Background/Purpose:   Anti-SSA/SSB antibodies represent the most specific serologic marker of Sjögren’s syndrome; however, in up to 30% of SS patients the test is negative. Anti-alpha-fodrin (AFA) antibodies have been associated with SS; thus, we aimed to evaluate the utility of AFA antibodies in combination with RF and/or ANA as alternative immunological criterion in SS.   

Methods: 350 patients (100 each diagnosed with RA, SLE, and scleroderma, each, according to current classification criteria, and 50 with clinical diagnosis of primary SS) were selected from our patient registry and assessed for SS using a structured approach. All patients were tested for ANA, RF, anti-SSA/SSB, and AFA antibodies.  Diagnosis of SS was made on clinical basis by two rheumatologists with expertise in SS who independently evaluated every patient considering the results of the 6-item screening questionnaire, history of parotid enlargement, Schirmer-I test, Wafer test, NSWSF rate, fluorescein staining test, autoantibodies, lip biopsy, medical notes from Ophthalmology and Oral Medicine, and medical chart review. Non-SS diagnosis was defined as lack of clinical diagnosis and not fulfilling either AECG and/or ACR criteria. Statistical analysis. We focused on patients testing negative for anti-SSA and/or anti-SSB antibodies. The 2012 ACR SS criteria were applied to each study participant substituting the immunological criterion as follows: 1) RF plus ANA >1:320, 2) RF plus AFA, 3) ANA plus AFA, 4) RF alone, and 5) Two positive tests out of RF, ANA >1:320, or AFA. We estimated the sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV), and positive likelihood-ratio with 95% CI, for each criterion item. 

Results: 236 (67%) patients tested negative for anti-SSA/SSB antibodies, of whom 65 (27.5%) were clinically diagnosed as SS, and 149 (63%) with non-SS. The performance of ACR criteria using diverse substitute immunological criterion is shown in the table. RF + AFA, and ANA + AFA performed similarly as RF + ANA >1:320 as substitute immunological criterion. Although RF + ANA >1:320 performed well, incorporating AFA improved the number of SS patients classified by the ACR criteria. Particularly, the model 2 out of RF, ANA, or AFA, improved the sensitivity of 2012 ACR SS Criteria to capture SS patients with negative anti-SSA and/or anti-SSB serology from 37 to 46 out of 65 patients studied. 

Conclusion:  RF plus AFA, and ANA plus AFA antibodies performed similarly as RF plus ANA >1:320, as a substitute immunological criterion in patients with SS with negative anti-SSA/SSB serology. However incorporating AFA to RF and ANA >1:320 in a 2 out of 3 model improves the sensitivity to capture SS patients with negative anti-SSA/SSB serology. This improvement will benefit clinical studies and clinical trials in SS. 

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/utility-of-iga-anti-alpha-fodrin-antibodies-in-combination-with-rheumatoid-factor-andor-antinuclear-antibodies-as-substitute-immunological-criterion-for-sjogrens-syndrome/