Autoantibodies have a long history in the diagnosis of lupus erythematosus, scleroderma, and other autoimmune diseases. However, primary care physicians routinely use antinuclear antibody (ANA) tests as a screening tool, leading to referrals to rheumatologists and further testing. A recent study, explored in this issue of Strategies, demonstrated the problems associated with unselective ANA testing.

ANA, as well as other autoantibody tests, remain important for diagnosing lupus erythematosus and other diseases. Yet a large number of people without such diseases can test positive for ANA, even at higher titers. As a result, growing use of ANA testing among primary care physicians has concerned both laboratorians and rheumatologists, as peer reviewed literature has reported for more than a decade on the rampant misuse of ANA screening.

Recently, Aryeh Abeles, MD, an assistant clinical professor and rheumatologist at the University of Connecticut Health Center, examined the number of patients referred to his tertiary rheumatology clinic based on positive ANA results (Am J Med 2013;126:342–8). The study is the first to investigate the positive predictive value of ANA testing in a cohort of adult patients referred to a rheumatology center specifically for a positive ANA test result.

Abeles and his co-author found that some 90% of patients who were referred to his clinic after a positive ANA had no evidence of an ANA-associated rheumatic disease. While for a long time rheumatologists and others have tried to underscore the limited utility of positive ANA in a patient with low pretest probability, the problem with unselective ordering of the test by primary care physicians has not abated, noted Abeles. “As a primarily clinical rheumatologist, probably the most common reason for referral is a positive ANA,” he said. “It’s fairly striking—and somewhat frustrating—to see so many patients have this lab test done with absolutely no clinical suspicion for having an ANA-associated rheumatic disease.”

Explaining the test to patients who are referred to his clinic has become almost a daily routine, Abeles said. “I just saw a new patient who clearly has psoriatic arthritis, which is an inflammatory arthritis seen in association with psoriasis. It’s very clinically distinct,” Abeles said. “Yet his doctor ordered an ANA, despite the fact that there was nothing suggestive of lupus. Worse, the patient was called and told that ‘the lupus test was positive,’ and that this individual had to come in right away.  This case also encapsulates my other concern regarding over-reliance on serologic testing. That is, I wonder if this patient— who needs a rheumatologist— would have been referred if the ‘arthritis panel’ had been normal.”

In the study, the researchers retrospectively reviewed records for all consultations presenting to them between July 2007 and July 2009. They included patients if they had been referred for subspecialty evaluation of a recently ordered positive ANA test result, a total of 232 patients. More than 80% were referred from primary care physicians. The researchers then calculated positive predictive values as the number of patients within the cohort with an ANA-associated rheumatic disease divided by the number of total patients in the study. The positive predictive value of a positive ANA test result in this cohort was 2.1% for lupus and 9.1% for any ANA-associated rheumatic disease. No patients with an ANA titer <1:160 had an antinuclear antibody-associated rheumatic disease.

According to Abeles, many physicians simply fail to understand how to properly interpret the test, referring patients to rheumatologists after misdiagnosing them with lupus. “There definitely is a lack of understanding as to when the test should be appropriately employed,” he said. “If a patient comes in to the primary care physician and says, ‘I hurt,’ and then an ANA is ordered, that’s when it becomes a really useless test. Any time you have a test that has a high background rate of positivity in the population, and you’re looking for diseases that have an extremely low prevalence, you do have to choose the people that you’re going to be testing very wisely, or you’ll end up with nothing but a lot of noise.”

In the study, the most common reason for ANA testing was widespread pain. Nearly a quarter of patients had ANA testing performed for this symptom, none of whom had a rheumatologic disease. Other common reasons for ANA testing, and consequent referral, included knee pain, chronic lower back pain, chronic headaches, and unilateral hip pain.

According to John Carey, MD, vice-chair of pathology and laboratory medicine at Henry Ford Health System in Detroit, gaps in medical education for many physicians lead to a black-and-white understanding of tests like ANA. “I think it starts in medical school, where we don’t always do a very good job teaching students about positive and negative predictive values. Too often physicians get the impression that certain tests have a high degree of specificity or sensitivity and don’t see the whole spectrum,” Carey said. “Systemic autoimmune disease remains predominantly a clinical diagnosis, and if you don’t have the clinical features, a positive ANA isn’t going to change that.” Carey was not associated with the study.

ANA testing can indeed be useful, but mostly for its negative predictive value, Carey noted. “If a physician is considering lupus or various types of scleroderma, for example, and the ANA result is negative, it should raise questions about that diagnosis,” he said. “The one caveat there is that in a fair minority of cases, lupus will have a negative ANA at first presentation, only testing positive after several months.”

What can laboratorians do? The researchers recommend that labs include information about positive predictive value in lab reports, based on in-house data on the rate of positivity for their population. “It would be enormously useful if labs provided data on how frequently ANA positivity occurs at their respective labs— by titer—to offer some context,” Abeles said. “There are some labs where perhaps 60 percent of all labs drawn have titers of 1:80 or greater, and then there are others that are going to be 10 percent. I don’t know that there should be a blanket statement on what should be negative or positive.”

Carey employs this strategy at his lab. “We use a commentary for both positive and negative ANA screening results,” he said. “If we get a negative result, we warn them that a variable minority of systemic autoimmune diseases lack a positive ANA, either at the beginning, or throughout the entire course of the disease. More significantly, with a positive result, even a relatively high titer, we warn of a significant lack of specificity—that there can be a variety of other non-autoimmune diseases, but still a strongly positive ANA.”

However, more work remains to be done to educate physicians, Carey emphasized. “I think having these interpretive comments has had some impact on clinicians, but I’m not sure if they always read it, because we still hear from our rheumatologists that they receive what they consider inappropriate referrals based on what amounts to a positive ANA without the clinical features.”