Background/Purpose: In the setting of a negative ANA, antibodies to extractable nuclear antigens (ENA) should be correspondingly negative, but alternative clinical scenarios occasionally arise.  This study evaluated the frequency of ANA negative/ENA positive results and associated clinical information, including diagnoses.

Methods: All patients from a single institution who underwent ANA and ENA testing on a single blood draw in 2014 were evaluated for occurrence of a negative ANA with positive ENA.  ANA testing was performed via enzyme-linked immunosorbent assay, and ENA via multiplex flow immunoassay, including SS-A, SS-B, Smith, RNP, Scl70, and Jo-1.  This testing was part of routine clinical practice and performed at the discretion of the clinical provider. The first 100 individuals in chronologic order of testing were further evaluated for clinical diagnoses by review of the complete medical record.

Results: A total of 4123 patients had ANA and ENA testing performed on the same draw.  The majority were ANA negative (3267, 79%).  Two hundred-eighty (6.8%) had at least one positive ENA result paired with a negative ANA.  Of these, the vast majority (270, 96%) had only a single positive ENA result.  The most common positive result was RNP (54%) followed by SS-A (19%), SS-B (16%), and Scl70 (14%).  Smith (1%) and Jo-1 (0%) were exceedingly rare.  Ten patients had double positive results, with the most common combination of RNP/Scl70 in 4.

Among the first 100 patients, 61 were female.  The mean (standard deviation) age at testing was 56.5 (16.0) years.  Ninety-nine had a single positive result; 1 patient had a double positive of RNP and Scl70.  The most common positive antibody was RNP (56%) followed by SS-A (18%), Scl70 (15%), and SS-B (12%).  No patients had positive Smith or Jo-1 antibodies.  Neurology was the most common specialty to order the test (28%) followed by Rheumatology (27%), Pulmonary (15%), and Primary Care (13%) with Dermatology and Internal Medicine subspecialities accounting for the remaining. 

Only 1 patient had a history of lupus with diagnosis occurring 20 years earlier and no current evidence of active disease.  One patient was diagnosed with drug induced lupus in the setting of TNF inhibitor use for inflammatory bowel disease.  One additional patient had lupus panniculitis.  Six patients were felt to have Sjögren’s syndrome while another 7 were diagnosed with undifferentiated connective tissue disease.  An additional 6 patients had what was felt to represent “possible” connective tissue disease.  Five patients had a diagnosis of rheumatoid arthritis or seronegative inflammatory arthritis.  Another patient was diagnosed with large/medium vessel vasculitis.  Ten patients had thyroid disease.  Four patients had diagnosis of new malignancy or recurrence.  Twenty individuals had peripheral neuropathy or dysesthesias.  An additional 11 patients had interstitial lung disease as a part of their presentation.

Conclusion: ANA negative/ENA positive results, while rare, do occur.  It is quite uncommon to have a diagnosis of lupus but does not exclude the possibility of connective tissue disease.  This emphasizes the importance of a corresponding clinical history and exam to interpret serologies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/clinical-evaluation-of-patients-with-positive-antibodies-to-extractable-nuclear-antigens-but-negative-ana/