Abstract
BackgroundDiagnosis of systemic autoimmune rheumatic diseases (SARD) relies on the presence of hallmark anti-nuclear antibodies (ANA), many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals, most of whom will not develop SARD. Here, we examined a unique cohort of asymptomatic ANA+ individuals to determine whether they share any of the cellular immunologic features seen in SARD.MethodsHealthy ANA− controls and ANA+ (ANA ≥1:160 by immunofluorescence) participants with no SARD criteria, with at least one criterion (undifferentiated connective tissue disease (UCTD)), or meeting SARD classification criteria were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry and transcript levels of BAFF, interferon (IFN)-induced and plasma cell-expressed genes were quantified by NanoString.ResultsA number of the immunologic abnormalities seen in SARD, including changes in peripheral B (switched memory) and T (iNKT, T regulatory, activated memory T follicular helper) subsets and B cell activation, were also seen in asymptomatic ANA+ subjects and those with UCTD. The extent of these immunologic changes correlated with ANA titer or the number of different specific ANAs produced. Principal component analysis of the cellular data indicated that a significant proportion of asymptomatic ANA+ subjects and subjects with UCTD clustered with patients with early SARD, rather than ANA− healthy controls.ConclusionsANA production is associated with altered T and B cell activation even in asymptomatic individuals. Some of the currently accepted cellular features of SARD may be associated with ANA production rather than the immunologic events that cause symptoms in SARD.
Highlights
Diagnosis of systemic autoimmune rheumatic diseases (SARD) relies on the presence of hallmark antinuclear antibodies (ANA), many of which can be detected years before clinical manifestations
We examined peripheral blood T and B cell populations and their activation in asymptomatic ANA+ individuals together with patients with undifferentiated connective tissue disease (UCTD) and early SARD to determine whether the cellular immune characteristics found in SARD are distinct from those seen in asymptomatic ANA+ individuals, most of whom will not progress to SARD
A small number (n = 5) of the asymptomatic ANA+ individuals were taking anti-malarials at the time of initial evaluation in clinic, which had been started for vague symptoms that could not be definitively attributed to SARD
Summary
Diagnosis of systemic autoimmune rheumatic diseases (SARD) relies on the presence of hallmark antinuclear antibodies (ANA), many of which can be detected years before clinical manifestations. Studies of patients with SLE and SjD prior to diagnosis indicate a prolonged pre-clinical phase during which ANAs can be detected in the absence of clinical symptoms [5,6,7,8] While this observation suggests that ANA positivity might serve as a biomarker for SARD development, ANAs are seen in the healthy population and based upon their prevalence together with that of SARD, it is estimated that > 90% of ANA+ individuals will not progress to SARD. We examined peripheral blood T and B cell populations and their activation in asymptomatic ANA+ individuals together with patients with undifferentiated connective tissue disease (UCTD) and early SARD to determine whether the cellular immune characteristics found in SARD are distinct from those seen in asymptomatic ANA+ individuals, most of whom will not progress to SARD. Several of the cellular changes seen in SARD are seen in asymptomatic ANA+ individuals, suggesting that they are associated with ANA production rather than development of symptoms in SARD
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