Does ANA-Negative Lupus Exist?

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The answer to the question, "Does ANA-negative lupus exist?" is technically "yes," with a large number of buts, ifs, and whens. It depends on what is meant by "lupus," and what is meant by "ANA. " There are many nuances in the definitions of both.

How do we define lupus?

To start with – the definition of lupus: Systemic lupus erythematosus (SLE) is one of many similar illnesses that primarily affect young women and which cause arthritis, rashes, low white blood cell counts, low platelet counts and kidney disease. (I'll ignore, for this discussion, discoid [skin], drug-induced and neonatal lupus, all of which share the name, but are considered to be separate illnesses.)

The features that unequivocally diagnose SLE are:

  1. high titer anti-double stranded DNA antibody
  2. anti-Smith (referred to as anti-Sm) antibody
  3. biopsy-proven kidney disease
  4. biopsy-proven skin disease combined with another symptom

Doctors have difficulty agreeing on a standard definition for individual patients (diagnostic criteria) because many organs can be involved and they can be involved in different ways. Diagnostic criteria, which are used to make a diagnosis in an individual patient, do not exist for lupus.

Classification criteria – which are used to select typical patients for studies like drug trials – have recently changed. The new American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) classification criteria [1] assign different points to different abnormalities.

Different abnormalities have different weights. For instance, a patient with kidney disease, depending on the type of kidney disease, will be assigned 4, 8, or 10 points; one with a low white blood count, 3 points; and one with arthritis, 6 points. Antibody tests count. Anti-DNA antibody or an anti-Sm antibody earns 6 points. (Only one counts; a patient who has both antibodies does not get 12 points.) According to the classification criteria, a patient who has 10 points has lupus; one who has only 9 does not.  Antibody tests count only if the patient has symptoms. One cannot be said to have lupus if the antibodies are abnormal but the person is well. The new criteria require that the test for antinuclear antibody (ANA) must be positive, at least once, but not necessarily at the time of the diagnosis decision because an ANA can become negative with treatment or remission.

There is no real consensus among physicians on how best to describe symptomatic patients who do not meet criteria, that is, who those do not have at least 10 criteria points [2, 3].  To describe these patients, this writer uses these terms:

  • "lupus-like" illness
  • "mixed connective tissue disease"
  • "undifferentiated connective tissue disease"
  • "forme fruste (meaning incipient, or hidden form) lupus"

Other physicians have also addressed this question [4]. Each of these vague terms has, nonetheless, a specific meaning that describes a different form of illness. “Mixed connective tissue disease,” describes a specific syndrome consisting of features of lupus, scleroderma, and dermatomyositis, together with a high-titer antibody to RNP. In this writer's practice, almost half of patients referred for suspect SLE fall into the not-quite-lupus category; conversely, persons who have compatible symptoms and high titer anti-DNA, anti-Sm antibody, and/or kidney disease have SLE. Most papers about patients with definite lupus include in that definition patients who:  

  • are untreated
  • are treated
  • have new onset illness
  • have long-standing illness

These papers report anti-DNA antibody in about half of patients, anti-Sm in about one-third, and ANA in 87% to 94% of patients. In studies that include only new, untreated patients, essentially all of those patients will have ANA and either anti-DNA or anti-Sm or both.

Some physicians use the term “lupus” to describe patients with the variant forms as well as those unequivocal lupus. For this author, another term would be preferable. Whether to diagnose a patient as having lupus or lupus-like disease is not either right or wrong, but a question of a physician's style. Either way, treatment options are the same.

What is a true positive ANA?

Now, to the question of the meaning of ANA. The antinuclear antibody test is performed with different techniques in different laboratories; some techniques are more sensitive than others. Because of the differences in the tests, one laboratory may find a (usually weak) positive test while another finds it negative.

Some laboratories dilute blood samples 10-fold (1:10) to screen, some 100-fold (1:100), and some not at all. A commonly used method starts with a dilution of 1:10, then doubles with every successive dilution, so the next specimen tested is 1:20, then 1:40, 1:80, etc., with the highest number positive being what the laboratory reports (for instance, 1:1280). A laboratory that begins at 1:40 may call a test positive, while a laboratory that begins at 1:100 would call it negative. Most lupus patients have very strongly positive tests – essentially always more than 1:80, often more than 1:5120. Most laboratories count 1:80 and higher as clearly positive.

The point is that ANA-negative does not necessarily mean completely negative; it just means it is below the laboratory’s threshold for calling it positive. Another point is that speckled (as opposed to diffuse or peripheral) ANA patterns do not read well in automated immunofluorescence tests, so may be reported as lower titer or negative than they would be if they were hand read by an experienced technician. The difficulty with standardizing the ANA test has received a lot of attention recently [5, 6]. There is a goal to achieve better consensus but as of the time of this writing, there is still controversy about how to define and interpret low-titer ANA.

What about other laboratory tests?

There is a further complication. The ANA is used to screen for lupus, not to diagnose it – meaning that, for practical purposes, if the ANA is negative, lupus does not exist and no further testing need be done. Indeed, some laboratories will not further screen sera that are ANA negative. The new ACR/EULAR classification criteria require that an ANA test is positive before adding up the other points. (Earlier criteria assigned separate points to ANA.)

A positive ANA  means only that lupus is possible. It means that that tests for antibody to double-stranded DNA, Sm, Ro/SSA (Sjogren's syndrome A), La/SSB (Sjogren's syndrome B), and RNP (ribonucleoprotein) – the “specific” antibodies – must be performed to determine whether lupus, or a lupus-like disease is or is not present.

Because of a variety of technical factors, it is possible to have a negative ANA but a positive specific antibody test, though this is very uncommon. Thus an "ANA-negative" person with strongly positive antibody to Sm is said to have lupus. Because laboratories vary in how they report and (to be efficient) this writer, when evaluating a new patient for lupus, simultaneously tests for ANA, anti-DNA, anti-Sm, anti-Ro/SSA, anti-La/SSB, anti-RNP, and sometimes other antibodies that may be relevant to the patient's specific condition. If the ANA test is negative, a diagnosis of lupus is much less likely, but not impossible.

Is new onset lupus different from long-standing lupus?

Now another complication: All of the rules of antibody testing apply to the evaluation of new symptoms in an untreated patient. Tests often revert to normal during treatment, and they can change, improving or worsening, over time.

If the question, "Can an ANA-negative person have SLE?" is asked of a new, untreated patient, the answer is probably no. If it is asked of a patient whose test is negative years after the diagnosis, it may be impossible to say yes or no. If a patient, even with active symptoms, is taking high doses of prednisone or immunosuppressive drugs, a negative ANA does not exclude the diagnosis.

Is the question of “ANA-negative” lupus important?

In this writer’s mind the question about ANA-negative or ANA-positive lupus is not important because symptomatic patients need to be treated, and treatment does not require a statement that a patient clearly does or does not have lupus. (I ignore the fact that insurance companies often disagree.) What is important is that the physician evaluates the current symptoms, puts those symptoms into an overall context that includes blood tests, duration of symptoms, other possible illnesses, and medications, and develops a treatment plan based on the total information rather than on a blood test alone.

References

[1] Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. 2019; Arthritis Rheum 71 (9):1400-1412.

[2] Lockshin MD, Levine AB, Erkan D. Patients with overlap autoimmune disease differ from those with 'pure' disease. Lupus Sci Med. 2015 May 6;2(1):e000084. doi: 10.1136/lupus-2015-000084. eCollection 2015. PubMed PMID: 25973214; PubMed Central PMCID: PMC4422903.

[3] Lockshin MD, Barbhaiya M, Izmirly P, et al. SLE: reconciling heterogeneity. Lupus Sci & Med 2019;6:e000280. doi:10.1136/lupus-2018-000280.

[4] Lambers WM, Westra J, Jonkman MF, et al. Incomplete systemic lupus erythematosus — what remains after application of ACR and SLICC criteria? Arthritis Care Res (Hoboken). 2019 Apr 1. doi: 10.1002/acr.23894. [Epub ahead of print].

[5] Pisetsky DS, Spencer DM, Lipsky PE, et al. Assay variation in the detection of antinuclear antibodies in the sera of patients with established SLE. Ann Rheum Dis 2018;77:911–913. DOI:10.1136/annrheumdis-2017-212599.

[6] Pisetsky DS, Thompson DK, Wajdula J, et al. Variability in antinuclear antibody testing to assess patient eligibility for clinical trials of novel treatments for systemic lupus erythematosus. Arthritis & Rheumatology 2019; 71 (9): Vol. 71, No. 9, September 2019, pp 1534–1538. DOI 10.1002/art.40910.

Authors

Headshot of Michael D. Lockshin, MD
Michael D. Lockshin, MD
Attending Rheumatologist, Hospital for Special Surgery
Director, Barbara Volcker Center for Women and Rheumatic Disease
 

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