Presence of an interferon signature in individuals who are anti-nuclear antibody positive lacking a systemic autoimmune rheumatic disease diagnosis

Joan Wither,Earl Silverman,Dennisse Bonilla,Carolina Landolt-Marticorena,Arthur Bookman,Babak Noamani,Larissa Lisnevskaia,Tony Liu,Sindhu R Johnson

doi:10.1186/s13075-017-1243-y

Abstract

BackgroundElevated levels of type I interferons (IFNs) are a characteristic feature of the systemic autoimmune rheumatic diseases (SARDs) and are thought to play an important pathogenic role. However, it is unknown whether these elevations are seen in anti-nuclear antibody–positive (ANA+) individuals who lack sufficient criteria for a SARD diagnosis. We examined IFN-induced gene expression in asymptomatic ANA+ individuals and patients with undifferentiated connective tissue disease (UCTD) to address this question.MethodsHealthy ANA− control subjects and ANA+ titre (≥1:160 by immunofluorescence) participants meeting no criteria, meeting at least one criterion (UCTD) or meeting SARD classification criteria were recruited. Whole peripheral blood IFN-induced and BAFF gene expression were quantified using NanoString technology. The normalized levels of five IFN-induced genes were summed to produce an IFN5 score.ResultsThe mean IFN5 scores were increased in all ANA+ participant subsets as compared with healthy control subjects. We found that 36.8% of asymptomatic ANA+ and 50% of UCTD participants had IFN5 scores >2 SD above the mean for healthy control subjects. In all ANA+ subsets, the IFN5 score correlated with the presence of anti-Ro/La antibodies. In the asymptomatic ANA+ subset, this score also correlated with the ANA titre, whereas in the other ANA+ subsets, it correlated with the number of different ANA specificities. Development of new SARD criteria was seen in individuals with normal and high IFN5 scores.ConclusionsAn IFN signature is seen in a significant proportion of ANA+ individuals and appears to be associated with ANA titre and type of autoantibodies, rather than with the presence or development of clinical SARD symptoms.

Highlights

Elevated levels of type I interferons (IFNs) are a characteristic feature of the systemic autoimmune rheumatic diseases (SARDs) and are thought to play an important pathogenic role
On the basis of their clinical and laboratory findings at their initial assessments, participants were stratified into three groups: (1) asymptomatic antinuclear antibody (ANA)+ individuals lacking any clinical symptoms of SARD, (2) patients with undifferentiated connective tissue disease (UCTD) with at least one clinical symptom of SARD and (3) patients with early SARD meeting classification criteria (1997 American College of Rheumatology [ACR] criteria for systemic lupus erythematosus (SLE) [18], 2013 ACR-European League Against Rheumatism [EULAR] criteria for systemic sclerosis (SSc) [19] or the revised American-European criteria for s syndrome (SS) [20]) and who had received their diagnosis within the previous 2 years
The mean levels of these genes were not significantly increased in asymptomatic ANA+ individuals or patients with UCTD (Fig. 1c), the same strong correlation between their expression levels and IFN5 scores was seen (Fig. 1d), with a significant proportion of both subsets of subjects having levels >2 SD above the mean for healthy control subjects (HC). These findings indicate strong induction of IFN-induced genes in a subset of non-SARD ANA+ individuals and suggest that the IFN-induced gene expression observed in a significant proportion of ANA+ individuals without SARD does not differ quantitatively or qualitatively from that observed in patients with early SARD or that previously reported for patients with SLE [17]

Summary

Introduction

Elevated levels of type I interferons (IFNs) are a characteristic feature of the systemic autoimmune rheumatic diseases (SARDs) and are thought to play an important pathogenic role. It is unknown whether these elevations are seen in anti-nuclear antibody–positive (ANA+) individuals who lack sufficient criteria for a SARD diagnosis. Types II and III IFNs can induce this signature, and there is emerging evidence that they may play a role in disease pathogenesis [17] It is not known whether individuals who are ANA+ who either lack symptoms or have insufficient symptoms to diagnose a SARD have an IFN signature. We assessed IFN-induced gene expression in these individuals and examined the serologic and clinical correlates

Methods

Results

Discussion

Conclusion