Autoantibodies associated with systemic sclerosis in three autoimmune diseases imprinted by type I interferon gene dysregulation: a comparison across SLE, primary Sjögren’s syndrome and systemic sclerosis

Abstract

ObjectiveSLE, primary Sjögren’s syndrome (pSS) and systemic sclerosis (SSc) are heterogeneous autoimmune diseases with a dysregulated type I interferon (IFN) system. The diseases often show overlapping clinical manifestations, which may result in diagnostic challenges. We asked to which extent SSc-associated autoantibodies are present in SLE and pSS, and whether these link to serum IFN-α, clinical phenotypes and sex. Samples with clinical data from patients with SSc and healthy blood donors (HBDs) served as controls. Finally, the diagnostic performance of SSc-associated autoantibodies was evaluated.MethodsSamples from well-characterised subjects with SLE (n=510), pSS (n=116), SSc (n=57) and HBDs (n=236) were analysed using a commercially available immunoassay (EuroLine Systemic Sclerosis Profile (IgG)). IFN-α was quantified by ELISA. Self-reported data on Raynaud’s phenomenon (RP) were available.ResultsWith exceptions for anti-Ro52/SSA and anti-Th/To, SSc-associated autoantibodies were more frequent in SSc than in SLE, pSS and HBDs regardless of sex. IFN-α levels correlated with the number of positive SSc-associated autoantibodies (r=0.29, p<0.0001) and associated with Ro52/SSA positivity (p<0.0001). By using data from SLE, SSc and HBDs, RP was significantly associated with topoisomerase I, centromere protein (CENP)-B, RNA polymerase III 11 kDa, RNA polymerase III 155 kDa and PM-Scl100 whereas Ro52/SSA associated inversely with RP. In SLE, CENP-A was associated with immunological disorder, CENP-B with serositis and Ku with lupus nephritis. By combining analysis of ANA (immunofluorescence) with SSc-associated autoantibodies, the diagnostic sensitivity reached 98% and the specificity 33%.ConclusionsThe 13 specificities included in the EuroLine immunoassay are commonly detected in SSc, but they are also frequent among individuals with other diseases imprinted by type I IFNs. These findings are valuable when interpreting serological data on patients with suspected SSc, especially as patients may present with disease manifestations overlapping different rheumatological diseases. In SLE, we observed associations between manifestations and SSc-associated autoantibodies which have not previously been reported.

Myositis‐Associated Autoantibodies in Patients With Juvenile Myositis Are Associated With Refractory Disease and Mortality

“…47 The number of SSc-associated autoantibodies among patients with SLE, too, has been found to be associated with IFNγ. 48 A higher IFN score was found in patients with IIM positive for multiple autoantibodies, including MSAs and MAAs, in particular among those with autoantibodies recognizing an RNA binding protein (RBP), which, in that study, included anti-ARS as well as anti-Ro60 and anti-U1-RNP autoantibodies. 49 Anti-RBP autoantibodies in patients with SLE and anti-Ro60 autoantibodies in autoimmune connective tissue diseases more broadly have been implicated in IFN upregulation.…”

“…In patients with preclinical RA, the number of ACPAs correlates with elevations in tumor necrosis factor α and interferon (IFN) γ, among other cytokines 47 . The number of SSc‐associated autoantibodies among patients with SLE, too, has been found to be associated with IFNγ 48 . A higher IFN score was found in patients with IIM positive for multiple autoantibodies, including MSAs and MAAs, in particular among those with autoantibodies recognizing an RNA binding protein (RBP), which, in that study, included anti‐ARS as well as anti‐Ro60 and anti‐U1‐RNP autoantibodies 49 .…”

Interferon and autoantigens: intersection in autoimmunity

“…An important pathologic function of these antibodies has been defined - maternal anti-Ro52 antibodies demonstrate pathogenic function by mediating congenital heart block ( 28 ). In SLE, antibodies against Ro52 are associated with higher levels of circulating IFN I ( 29 , 30 ). Ro52 is an IFN-induced E3 ligase that targets various substrates for removal via proteasomal degradation.…”

Machine learning approaches to identify systemic lupus erythematosus in anti-nuclear antibody-positive patients using genomic data and electronic health records

“…The 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria for SLE stipulated the need for a positive anti-nuclear antibody (ANA) test with a titer equal to or exceeding 1:80 [ 2 ]. Despite this advancement, the precise identification of SLE patients continues to pose significant challenges for clinicians, mainly due to the heterogeneity of the disease and its overlap with other autoimmune diseases [ 3 ].…”