ANA panel?

PCPs should consider expediting comprehensive rheumatoid arthritis testing and other autoimmune testing for patients exhibiting the following symptoms:

• Digestive problems
• Fever
• Fatigue
• Joint pain
• Muscle weakness or pain
• Rash
• Shortness of breath

Related tests for autoimmune screening

ANA, IFA, Cascade and Rheumatoid Arthritis Panel 2, with Reflexes

This panel can be used to test for the 8 most common autoimmune diseases using a tiered cascade approach when ANA results are positive.

• Test code: 94954 
• CPT codes: 83520, 86038, 86200, 86431 

Note: Each of the component tests may also be ordered individually.  

Includes

• ANA Cascade (ANA, IFA With Reflex to Titer and Pattern, and Reflex to 11 Ab Cascade) (16814) 
• ANA Screen, IFA, With Reflex to Titer and Pattern (249) 
• Chromatin (Nucleosomal) Antibody (34088) 
• DNA (ds) Antibody (255) 
• RNP Antibody (19887) 
• Sm/RNP Antibody (38567) 
• Sm Antibody (37923) 
• Jo-1 Antibody (5810) 
• Sjögren’s Antibody (SS-A) (38568) 
• Sjögren’s Antibody (SS-B) (38569) 
• Scleroderma Antibody (Scl-70) (4942) 
• Centromere B Antibody (16088) 
• Ribosomal P Antibody (34283) 
• Rheumatoid Arthritis Diagnostic Panel 2 (91472) 

ANA Screen, IFA, with Reflex to Titer and Pattern

The single ANA blood test is often ordered as part of an initial diagnostic evaluation of individuals with clinical suspicion of autoimmune diseases associated with antinuclear antibodies.

• Test code: 249
• CPT code: 86038

Interpreting positive and negative ANA panel results together 

If the overall ANA IFA result is positive, but specific antibody results in the panel are negative, an autoimmune disease may still be present.  

Negative results won’t lead to a differential diagnosis; however, they can be an important part of an informed referral to a rheumatologist. 

Role of ANA titer levels in positive ANA results 

Use the ANA titer to support interpreting positive ANA results.  

• High titers (>1:160) strongly suggest an autoimmune condition is present. 
• Low titers (1:40 or 1:80) do not rule out autoimmune disease, but may also indicate a false positive. Higher titers are generally associated with greater likelihood of autoimmune disease.¹ 

Next steps: When to refer, when to watch

Initiate a referral to a rheumatology specialist if the patient’s ANAlyzeR™ panel results are positive with high titer levels. The documentation provided by these tests can help the rheumatologist fast-track treatment and care.

For other patients with negative results or low titers, they may best benefit from watchful monitoring and a periodic reassessment by their PCP.

Comorbidity risk management

Patients with an autoimmune disorder are at increased comorbidity risk for many other conditions, including but not limited to:

• Atherosclerosis
• Cancer
• Cardiometabolic disease
• Depression
• Heart disease
• Interstitial lung disease
• Kidney disease
• Osteoporosis
• Pregnancy complications

Both primary care providers and rheumatology specialists share in the responsibility to monitor and manage comorbidity risk in autoimmune patients.

Supporting resources