Background/Purpose: Patients with systemic autoimmune rheumatic diseases (SARD) often have a prolonged pre-clinical phase during which they are anti-nuclear antibody (ANA)⁺ but lack clinical symptoms.  It has been proposed that progression from asymptomatic autoimmunity to clinical disease is accompanied by immunologic changes that could be used as predictors of disease development.  Elevated levels of interferon (IFN)-induced gene expression, termed the IFN signature, are found in several SARD conditions, and IFNs appear to play an important role in disease pathogenesis.  In this study we examined whether ANA⁺individuals who lack sufficient symptoms for a SARD diagnosis share the IFN-signature.

Methods: ANA⁺individuals who: 1) lacked clinical symptoms of SARD (ANS); 2) had a least one clinical symptom of SARD (UCTD); or 3) had a recently diagnosed steroid and immunosuppressive naïve SARD (SLE, SS, SSc, MCTD, DM) were recruited from clinics at UHN/MSH hospitals.  Healthy controls (HC) were also recruited.  RNA was prepared from blood archived in Tempus tubes.  Expression of 5 IFN-induced genes was quantified by NanoString, normalized to expression of housekeeping genes, and summed to generate an IFN5 score.  ANAs, serum complements, and levels of specific autoantibodies were measured by the hospital laboratory.

Results: :   To date we have measured the IFN signature on 96 individuals (17 HC, 24 ANS, 17 UCTD, 22 SS, 8 SSc, 6 SLE, 1 MCTD, 1 DM).  Higher mean IFN scores were seen in all ANA+ sub-groups as compared to HC (mean ± SD: HC 5,380 ± 1,619; ANS 25,886 ± 34,092; UCTD 28,252 ± 24,827; SSc 34,940 ± 40,940; SS 61,877 ± 33,404; SLE 62,769 ± 50,233; MCTD/DM 97,716 ± 24,973), which achieved statistical significance for ANS, UCTD, SSc, SS, and SLE subsets (corrected p = 0.0036, 0.0006, 0.048, < 0.0001, 0.0054, respectively).  Using a cutoff of 3 SD above the mean of HC as indicative of an elevated IFN5 score, 10/24 ANS, 10/17 UCTD, 5/7 SSc, 19/22 SS, 5/6 SLE, and 2/2 MCTD/DM participants had elevated IFN levels.  Marked elevations of the IFN5 score were seen in a subset of ANS and UCTD participants, which could not be attributed to recent infection.  Although there was a significant correlation between the ANA titer (p = 0.0006) and IFN5 score for all ANA⁺ individuals, this was not seen in the ANS or UCTD subsets of this population.  However the IFN5 score was positively correlated with the number of different ANA specificities present in the UCTD subset (p = 0.026) and all ANA⁺ individuals (p < 0.0001).  The IFN5 score was significantly higher in ANA⁺ individuals who were anti-Ro antibody positive, as compared to those who were negative.  Within the ANS subset, there was a strong correlation between the presence of anti-Ro/La antibodies with 6/10 IFN5^high as compared to 1/14 IFN^lowindividuals being antibody positive (p = 0.009).  There was no association between the IFN5 score and the presence or absence of other autoantibody specificities, or complement levels.

Conclusion: An IFN signature is seen in a subset of ANA⁺ individuals prior to a confirmed diagnosis of SARD and appears to correlate with the number and type of specific ANAs rather than clinical disease.

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/presence-of-the-interferon-signature-in-anti-nuclear-antibody-positive-individuals-prior-to-the-onset-of-systemic-autoimmune-rheumatic-disease/